WorldWideScience

Sample records for screen identifies design

  1. Identifying Communication Barriers to Colorectal Cancer Screening Adherence among Appalachian Kentuckians.

    Science.gov (United States)

    Bachman, Audrey Smith; Cohen, Elisia L; Collins, Tom; Hatcher, Jennifer; Crosby, Richard; Vanderpool, Robin C

    2017-08-18

    Utilizing data from 40 in-depth interviews, this article identifies both barriers and facilitators to colorectal screening guideline adherence among Appalachian Kentucky adults recruited through a community-based research network. Key findings identify (a) varying levels of knowledge about screening guidelines, (b) reticence to engage in screening processes, and (c) nuanced communication with healthcare providers and family members regarding screening adherence. What participants knew about the screening process was often derived from personal stories or recalled stories from family members about their screening experiences. Reticence to engage in screening processes reflected reports of cumbersome preparation, privacy issues, embarrassment, medical mistrust, fear of receiving a cancer diagnosis, and lack of symptoms. Participants cited many ways to enhance patient-centered communication, and the findings from this study have implications for health communication message design and communication strategies for healthcare practices in Appalachian Kentucky clinics.

  2. Tiered High-Throughput Screening Approach to Identify ...

    Science.gov (United States)

    High-throughput screening (HTS) for potential thyroid–disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the US EPA ToxCast screening assay portfolio. To fill one critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast Phase I and II chemical libraries, comprised of 1,074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single concentration screen were retested in concentration-response. Due to high false positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed two additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using

  3. An Xpert screen to identify carbapenemases

    Directory of Open Access Journals (Sweden)

    Mubin Kazi

    2016-01-01

    Full Text Available To prevent the spread of carbapenemases-producing Enterobacteriaceae (CPE active surveillance, contact isolation and cohorting infected patients should be practiced. Rectal swabs for the Xpert MDRO-assay of 32 patients were included. 71.85% were positive for targets incorporated into the MDRO-assay; whereas 28% were phenotypically not CRE and Xpert negative (9.37% had different mechanism [bla OXA]. The assay identified 59.3%, 9.37% and 3.1% as bla NDM, bla NDM+VIM and bla VIM, respectively. The assay is a screening test that identifies CPE harbouring organism within an hour and can be installed at tertiary-care facilities to screen colonized patients.

  4. Screen Design Guidelines for Motivation in Interactive Multimedia Instruction: A Survey and Framework for Designers.

    Science.gov (United States)

    Lee, Sung Heum; Boling, Elizabeth

    1999-01-01

    Identifies guidelines from the literature relating to screen design and design of interactive instructional materials. Describes two types of guidelines--those aimed at enhancing motivation and those aimed at preventing loss of motivation--for typography, graphics, color, and animation and audio. Proposes a framework for considering motivation in…

  5. School-Based Screening to Identify At-Risk Students Not Already Known to School Professionals: The Columbia Suicide Screen

    Science.gov (United States)

    Wilcox, Holly C.; Schonfeld, Irvin Sam; Davies, Mark; Hicks, Roger C.; Turner, J. Blake; Shaffer, David

    2009-01-01

    Objectives. We sought to determine the degree of overlap between students identified through school-based suicide screening and those thought to be at risk by school administrative and clinical professionals. Methods. Students from 7 high schools in the New York metropolitan area completed the Columbia Suicide Screen; 489 of the 1729 students screened had positive results. The clinical status of 641 students (73% of those who had screened positive and 23% of those who had screened negative) was assessed with modules from the Diagnostic Interview Schedule for Children. School professionals nominated by their principal and unaware of students' screening and diagnostic status were asked to indicate whether they were concerned about the emotional well-being of each participating student. Results. Approximately 34% of students with significant mental health problems were identified only through screening, 13.0% were identified only by school professionals, 34.9% were identified both through screening and by school professionals, and 18.3% were identified neither through screening nor by school professionals. The corresponding percentages among students without mental health problems were 9.1%, 24.0%, 5.5%, and 61.3%. Conclusions. School-based screening can identify suicidal and emotionally troubled students not recognized by school professionals. PMID:19059865

  6. The Performance of Step-Wise Group Screening Designs

    Directory of Open Access Journals (Sweden)

    M.M. Manene

    2005-06-01

    Full Text Available In this paper we evaluate the performance of step-wise group screening designs in which group-factors contain an equal number of factors in the initial step.  A usual assumption in group screening designs is that the directions of possible effects are known a-priori. In practice, however, this assumption is unreasonable. We shall examine step-wise group screening designs without errors in observations when this assumption is relaxed. We shall consider cancellations of effects within group-factors. The performance of step-wise group-screening designs shall then be compared with the performance of multistage group screening designs.

  7. Gestalt Theory in Visual Screen Design — A New Look at an old subject

    OpenAIRE

    Chang, D.; Dooley, L.; Tuovinen, J. E

    2002-01-01

    Although often presented as a single basis for educational visual screen design, Gestalt theory is not a single small set of visual principles uniformly applied by all designers. In fact, it appears that instructional visual design literature often deals with only a small set of Gestalt laws. In this project Gestalt literature was consulted to distil the most relevant Gestalt laws for educational visual screen design. Eleven laws were identified. They deal with balance/symmetry, continuation,...

  8. Design of low cost glaucoma screening

    NARCIS (Netherlands)

    Niessen, A. G.; Langerhorst, C. T.; Geijssen, H. C.; Greve, E. L.

    1997-01-01

    In 1991 the Netherlands Glaucoma Patient Association organized a glaucoma screening survey. This survey was designed to evaluate the effectiveness of a low cost screening setting. During a screening period of 8 days, 1259 subjects over the age of 49 years were examined by a team of

  9. Automated recycling of chemistry for virtual screening and library design.

    Science.gov (United States)

    Vainio, Mikko J; Kogej, Thierry; Raubacher, Florian

    2012-07-23

    An early stage drug discovery project needs to identify a number of chemically diverse and attractive compounds. These hit compounds are typically found through high-throughput screening campaigns. The diversity of the chemical libraries used in screening is therefore important. In this study, we describe a virtual high-throughput screening system called Virtual Library. The system automatically "recycles" validated synthetic protocols and available starting materials to generate a large number of virtual compound libraries, and allows for fast searches in the generated libraries using a 2D fingerprint based screening method. Virtual Library links the returned virtual hit compounds back to experimental protocols to quickly assess the synthetic accessibility of the hits. The system can be used as an idea generator for library design to enrich the screening collection and to explore the structure-activity landscape around a specific active compound.

  10. Is Telephone Screening Feasible? Accuracy and Cost-Effectiveness of Identifying People Medically Eligible for Home- And Community-Based Services.

    Science.gov (United States)

    Fries, Brant E.; James, Mary; Hammer, Susan S.; Shugarman, Lisa R.; Morris, John N.

    2004-01-01

    Purpose: To determine the accuracy of a telephone-screening system to identify persons eligible for home- and community-based long-term care. Design and Methods: Data from Michigan telephone screens were compared to data from in-person assessments using the Minimum Data Set for Home Care (MDS-HC). Weighted kappa statistics measured the level of…

  11. Genetic screens to identify new Notch pathway mutants in Drosophila.

    Science.gov (United States)

    Giagtzoglou, Nikolaos

    2014-01-01

    Notch signaling controls a wide range of developmental processes, including proliferation, apoptosis, and cell fate specification during both development and adult tissue homeostasis. The functional versatility of the Notch signaling pathway is tightly linked with the complexity of its regulation in different cellular contexts. To unravel the complexity of Notch signaling, it is important to identify the different components of the Notch signaling pathway. A powerful strategy to accomplish this task is based on genetic screens. Given that the developmental context of signaling is important, these screens should be customized to specific cell populations or tissues. Here, I describe how to perform F1 clonal forward genetic screens in Drosophila to identify novel components of the Notch signaling pathway. These screens combine a classical EMS (ethyl methanesulfonate) chemical mutagenesis protocol along with clonal analysis via FRT-mediated mitotic recombination. These F1 clonal screens allow rapid phenotypic screening within clones of mutant cells induced at specific developmental stages and in tissues of interest, bypassing the pleiotropic effects of isolated mutations. More importantly, since EMS mutations have been notoriously difficult to map to specific genes in the past, I briefly discuss mapping methods that allow rapid identification of the causative mutations.

  12. Information Engineering and Workflow Design in a Clinical Decision Support System for Colorectal Cancer Screening in Iran.

    Science.gov (United States)

    Maserat, Elham; Seied Farajollah, Seiede Sedigheh; Safdari, Reza; Ghazisaeedi, Marjan; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza

    2015-01-01

    Colorectal cancer is a major cause of morbidity and mortality throughout the world. Colorectal cancer screening is an optimal way for reducing of morbidity and mortality and a clinical decision support system (CDSS) plays an important role in predicting success of screening processes. DSS is a computer-based information system that improves the delivery of preventive care services. The aim of this article was to detail engineering of information requirements and work flow design of CDSS for a colorectal cancer screening program. In the first stage a screening minimum data set was determined. Developed and developing countries were analyzed for identifying this data set. Then information deficiencies and gaps were determined by check list. The second stage was a qualitative survey with a semi-structured interview as the study tool. A total of 15 users and stakeholders' perspectives about workflow of CDSS were studied. Finally workflow of DSS of control program was designed by standard clinical practice guidelines and perspectives. Screening minimum data set of national colorectal cancer screening program was defined in five sections, including colonoscopy data set, surgery, pathology, genetics and pedigree data set. Deficiencies and information gaps were analyzed. Then we designed a work process standard of screening. Finally workflow of DSS and entry stage were determined. A CDSS facilitates complex decision making for screening and has key roles in designing optimal interactions between colonoscopy, pathology and laboratory departments. Also workflow analysis is useful to identify data reconciliation strategies to address documentation gaps. Following recommendations of CDSS should improve quality of colorectal cancer screening.

  13. A new efficient mixture screening design for optimization of media.

    Science.gov (United States)

    Rispoli, Fred; Shah, Vishal

    2009-01-01

    Screening ingredients for the optimization of media is an important first step to reduce the many potential ingredients down to the vital few components. In this study, we propose a new method of screening for mixture experiments called the centroid screening design. Comparison of the proposed design with Plackett-Burman, fractional factorial, simplex lattice design, and modified mixture design shows that the centroid screening design is the most efficient of all the designs in terms of the small number of experimental runs needed and for detecting high-order interaction among ingredients. (c) 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009.

  14. Inter-rater reliability and stability of diagnoses of autism spectrum disorder in children identified through screening at a very young age

    NARCIS (Netherlands)

    van Daalen, Emma; Kemner, Chantal; Dietz, Claudine; Swinkels, Sophie H. N.; Buitelaar, Jan K.; van Engeland, Herman

    2009-01-01

    To examine the inter-rater reliability and stability of autism spectrum disorder (ASD) diagnoses made at a very early age in children identified through a screening procedure around 14 months of age. In a prospective design, preschoolers were recruited from a screening study for ASD. The inter-rater

  15. Inter-rater reliability and stability of diagnoses of autism spectrum disorder in children identified through screening at a very young age.

    NARCIS (Netherlands)

    Daalen, E. van; Kemner, C.; Dietz, C.; Swinkels, S.H.N.; Buitelaar, J.K.; Engeland, H.M. van

    2009-01-01

    To examine the inter-rater reliability and stability of autism spectrum disorder (ASD) diagnoses made at a very early age in children identified through a screening procedure around 14 months of age. In a prospective design, preschoolers were recruited from a screening study for ASD. The inter-rater

  16. High-throughput screening to identify inhibitors of lysine demethylases.

    Science.gov (United States)

    Gale, Molly; Yan, Qin

    2015-01-01

    Lysine demethylases (KDMs) are epigenetic regulators whose dysfunction is implicated in the pathology of many human diseases including various types of cancer, inflammation and X-linked intellectual disability. Particular demethylases have been identified as promising therapeutic targets, and tremendous efforts are being devoted toward developing suitable small-molecule inhibitors for clinical and research use. Several High-throughput screening strategies have been developed to screen for small-molecule inhibitors of KDMs, each with advantages and disadvantages in terms of time, cost, effort, reliability and sensitivity. In this Special Report, we review and evaluate the High-throughput screening methods utilized for discovery of novel small-molecule KDM inhibitors.

  17. poolHiTS: A Shifted Transversal Design based pooling strategy for high-throughput drug screening

    Directory of Open Access Journals (Sweden)

    Woolf Peter J

    2008-05-01

    Full Text Available Abstract Background A key goal of drug discovery is to increase the throughput of small molecule screens without sacrificing screening accuracy. High-throughput screening (HTS in drug discovery involves testing a large number of compounds in a biological assay to identify active compounds. Normally, molecules from a large compound library are tested individually to identify the activity of each molecule. Usually a small number of compounds are found to be active, however the presence of false positive and negative testing errors suggests that this one-drug one-assay screening strategy can be significantly improved. Pooling designs are testing schemes that test mixtures of compounds in each assay, thereby generating a screen of the whole compound library in fewer tests. By repeatedly testing compounds in different combinations, pooling designs also allow for error-correction. These pooled designs, for specific experiment parameters, can be simply and efficiently created using the Shifted Transversal Design (STD pooling algorithm. However, drug screening contains a number of key constraints that require specific modifications if this pooling approach is to be useful for practical screen designs. Results In this paper, we introduce a pooling strategy called poolHiTS (Pooled High-Throughput Screening which is based on the STD algorithm. In poolHiTS, we implement a limit on the number of compounds that can be mixed in a single assay. In addition, we show that the STD-based pooling strategy is limited in the error-correction that it can achieve. Due to the mixing constraint, we show that it is more efficient to split a large library into smaller blocks of compounds, which are then tested using an optimized strategy repeated for each block. We package the optimal block selection algorithm into poolHiTS. The MATLAB codes for the poolHiTS algorithm and the corresponding decoding strategy are also provided. Conclusion We have produced a practical version

  18. NMR screening in fragment-based drug design: a practical guide.

    Science.gov (United States)

    Kim, Hai-Young; Wyss, Daniel F

    2015-01-01

    Fragment-based drug design (FBDD) comprises both fragment-based screening (FBS) to find hits and elaboration of these hits to lead compounds. Typical fragment hits have lower molecular weight (FBDD since it identifies and localizes the binding site of weakly interacting hits on the target protein. Here we describe ligand-based NMR methods for hit identification from fragment libraries and for functional cross-validation of primary hits.

  19. Screening candidate systems engineers: a research design

    CSIR Research Space (South Africa)

    Goncalves, DP

    2009-07-01

    Full Text Available engineering screening methodology that could be used to screen potential systems engineers. According to their design, this can be achieved by defining a system engineering profile according to specific psychological attributes, and using this profile...

  20. Screening of chemical compound libraries identified new anti-Toxoplasma gondii agents.

    Science.gov (United States)

    Adeyemi, Oluyomi Stephen; Sugi, Tatsuki; Han, Yongmei; Kato, Kentaro

    2018-02-01

    Toxoplasma gondii is the etiological agent of toxoplasmosis, a common parasitic disease that affects nearly one-third of the human population. The primary infection can be asymptomatic in healthy individuals but may prove fatal in immunocompromised individuals. Available treatment options for toxoplasmosis patients are limited, underscoring the urgent need to identify and develop new therapies. Non-biased screening of libraries of chemical compounds including the repurposing of well-characterized compounds is emerging as viable approach to achieving this goal. In the present investigation, we screened libraries of natural product and FDA-approved compounds to identify those that inhibited T. gondii growth. We identified 32 new compounds that potently inhibit T. gondii growth. Our findings are new and promising, and further strengthen the prospects of drug repurposing as well as the screening of a wide range of chemical compounds as a viable source of alternative anti-parasitic therapeutic agents.

  1. Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Philip W. Brownjohn

    2017-04-01

    Full Text Available Summary: Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP processing and the accumulation of APP-derived amyloid β (Aβ peptides are key processes in Alzheimer's disease (AD. We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation. : In this article, Livesey and colleagues perform a phenotypic drug screen in a human stem cell model of Alzheimer's disease. The anthelminthic avermectins are identified as a family of compounds that increase the production of short Aβ peptides over longer more toxic Aβ forms. The effect is analogous to existing γ-secretase modulators, but is independent of the core γ-secretase complex. Keywords: neural stem cells, Alzheimer's disease, phenotypic screening, iPSCs, human neurons, dementia, Down syndrome, amyloid beta, ivermectin, selamectin

  2. Measuring lip force by oral screens Part 2: The importance of screen design, instruction and suction.

    Science.gov (United States)

    Wertsén, Madeleine; Stenberg, Manne

    2017-10-01

    The aim of this study was to find a reliable method for measuring lip force and to find the most important factors that influence the measurements in terms of magnitude and variability. The hypothesis tested was that suction is involved and thus the instruction and the design of the oral screen are of importance when measuring lip force. This is a methodological study in a healthy population. This study was conducted in a general community. The designs of the screens were soft and hard prefabricated screens and 2 semi-individually made with a tube allowing air to pass. The screens and the instructions squeeze or suck were tested on 29 healthy adults, one at a time and on 4 occasions. The test order of the screens was randomized. Data were collected during 4 consecutive days, and the procedure was repeated after 1 month. The participants were 29 healthy adult volunteers. The instruction was an important mean to distinguish between squeezing and sucking. The design of the screen affected the lip force so that it increases in relation to the projected area of the screen. A screen design with a tube allowing air to pass made it possible to avoid suction when squeezing. By measuring with and without allowing air to pass, it was possible to distinguish between suction related and not suction related lip force. The additional screen pressure when sucking was related to the ability to produce a negative intraoral pressure. In conclusion lip force increases in relation to the projected area of the screen, sucking generally increases the measured lip force and the additional screen pressure when sucking is related to the ability to produce a negative intraoral pressure.

  3. A screen to identify drug resistant variants to target-directed anti-cancer agents

    Directory of Open Access Journals (Sweden)

    Azam Mohammad

    2003-01-01

    Full Text Available The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec, a specific inhibitor of the Chronic Myeloid Leukemia (CML-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair.

  4. HAMS: High-Affinity Mass Spectrometry Screening. A High-Throughput Screening Method for Identifying the Tightest-Binding Lead Compounds for Target Proteins with No False Positive Identifications.

    Science.gov (United States)

    Imaduwage, Kasun P; Go, Eden P; Zhu, Zhikai; Desaire, Heather

    2016-11-01

    A major challenge in drug discovery is the identification of high affinity lead compounds that bind a particular target protein; these leads are typically identified by high throughput screens. Mass spectrometry has become a detection method of choice in drug screening assays because the target and the ligand need not be modified. Label-free assays are advantageous because they can be developed more rapidly than assays requiring labels, and they eliminate the risk of the label interfering with the binding event. However, in commonly used MS-based screening methods, detection of false positives is a major challenge. Here, we describe a detection strategy designed to eliminate false positives. In this approach, the protein and the ligands are incubated together, and the non-binders are separated for detection. Hits (protein binders) are not detectable by MS after incubation with the protein, but readily identifiable by MS when the target protein is not present in the incubation media. The assay was demonstrated using three different proteins and hundreds of non-inhibitors; no false positive hits were identified in any experiment. The assay can be tuned to select for ligands of a particular binding affinity by varying the quantity of protein used and the immobilization method. As examples, the method selectively detected inhibitors that have K i values of 0.2 μM, 50 pM, and 700 pM. These findings demonstrate that the approach described here compares favorably with traditional MS-based screening methods. Graphical Abstract ᅟ.

  5. Identifying Relationships between High-Risk Sexual Behaviors and Screening Positive for Chlamydia and Gonorrhea in School-Wide Screening Events

    Science.gov (United States)

    Salerno, Jennifer; Darling-Fisher, Cindy; Hawkins, Nicole M.; Fraker, Elizabeth

    2013-01-01

    Background: This article describes a school-wide sexually transmitted infection (STI) screening to identify adolescent high-risk sexual behaviors, STI history/incidence, and presence of chlamydia and gonorrhea, and examines relationships between high-risk behaviors and screening positive for chlamydia and gonorrhea in an alternative high school…

  6. Multi-type Step-wise group screening designs with unequal A-priori ...

    African Journals Online (AJOL)

    ... design with unequal group sizes and obtain values of the group sizes that minimize the expected number of runs.. Keywords: Group Screening, Group factors, multi-type step-wise group screening, expected number of runs, Optimum group screening designs > East African Journal of Statistics Vol. 1 (1) 2005: pp. 49-67 ...

  7. Small molecule screening identifies targetable zebrafish pigmentation pathways

    DEFF Research Database (Denmark)

    Colanesi, Sarah; Taylor, Kerrie L; Temperley, Nicholas D

    2012-01-01

    Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investig......Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish...... and investigate the effects of a few of these compounds in further detail. We identified and confirmed 57 compounds that altered pigment cell patterning, number, survival, or differentiation. Additional tissue targets and toxicity of small molecules are also discussed. Given that the majority of cell types...

  8. Essential attributes identified in the design of a Laboratory Information Management System for a high throughput siRNA screening laboratory.

    Science.gov (United States)

    Grandjean, Geoffrey; Graham, Ryan; Bartholomeusz, Geoffrey

    2011-11-01

    In recent years high throughput screening operations have become a critical application in functional and translational research. Although a seemingly unmanageable amount of data is generated by these high-throughput, large-scale techniques, through careful planning, an effective Laboratory Information Management System (LIMS) can be developed and implemented in order to streamline all phases of a workflow. Just as important as data mining and analysis procedures at the end of complex processes is the tracking of individual steps of applications that generate such data. Ultimately, the use of a customized LIMS will enable users to extract meaningful results from large datasets while trusting the robustness of their assays. To illustrate the design of a custom LIMS, this practical example is provided to highlight the important aspects of the design of a LIMS to effectively modulate all aspects of an siRNA screening service. This system incorporates inventory management, control of workflow, data handling and interaction with investigators, statisticians and administrators. All these modules are regulated in a synchronous manner within the LIMS. © 2011 Bentham Science Publishers

  9. Efficient pooling designs for library screening

    OpenAIRE

    Bruno, William J.; Knill, Emanuel; Balding, David J.; Bruce, D. C.; Doggett, N. A.; Sawhill, W. W.; Stallings, R. L.; Whittaker, Craig C.; Torney, David C.

    1994-01-01

    We describe efficient methods for screening clone libraries, based on pooling schemes which we call ``random $k$-sets designs''. In these designs, the pools in which any clone occurs are equally likely to be any possible selection of $k$ from the $v$ pools. The values of $k$ and $v$ can be chosen to optimize desirable properties. Random $k$-sets designs have substantial advantages over alternative pooling schemes: they are efficient, flexible, easy to specify, require fewer pools, and have er...

  10. City and County Solar PV Training Program, Module 2: Screening and Identifying PV Projects

    Energy Technology Data Exchange (ETDEWEB)

    Elgqvist, Emma M [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

    2018-04-09

    When screening and identifying PV projects, cities and counties should understand the different factors that impact the technical and economic potential of a PV project, the steps of the PV screening process, and how to use REopt Lite to screen a site for PV and storage project potential.

  11. A Multimedia Child Developmental Screening Checklist: Design and Validation.

    Science.gov (United States)

    Cheng, Hsin-Yi Kathy; Chen, Li-Ying; Cheng, Chih-Hsiu; Ju, Yan-Ying; Chen, Chia-Ling; Tseng, Kevin C

    2016-10-24

    Identifying disability early in life confers long-term benefits for children. The Taipei City Child Development Screening tool, second version (Taipei II) provides checklists for 13 child age groups from 4 months to 6 years. However, the usability of a text-based screening tool largely depends on the literacy level and logical reasoning ability of the caregivers, as well as language barriers caused by increasing numbers of immigrants. The objectives of this study were to (1) design and develop a Web-based multimedia version of the current Taipei II developmental screening tool, and (2) investigate the measurement equivalence of this multimedia version to the original paper-based version. To develop the multimedia version of Taipei II, a team of experts created illustrations, translations, and dubbing of the original checklists. The developmental screening test was administered to a total of 390 primary caregivers of children aged between 4 months and 6 years. Psychometric testing revealed excellent agreement between the paper and multimedia versions of Taipei II. Good to excellent reliabilities were demonstrated for all age groups for both the cross-mode similarity (mode intraclass correlation range 0.85-0.96) and the test-retest reliability (r=.93). Regarding the usability, the mean score was 4.80 (SD 0.03), indicating that users were satisfied with their multimedia website experience. The multimedia tool produced essentially equivalent results to the paper-based tool. In addition, it had numerous advantages, such as it can facilitate active participation and promote early screening of target populations. Clinicaltrials.gov NCT02359591; https://clinicaltrials.gov/ct2/show/NCT02359591 (Archived by WebCite at http://www.webcitation.org/6l21mmdNn).

  12. The design of light pipe with microstructures for touch screen

    Science.gov (United States)

    Yang, Bo; Lu, Kan; Liu, Pengfei; Wei, Xiaona

    2010-11-01

    Touch screen has a very wide range of applications. Most of them are used in public information inquiries, for instance, service inquiries in telecommunication bureau, tax bureau, bank system, electric department, etc...Touch screen can also be used for entertainment and virtual reality applications too. Traditionally, touch screen was composed of pairs of infrared LED and correspondent receivers which were all installed in the screen frame. Arrays of LED were set in the adjacent sides of the frame of an infrared touch screen while arrays of the infrared receivers were fixed in each opposite side, so that the infrared detecting network was formed. While the infrared touch screen has some technical limitations nowadays such as the low resolution, limitations of touching methods and fault response due to environmental disturbances. The plastic material has a relatively high absorption rate for infrared light, which greatly limits the size of the touch screen. Our design uses laser diode as source and change the traditional inner structure of touch screen by using a light pipe with microstructures. The geometric parameters of the light pipe and the microstructures were obtained through equation solving. Simulation results prove that the design method for touch screen proposed in this paper could achieve high resolution and large size of touch screen.

  13. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

    Science.gov (United States)

    Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

    2015-01-01

    Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

  14. Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

    Directory of Open Access Journals (Sweden)

    Thomas S Peat

    Full Text Available A fragment-based screen against human immunodeficiency virus type 1 (HIV integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

  15. Human factors engineering review for CRT screen design

    International Nuclear Information System (INIS)

    Yi, S. M.; Joo, C. Y.; Ra, J. C.

    1999-01-01

    The information interface between man and machine may be more important than hardware and workplace layout considerations. Transmitting and receiving data through this information interface can be characterized as a communication or interface problem. Management of man-machine interface is essential for the enhancement of the information processing and decision-making capability of computer users working in real time, demanding task. The design of human-computer interface is not a rigid and static procedure. The content and context of each interface varies according to the specific application. So, the purpose of this study is to review the human factor design process for interfaces, to make human factor guidelines for CRT screen and to apply these to CRT screen design. (author)

  16. The utility of screening in the design of trials for symptom management in cancer.

    Science.gov (United States)

    Jeon, Sangchoon; Given, Charles W; Sikorskii, Alla; Given, Barbara

    2009-10-01

    Clinical trials that test interventions for symptom management must target patients whose symptoms are severe and can benefit from participation. Screening symptoms for their severity prior to trial entry may be an important element of trial design. This research describes the utility of screening for severity of symptoms prior to entry into clinical trials for symptom management in cancer. To accomplish this, 601 cancer patients undergoing chemotherapy were assessed at screening and at the initial intervention contact, using the 0-10 rating scale for severity of nine symptoms. Post-test probabilities and likelihood ratios (LRs) were estimated across cut-offs in screening severity scores. Areas under receiver operating characteristic curves for reaching threshold of four at the initial intervention contact were estimated by a nonparametric method. It was found that screening severity scores were good predictors for identifying patients who would not reach threshold but did not always accurately predict patients who would. The cut-offs between 2 and 4 on a 0-10 scale could be used to identify patients that might benefit from receipt of interventions. For all symptoms, the LRs were greater than one across possible screening cut-offs. The findings indicate that decision rules based on screening prior to entry into cancer symptom management trials can provide reasonable discriminative accuracy by differentiating among patients who are likely to reach higher levels of severity later in the trial from those who are not. Optimal severity cut-offs can be established based on LRs and desired sensitivity and specificity.

  17. High-throughput bioaffinity mass spectrometry for screening and identification of designer anabolic steroids in dietary supplements.

    Science.gov (United States)

    Aqai, Payam; Cevik, Ebru; Gerssen, Arjen; Haasnoot, Willem; Nielen, Michel W F

    2013-03-19

    A generic high-throughput bioaffinity liquid chromatography-mass spectrometry (BioMS) approach was developed and applied for the screening and identification of known and unknown recombinant human sex hormone-binding globulin (rhSHBG)-binding designer steroids in dietary supplements. For screening, a semi-automated competitive inhibition binding assay was combined with fast ultrahigh-performance-LC-electrospray ionization-triple-quadrupole-MS (UPLC-QqQ-MS). 17β-Testosterone-D3 was used as the stable isotope label of which the binding to rhSHBG-coated paramagnetic microbeads was inhibited by any other binding (designer) steroid. The assay was performed in a 96-well plate and combined with the fast LC-MS, 96 measurements could be performed within 4 h. The concentration-dependent inhibition of the label by steroids in buffer and dietary supplements was demonstrated. Following an adjusted bioaffinity isolation procedure, suspect extracts were injected into a chip-UPLC(NanoTile)-Q-time-of-flight-MS system for full-scan accurate mass identification. Next to known steroids, 1-testosterone was identified in three of the supplements studied and the designer steroid tetrahydrogestrinone was identified in a spiked supplement. The generic steroid-binding assay can be used for high-throughput screening of androgens, estrogens, and gestagens in dietary supplements to fight doping. When combined with chip-UPLC-MS, it is a powerful tool for early warning of unknown emerging rhSHBG bioactive designer steroids in dietary supplements.

  18. A novel yeast cell-based screen identifies flavone as a tankyrase inhibitor

    International Nuclear Information System (INIS)

    Yashiroda, Yoko; Okamoto, Reika; Hatsugai, Kaori; Takemoto, Yasushi; Goshima, Naoki; Saito, Tamio; Hamamoto, Makiko; Sugimoto, Yoshikazu; Osada, Hiroyuki; Seimiya, Hiroyuki; Yoshida, Minoru

    2010-01-01

    The telomere-associated protein tankyrase 1 is a poly(ADP-ribose) polymerase and is considered to be a promising target for cancer therapy, especially for BRCA-associated cancers. However, an efficient assay system for inhibitor screening has not been established, mainly due to the difficulty of efficient preparation of the enzyme and its substrate. Here, we report a cell-based assay system for detecting inhibitory activity against tankyrase 1. We found that overexpression of the human tankyrase 1 gene causes a growth defect in the fission yeast Schizosaccharomyces pombe. Chemicals that restore the growth defect phenotype can be identified as potential tankyrase 1 inhibitors. We performed a high-throughput screen using this system, and identified flavone as a compound that restores the growth of yeast cells overexpressing tankyrase 1. Indeed, flavone inhibited poly(ADP-ribosyl)ation of proteins caused by overexpression of tankyrase 1 in yeast cells. This system allows rapid identification of inhibitory activity against tankyrase 1 and is amenable to high-throughput screening using robotics.

  19. Rigorous Screening Technology for Identifying Suitable CO2 Storage Sites II

    Energy Technology Data Exchange (ETDEWEB)

    George J. Koperna Jr.; Vello A. Kuuskraa; David E. Riestenberg; Aiysha Sultana; Tyler Van Leeuwen

    2009-06-01

    This report serves as the final technical report and users manual for the 'Rigorous Screening Technology for Identifying Suitable CO2 Storage Sites II SBIR project. Advanced Resources International has developed a screening tool by which users can technically screen, assess the storage capacity and quantify the costs of CO2 storage in four types of CO2 storage reservoirs. These include CO2-enhanced oil recovery reservoirs, depleted oil and gas fields (non-enhanced oil recovery candidates), deep coal seems that are amenable to CO2-enhanced methane recovery, and saline reservoirs. The screening function assessed whether the reservoir could likely serve as a safe, long-term CO2 storage reservoir. The storage capacity assessment uses rigorous reservoir simulation models to determine the timing, ultimate storage capacity, and potential for enhanced hydrocarbon recovery. Finally, the economic assessment function determines both the field-level and pipeline (transportation) costs for CO2 sequestration in a given reservoir. The screening tool has been peer reviewed at an Electrical Power Research Institute (EPRI) technical meeting in March 2009. A number of useful observations and recommendations emerged from the Workshop on the costs of CO2 transport and storage that could be readily incorporated into a commercial version of the Screening Tool in a Phase III SBIR.

  20. A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein.

    Directory of Open Access Journals (Sweden)

    Michael S Rogers

    Full Text Available Anti-angiogenic therapies are effective for the treatment of cancer, a variety of ocular diseases, and have potential benefits in cardiovascular disease, arthritis, and psoriasis. We have previously shown that anthrax protective antigen (PA, a non-pathogenic component of anthrax toxin, is an inhibitor of angiogenesis, apparently as a result of interaction with the cell surface receptors capillary morphogenesis gene 2 (CMG2 protein and tumor endothelial marker 8 (TEM8. Hence, molecules that bind the anthrax toxin receptors may be effective to slow or halt pathological vascular growth. Here we describe development and testing of an effective homogeneous steady-state fluorescence resonance energy transfer (FRET high throughput screening assay designed to identify molecules that inhibit binding of PA to CMG2. Molecules identified in the screen can serve as potential lead compounds for the development of anti-angiogenic and anti-anthrax therapies. The assay to screen for inhibitors of this protein-protein interaction is sensitive and robust, with observed Z' values as high as 0.92. Preliminary screens conducted with a library of known bioactive compounds identified tannic acid and cisplatin as inhibitors of the PA-CMG2 interaction. We have confirmed that tannic acid both binds CMG2 and has anti-endothelial properties. In contrast, cisplatin appears to inhibit PA-CMG2 interaction by binding both PA and CMG2, and observed cisplatin anti-angiogenic effects are not mediated by interaction with CMG2. This work represents the first reported high throughput screening assay targeting CMG2 to identify possible inhibitors of both angiogenesis and anthrax intoxication.

  1. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth

    Directory of Open Access Journals (Sweden)

    Gregory D. Bowden

    2018-04-01

    Full Text Available The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM, a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60–70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83% have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18 of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036–0.12; 95% CI] or 21.9 ng/ml [12.1–40.3; 95% CI]. These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection. Keywords: Drug repurposing, High-throughput screen, Sarcocystis neurona, Equine protozoal myeloencephalitis

  2. Screening and syndromic approaches to identify gonorrhea and chlamydial infection among women.

    Science.gov (United States)

    Sloan, N L; Winikoff, B; Haberland, N; Coggins, C; Elias, C

    2000-03-01

    The standard diagnostic tools to identify sexually transmitted infections are often expensive and have laboratory and infrastructure requirements that make them unavailable to family planning and primary health-care clinics in developing countries. Therefore, inexpensive, accessible tools that rely on symptoms, signs, and/or risk factors have been developed to identify and treat reproductive tract infections without the need for laboratory diagnostics. Studies were reviewed that used standard diagnostic tests to identify gonorrhea and cervical chlamydial infection among women and that provided adequate information about the usefulness of the tools for screening. Aggregation of the studies' results suggest that risk factors, algorithms, and risk scoring for syndromic management are poor indicators of gonorrhea and chlamydial infection in samples of both low and high prevalence and, consequently, are not effective mechanisms with which to identify or manage these conditions. The development and evaluation of other approaches to identify gonorrhea and chlamydial infections, including inexpensive and simple laboratory screening tools, periodic universal treatment, and other alternatives must be given priority.

  3. Structural and mechanistic analysis of a β-glycoside phosphorylase identified by screening a metagenomic library.

    Science.gov (United States)

    Macdonald, Spencer S; Patel, Ankoor; Larmour, Veronica L C; Morgan-Lang, Connor; Hallam, Steven J; Mark, Brian L; Withers, Stephen G

    2018-03-02

    Glycoside phosphorylases have considerable potential as catalysts for the assembly of useful glycans for products ranging from functional foods and prebiotics to novel materials. However, the substrate diversity of currently identified phosphorylases is relatively small, limiting their practical applications. To address this limitation, we developed a high-throughput screening approach using the activated substrate 2,4-dinitrophenyl β-d-glucoside (DNPGlc) and inorganic phosphate for identifying glycoside phosphorylase activity and used it to screen a large insert metagenomic library. The initial screen, based on release of 2,4-dinitrophenyl from DNPGlc in the presence of phosphate, identified the gene bglP, encoding a retaining β-glycoside phosphorylase from the CAZy GH3 family. Kinetic and mechanistic analysis of the gene product, BglP, confirmed a double displacement ping-pong mechanism involving a covalent glycosyl-enzyme intermediate. X-ray crystallographic analysis provided insights into the phosphate-binding mode and identified a key glutamine residue in the active site important for substrate recognition. Substituting this glutamine for a serine swapped the substrate specificity from glucoside to N -acetylglucosaminide. In summary, we present a high-throughput screening approach for identifying β-glycoside phosphorylases, which was robust, simple to implement, and useful in identifying active clones within a metagenomics library. Implementation of this screen enabled discovery of a new glycoside phosphorylase class and has paved the way to devising simple ways in which enzyme specificity can be encoded and swapped, which has implications for biotechnological applications. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan.

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  5. iScreen: world's first cloud-computing web server for virtual screening and de novo drug design based on TCM database@Taiwan

    Science.gov (United States)

    Tsai, Tsung-Ying; Chang, Kai-Wei; Chen, Calvin Yu-Chian

    2011-06-01

    The rapidly advancing researches on traditional Chinese medicine (TCM) have greatly intrigued pharmaceutical industries worldwide. To take initiative in the next generation of drug development, we constructed a cloud-computing system for TCM intelligent screening system (iScreen) based on TCM Database@Taiwan. iScreen is compacted web server for TCM docking and followed by customized de novo drug design. We further implemented a protein preparation tool that both extract protein of interest from a raw input file and estimate the size of ligand bind site. In addition, iScreen is designed in user-friendly graphic interface for users who have less experience with the command line systems. For customized docking, multiple docking services, including standard, in-water, pH environment, and flexible docking modes are implemented. Users can download first 200 TCM compounds of best docking results. For TCM de novo drug design, iScreen provides multiple molecular descriptors for a user's interest. iScreen is the world's first web server that employs world's largest TCM database for virtual screening and de novo drug design. We believe our web server can lead TCM research to a new era of drug development. The TCM docking and screening server is available at http://iScreen.cmu.edu.tw/.

  6. Viral load in children with congenital cytomegalovirus infection identified on newborn hearing screening.

    Science.gov (United States)

    Kawada, Jun-ichi; Torii, Yuka; Kawano, Yoshihiko; Suzuki, Michio; Kamiya, Yasuko; Kotani, Tomomi; Kikkawa, Fumitaka; Kimura, Hiroshi; Ito, Yoshinori

    2015-04-01

    Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of sensorineural hearing loss (SNHL) in children. However, congenital SNHL without other clinical abnormalities is rarely diagnosed as CMV-related in early infancy. The aim of this study was to identify and treat patients with congenital CMV-related SNHL or CMV-related clinical abnormalities other than SNHL. The association between CMV load and SNHL was also evaluated. Newborns who had abnormal hearing screening results or other clinical abnormalities were screened for congenital CMV infection by PCR of saliva or urine specimens, and identified infected patients were treated with valganciclovir (VGCV) for 6 weeks. The CMV load of patients with or without SNHL was compared at regular intervals during as well as after VGCV treatment. Of 127 infants with abnormal hearing screening results, and 31 infants with other clinical abnormalities, CMV infection was identified in 6 and 3 infants, respectively. After VGCV treatment, 1 case had improved hearing but the other 5 SNHL cases had little or no improvement. Among these 9 patients with or without SNHL at 1 year of age, there was no significant difference in CMV blood or urine load at diagnosis, but both were significantly higher in patients with SNHL during VGCV treatment. Selective CMV screening of newborns having an abnormal hearing screening result would be a reasonable strategy for identification of symptomatic congenital CMV infection. Prolonged detection of CMV in blood could be a risk factor for SNHL. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B.

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any...... associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents...... including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong...

  8. Design of Screens for Sand Control of Wells

    Directory of Open Access Journals (Sweden)

    Ján Pinka

    2006-04-01

    Full Text Available Drilling, completion, production, and reservoir engineers, supervisors, foremen, superintendents, service company personnel, technologists and anyone involved with recommending, selecting, designing or on-site performance of well completions or workovers where sand production is, or may become, a serious problem will benefit from this course. Less sand influx can be expected in a horizontal well than in a vertical well. If horizontal holes in weak formation sands can be successfully gravel packed, the result could be significantly higher well productivity than with a liner, screen or pre-packed screen alone. The article covers innovative screens for sand control used in oil and gas industry from the world leaders in total completion. The type of screen (wire wrapped, reinforced, pre-packed, ect. should also be chosen with due consideration to running-in condition (curve radius, compression when the screens are pushed along the drain hole, etc..

  9. Two-dimensional combinatorial screening enables the bottom-up design of a microRNA-10b inhibitor.

    Science.gov (United States)

    Velagapudi, Sai Pradeep; Disney, Matthew D

    2014-03-21

    The RNA motifs that bind guanidinylated kanamycin A (G Kan A) and guanidinylated neomycin B (G Neo B) were identified via two-dimensional combinatorial screening (2DCS). The results of these studies enabled the "bottom-up" design of a small molecule inhibitor of oncogenic microRNA-10b.

  10. Brief screening questionnaires to identify problem drinking during pregnancy: a systematic review.

    Science.gov (United States)

    Burns, Ethel; Gray, Ron; Smith, Lesley A

    2010-04-01

    Although prenatal screening for problem drinking during pregnancy has been recommended, guidance on screening instruments is lacking. We investigated the sensitivity, specificity and predictive value of brief alcohol screening questionnaires to identify problem drinking in pregnant women. Electronic databases from their inception to June 2008 were searched, as well as reference lists of eligible papers and related review papers. We sought cohort or cross-sectional studies that compared one or more brief alcohol screening questionnaire(s) with reference criteria obtained using structured interviews to detect 'at-risk' drinking, alcohol abuse or dependency in pregnant women receiving prenatal care. Five studies (6724 participants) were included. In total, seven instruments were evaluated: TWEAK (Tolerance, Worried, Eye-opener, Amnesia, Kut down), T-ACE [Take (number of drinks), Annoyed, Cut down, Eye-opener], CAGE (Cut down, Annoyed, Guilt, Eye-opener], NET (Normal drinker, Eye-opener, Tolerance), AUDIT (Alcohol Use Disorder Identification Test), AUDIT-C (AUDIT-consumption) and SMAST (Short Michigan Alcohol Screening Test). Study quality was generally good, but lack of blinding was a common weakness. For risk drinking sensitivity was highest for T-ACE (69-88%), TWEAK (71-91%) and AUDIT-C (95%), with high specificity (71-89%, 73-83% and 85%, respectively). CAGE and SMAST performed poorly. Sensitivity of AUDIT-C at score >or=3 was high for past year alcohol dependence (100%) or alcohol use disorder (96%) with moderate specificity (71% each). For life-time alcohol dependency the AUDIT at score >or=8 performed poorly. T-ACE, TWEAK and AUDIT-C show promise for screening for risk drinking, and AUDIT-C may also be useful for identifying alcohol dependency or abuse. However, their performance as stand-alone tools is uncertain, and further evaluation of questionnaires for prenatal alcohol use is warranted.

  11. Design and Polarization Characteristics Analysis of Dihedral Based on Salisbury Screen

    Directory of Open Access Journals (Sweden)

    Zhang Ran

    2016-12-01

    Full Text Available Salisbury screens have a number of unique electromagnetic scattering characteristics. When appropriately designed, the Salisbury screen can reach the radar target signature transform. Based on the electromagnetic scattering characteristics of the Salisbury screen, we designed a novel dihedral corner, and theoretically analyzed and simulated its electromagnetic scattering characteristics in this study. The results reveal the monostatic radar cross section curves of the 90°and 60° Salisbury screen dihedral and metal dihedral, respectively. Taking an orthogonal dihedral corner as an example, we obtained the polarization scattering matrixes for different incident degrees. In addition, we investigated the influence of illumination frequency, target gestures, and other key factors on the polarization characteristics of the Salisbury screen dihedral corner. The theoretical and simulation analysis results show that compared with the conventional metal dihedral corner, the Salisbury screen dihedral corner significantly influences the scattering characteristics and will have potential application in electronic warfare.

  12. A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing

    DEFF Research Database (Denmark)

    Thomas Danielsen, E.; E. Møller, Morten; Yamanaka, Naoki

    2016-01-01

    Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis...... and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition...... and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms...

  13. High-throughput screen of drug repurposing library identifies inhibitors of Sarcocystis neurona growth.

    Science.gov (United States)

    Bowden, Gregory D; Land, Kirkwood M; O'Connor, Roberta M; Fritz, Heather M

    2018-04-01

    The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60-70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed inhibitory activity against S. neurona growth, including compounds active in the nM concentration range. Many identified inhibitory compounds have well-defined mechanisms of action, making them useful tools to study parasite biology in addition to being potential therapeutic agents. In comparing the activity of inhibitory compounds identified by our screen to that of other screens against other apicomplexan parasites, we found that most compounds (15/18; 83%) have activity against one or more related apicomplexans. Interestingly, nearly half (44%; 8/18) of the inhibitory compounds have reported activity against dopamine receptors. We also found that dantrolene, a compound already formulated for horses with a peak plasma concentration of 37.8 ± 12.8 ng/ml after 500 mg dose, inhibits S. neurona parasites at low concentrations (0.065 μM [0.036-0.12; 95% CI] or 21.9 ng/ml [12.1-40.3; 95% CI]). These studies demonstrate the use of a new tool for discovering new chemotherapeutic agents for EPM and potentially providing new reagents to elucidate biologic pathways required for successful S. neurona infection. Copyright © 2018. Published by Elsevier Ltd.

  14. Current and emerging screening methods to identify post-head-emergence frost adaptation in wheat and barley.

    Science.gov (United States)

    Frederiks, T M; Christopher, J T; Harvey, G L; Sutherland, M W; Borrell, A K

    2012-09-01

    Cereal crops can suffer substantial damage if frosts occur at heading. Identification of post-head-emergence frost (PHEF) resistance in cereals poses a number of unique and difficult challenges. Many decades of research have failed to identify genotypes with PHEF resistance that could offer economically significant benefit to growers. Research and breeding gains have been limited by the available screening systems. Using traditional frost screening systems, genotypes that escape frost injury in trials due to spatial temperature differences and/or small differences in phenology can be misidentified as resistant. We believe that by improving techniques to minimize frost escapes, such 'false-positive' results can be confidently identified and eliminated. Artificial freezing chambers or manipulated natural frost treatments offer many potential advantages but are not yet at the stage where they can be reliably used for frost screening in breeding programmes. Here we describe the development of a novel photoperiod gradient method (PGM) that facilitates screening of genotypes of different phenology under natural field frosts at matched developmental stages. By identifying frost escapes and increasing the efficiency of field screening, the PGM ensures that research effort can be focused on finding genotypes with improved PHEF resistance. To maximize the likelihood of identifying PHEF resistance, we propose that the PGM form part of an integrated strategy to (i) source germplasm;(ii) facilitate high throughput screening; and (iii) permit detailed validation. PGM may also be useful in other studies where either a range of developmental stages and/or synchronized development are desired.

  15. An AICD-based functional screen to identify APP metabolism regulators

    Directory of Open Access Journals (Sweden)

    Lee Jeremy C

    2007-08-01

    Full Text Available Abstract Background A central event in Alzheimer's disease (AD is the regulated intramembraneous proteolysis of the β-amyloid precursor protein (APP, to generate the β-amyloid (Aβ peptide and the APP intracellular domain (AICD. Aβ is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered. Results To validate this experimental approach we modulated α-, β-, and γ-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis. Conclusion Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.

  16. Novel high-throughput screening system for identifying STAT3-SH2 antagonists

    International Nuclear Information System (INIS)

    Uehara, Yutaka; Mochizuki, Masato; Matsuno, Kenji; Haino, Takeharu; Asai, Akira

    2009-01-01

    Constitutive activation of the oncogenic transcription factor STAT3 frequently occurs in various human malignancies. STAT3 activation involves dimerization via intermolecular pTyr-SH2 interaction. Thus, antagonizing this interaction is a feasible approach to inhibit STAT3 activation for cancer therapy. In order to identify selective STAT3 inhibitors, we developed a biochemical HTS system based on AlphaScreen technology, which measures the abilities of test compounds to antagonize pTyr-SH2 interactions. We screened our chemical libraries using this system and identified 5,15-diphenylporphyrin (5,15-DPP) as a selective STAT3-SH2 antagonist. Selective inhibition of STAT3 nuclear translocation and DNA biding activity was observed in cells treated with 5,15-DPP. IL-6-dependent dimerization of STAT3, c-myc promoter binding and c-myc protein expression were all suppressed by 5,15-DPP, whereas no decrement in either expression or phosphorylation level of STAT3 was observed. Thus, the HTS assay system represented herein may be useful for identifying novel STAT3-SH2 antagonists.

  17. The Role and Design of Screen Images in Software Documentation.

    Science.gov (United States)

    van der Meij, Hans

    2000-01-01

    Discussion of learning a new computer software program focuses on how to support the joint handling of a manual, input devices, and screen display. Describes a study that examined three design styles for manuals that included screen images to reduce split-attention problems and discusses theory versus practice and cognitive load theory.…

  18. CRISPR-FOCUS: A web server for designing focused CRISPR screening experiments

    OpenAIRE

    Cao, Qingyi; Ma, Jian; Chen, Chen-Hao; Xu, Han; Chen, Zhi; Li, Wei; Liu, X. Shirley

    2017-01-01

    The recently developed CRISPR screen technology, based on the CRISPR/Cas9 genome editing system, enables genome-wide interrogation of gene functions in an efficient and cost-effective manner. Although many computational algorithms and web servers have been developed to design single-guide RNAs (sgRNAs) with high specificity and efficiency, algorithms specifically designed for conducting CRISPR screens are still lacking. Here we present CRISPR-FOCUS, a web-based platform to search and prioriti...

  19. High-Throughput Screening to Identify Regulators of Meiosis-Specific Gene Expression in Saccharomyces cerevisiae.

    Science.gov (United States)

    Kassir, Yona

    2017-01-01

    Meiosis and gamete formation are processes that are essential for sexual reproduction in all eukaryotic organisms. Multiple intracellular and extracellular signals feed into pathways that converge on transcription factors that induce the expression of meiosis-specific genes. Once triggered the meiosis-specific gene expression program proceeds in a cascade that drives progress through the events of meiosis and gamete formation. Meiosis-specific gene expression is tightly controlled by a balance of positive and negative regulatory factors that respond to a plethora of signaling pathways. The budding yeast Saccharomyces cerevisiae has proven to be an outstanding model for the dissection of gametogenesis owing to the sophisticated genetic manipulations that can be performed with the cells. It is possible to use a variety selection and screening methods to identify genes and their functions. High-throughput screening technology has been developed to allow an array of all viable yeast gene deletion mutants to be screened for phenotypes and for regulators of gene expression. This chapter describes a protocol that has been used to screen a library of homozygous diploid yeast deletion strains to identify regulators of the meiosis-specific IME1 gene.

  20. Designing an idea screening framework for employee-driven innovation

    OpenAIRE

    Ciriello, Raffaele Fabio; Richter, Alexander; Schwabe, Gerhard

    2016-01-01

    As ever more companies encourage their employees to realize innovations, a surplus of ideas that exceeds the available resources to implement them has become reality in many organizations. With this paper, we follow recent calls for designing IT-supported, comprehensive, multi-attributive idea screening throughout the whole innovation cycle. Our Idea Screening Framework is grounded in literature and empirical data we collected from a two-year field study in a multinational European banking so...

  1. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.

    Science.gov (United States)

    Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F; Lecuit, Marc

    2016-05-12

    Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents.

  2. Design of a general-purpose European compound screening library for EU-OPENSCREEN.

    Science.gov (United States)

    Horvath, Dragos; Lisurek, Michael; Rupp, Bernd; Kühne, Ronald; Specker, Edgar; von Kries, Jens; Rognan, Didier; Andersson, C David; Almqvist, Fredrik; Elofsson, Mikael; Enqvist, Per-Anders; Gustavsson, Anna-Lena; Remez, Nikita; Mestres, Jordi; Marcou, Gilles; Varnek, Alexander; Hibert, Marcel; Quintana, Jordi; Frank, Ronald

    2014-10-01

    This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could

  3. Development of the Aboriginal Communication Assessment After Brain Injury (ACAABI): A screening tool for identifying acquired communication disorders in Aboriginal Australians.

    Science.gov (United States)

    Armstrong, Elizabeth M; Ciccone, Natalie; Hersh, Deborah; Katzenellebogen, Judith; Coffin, Juli; Thompson, Sandra; Flicker, Leon; Hayward, Colleen; Woods, Deborah; McAllister, Meaghan

    2017-06-01

    Acquired communication disorders (ACD), following stroke and traumatic brain injury, may not be correctly identified in Aboriginal Australians due to a lack of linguistically and culturally appropriate assessment tools. Within this paper we explore key issues that were considered in the development of the Aboriginal Communication Assessment After Brain Injury (ACAABI) - a screening tool designed to assess the presence of ACD in Aboriginal populations. A literature review and consultation with key stakeholders were undertaken to explore directions needed to develop a new tool, based on existing tools and recommendations for future developments. The literature searches revealed no existing screening tool for ACD in these populations, but identified tools in the areas of cognition and social-emotional wellbeing. Articles retrieved described details of the content and style of these tools, with recommendations for the development and administration of a new tool. The findings from the interview and focus group views were consistent with the approach recommended in the literature. There is a need for a screening tool for ACD to be developed but any tool must be informed by knowledge of Aboriginal language, culture and community input in order to be acceptable and valid.

  4. Accuracy of Brief Screening Tools for Identifying Postpartum Depression Among Adolescent Mothers

    Science.gov (United States)

    Venkatesh, Kartik K.; Zlotnick, Caron; Triche, Elizabeth W.; Ware, Crystal

    2014-01-01

    OBJECTIVE: To evaluate the accuracy of the Edinburgh Postnatal Depression Scale (EPDS) and 3 subscales for identifying postpartum depression among primiparous adolescent mothers. METHODS: Mothers enrolled in a randomized controlled trial to prevent postpartum depression completed a psychiatric diagnostic interview and the 10-item EPDS at 6 weeks, 3 months, and 6 months postpartum. Three subscales of the EPDS were assessed as brief screening tools: 3-item anxiety subscale (EPDS-3), 7-item depressive symptoms subscale (EPDS-7), and 2-item subscale (EPDS-2) that resemble the Patient Health Questionnaire-2. Receiver operating characteristic curves and the areas under the curves for each tool were compared to assess accuracy. The sensitivities and specificities of each screening tool were calculated in comparison with diagnostic criteria for a major depressive disorder. Repeated-measures longitudinal analytical techniques were used. RESULTS: A total of 106 women contributed 289 postpartum visits; 18% of the women met criteria for incident postpartum depression by psychiatric diagnostic interview. When used as continuous measures, the full EPDS, EPDS-7, and EPDS-2 performed equally well (area under the curve >0.9). Optimal cutoff scores for a positive depression screen for the EPDS and EPDS-7 were lower (≥9 and ≥7, respectively) than currently recommended cutoff scores (≥10). At optimal cutoff scores, the EPDS and EPDS-7 both had sensitivities of 90% and specificities of >85%. CONCLUSIONS: The EPDS, EPDS-7, and EPDS-2 are highly accurate at identifying postpartum depression among adolescent mothers. In primary care pediatric settings, the EPDS and its shorter subscales have potential for use as effective depression screening tools. PMID:24344102

  5. Testing the woman abuse screening tool to identify intimate partner violence in Indonesia.

    Science.gov (United States)

    Iskandar, Livia; Braun, Kathryn L; Katz, Alan R

    2015-04-01

    Intimate Partner Violence (IPV) is a global public health problem. IPV prevalence in Indonesia has been estimated to be less than 1%, based on reported cases. It is likely that IPV prevalence is underreported in Indonesia, as it is in many other countries. Screening for IPV has been found to increase IPV identification, but no screening tools are in use in Indonesia. The aim of this study was to test the translated Woman Abuse Screening Tool (WAST) for detecting IPV in Indonesia. The WAST was tested against a diagnostic interview by a trained psychologist on 240 women attending two Primary Health Centers in Jakarta. IPV prevalence and the reliability, sensitivity, and specificity of the WAST were estimated. Prevalence of IPV by diagnostic interview was 36.3%, much higher than published estimates. The most common forms of IPV identified were psychological (85%) and physical abuse (24%). Internal reliability of the WAST was high (α = .801). A WAST score of 13 (out of 24) is the recommended cutoff for identifying IPV, but only 17% of the Indonesian sample scored 13 or higher. Test sensitivity of the WAST with a cutoff score of 13 was only 41.9%, with a specificity of 96.8%. With a cutoff score of 10, the sensitivity improved to 84.9%, while the specificity decreased to 61.0%. Use of the WAST with a cutoff score of 10 provides good sensitivity and reasonable specificity and would provide a much-needed screening tool for use in Indonesia. Although a lower cutoff would yield a greater proportion of false positives, most of the true cases would be identified, increasing the possibility that women experiencing abuse would receive needed assistance. © The Author(s) 2014.

  6. The comparison of the performance of two screening strategies identifying newly-diagnosed HIV during pregnancy.

    Science.gov (United States)

    Boer, Kees; Smit, Colette; van der Flier, Michiel; de Wolf, Frank

    2011-10-01

    In the Netherlands, a non-selective opt-out instead of a selective opt-in antenatal HIV screening strategy was implemented in 2004. In case of infection, screening was followed by prevention of mother-to-child-transmission (PMTCT). We compared the performance of the two strategies in terms of detection of new cases of HIV and vertical transmission. HIV-infected pregnant women were identified retrospectively from the Dutch HIV cohort ATHENA January 2000 to January 2008. Apart from demographic, virological and immunological data, the date of HIV infection in relation to the index pregnancy was established. Separately, all infants diagnosed with HIV born following implementation of the screening program were identified by a questionnaire via the paediatric HIV centres. 162/481 (33.7%) HIV-positive pregnant women were diagnosed with HIV before 2004 and 172/214 (80.3%) after January 2004. Multivariate analysis showed an 8-fold (95% confidence interval 5.47-11.87) increase in the odds of HIV detection during pregnancy after the national introduction of the opt-out strategy. Still, three children born during a 5-year period after July 2004 were infected due to de novo infection in pregnancy. Implementation of a nation-wide screening strategy based upon non-selective opt-out screening followed by effective PMTCT appeared to detect more HIV-infected women for the first time in pregnancy and to reduce vertical transmission of HIV substantially. Nonetheless, still few children are infected because of maternal infection after the first trimester. We propose the introduction of partner screening on HIV as part of the antenatal screening strategy.

  7. Design of a projection display screen with vanishing color shift for rear-projection HDTV

    Science.gov (United States)

    Liu, Xiu; Zhu, Jin-lin

    1996-09-01

    Using bi-convex cylinder lens with matrix structure, the transmissive projection display screen with high contrast and wider viewing angle has been widely used in large rear projection TV and video projectors, it obtained a inhere color shift and puzzled the designer of display screen for RGB projection tube in-line adjustment. Based on the method of light beam racing, the general software of designing projection display screen has been developed and the computer model of vanishing color shift for rear projection HDTV has bee completed. This paper discussed the practical designing method to vanish the defect of color shift and mentioned the relations between the primary optical parameters of display screen and relative geometry sizes of lens' surface. The distributions of optical gain to viewing angle and the influences on engineering design are briefly analyzed.

  8. Design, synthesis, and validation of an in vitro platform peptide-whole cell screening assay using MTT reagent

    Directory of Open Access Journals (Sweden)

    Sahar Ahmed

    2017-05-01

    Full Text Available An in vitro platform to perform peptide screening against different cancer cell lines was designed. The strategy for this screening relied on the design and detection of high-affinity cancer-targeting peptides based on the sequences of NGR and P160. Evaluation of the best binding peptides was performed via incubation of the peptide array-bounded cells with MTT reagent, which is reduced to purple formazan in living cells and further quantified using an Elispot and Kodak imager. For proof of concept, a peptide library (132 spots, and 66 different peptides was designed, synthesized, and screened against different cancer cell lines. The current strategy assists in the identification of positive and negative peptides as well as the relative binding between positive ones. Better binding peptide sequences of the NGR motif were demonstrated to show up to a 2.6-fold increase in CD13+ cell lines with insignificant binding to CD13− ones. Comparable results were observed for P160 peptide sequences, to which different peptides had increased binding, with an up to 3-fold increase relative to the native P160 peptide. Based on our results, new peptide sequences for cancer targeting were identified, and the developed strategy was applied to two different peptide libraries.

  9. Design of extended length submerged traveling screen and submerged bar screen fish guidance equipment

    International Nuclear Information System (INIS)

    Bardy, D.; Lindstrom, M.; Fechner, D.

    1991-01-01

    The hydropower projects on the Snake and lower Columbia Rivers in the Pacific Northwest are unique because these rivers are also the spawning grounds for migratory salmon. The salmon swim upstream from the ocean, lay their eggs, and die. The newly hatched fingerlings must then make their way past the hydroelectric dams to the ocean. Two separate bypass systems are needed, one to pass the adult fish going upstream, and one to pass the fingerlings going downstream. This paper addresses the design considerations for two of the components of the downstream migrant fish passage facilities, the extended Submerged Traveling Screen and Submerged Bar Screen

  10. Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy.

    Science.gov (United States)

    Allan, Kristina J; Mahoney, Douglas J; Baird, Stephen D; Lefebvre, Charles A; Stojdl, David F

    2018-04-03

    High-throughput genome-wide RNAi (RNA interference) screening technology has been widely used for discovering host factors that impact virus replication. Here we present the application of this technology to uncovering host targets that specifically modulate the replication of Maraba virus, an oncolytic rhabdovirus, and vaccinia virus with the goal of enhancing therapy. While the protocol has been tested for use with oncolytic Maraba virus and oncolytic vaccinia virus, this approach is applicable to other oncolytic viruses and can also be utilized for identifying host targets that modulate virus replication in mammalian cells in general. This protocol describes the development and validation of an assay for high-throughput RNAi screening in mammalian cells, the key considerations and preparation steps important for conducting a primary high-throughput RNAi screen, and a step-by-step guide for conducting a primary high-throughput RNAi screen; in addition, it broadly outlines the methods for conducting secondary screen validation and tertiary validation studies. The benefit of high-throughput RNAi screening is that it allows one to catalogue, in an extensive and unbiased fashion, host factors that modulate any aspect of virus replication for which one can develop an in vitro assay such as infectivity, burst size, and cytotoxicity. It has the power to uncover biotherapeutic targets unforeseen based on current knowledge.

  11. Quantitative high-throughput screen identifies inhibitors of the Schistosoma mansoni redox cascade.

    Directory of Open Access Journals (Sweden)

    Anton Simeonov

    2008-01-01

    Full Text Available Schistosomiasis is a tropical disease associated with high morbidity and mortality, currently affecting over 200 million people worldwide. Praziquantel is the only drug used to treat the disease, and with its increased use the probability of developing drug resistance has grown significantly. The Schistosoma parasites can survive for up to decades in the human host due in part to a unique set of antioxidant enzymes that continuously degrade the reactive oxygen species produced by the host's innate immune response. Two principal components of this defense system have been recently identified in S. mansoni as thioredoxin/glutathione reductase (TGR and peroxiredoxin (Prx and as such these enzymes present attractive new targets for anti-schistosomiasis drug development. Inhibition of TGR/Prx activity was screened in a dual-enzyme format with reducing equivalents being transferred from NADPH to glutathione via a TGR-catalyzed reaction and then to hydrogen peroxide via a Prx-catalyzed step. A fully automated quantitative high-throughput (qHTS experiment was performed against a collection of 71,028 compounds tested as 7- to 15-point concentration series at 5 microL reaction volume in 1536-well plate format. In order to generate a robust data set and to minimize the effect of compound autofluorescence, apparent reaction rates derived from a kinetic read were utilized instead of end-point measurements. Actives identified from the screen, along with previously untested analogues, were subjected to confirmatory experiments using the screening assay and subsequently against the individual targets in secondary assays. Several novel active series were identified which inhibited TGR at a range of potencies, with IC(50s ranging from micromolar to the assay response limit ( approximately 25 nM. This is, to our knowledge, the first report of a large-scale HTS to identify lead compounds for a helminthic disease, and provides a paradigm that can be used to jump

  12. High-content screening in zebrafish embryos identifies butafenacil as a potent inducer of anemia.

    Directory of Open Access Journals (Sweden)

    Jessica K Leet

    Full Text Available Using transgenic zebrafish (fli1:egfp that stably express enhanced green fluorescent protein (eGFP within vascular endothelial cells, we recently developed and optimized a 384-well high-content screening (HCS assay that enables us to screen and identify chemicals affecting cardiovascular development and function at non-teratogenic concentrations. Within this assay, automated image acquisition procedures and custom image analysis protocols are used to quantify body length, heart rate, circulation, pericardial area, and intersegmental vessel area within individual live embryos exposed from 5 to 72 hours post-fertilization. After ranking developmental toxicity data generated from the U.S. Environmental Protection Agency's (EPA's zebrafish teratogenesis assay, we screened 26 of the most acutely toxic chemicals within EPA's ToxCast Phase-I library in concentration-response format (0.05-50 µM using this HCS assay. Based on this screen, we identified butafenacil as a potent inducer of anemia, as exposure from 0.39 to 3.125 µM butafenacil completely abolished arterial circulation in the absence of effects on all other endpoints evaluated. Butafenacil is an herbicide that inhibits protoporphyrinogen oxidase (PPO--an enzyme necessary for heme production in vertebrates. Using o-dianisidine staining, we then revealed that severe butafenacil-induced anemia in zebrafish was due to a complete loss of hemoglobin following exposure during early development. Therefore, six additional PPO inhibitors within the ToxCast Phase-I library were screened to determine whether anemia represents a common adverse outcome for these herbicides. Embryonic exposure to only one of these PPO inhibitors--flumioxazin--resulted in a similar phenotype as butafenacil, albeit not as severe as butafenacil. Overall, this study highlights the potential utility of this assay for (1 screening chemicals for cardiovascular toxicity and (2 prioritizing chemicals for future hypothesis

  13. WE-D-207-03: CT Protocols for Screening and the ACR Designated Lung Screening Program

    International Nuclear Information System (INIS)

    McNitt-Gray, M.

    2015-01-01

    implementing Lung Cancer Screening protocols for CT, including utilizing resources such as the AAPM Protocols and the ACR Designated Lung Screening Center program. UCLA Department of Radiology has an Institutional research agreement with Siemens Healthcare; Dr. McNitt-Gray has been a recipient of Research Support from Siemens Healthcare in the past. Dr. Aberle has been a Member of Advisory Boards for the LUNGevity Foundation (2011-present) and Siemens Medical Solutions. (2013)

  14. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.

    Science.gov (United States)

    Manguso, Robert T; Pope, Hans W; Zimmer, Margaret D; Brown, Flavian D; Yates, Kathleen B; Miller, Brian C; Collins, Natalie B; Bi, Kevin; LaFleur, Martin W; Juneja, Vikram R; Weiss, Sarah A; Lo, Jennifer; Fisher, David E; Miao, Diana; Van Allen, Eliezer; Root, David E; Sharpe, Arlene H; Doench, John G; Haining, W Nicholas

    2017-07-27

    Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

  15. Screening of pharmacologically active small molecule compounds identifies antifungal agents against Candida biofilms

    Directory of Open Access Journals (Sweden)

    Takao eWatamoto

    2015-12-01

    Full Text Available Candida species have emerged as important and common opportunistic human pathogens, particularly in immunocompromised individuals. The current antifungal therapies either have toxic side effects or are insufficiently effect. The aim of this study is develop new small-molecule antifungal compounds by library screening methods using C. albicans, and to evaluate their antifungal effects on Candida biofilms and cytotoxic effects on human cells. Wild-type C. albicans strain SC5314 was used in library screening. To identify antifungal compounds, we screened a small-molecule library of 1,280 pharmacologically active compounds (LOPAC1280TM using an antifungal susceptibility test (AST. To investigate the antifungal effects of the hit compounds, ASTs were conducted using Candida strains in various growth modes, including biofilms. We tested the cytotoxicity of the hit compounds using human gingival fibroblast (hGF cells to evaluate their clinical safety. Only 35 compounds were identified by screening, which inhibited the metabolic activity of C. albicans by >50%. Of these, 26 compounds had fungistatic effects and 9 compounds had fungicidal effects on C. albicans. Five compounds, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate, ellipticine and CV-3988, had strong fungicidal effects and could inhibit the metabolic activity of Candida biofilms. However, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine were cytotoxic to hGF cells at low concentrations. CV-3988 showed no cytotoxicity at a fungicidal concentration.Four of the compounds identified, BAY11-7082, BAY11-7085, sanguinarine chloride hydrate and ellipticine, had toxic effects on Candida strains and hGF cells. In contrast, CV-3988 had fungicidal effects on Candida strains, but low cytotoxic effects on hGF cells. Therefore, this screening reveals agent, CV-3988 that was previously unknown to be antifungal agent, which could be a novel therapies for superficial mucosal

  16. Investigating Effects of Screen Layout Elements on Interface and Screen Design Aesthetics

    OpenAIRE

    Altaboli, Ahamed; Lin, Yingzi

    2011-01-01

    A recent study suggested the use of the screen layout elements of balance, unity, and sequence as a part of a computational model of interface aesthetics. It is argued that these three elements are the most contributed terms in the model. In the current study, a controlled experiment was designed and conducted to systematically investigate effects of these three elements (balance, unity, and sequence) on the perceived interface aesthetics. Results showed that the three elements have signific...

  17. Genome-wide RNAi screening identifies genes inhibiting the migration of glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Jian Yang

    Full Text Available Glioblastoma Multiforme (GBM cells are highly invasive, infiltrating into the surrounding normal brain tissue, making it impossible to completely eradicate GBM tumors by surgery or radiation. Increasing evidence also shows that these migratory cells are highly resistant to cytotoxic reagents, but decreasing their migratory capability can re-sensitize them to chemotherapy. These evidences suggest that the migratory cell population may serve as a better therapeutic target for more effective treatment of GBM. In order to understand the regulatory mechanism underlying the motile phenotype, we carried out a genome-wide RNAi screen for genes inhibiting the migration of GBM cells. The screening identified a total of twenty-five primary hits; seven of them were confirmed by secondary screening. Further study showed that three of the genes, FLNA, KHSRP and HCFC1, also functioned in vivo, and knocking them down caused multifocal tumor in a mouse model. Interestingly, two genes, KHSRP and HCFC1, were also found to be correlated with the clinical outcome of GBM patients. These two genes have not been previously associated with cell migration.

  18. Design-corrected variation by centre in mortality reduction in the ERSPC randomised prostate cancer screening trial.

    Science.gov (United States)

    Hakama, Matti; Moss, Sue M; Stenman, Ulf-Hakan; Roobol, Monique J; Zappa, Marco; Carlsson, Sigrid; Randazzo, Marco; Nelen, Vera; Hugosson, Jonas

    2017-06-01

    Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years' follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.

  19. Identifying factors to improve oral cancer screening uptake: a qualitative study.

    Directory of Open Access Journals (Sweden)

    Fatemeh Vida Zohoori

    Full Text Available To engage with high risk groups to identify knowledge and awareness of oral cancer signs and symptoms and the factors likely to contribute to improved screening uptake.Focus group discussions were undertaken with 18 males; 40+ years of age; smokers and/or drinkers (15+ cigarettes per day and/or 15+ units of alcohol per week, irregular dental attenders living in economically deprived areas of Teesside.There was a striking reported lack of knowledge and awareness of oral cancer and its signs and symptoms among the participants. When oral/mouth cancer leaflets produced by Cancer Research UK were presented to the participants, they claimed that they would seek help on noticing such a condition. There was a preference to seek help from their general practitioner rather than their dentist due to perceptions that a dentist is 'inaccessible' on a physical and psychological level, costly, a 'tooth specialist' not a 'mouth specialist', and also not able to prescribe medication and make referrals to specialists. Interestingly, none of the 18 participants who were offered a free oral cancer examination at a dental practice took up this offer.The uptake of oral cancer screening may be improved by increasing knowledge of the existence and signs and symptoms of oral cancer. Other factors that may increase uptake are increased awareness of the role of dentists in diagnosing oral cancer, promotion of oral cancer screening by health professionals during routine health checks, and the use of a "health" screening setting as opposed to a "dental" setting for such checks.

  20. Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets.

    Science.gov (United States)

    McCutcheon, Krista M; Gray, Julia; Chen, Natalie Y; Liu, Keyi; Park, Minha; Ellsworth, Stote; Tripp, Ralph A; Tompkins, S Mark; Johnson, Scott K; Samet, Shelly; Pereira, Lenore; Kauvar, Lawrence M

    2014-01-01

    Viral entry targets with therapeutic neutralizing potential are subject to multiple escape mechanisms, including antigenic drift, immune dominance of functionally irrelevant epitopes, and subtle variations in host cell mechanisms. A surprising finding of recent years is that potent neutralizing antibodies to viral epitopes independent of strain exist, but are poorly represented across the diverse human population. Identifying these antibodies and understanding the biology mediating the specific immune response is thus difficult. An effective strategy for meeting this challenge is to incorporate multiplexed antigen screening into a high throughput survey of the memory B cell repertoire from immune individuals. We used this approach to discover suites of cross-clade antibodies directed to conformational epitopes in the stalk region of the influenza A hemagglutinin (HA) protein and to select high-affinity anti-peptide antibodies to the glycoprotein B (gB) of human cytomegalovirus. In each case, our screens revealed a restricted VH and VL germline usage, including published and previously unidentified gene families. The in vivo evolution of paratope specificity with optimal neutralizing activity was understandable after correlating biological activities with kinetic binding and epitope recognition. Iterative feedback between antigen probe design based on structure and function information with high throughput multiplexed screening demonstrated a generally applicable strategy for efficient identification of safe, native, finely tuned antibodies with the potential for high genetic barriers to viral escape.

  1. High-content phenotypic screening and triaging strategy to identify small molecules driving oligodendrocyte progenitor cell differentiation.

    Science.gov (United States)

    Peppard, Jane V; Rugg, Catherine A; Smicker, Matthew A; Powers, Elaine; Harnish, Erica; Prisco, Joy; Cirovic, Dragan; Wright, Paul S; August, Paul R; Chandross, Karen J

    2015-03-01

    Multiple Sclerosis is a demyelinating disease of the CNS and the primary cause of neurological disability in young adults. Loss of myelinating oligodendrocytes leads to neuronal dysfunction and death and is an important contributing factor to this disease. Endogenous oligodendrocyte precursor cells (OPCs), which on differentiation are responsible for replacing myelin, are present in the adult CNS. As such, therapeutic agents that can stimulate OPCs to differentiate and remyelinate demyelinated axons under pathologic conditions may improve neuronal function and clinical outcome. We describe the details of an automated, cell-based, morphometric-based, high-content screen that is used to identify small molecules eliciting the differentiation of OPCs after 3 days. Primary screening was performed using rat CG-4 cells maintained in culture conditions that normally support a progenitor cell-like state. From a library of 73,000 diverse small molecules within the Sanofi collection, 342 compounds were identified that increased OPC morphological complexity as an indicator of oligodendrocyte maturation. Subsequent to the primary high-content screen, a suite of cellular assays was established that identified 22 nontoxic compounds that selectively stimulated primary rat OPCs but not C2C12 muscle cell differentiation. This rigorous triaging yielded several chemical series for further expansion and bio- or cheminformatics studies, and their compelling biological activity merits further investigation. © 2014 Society for Laboratory Automation and Screening.

  2. Transposon activation mutagenesis as a screening tool for identifying resistance to cancer therapeutics

    International Nuclear Information System (INIS)

    Chen, Li; Schmidt, Emmett V; Stuart, Lynda; Ohsumi, Toshiro K; Burgess, Shawn; Varshney, Gaurav K; Dastur, Anahita; Borowsky, Mark; Benes, Cyril; Lacy-Hulbert, Adam

    2013-01-01

    The development of resistance to chemotherapies represents a significant barrier to successful cancer treatment. Resistance mechanisms are complex, can involve diverse and often unexpected cellular processes, and can vary with both the underlying genetic lesion and the origin or type of tumor. For these reasons developing experimental strategies that could be used to understand, identify and predict mechanisms of resistance in different malignant cells would be a major advance. Here we describe a gain-of-function forward genetic approach for identifying mechanisms of resistance. This approach uses a modified piggyBac transposon to generate libraries of mutagenized cells, each containing transposon insertions that randomly activate nearby gene expression. Genes of interest are identified using next-gen high-throughput sequencing and barcode multiplexing is used to reduce experimental cost. Using this approach we successfully identify genes involved in paclitaxel resistance in a variety of cancer cell lines, including the multidrug transporter ABCB1, a previously identified major paclitaxel resistance gene. Analysis of co-occurring transposons integration sites in single cell clone allows for the identification of genes that might act cooperatively to produce drug resistance a level of information not accessible using RNAi or ORF expression screening approaches. We have developed a powerful pipeline to systematically discover drug resistance in mammalian cells in vitro. This cost-effective approach can be readily applied to different cell lines, to identify canonical or context specific resistance mechanisms. Its ability to probe complex genetic context and non-coding genomic elements as well as cooperative resistance events makes it a good complement to RNAi or ORF expression based screens

  3. Kinase profiling of liposarcomas using RNAi and drug screening assays identified druggable targets

    Directory of Open Access Journals (Sweden)

    Deepika Kanojia

    2017-11-01

    Full Text Available Abstract Background Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. Methods Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial. Results Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model. Conclusions Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor.

  4. Identifying a borderline personality disorder prodrome: Implications for community screening.

    Science.gov (United States)

    Stepp, Stephanie D; Lazarus, Sophie A

    2017-08-01

    Elucidating early signs and symptoms of borderline personality disorder (BPD) has important implications for screening and identifying youth appropriate for early intervention. The purpose of this study was to identify dimensions of child temperament and psychopathology symptom severity that predict conversion to a positive screen for BPD over a 14-year follow-up period in a large, urban community sample of girls (n = 2 450). Parent and teacher reports of child temperament and psychopathology symptom severity assessed when girls were ages 5-8 years were examined as predictors of new-onset BPD cases when girls were ages 14-22 years. In the final model, parent and teacher ratings of emotionality remained significant predictors of new-onset BPD. Additionally, parent ratings of hyperactivity/impulsivity and depression severity, as well as teacher ratings of inattention severity, were also predictive. Results also revealed that elevations in these dimensions pose a notable increase in risk for conversion to BPD over the follow-up period. Supplementary analyses revealed that with the exception of parent-reported depression severity, these same predictors were associated with increases in BPD symptom severity over the follow-up period. These findings suggest BPD onset in adolescence and early adulthood can be detected from parent and teacher reports of temperament and symptom severity dimensions assessed in childhood. The identification of this prodrome holds promise for advancing early detection of children at risk prior to the development of the full-blown disorder. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  5. Crizotinib-Resistant Mutants of EML4-ALK Identified Through an Accelerated Mutagenesis Screen

    Science.gov (United States)

    Zhang, Sen; Wang, Frank; Keats, Jeffrey; Zhu, Xiaotian; Ning, Yaoyu; Wardwell, Scott D; Moran, Lauren; Mohemmad, Qurish K; Anjum, Rana; Wang, Yihan; Narasimhan, Narayana I; Dalgarno, David; Shakespeare, William C; Miret, Juan J; Clackson, Tim; Rivera, Victor M

    2011-01-01

    Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non-small-cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non-small-cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase active site, which conferred varying degrees of resistance. The screen successfully predicted the L1196M, C1156Y, and F1174L mutations, recently identified in crizotinib-resistant patients. In separate studies, we demonstrated that crizotinib has relatively modest potency in ALK-positive non-small-cell lung cancer cell lines. A more potent ALK inhibitor, TAE684, maintained substantial activity against mutations that conferred resistance to crizotinib. Our study identifies multiple novel mutations in ALK that may confer clinical resistance to crizotinib, suggests that crizotinib's narrow selectivity window may underlie its susceptibility to such resistance and demonstrates that a more potent ALK inhibitor may be effective at overcoming resistance. PMID:22034911

  6. Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth

    Science.gov (United States)

    Dittmar, Ashley J.; Drozda, Allison A.

    2016-01-01

    ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several compounds with significant antiparasitic activities. Among these were pimozide and tamoxifen, which are well-characterized drugs prescribed to treat patients with psychiatric disorders and breast cancer

  7. Design and evaluation of a theory-based, culturally relevant outreach model for breast and cervical cancer screening for Latina immigrants.

    Science.gov (United States)

    White, Kari; Garces, Isabel C; Bandura, Lisa; McGuire, Allison A; Scarinci, Isabel C

    2012-01-01

    Breast and cervical cancer are common among Latinas, but screening rates among foreign-born Latinas are relatively low. In this article we describe the design and implementation of a theory-based (PEN-3) outreach program to promote breast and cervical cancer screening to Latina immigrants, and evaluate the program's effectiveness. We used data from self-administered questionnaires completed at six annual outreach events to examine the sociodemographic characteristics of attendees and evaluate whether the program reached the priority population - foreign-born Latina immigrants with limited access to health care and screening services. To evaluate the program's effectiveness in connecting women to screening, we examined the proportion and characteristics of women who scheduled and attended Pap smear and mammography appointments. Among the 782 Latinas who attended the outreach program, 60% and 83% had not had a Pap smear or mammogram, respectively, in at least a year. Overall, 80% scheduled a Pap smear and 78% scheduled a mammogram. Women without insurance, who did not know where to get screening and had not been screened in the last year were more likely to schedule appointments (P < .05). Among women who scheduled appointments, 65% attended their Pap smear and 79% attended the mammogram. We did not identify significant differences in sociodemographic characteristics associated with appointment attendance. Using a theoretical approach to outreach design and implementation, it is possible to reach a substantial number of Latina immigrants and connect them to cancer screening services.

  8. An epithelial marker promoter induction screen identifies histone deacetylase inhibitors to restore epithelial differentiation and abolishes anchorage independence growth in cancers.

    Science.gov (United States)

    Tang, H M; Kuay, K T; Koh, P F; Asad, M; Tan, T Z; Chung, V Y; Lee, S C; Thiery, J P; Huang, Ry-J

    2016-01-01

    Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin. An expanded screen on 41 HDACi further identifies 28 compounds, such as class I-specific HDACi Mocetinosat, Entinostat and CI994, to restore E-cadherin and ErbB3 expressions in ovarian, pancreatic and bladder carcinoma cells. Mocetinostat is the most potent HDACi to restore epithelial differentiation with the lowest concentration required for 50% induction of epithelial promoter activity (EpIC-50).The HDACi exerts paradoxical effects on EMT transcriptional factors such as SNAI and ZEB family and the effects are context-dependent in epithelial- and mesenchymal-like cells. In vitro functional studies further show that HDACi induced significant increase in anoikis and decrease in spheroid formation in ovarian and bladder carcinoma cells with mesenchymal features. This study demonstrates a robust drug screening pipeline for the discovery of compounds capable of restoring epithelial differentiation that lead to significant functional lethality.

  9. A high throughput screening assay for identifying glycation inhibitors on MALDI-TOF target.

    Science.gov (United States)

    Zhang, Qiuting; Tu, Zongcai; Wang, Hui; Fan, Liangliang; Huang, Xiaoqin; Xiao, Hui

    2015-03-01

    The Maillard reaction plays an important role in the food industry, however, the deleterious effects generated by the advanced glycation end-products (AGEs) have been well recognized. Many efforts have been made to seek new AGE inhibitors, in particular those natural ones without adverse effect. We have developed a rapid, mass spectrometry based, on-plate screening assay for novel AGE inhibitors. The glycation reaction, inhibition feedback as well as the subsequent MALDI mass spectrometric analysis occurred on one single MALDI plate. At 1:10 M ratio of peptide to sugar, as little as 4h incubation time allowed the screening test to be ready for analysis. DSP, inhibition and IC50 were calculated to evaluate selected inhibitors and resulting inhibition efficiencies were consistent with available references. We demonstrated that this method provide a potential high throughput screening assay to analyze and identify the anti-glycation agents. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Genome-wide screen of Pseudomonas aeruginosa In Saccharomyces cerevisiae identifies new virulence factors

    Directory of Open Access Journals (Sweden)

    Rafat eZrieq

    2015-11-01

    Full Text Available Pseudomonas aeruginosa is a human opportunistic pathogen that causes mortality in cystic fibrosis and immunocompromised patients. While many virulence factors of this pathogen have already been identified, several remain to be discovered. In this respect we set an unprecedented genome-wide screen of a P. aeruginosa expression library based on a yeast growth phenotype. 51 candidates were selected in a three-round screening process. The robustness of the screen was validated by the selection of three well known secreted proteins including one demonstrated virulence factor, the protease LepA. Further in silico sorting of the 51 candidates highlighted three potential new Pseudomonas effector candidates (Pec. By testing the cytotoxicity of wild type P. aeruginosa vs pec mutants towards macrophages and the virulence in the Caenorhabditis elegans model, we demonstrated that the three selected Pecs are novel virulence factors of P. aeruginosa. Additional cellular localization experiments in the host revealed specific localization for Pec1 and Pec2 that could inform about their respective functions.

  11. Factors Influencing Colorectal Cancer Screening Participation

    Directory of Open Access Journals (Sweden)

    Antonio Z. Gimeno García

    2012-01-01

    Full Text Available Colorectal cancer (CRC is a major health problem worldwide. Although population-based CRC screening is strongly recommended in average-risk population, compliance rates are still far from the desirable rates. High levels of screening uptake are necessary for the success of any screening program. Therefore, the investigation of factors influencing participation is crucial prior to design and launches a population-based organized screening campaign. Several studies have identified screening behaviour factors related to potential participants, providers, or health care system. These influencing factors can also be classified in non-modifiable (i.e., demographic factors, education, health insurance, or income and modifiable factors (i.e., knowledge about CRC and screening, patient and provider attitudes or structural barriers for screening. Modifiable determinants are of great interest as they are plausible targets for interventions. Interventions at different levels (patient, providers or health care system have been tested across the studies with different results. This paper analyzes factors related to CRC screening behaviour and potential interventions designed to improve screening uptake.

  12. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown

    DEFF Research Database (Denmark)

    Higgins, Geoff S; Prevo, Remko; Lee, Yin-Fai

    2010-01-01

    The effectiveness of radiotherapy treatment could be significantly improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues. However, many of the key therapeutically exploitable mechanisms that determine intrinsic tumor...... radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B......) and irradiated normal tissue cells (MRC5). Using gammaH2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA...

  13. Quantitative and mixed analyses to identify factors that affect cervical cancer screening uptake among lesbian and bisexual women and transgender men.

    Science.gov (United States)

    Johnson, Michael J; Mueller, Martina; Eliason, Michele J; Stuart, Gail; Nemeth, Lynne S

    2016-12-01

    The purposes of this study were to measure the prevalence of, and identify factors associated with, cervical cancer screening among a sample of lesbian, bisexual and queer women, and transgender men. Past research has found that lesbian, bisexual and queer women underuse cervical screening service. Because deficient screening remains the most significant risk factor for cervical cancer, it is essential to understand the differences between routine and nonroutine screeners. A convergent-parallel mixed methods design. A convenience sample of 21- to 65-year-old lesbian and bisexual women and transgender men were recruited in the USA from August-December 2014. Quantitative data were collected via a 48-item Internet questionnaire (N = 226), and qualitative data were collected through in-depth telephone interviews (N = 20) and open-ended questions on the Internet questionnaire. Seventy-three per cent of the sample was routine cervical screeners. The results showed that a constellation of factors influence the use of cervical cancer screening among lesbian, bisexual and queer women. Some of those factors overlap with the general female population, whereas others are specific to the lesbian, bisexual or queer identity. Routine screeners reported feeling more welcome in the health care setting, while nonroutine screeners reported more discrimination related to their sexual orientation and gender expression. Routine screeners were also more likely to 'out' to their provider. The quantitative and qualitative factors were also compared and contrasted. Many of the factors identified in this study to influence cervical cancer screening relate to the health care environment and to interactions between the patient and provider. Nurses should be involved with creating welcoming environments for lesbian, bisexual and queer women and their partners. Moreover, nurses play a large role in patient education and should promote self-care behaviours among lesbian women and transgender

  14. A Comparison Study of Second-Order Screening Designs and Their Extension

    Science.gov (United States)

    2013-12-01

    H2 97 V. Nonlinear Screening Designs for Defense Testing: An Overview and Case Study 5.1 Introduction “Necessity is the Mother of Invention.” Plato is...involved concepts like design resolution, minimum aber- ration , power, the number of clear (non-confounded) effects, concepts like rotatability

  15. A genome-wide siRNA screen to identify modulators of insulin sensitivity and gluconeogenesis.

    Directory of Open Access Journals (Sweden)

    Ruojing Yang

    Full Text Available BACKGROUND: Hepatic insulin resistance impairs insulin's ability to suppress hepatic glucose production (HGP and contributes to the development of type 2 diabetes (T2D. Although the interests to discover novel genes that modulate insulin sensitivity and HGP are high, it remains challenging to have a human cell based system to identify novel genes. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that modulate hepatic insulin signaling and HGP, we generated a human cell line stably expressing beta-lactamase under the control of the human glucose-6-phosphatase (G6PC promoter (AH-G6PC cells. Both beta-lactamase activity and endogenous G6PC mRNA were increased in AH-G6PC cells by a combination of dexamethasone and pCPT-cAMP, and reduced by insulin. A 4-gene High-Throughput-Genomics assay was developed to concomitantly measure G6PC and pyruvate-dehydrogenase-kinase-4 (PDK4 mRNA levels. Using this assay, we screened an siRNA library containing pooled siRNA targeting 6650 druggable genes and identified 614 hits that lowered G6PC expression without increasing PDK4 mRNA levels. Pathway analysis indicated that siRNA-mediated knockdown (KD of genes known to positively or negatively affect insulin signaling increased or decreased G6PC mRNA expression, respectively, thus validating our screening platform. A subset of 270 primary screen hits was selected and 149 hits were confirmed by target gene KD by pooled siRNA and 7 single siRNA for each gene to reduce G6PC expression in 4-gene HTG assay. Subsequently, pooled siRNA KD of 113 genes decreased PEPCK and/or PGC1alpha mRNA expression thereby demonstrating their role in regulating key gluconeogenic genes in addition to G6PC. Last, KD of 61 of the above 113 genes potentiated insulin-stimulated Akt phosphorylation, suggesting that they suppress gluconeogenic gene by enhancing insulin signaling. CONCLUSIONS/SIGNIFICANCE: These results support the proposition that the proteins encoded by the genes identified in

  16. An internal pilot design for prospective cancer screening trials with unknown disease prevalence.

    Science.gov (United States)

    Brinton, John T; Ringham, Brandy M; Glueck, Deborah H

    2015-10-13

    For studies that compare the diagnostic accuracy of two screening tests, the sample size depends on the prevalence of disease in the study population, and on the variance of the outcome. Both parameters may be unknown during the design stage, which makes finding an accurate sample size difficult. To solve this problem, we propose adapting an internal pilot design. In this adapted design, researchers will accrue some percentage of the planned sample size, then estimate both the disease prevalence and the variances of the screening tests. The updated estimates of the disease prevalence and variance are used to conduct a more accurate power and sample size calculation. We demonstrate that in large samples, the adapted internal pilot design produces no Type I inflation. For small samples (N less than 50), we introduce a novel adjustment of the critical value to control the Type I error rate. We apply the method to two proposed prospective cancer screening studies: 1) a small oral cancer screening study in individuals with Fanconi anemia and 2) a large oral cancer screening trial. Conducting an internal pilot study without adjusting the critical value can cause Type I error rate inflation in small samples, but not in large samples. An internal pilot approach usually achieves goal power and, for most studies with sample size greater than 50, requires no Type I error correction. Further, we have provided a flexible and accurate approach to bound Type I error below a goal level for studies with small sample size.

  17. Design and evaluation of new overview screens for the LABIHS simulator

    International Nuclear Information System (INIS)

    Oliveira, Mauro V.; Almeida, Jose C.S.; Jaime, Guilherme D.G.; Augusto, Silas C.

    2015-01-01

    The development and evaluation of Human-System Interfaces (HSIs) for control rooms is a research area at the Human-System Interface Laboratory (LABIHS). The main objective of this laboratory is to develop and evaluate projects of HSIs for industrial plants using different methodology construction. The evaluation of the interfaces is carried out in the LABIHS simulator at the Nuclear Engineering Institute (IEN). Previous evaluation of the overview screen of the nuclear power plant (NPP) simulator of the LABIHS showed the necessity of additional information to reduce the operator workload. To overcome this issue, a set of three 52-inch LCD TV was acquired to replace the projector in the task of showing the overview screen to the simulator operators. A new set of screens was developed to gather information in the three LCD screens. The approach used on the development of the new screens was based on human factors guidelines and recommendations. The objective of this work is present the design of these new overview screens and to evaluate their contribution to reduce the operators mental workload in this new scenario. (author)

  18. Integrative screening approach identifies regulators of polyploidization and targets for acute megakaryocytic leukemia

    Science.gov (United States)

    Wen, Qiang; Goldenson, Benjamin; Silver, Serena J.; Schenone, Monica; Dancik, Vladimir; Huang, Zan; Wang, Ling-Zhi; Lewis, Timothy; An, W. Frank; Li, Xiaoyu; Bray, Mark-Anthony; Thiollier, Clarisse; Diebold, Lauren; Gilles, Laure; Vokes, Martha S.; Moore, Christopher B.; Bliss-Moreau, Meghan; VerPlank, Lynn; Tolliday, Nicola J.; Mishra, Rama; Vemula, Sasidhar; Shi, Jianjian; Wei, Lei; Kapur, Reuben; Lopez, Cécile K.; Gerby, Bastien; Ballerini, Paola; Pflumio, Francoise; Gilliland, D. Gary; Goldberg, Liat; Birger, Yehudit; Izraeli, Shai; Gamis, Alan S.; Smith, Franklin O.; Woods, William G.; Taub, Jeffrey; Scherer, Christina A.; Bradner, James; Goh, Boon-Cher; Mercher, Thomas; Carpenter, Anne E.; Gould, Robert J.; Clemons, Paul A.; Carr, Steven A.; Root, David E.; Schreiber, Stuart L.; Stern, Andrew M.; Crispino, John D.

    2012-01-01

    Summary The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. We found that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. A broadly applicable, highly integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora A kinase (AURKA), which has not been studied extensively in megakaryocytes. Moreover, we discovered that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in AMKL blasts and displayed potent anti-AMKL activity in vivo. This research provides the rationale to support clinical trials of MLN8237 and other inducers of polyploidization in AMKL. Finally, we have identified five networks of kinases that regulate the switch to polyploidy. PMID:22863010

  19. Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen*

    Science.gov (United States)

    Kozlov, Sergei V.; Waardenberg, Ashley J.; Engholm-Keller, Kasper; Arthur, Jonathan W.; Graham, Mark E.; Lavin, Martin

    2016-01-01

    Ataxia-telangiectasia, mutated (ATM) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signaling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress. Here, we confirmed activation of cytoplasmic ATM by autophosphorylation at multiple sites. Then we employed a global quantitative phosphoproteomics approach to identify cytoplasmic proteins altered in their phosphorylation state in control and ataxia-telangiectasia (A-T) cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,833 phosphorylation sites, including 6,686 high-confidence sites mapping to 2,536 unique proteins. A total of 62 differentially phosphorylated peptides were identified; of these, 43 were phosphorylated in control but not in A-T cells, and 19 varied in their level of phosphorylation. Motif enrichment analysis of phosphopeptides revealed that consensus ATM serine glutamine sites were overrepresented. When considering phosphorylation events, only observed in control cells (not observed in A-T cells), with predicted ATM sites phosphoSerine/phosphoThreonine glutamine, we narrowed this list to 11 candidate ATM-dependent cytoplasmic proteins. Two of these 11 were previously described as ATM substrates (HMGA1 and UIMCI/RAP80), another five were identified in a whole cell extract phosphoproteomic screens, and the remaining four proteins had not been identified previously in DNA damage response screens. We validated the phosphorylation of three of these proteins (oxidative stress responsive 1 (OSR1), HDGF, and ccdc82) as ATM dependent after H2O2 exposure, and another protein (S100A11) demonstrated ATM

  20. Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach

    Science.gov (United States)

    Gómez-Bombarelli, Rafael; Aguilera-Iparraguirre, Jorge; Hirzel, Timothy D.; Duvenaud, David; MacLaurin, Dougal; Blood-Forsythe, Martin A.; Chae, Hyun Sik; Einzinger, Markus; Ha, Dong-Gwang; Wu, Tony; Markopoulos, Georgios; Jeon, Soonok; Kang, Hosuk; Miyazaki, Hiroshi; Numata, Masaki; Kim, Sunghan; Huang, Wenliang; Hong, Seong Ik; Baldo, Marc; Adams, Ryan P.; Aspuru-Guzik, Alán

    2016-10-01

    Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%.

  1. Automated NMR fragment based screening identified a novel interface blocker to the LARG/RhoA complex.

    Directory of Open Access Journals (Sweden)

    Jia Gao

    Full Text Available The small GTPase cycles between the inactive GDP form and the activated GTP form, catalyzed by the upstream guanine exchange factors. The modulation of such process by small molecules has been proven to be a fruitful route for therapeutic intervention to prevent the over-activation of the small GTPase. The fragment based approach emerging in the past decade has demonstrated its paramount potential in the discovery of inhibitors targeting such novel and challenging protein-protein interactions. The details regarding the procedure of NMR fragment screening from scratch have been rarely disclosed comprehensively, thus restricts its wider applications. To achieve a consistent screening applicable to a number of targets, we developed a highly automated protocol to cover every aspect of NMR fragment screening as possible, including the construction of small but diverse libray, determination of the aqueous solubility by NMR, grouping compounds with mutual dispersity to a cocktail, and the automated processing and visualization of the ligand based screening spectra. We exemplified our streamlined screening in RhoA alone and the complex of the small GTPase RhoA and its upstream guanine exchange factor LARG. Two hits were confirmed from the primary screening in cocktail and secondary screening over individual hits for LARG/RhoA complex, while one of them was also identified from the screening for RhoA alone. HSQC titration of the two hits over RhoA and LARG alone, respectively, identified one compound binding to RhoA.GDP at a 0.11 mM affinity, and perturbed the residues at the switch II region of RhoA. This hit blocked the formation of the LARG/RhoA complex, validated by the native gel electrophoresis, and the titration of RhoA to ¹⁵N labeled LARG in the absence and presence the compound, respectively. It therefore provides us a starting point toward a more potent inhibitor to RhoA activation catalyzed by LARG.

  2. Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities.

    Science.gov (United States)

    Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B; Papamarkou, Theodore; Huber, Kilian V M; Mutz, Cornelia; Toretsky, Jeffrey A; Bennett, Keiryn L; Olsen, Jesper V; Brunak, Søren; Kovar, Heinrich; Superti-Furga, Giulio

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88-101. ©2016 AACR. ©2016 American Association for Cancer Research.

  3. Guided genetic screen to identify genes essential in the regeneration of hair cells and other tissues.

    Science.gov (United States)

    Pei, Wuhong; Xu, Lisha; Huang, Sunny C; Pettie, Kade; Idol, Jennifer; Rissone, Alberto; Jimenez, Erin; Sinclair, Jason W; Slevin, Claire; Varshney, Gaurav K; Jones, MaryPat; Carrington, Blake; Bishop, Kevin; Huang, Haigen; Sood, Raman; Lin, Shuo; Burgess, Shawn M

    2018-01-01

    Regenerative medicine holds great promise for both degenerative diseases and traumatic tissue injury which represent significant challenges to the health care system. Hearing loss, which affects hundreds of millions of people worldwide, is caused primarily by a permanent loss of the mechanosensory receptors of the inner ear known as hair cells. This failure to regenerate hair cells after loss is limited to mammals, while all other non-mammalian vertebrates tested were able to completely regenerate these mechanosensory receptors after injury. To understand the mechanism of hair cell regeneration and its association with regeneration of other tissues, we performed a guided mutagenesis screen using zebrafish lateral line hair cells as a screening platform to identify genes that are essential for hair cell regeneration, and further investigated how genes essential for hair cell regeneration were involved in the regeneration of other tissues. We created genetic mutations either by retroviral insertion or CRISPR/Cas9 approaches, and developed a high-throughput screening pipeline for analyzing hair cell development and regeneration. We screened 254 gene mutations and identified 7 genes specifically affecting hair cell regeneration. These hair cell regeneration genes fell into distinct and somewhat surprising functional categories. By examining the regeneration of caudal fin and liver, we found these hair cell regeneration genes often also affected other types of tissue regeneration. Therefore, our results demonstrate guided screening is an effective approach to discover regeneration candidates, and hair cell regeneration is associated with other tissue regeneration.

  4. Is the screening of product ideas supported by the NPD process design?

    DEFF Research Database (Denmark)

    Jespersen, Kristina Risom

    2007-01-01

    literature will benefit from knowledge of the process of implementing "best practices" of NPD. Companies follow guidelines, but how is the NPD process followed through? This paper supports the need for improved insight into the complexity of screening decisions as well as knowledge of the screening...... determinants. Practical implications - The implementation of cross-functional teams and interacting phases demands more attention by management in order to reduce costs of NPD relative to the ROI of new products. Originality/value - By showing that the screening is detached from the NPD process design...

  5. RNAi-Mediated Reverse Genetic Screen Identified Drosophila Chaperones Regulating Eye and Neuromuscular Junction Morphology

    Directory of Open Access Journals (Sweden)

    Sandeep Raut

    2017-07-01

    Full Text Available Accumulation of toxic proteins in neurons has been linked with the onset of neurodegenerative diseases, which in many cases are characterized by altered neuronal function and synapse loss. Molecular chaperones help protein folding and the resolubilization of unfolded proteins, thereby reducing the protein aggregation stress. While most of the chaperones are expressed in neurons, their functional relevance remains largely unknown. Here, using bioinformatics analysis, we identified 95 Drosophila chaperones and classified them into seven different classes. Ubiquitous actin5C-Gal4-mediated RNAi knockdown revealed that ∼50% of the chaperones are essential in Drosophila. Knocking down these genes in eyes revealed that ∼30% of the essential chaperones are crucial for eye development. Using neuron-specific knockdown, immunocytochemistry, and robust behavioral assays, we identified a new set of chaperones that play critical roles in the regulation of Drosophila NMJ structural organization. Together, our data present the first classification and comprehensive analysis of Drosophila chaperones. Our screen identified a new set of chaperones that regulate eye and NMJ morphogenesis. The outcome of the screen reported here provides a useful resource for further elucidating the role of individual chaperones in Drosophila eye morphogenesis and synaptic development.

  6. A novel glutamine–RNA interaction identified by screening libraries in mammalian cells

    OpenAIRE

    Tan, Ruoying; Frankel, Alan D.

    1998-01-01

    The arginine-rich motif provides a versatile framework for RNA recognition in which few amino acids other than arginine are needed to mediate specific binding. Using a mammalian screening system based on transcriptional activation by HIV Tat, we identified novel arginine-rich peptides from combinatorial libraries that bind tightly to the Rev response element of HIV. Remarkably, a single glutamine, but not asparagine, within a stretch of polyarginine can mediate high-affinity binding. These re...

  7. Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Aman C. Kaushik

    2018-02-01

    Full Text Available GPR142 (G protein receptor 142 is a novel orphan GPCR (G protein coupled receptor belonging to “Class A” of GPCR family and expressed in β cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling, and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

  8. Structure Based Virtual Screening Studies to Identify Novel Potential Compounds for GPR142 and Their Relative Dynamic Analysis for Study of Type 2 Diabetes

    Science.gov (United States)

    Kaushik, Aman C.; Kumar, Sanjay; Wei, Dong Q.; Sahi, Shakti

    2018-02-01

    GPR142 (G protein receptor 142) is a novel orphan GPCR (G protein coupled receptor) belonging to ‘Class A’ of GPCR family and expressed in beta cells of pancreas. In this study, we reported the structure based virtual screening to identify the hit compounds which can be developed as leads for potential agonists. The results were validated through induced fit docking, pharmacophore modeling and system biology approaches. Since, there is no solved crystal structure of GPR142, we attempted to predict the 3D structure followed by validation and then identification of active site using threading and ab initio methods. Also, structure based virtual screening was performed against a total of 1171519 compounds from different libraries and only top 20 best hit compounds were screened and analyzed. Moreover, the biochemical pathway of GPR142 complex with screened compound2 was also designed and compared with experimental data. Interestingly, compound2 showed an increase in insulin production via Gq mediated signaling pathway suggesting the possible role of novel GPR142 agonists in therapy against type 2 diabetes.

  9. Third-Generation Sequencing and Analysis of Four Complete Pig Liver Esterase Gene Sequences in Clones Identified by Screening BAC Library.

    Science.gov (United States)

    Zhou, Qiongqiong; Sun, Wenjuan; Liu, Xiyan; Wang, Xiliang; Xiao, Yuncai; Bi, Dingren; Yin, Jingdong; Shi, Deshi

    2016-01-01

    Pig liver carboxylesterase (PLE) gene sequences in GenBank are incomplete, which has led to difficulties in studying the genetic structure and regulation mechanisms of gene expression of PLE family genes. The aim of this study was to obtain and analysis of complete gene sequences of PLE family by screening from a Rongchang pig BAC library and third-generation PacBio gene sequencing. After a number of existing incomplete PLE isoform gene sequences were analysed, primers were designed based on conserved regions in PLE exons, and the whole pig genome used as a template for Polymerase chain reaction (PCR) amplification. Specific primers were then selected based on the PCR amplification results. A three-step PCR screening method was used to identify PLE-positive clones by screening a Rongchang pig BAC library and PacBio third-generation sequencing was performed. BLAST comparisons and other bioinformatics methods were applied for sequence analysis. Five PLE-positive BAC clones, designated BAC-10, BAC-70, BAC-75, BAC-119 and BAC-206, were identified. Sequence analysis yielded the complete sequences of four PLE genes, PLE1, PLE-B9, PLE-C4, and PLE-G2. Complete PLE gene sequences were defined as those containing regulatory sequences, exons, and introns. It was found that, not only did the PLE exon sequences of the four genes show a high degree of homology, but also that the intron sequences were highly similar. Additionally, the regulatory region of the genes contained two 720bps reverse complement sequences that may have an important function in the regulation of PLE gene expression. This is the first report to confirm the complete sequences of four PLE genes. In addition, the study demonstrates that each PLE isoform is encoded by a single gene and that the various genes exhibit a high degree of sequence homology, suggesting that the PLE family evolved from a single ancestral gene. Obtaining the complete sequences of these PLE genes provides the necessary foundation for

  10. A large-scale RNA interference screen identifies genes that regulate autophagy at different stages.

    Science.gov (United States)

    Guo, Sujuan; Pridham, Kevin J; Virbasius, Ching-Man; He, Bin; Zhang, Liqing; Varmark, Hanne; Green, Michael R; Sheng, Zhi

    2018-02-12

    Dysregulated autophagy is central to the pathogenesis and therapeutic development of cancer. However, how autophagy is regulated in cancer is not well understood and genes that modulate cancer autophagy are not fully defined. To gain more insights into autophagy regulation in cancer, we performed a large-scale RNA interference screen in K562 human chronic myeloid leukemia cells using monodansylcadaverine staining, an autophagy-detecting approach equivalent to immunoblotting of the autophagy marker LC3B or fluorescence microscopy of GFP-LC3B. By coupling monodansylcadaverine staining with fluorescence-activated cell sorting, we successfully isolated autophagic K562 cells where we identified 336 short hairpin RNAs. After candidate validation using Cyto-ID fluorescence spectrophotometry, LC3B immunoblotting, and quantitative RT-PCR, 82 genes were identified as autophagy-regulating genes. 20 genes have been reported previously and the remaining 62 candidates are novel autophagy mediators. Bioinformatic analyses revealed that most candidate genes were involved in molecular pathways regulating autophagy, rather than directly participating in the autophagy process. Further autophagy flux assays revealed that 57 autophagy-regulating genes suppressed autophagy initiation, whereas 21 candidates promoted autophagy maturation. Our RNA interference screen identifies identified genes that regulate autophagy at different stages, which helps decode autophagy regulation in cancer and offers novel avenues to develop autophagy-related therapies for cancer.

  11. A genetic screen identifies interferon-α effector genes required to suppress hepatitis C virus replication.

    Science.gov (United States)

    Fusco, Dahlene N; Brisac, Cynthia; John, Sinu P; Huang, Yi-Wen; Chin, Christopher R; Xie, Tiao; Zhao, Hong; Jilg, Nikolaus; Zhang, Leiliang; Chevaliez, Stephane; Wambua, Daniel; Lin, Wenyu; Peng, Lee; Chung, Raymond T; Brass, Abraham L

    2013-06-01

    Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease. Interferon-α (IFNα) is an important component of anti-HCV therapy; it up-regulates transcription of IFN-stimulated genes, many of which have been investigated for their antiviral effects. However, all of the genes required for the antiviral function of IFNα (IFN effector genes [IEGs]) are not known. IEGs include not only IFN-stimulated genes, but other nontranscriptionally induced genes that are required for the antiviral effect of IFNα. In contrast to candidate approaches based on analyses of messenger RNA (mRNA) expression, identification of IEGs requires a broad functional approach. We performed an unbiased genome-wide small interfering RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with small interfering RNAs incubated with IFNα and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further. The screen identified 120 previously unreported IEGs. From these, we more fully evaluated the following: asparagine-linked glycosylation 10 homolog (yeast, α-1,2-glucosyltransferase); butyrylcholinesterase; dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2); glucokinase (hexokinase 4) regulator; guanylate cyclase 1, soluble, β 3; MYST histone acetyltransferase 1; protein phosphatase 3 (formerly 2B), catalytic subunit, β isoform; peroxisomal proliferator-activated receptor-γ-DBD-interacting protein 1; and solute carrier family 27 (fatty acid transporter), member 2; and demonstrated that they enabled IFNα-mediated suppression of HCV at multiple steps of its life cycle. Expression of these genes had more potent effects against flaviviridae because a subset was required for IFNα to suppress dengue virus but not influenza A virus. In addition, many of the host genes detected in this

  12. Fractal apertures in waveguides, conducting screens and cavities analysis and design

    CERN Document Server

    Ghosh, Basudeb; Kartikeyan, M V

    2014-01-01

    This book deals with the design and analysis of fractal apertures in waveguides, conducting screens and cavities using numerical electromagnetics and field-solvers. The aim is to obtain design solutions with improved accuracy for a wide range of applications. To achieve this goal, a few diverse problems are considered. The book is organized with adequate space dedicated for the design and analysis of fractal apertures in waveguides, conducting screens, and cavities, microwave/millimeter wave applications followed by detailed case-study problems to infuse better insight and understanding of the subject. Finally, summaries and suggestions are given for future work. Fractal geometries were widely used in electromagnetics, specifically for antennas and frequency selective surfaces (FSS). The self-similarity of fractal geometry gives rise to a multiband response, whereas the  space-filling nature of the fractal geometries makes it an efficient element in antenna and FSS unit cell miniaturization. Until now, no e...

  13. Virtual high screening throughput and design of 14α-lanosterol ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-07-06

    Jul 6, 2009 ... Virtual high screening throughput and design of. 14α-lanosterol demethylase inhibitors against. Mycobacterium tuberculosis. Hildebert B. Maurice1*, Esther Tuarira1 and Kennedy Mwambete2. 1School of Pharmaceutical Sciences, Institute of Allied Health Sciences, Muhimbili University of Health and.

  14. Novel inhibitors to Taenia solium Cu/Zn superoxide dismutase identified by virtual screening

    Science.gov (United States)

    García-Gutiérrez, P.; Landa-Piedra, A.; Rodríguez-Romero, A.; Parra-Unda, R.; Rojo-Domínguez, A.

    2011-12-01

    We describe in this work a successful virtual screening and experimental testing aimed to the identification of novel inhibitors of superoxide dismutase of the worm Taenia solium ( TsCu/Zn-SOD), a human parasite. Conformers from LeadQuest® database of drug-like compounds were selected and then docked on the surface of TsCu/Zn-SOD. Results were screened looking for ligand contacts with receptor side-chains not conserved in the human homologue, with a subsequent development of a score optimization by a set of energy minimization steps, aimed to identify lead compounds for in vitro experiments. Six out of fifty experimentally tested compounds showed μM inhibitory activity toward TsCu/Zn-SOD. Two of them showed species selectivity since did not inhibit the homologous human enzyme when assayed in vitro.

  15. A new screening method to identify inhibitors of the Lol (localization of lipoproteins) system, a novel antibacterial target.

    Science.gov (United States)

    Ito, Hideaki; Ura, Atsushi; Oyamada, Yoshihiro; Yoshida, Hiroaki; Yamagishi, Jun-Ichi; Narita, Shin-Ichiro; Matsuyama, Shin-Ichi; Tokuda, Hajime

    2007-01-01

    As the Lol system, which is involved in localization of lipoproteins, is essential for Escherichia coli growth and widely conserved among gram-negative bacteria, it is considered to be a promising target for the development of anti-gram-negative bacterial agents. However, no high-throughput screening method has so far been developed to screen for Lol system inhibitors. By combining three assay systems (anucleate cell blue assay, Lpp assay, and LolA-dependent release inhibition assay) and a drug susceptibility test, we have successfully developed a new screening method for identification of compounds that inhibit the Lol system. Using this new screening method, we screened 23,600 in-house chemical compounds and found 2 Lol system inhibitors. We therefore conclude that our new screening method can efficiently identify new antibacterial agents that target the Lol system.

  16. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y

    2011-01-01

    Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1...... and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1......, the presumed significance of the missense mutations was predicted in silico using the align GVGD algorithm. In conclusion, the mutation screening identified 40 novel variants in the BRCA1 and BRCA2 genes and thereby extends the knowledge of the BRCA1/BRCA2 mutation spectrum. Nineteen of the mutations were...

  17. MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia

    Directory of Open Access Journals (Sweden)

    Dong Xu

    2017-12-01

    Full Text Available In 2009 the U.S. Food and Drug Administration (FDA placed a black box warning on metoclopramide (MCP due to the increased risks and prevalence of tardive dyskinesia (TD. In this study, we developed a multi-step biomedical informatics screening (MSBIS approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1 TargetSearch (http://dxulab.org/software bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2 unadjusted odds ratio (UOR scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS; (3 adjusted odds ratio (AOR re-scoring by removing the effect of cofounding factors (age, gender, reporting year; (4 logistic regression (LR coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: −2.68; p-value < 0.01. The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design.

  18. MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia.

    Science.gov (United States)

    Xu, Dong; Ham, Alexandrea G; Tivis, Rickey D; Caylor, Matthew L; Tao, Aoxiang; Flynn, Steve T; Economen, Peter J; Dang, Hung K; Johnson, Royal W; Culbertson, Vaughn L

    2017-12-01

    In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-valueTD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  19. IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Naomi Tidten-Luksch

    Full Text Available CDP-ME kinase (IspE contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens.

  20. Small-molecule inhibitors of phosphatidylcholine transfer protein/StarD2 identified by high-throughput screening.

    Science.gov (United States)

    Wagle, Neil; Xian, Jun; Shishova, Ekaterina Y; Wei, Jie; Glicksman, Marcie A; Cuny, Gregory D; Stein, Ross L; Cohen, David E

    2008-12-01

    Phosphatidylcholine transfer protein (PC-TP, also referred to as StarD2) is a highly specific intracellular lipid-binding protein that catalyzes the transfer of phosphatidylcholines between membranes in vitro. Recent studies have suggested that PC-TP in vivo functions to regulate fatty acid and glucose metabolism, possibly via interactions with selected other proteins. To begin to address the relationship between activity in vitro and biological function, we undertook a high-throughput screen to identify small-molecule inhibitors of the phosphatidylcholine transfer activity of PC-TP. After adapting a fluorescence quench assay to measure phosphatidylcholine transfer activity, we screened 114,752 compounds of a small-molecule library. The high-throughput screen identified 14 potential PC-TP inhibitors. Of these, 6 compounds exhibited characteristics consistent with specific inhibition of PC-TP activity, with IC(50) values that ranged from 4.1 to 95.0muM under conditions of the in vitro assay. These compounds should serve as valuable reagents to elucidate the biological function of PC-TP. Because mice with homozygous disruption of the PC-TP gene (Pctp) are sensitized to insulin action and relatively resistant to the development of atherosclerosis, these inhibitors may also prove to be of value in the management of diabetes and atherosclerotic cardiovascular diseases.

  1. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  2. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  3. Identifying parents with risky alcohol consumption habits in a paediatric unit--are screening and brief intervention appropriate methods?

    Science.gov (United States)

    Bjerregaard, Lene B L; Gerke, Oke; Rubak, Sune; Høst, Arne; Wagner, Lis

    2011-06-01

    There is no systematic identification of parents with excessive alcohol use who have a child admitted to hospital. Children in families with excessive alcohol issues form a high risk group as substantial alcohol consumption has a damaging influence on a child emotionally, cognitively, socially and physically. Alcohol consumption is a sensitive issue, and health staff needs knowledge, qualifications and adequate training in communicating with parents about this taboo. • To identify specific patterns in subgroups of parents by comparing results from screening and demographic variables • To identify systematic patterns in staff members by demographic variables to decide whether these factors influence the screening results. During 1 year, screening and brief intervention (SBI) was accomplished, including health staff conducting dialogues with parents of a hospitalized child using motivational interviewing (MI) and screening for risky alcohol behaviour by Cut down, Annoyance from others, feel Guilty, Early-morning Craving (CAGE)-C. Data were analysed by descriptive statistics, and relationships were tested with a statistical significance level of 0.05, using SPSS (version 16.0). Motivational dialogues with 779 parents were conducted by 43 staff members, and 11% of the parents were screened positive for risky alcohol behaviour. Drinking alcohol 4 days a week or more and drinking alcohol outside mealtimes were main risk factors. Parents' gender was the strongest predictor of screening positive and OR was 6.8 for men (CI 4.03-11.74) compared to women, pparents' age (CI 1.02-1.42) indicates the risk of screening positive increases with age, p=0.027. Brief intervention using CAGE-C and MI has proven successful in mapping parents' alcohol consumption patterns and in identifying parents with risky alcohol consumption habits. Health staff is able to manage health promotion and prevention when having the right competences and when being supervised. © 2010 The Authors

  4. A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity.

    Science.gov (United States)

    Falkenberg, K J; Newbold, A; Gould, C M; Luu, J; Trapani, J A; Matthews, G M; Simpson, K J; Johnstone, R W

    2016-07-01

    Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostat-resistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 small-molecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

  5. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

    Science.gov (United States)

    Zanotto-Filho, Alfeu; Dashnamoorthy, Ravi; Loranc, Eva; de Souza, Luis H T; Moreira, José C F; Suresh, Uthra; Chen, Yidong; Bishop, Alexander J R

    2016-01-01

    Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray) prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair), DNA-mRNA-protein metabolism (transcription/translation) and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH)-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress)/Unfolded Protein Responses (UPR) in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

  6. Combined Gene Expression and RNAi Screening to Identify Alkylation Damage Survival Pathways from Fly to Human.

    Directory of Open Access Journals (Sweden)

    Alfeu Zanotto-Filho

    Full Text Available Alkylating agents are a key component of cancer chemotherapy. Several cellular mechanisms are known to be important for its survival, particularly DNA repair and xenobiotic detoxification, yet genomic screens indicate that additional cellular components may be involved. Elucidating these components has value in either identifying key processes that can be modulated to improve chemotherapeutic efficacy or may be altered in some cancers to confer chemoresistance. We therefore set out to reevaluate our prior Drosophila RNAi screening data by comparison to gene expression arrays in order to determine if we could identify any novel processes in alkylation damage survival. We noted a consistent conservation of alkylation survival pathways across platforms and species when the analysis was conducted on a pathway/process level rather than at an individual gene level. Better results were obtained when combining gene lists from two datasets (RNAi screen plus microarray prior to analysis. In addition to previously identified DNA damage responses (p53 signaling and Nucleotide Excision Repair, DNA-mRNA-protein metabolism (transcription/translation and proteasome machinery, we also noted a highly conserved cross-species requirement for NRF2, glutathione (GSH-mediated drug detoxification and Endoplasmic Reticulum stress (ER stress/Unfolded Protein Responses (UPR in cells exposed to alkylation. The requirement for GSH, NRF2 and UPR in alkylation survival was validated by metabolomics, protein studies and functional cell assays. From this we conclude that RNAi/gene expression fusion is a valid strategy to rapidly identify key processes that may be extendable to other contexts beyond damage survival.

  7. Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors.

    Directory of Open Access Journals (Sweden)

    Oliver N F King

    2010-11-01

    Full Text Available Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4 family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II and to modulate demethylation at the H3K9 locus in a cell-based assay.These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation.

  8. Genome-wide CRISPR/Cas9 Screen Identifies Host Factors Essential for Influenza Virus Replication

    Directory of Open Access Journals (Sweden)

    Julianna Han

    2018-04-01

    Full Text Available Summary: The emergence of influenza A viruses (IAVs from zoonotic reservoirs poses a great threat to human health. As seasonal vaccines are ineffective against zoonotic strains, and newly transmitted viruses can quickly acquire drug resistance, there remains a need for host-directed therapeutics against IAVs. Here, we performed a genome-scale CRISPR/Cas9 knockout screen in human lung epithelial cells with a human isolate of an avian H5N1 strain. Several genes involved in sialic acid biosynthesis and related glycosylation pathways were highly enriched post-H5N1 selection, including SLC35A1, a sialic acid transporter essential for IAV receptor expression and thus viral entry. Importantly, we have identified capicua (CIC as a negative regulator of cell-intrinsic immunity, as loss of CIC resulted in heightened antiviral responses and restricted replication of multiple viruses. Therefore, our study demonstrates that the CRISPR/Cas9 system can be utilized for the discovery of host factors critical for the replication of intracellular pathogens. : Using a genome-wide CRISPR/Cas9 screen, Han et al. demonstrate that the major hit, the sialic acid transporter SLC35A1, is an essential host factor for IAV entry. In addition, they identify the DNA-binding transcriptional repressor CIC as a negative regulator of cell-intrinsic immunity. Keywords: CRISPR/Cas9 screen, GeCKO, influenza virus, host factors, sialic acid pathway, SLC35A1, Capicua, CIC, cell-intrinsic immunity, H5N1

  9. ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis.

    Science.gov (United States)

    Trümbach, Dietrich; Pfeiffer, Susanne; Poppe, Manuel; Scherb, Hagen; Doll, Sebastian; Wurst, Wolfgang; Schick, Joel A

    2017-11-25

    As CRISPR/Cas9 mediated screens with pooled guide libraries in somatic cells become increasingly established, an unmet need for rapid and accurate companion informatics tools has emerged. We have developed a lightweight and efficient software to easily manipulate large raw next generation sequencing datasets derived from such screens into informative relational context with graphical support. The advantages of the software entitled ENCoRE (Easy NGS-to-Gene CRISPR REsults) include a simple graphical workflow, platform independence, local and fast multithreaded processing, data pre-processing and gene mapping with custom library import. We demonstrate the capabilities of ENCoRE to interrogate results from a pooled CRISPR cellular viability screen following Tumor Necrosis Factor-alpha challenge. The results not only identified stereotypical players in extrinsic apoptotic signaling but two as yet uncharacterized members of the extrinsic apoptotic cascade, Smg7 and Ces2a. We further validated and characterized cell lines containing mutations in these genes against a panel of cell death stimuli and involvement in p53 signaling. In summary, this software enables bench scientists with sensitive data or without access to informatic cores to rapidly interpret results from large scale experiments resulting from pooled CRISPR/Cas9 library screens.

  10. Approaches to virtual screening and screening library selection.

    Science.gov (United States)

    Wildman, Scott A

    2013-01-01

    The ease of access to virtual screening (VS) software in recent years has resulted in a large increase in literature reports. Over 300 publications in the last year report the use of virtual screening techniques to identify new chemical matter or present the development of new virtual screening techniques. The increased use is accompanied by a corresponding increase in misuse and misinterpretation of virtual screening results. This review aims to identify many of the common difficulties associated with virtual screening and allow researchers to better assess the reliability of their virtual screening effort.

  11. Sensitivity study of the monogroove with screen heat pipe design

    Science.gov (United States)

    Evans, Austin L.; Joyce, Martin

    1988-01-01

    The present sensitivity study of design variable effects on the performance of a monogroove-with-screen heat pipe obtains performance curves for maximum heat-transfer rates vs. operating temperatures by means of a computer code; performance projections for both 1-g and zero-g conditions are obtainable. The variables in question were liquid and vapor channel design, wall groove design, and the number of feed lines in the evaporator and condenser. The effect on performance of three different working fluids, namely ammonia, methanol, and water, were also determined. Greatest sensitivity was to changes in liquid and vapor channel diameters.

  12. An automated high throughput screening-compatible assay to identify regulators of stem cell neural differentiation.

    Science.gov (United States)

    Casalino, Laura; Magnani, Dario; De Falco, Sandro; Filosa, Stefania; Minchiotti, Gabriella; Patriarca, Eduardo J; De Cesare, Dario

    2012-03-01

    The use of Embryonic Stem Cells (ESCs) holds considerable promise both for drug discovery programs and the treatment of degenerative disorders in regenerative medicine approaches. Nevertheless, the successful use of ESCs is still limited by the lack of efficient control of ESC self-renewal and differentiation capabilities. In this context, the possibility to modulate ESC biological properties and to obtain homogenous populations of correctly specified cells will help developing physiologically relevant screens, designed for the identification of stem cell modulators. Here, we developed a high throughput screening-suitable ESC neural differentiation assay by exploiting the Cell(maker) robotic platform and demonstrated that neural progenies can be generated from ESCs in complete automation, with high standards of accuracy and reliability. Moreover, we performed a pilot screening providing proof of concept that this assay allows the identification of regulators of ESC neural differentiation in full automation.

  13. Idea Screening in Engineering Design Using Employee-driven Wisdom of the Crowds

    OpenAIRE

    Onarheim, Balder; Christensen, Bo T.

    2011-01-01

    The paper investigates the question of screening ideas in the ‘fuzzy front end’ of engineering design, examining the validity of employee voting schemes and related biases. After an employee-driven innovation project at {Company Name removed for review}, 99 ideas were to be screened for further development. Based on the concept of ‘wisdom of the crowds’, all ideas were individually rated by a broad selection of employees, and their choices of ideas and idea categories compared ...

  14. Evaluation of an inpatient fall risk screening tool to identify the most critical fall risk factors in inpatients.

    Science.gov (United States)

    Hou, Wen-Hsuan; Kang, Chun-Mei; Ho, Mu-Hsing; Kuo, Jessie Ming-Chuan; Chen, Hsiao-Lien; Chang, Wen-Yin

    2017-03-01

    To evaluate the accuracy of the inpatient fall risk screening tool and to identify the most critical fall risk factors in inpatients. Variations exist in several screening tools applied in acute care hospitals for examining risk factors for falls and identifying high-risk inpatients. Secondary data analysis. A subset of inpatient data for the period from June 2011-June 2014 was extracted from the nursing information system and adverse event reporting system of an 818-bed teaching medical centre in Taipei. Data were analysed using descriptive statistics, receiver operating characteristic curve analysis and logistic regression analysis. During the study period, 205 fallers and 37,232 nonfallers were identified. The results revealed that the inpatient fall risk screening tool (cut-off point of ≥3) had a low sensitivity level (60%), satisfactory specificity (87%), a positive predictive value of 2·0% and a negative predictive value of 99%. The receiver operating characteristic curve analysis revealed an area under the curve of 0·805 (sensitivity, 71·8%; specificity, 78%). To increase the sensitivity values, the Youden index suggests at least 1·5 points to be the most suitable cut-off point for the inpatient fall risk screening tool. Multivariate logistic regression analysis revealed a considerably increased fall risk in patients with impaired balance and impaired elimination. The fall risk factor was also significantly associated with days of hospital stay and with admission to surgical wards. The findings can raise awareness about the two most critical risk factors for falls among future clinical nurses and other healthcare professionals and thus facilitate the development of fall prevention interventions. This study highlights the needs for redefining the cut-off points of the inpatient fall risk screening tool to effectively identify inpatients at a high risk of falls. Furthermore, inpatients with impaired balance and impaired elimination should be closely

  15. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

    Science.gov (United States)

    Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

    2017-06-01

    The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

  16. Nutrition screening tools: an analysis of the evidence.

    Science.gov (United States)

    Skipper, Annalynn; Ferguson, Maree; Thompson, Kyle; Castellanos, Victoria H; Porcari, Judy

    2012-05-01

    In response to questions about tools for nutrition screening, an evidence analysis project was developed to identify the most valid and reliable nutrition screening tools for use in acute care and hospital-based ambulatory care settings. An oversight group defined nutrition screening and literature search criteria. A trained analyst conducted structured searches of the literature for studies of nutrition screening tools according to predetermined criteria. Eleven nutrition screening tools designed to detect undernutrition in patients in acute care and hospital-based ambulatory care were identified. Trained analysts evaluated articles for quality using criteria specified by the American Dietetic Association's Evidence Analysis Library. Members of the oversight group assigned quality grades to the tools based on the quality of the supporting evidence, including reliability and validity data. One tool, the NRS-2002, received a grade I, and 4 tools-the Simple Two-Part Tool, the Mini-Nutritional Assessment-Short Form (MNA-SF), the Malnutrition Screening Tool (MST), and Malnutrition Universal Screening Tool (MUST)-received a grade II. The MST was the only tool shown to be both valid and reliable for identifying undernutrition in the settings studied. Thus, validated nutrition screening tools that are simple and easy to use are available for application in acute care and hospital-based ambulatory care settings.

  17. Identifying children at risk for language impairment: screening of communication at 18 months.

    Science.gov (United States)

    Bruce, B; Kornfält, R; Radeborg, K; Hansson, K; Nettelbladt, U

    2003-09-01

    To investigate the possibility of identifying children at risk for language impairment based on a new screening instrument to assess communication and language skills at 18 mo of age. At 18 mo, 58 children were assessed with a screening instrument for communication and language consisting of a professional assessment and a parents' questionnaire. Students of speech and language pathology, well trained in child language assessment, carried out the professional assessment, which was based on observations of play behaviour, interaction and expressive and receptive language skills. Of the 58 children, 43 attended a follow-up assessment of language skills at 54 mo of age. Nine children were considered to be at risk for language impairment at 18 mo and 10 children were evaluated as being at risk at 54 mo. A significant positive correlation was found between the professional evaluations at 18 mo and the language tests at 54 mo. Verbal comprehension and pretend play correlated significantly with the results on the language tests. A professional screening of communication and language at 18 mo of age is worthwhile for predicting problems in language development. The results further show that language comprehension and pretend play rather than expressive skills should be emphasized.

  18. Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications

    Directory of Open Access Journals (Sweden)

    John Ong

    2018-03-01

    Full Text Available Summary: Use of hepatocytes derived from induced pluripotent stem cells (i-Heps is limited by their functional differences in comparison with primary cells. Extracellular niche factors likely play a critical role in bridging this gap. Using image-based characterization (high content analysis; HCA of freshly isolated hepatocytes from 17 human donors, we devised and validated an algorithm (Hepatocyte Likeness Index; HLI for comparing the hepatic properties of cells against a physiological gold standard. The HLI was then applied in a targeted screen of extracellular niche factors to identify substrates driving i-Heps closer to the standard. Laminin 411, the top hit, was validated in two additional induced pluripotent stem cell (iPSC lines, primary tissue, and an in vitro model of α1-antitrypsin deficiency. Cumulatively, these data provide a reference method to control and screen for i-Hep differentiation, identify Laminin 411 as a key niche protein, and underscore the importance of combining substrates, soluble factors, and HCA when developing iPSC applications. : Rashid and colleagues demonstrate the utility of a high-throughput imaging platform for identification of physiologically relevant extracellular niche factors to advance i-Heps closer to their primary tissue counterparts. The extracellular matrix (ECM protein screen identified Laminin 411 as an important niche factor facilitating i-Hep-based disease modeling in vitro. Keywords: iPS hepatocytes, extracellular niche, image-based screening, disease modeling, laminin

  19. SDOCT imaging to identify macular pathology in patients diagnosed with diabetic maculopathy by a digital photographic retinal screening programme.

    Directory of Open Access Journals (Sweden)

    Sarah Mackenzie

    Full Text Available INTRODUCTION: Diabetic macular edema (DME is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT clinic to identify macular pathology in this subset of patients. METHODS: A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1 and surrogate markers for diabetic macular edema (M1 attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months. RESULTS: From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009. We analyzed images from 311 patients' SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist. DISCUSSION: This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1 and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1 have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population.

  20. Effect of transient liquid flow on retention characteristics of screen acquisition systems. [design of Space Shuttle feed system

    Science.gov (United States)

    Cady, E. C.

    1977-01-01

    A design analysis, is developed based on experimental data, to predict the effects of transient flow and pressure surges (caused either by valve or pump operation, or by boiling of liquids in warm lines) on the retention performance of screen acquisition systems. A survey of screen liquid acquisition system applications was performed to determine appropriate system environment and classification. A screen model was developed which assumed that the screen device was a uniformly distributed composite orthotropic structure, and which accounted for liquid inflow/outflow, gas ingestion quality, screen stress, and liquid spill. A series of 177 tests using 13 specimens (5 screen meshes, 4 screen device construction/backup methods, and 2 orientations) with three test fluids (isopropyl alcohol, Freon 114, and LH2) provided data which verified important features of the screen model and resulted in a design tool which could accurately predict the transient startup performance acquisition devices.

  1. Best practices in identifying, reporting and screening operating experience at nuclear power plants

    International Nuclear Information System (INIS)

    2008-03-01

    IAEA Safety Standards Series No. SF-1 entitled Fundamental Safety Principles: Safety Fundamentals states the need for operating organizations to establish a programme for the collection and analysis of operating experience in nuclear power plants. Such a programme ensures that operating experience is analysed, events important to safety are reviewed in depth, lessons learned are disseminated to the staff of the organization and to relevant national and international organizations, and corrective actions are effectively implemented. This publication has been developed to provide advice and assistance to nuclear installations, and related institutions including contractors and support organizations to strengthen and enhance their own feedback process through the implementation of best practices in identifying, reporting and screening processes and to assess the effectiveness of the above areas. To support a proactive safety management approach the nuclear installations are enhancing the operating experience feedback (OEF) processes. For this purpose, the nuclear industry is striving to collect more information on occurrences that are useful to address the early signs of declining performance and improve operational safety performance. In this environment a strong reporting culture that motivates people to identify and report issues is an important attribute. As a consequence, the number and diversity of issues identified increases, and there is a need to set thresholds of screening for further treatment. Thus, the establishment of an effective identification, reporting and screening process is very beneficial to streamline the efforts, and ensure that major incidents and latent weaknesses are being addressed and that operating experience is treated according to its significance. This leads to improved safety and production. This publication was written to complement the publication IAEA Services Series No. 10 - PROSPER Guidelines - Guidelines for Peer Review and for

  2. Design of High-Precision Infrared Multi-Touch Screen Based on the EFM32

    Directory of Open Access Journals (Sweden)

    Zhong XIAOLING

    2014-07-01

    Full Text Available Due to the low accuracy of traditional infrared multi-touch screen, it’s difficult to ascertain the touch point. Putting forward a design scheme based on ARM Cortex-M3 kernel EFM32 processor of high precision infrared multi-touch screen. Using tracking scanning area algorithm after accessed electricity for the first time to scan, it greatly improved the scanning efficiency and response speed. Based on the infrared characteristic difference, putting forward a data fitting algorithm, employing the subtraction relationship between the covering area and sampling value to curve fitting, concluding the infrared sampling value of subtraction characteristic curve, establishing a sampling value differential data tables, at last ensuring the precise location of touch point. Besides, practices have proved that the accuracy of the infrared touch screen can up to 0.5 mm. The design uses standard USB port which connected to the PC can also be widely used in various terminals.

  3. Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.

    Science.gov (United States)

    Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen

    2017-03-07

    Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

  4. High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists

    Science.gov (United States)

    Fung, Eileen; Sugianto, Priscilla; Hsu, Jason; Damoiseaux, Robert; Ganz, Tomas

    2013-01-01

    Anemia of inflammation (AI) is common in patients with infection, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be reversed, treatment options are limited to erythropoiesis-stimulating agents with or without intravenous iron therapy, modalities that are not always effective and can cause serious adverse effects. Hepcidin, the iron regulatory hormone, has been identified as a pathogenic factor in the development of AI. To explore new therapeutic options for AI and other iron-related disorders caused by hepcidin excess, we developed a cell-based screen to identify hepcidin antagonists. Of the 70,000 small molecules in the library, we identified 14 compounds that antagonized the hepcidin effect on ferroportin. One of these was fursultiamine, a Food and Drug Administration (FDA)–approved thiamine derivative. Fursultiamine directly interfered with hepcidin binding to its receptor, ferroportin, by blocking ferroportin C326 thiol residue essential for hepcidin binding. Consequently, fursultiamine prevented hepcidin-induced ferroportin ubiquitination, endocytosis, and degradation in vitro and allowed continuous cellular iron export despite the presence of hepcidin, with IC50 in the submicromolar range. Thiamine, the fursultiamine metabolite, and benfotiamine, another thiamine derivative, did not interfere with the effect of hepcidin on ferroportin. Other FDA-approved thiol-reactive compounds were at least 1000-fold less potent than fursultiamine in antagonizing hepcidin. In vivo, fursultiamine did not reproducibly antagonize the effect of hepcidin on serum iron, likely because of its rapid conversion to inactive metabolites. Fursultiamine is a unique antagonist of hepcidin in vitro that could serve as a template for the development of drug candidates that inhibit the hepcidin-ferroportin interaction. PMID:23292796

  5. A new pooling strategy for high-throughput screening: the Shifted Transversal Design

    Directory of Open Access Journals (Sweden)

    Thierry-Mieg Nicolas

    2006-01-01

    Full Text Available Abstract Background In binary high-throughput screening projects where the goal is the identification of low-frequency events, beyond the obvious issue of efficiency, false positives and false negatives are a major concern. Pooling constitutes a natural solution: it reduces the number of tests, while providing critical duplication of the individual experiments, thereby correcting for experimental noise. The main difficulty consists in designing the pools in a manner that is both efficient and robust: few pools should be necessary to correct the errors and identify the positives, yet the experiment should not be too vulnerable to biological shakiness. For example, some information should still be obtained even if there are slightly more positives or errors than expected. This is known as the group testing problem, or pooling problem. Results In this paper, we present a new non-adaptive combinatorial pooling design: the "shifted transversal design" (STD. It relies on arithmetics, and rests on two intuitive ideas: minimizing the co-occurrence of objects, and constructing pools of constant-sized intersections. We prove that it allows unambiguous decoding of noisy experimental observations. This design is highly flexible, and can be tailored to function robustly in a wide range of experimental settings (i.e., numbers of objects, fractions of positives, and expected error-rates. Furthermore, we show that our design compares favorably, in terms of efficiency, to the previously described non-adaptive combinatorial pooling designs. Conclusion This method is currently being validated by field-testing in the context of yeast-two-hybrid interactome mapping, in collaboration with Marc Vidal's lab at the Dana Farber Cancer Institute. Many similar projects could benefit from using the Shifted Transversal Design.

  6. 3D mosquito screens to create window double screen traps for mosquito control.

    Science.gov (United States)

    Khattab, Ayman; Jylhä, Kaisa; Hakala, Tomi; Aalto, Mikko; Malima, Robert; Kisinza, William; Honkala, Markku; Nousiainen, Pertti; Meri, Seppo

    2017-08-29

    Mosquitoes are vectors for many diseases such as malaria. Insecticide-treated bed nets and indoor residual spraying of insecticides are the principal malaria vector control tools used to prevent malaria in the tropics. Other interventions aim at reducing man-vector contact. For example, house screening provides additive or synergistic effects to other implemented measures. We used commercial screen materials made of polyester, polyethylene or polypropylene to design novel mosquito screens that provide remarkable additional benefits to those commonly used in house screening. The novel design is based on a double screen setup made of a screen with 3D geometric structures parallel to a commercial mosquito screen creating a trap between the two screens. Owing to the design of the 3D screen, mosquitoes can penetrate the 3D screen from one side but cannot return through the other side, making it a unidirectional mosquito screen. Therefore, the mosquitoes are trapped inside the double screen system. The permissiveness of both sides of the 3D screens for mosquitoes to pass through was tested in a wind tunnel using the insectary strain of Anopheles stephensi. Among twenty-five tested 3D screen designs, three designs from the cone, prism, or cylinder design groups were the most efficient in acting as unidirectional mosquito screens. The three cone-, prism-, and cylinder-based screens allowed, on average, 92, 75 and 64% of Anopheles stephensi mosquitoes released into the wind tunnel to penetrate the permissive side and 0, 0 and 6% of mosquitoes to escape through the non-permissive side, respectively. A cone-based 3D screen fulfilled the study objective. It allowed capturing 92% of mosquitoes within the double screen setup inside the wind tunnel and blocked 100% from escaping. Thus, the cone-based screen effectively acted as a unidirectional mosquito screen. This 3D screen-based trap design could therefore be used in house screening as a means of avoiding infective bites and

  7. A Quick Drinking Screen for identifying women at risk for an alcohol-exposed pregnancy.

    Science.gov (United States)

    Dum, Mariam; Sobell, Linda Carter; Sobell, Mark B; Heinecke, Nicholas; Voluse, Andrew; Johnson, Kenneth

    2009-09-01

    Two previous studies comparing the Quick Drinking Screen (QDS) with the Timeline Followback (TLFB) found that these two instruments yielded similar reports of alcohol use for clinical and nonclinical populations of problem drinkers. The current study evaluated the correspondence between these two drinking measures with women at risk of an Alcohol-Exposed Pregnancy (AEP). Participants were 355 women who voluntarily participated in a research study during 2005 through 2007 designed to prevent AEPs. All women were screened by phone for eligibility using the QDS and approximately 2 weeks later completed a 3-month TLFB by mail. Results of this study, analyzed in 2008, paralleled previous studies showing that the QDS and the TLFB, two very different drinking measures, collected similar aggregate drinking data for women who drink heavily and are at risk of an AEP. Correspondence between the two drinking measures met acceptable levels of reliability. The present study found that the QDS has demonstrated efficacy for screening women whose level of alcohol use puts them at risk for an AEP. Although the QDS does not yield detailed drinking information, it could be used when it is not possible or necessary to gather daily drinking data.

  8. An Investigation to Validate the Grammar and Phonology Screening (GAPS) Test to Identify Children with Specific Language Impairment

    Science.gov (United States)

    van der Lely, Heather K. J.; Payne, Elisabeth; McClelland, Alastair

    2011-01-01

    Background The extraordinarily high incidence of grammatical language impairments in developmental disorders suggests that this uniquely human cognitive function is “fragile”. Yet our understanding of the neurobiology of grammatical impairments is limited. Furthermore, there is no “gold-standard” to identify grammatical impairments and routine screening is not undertaken. An accurate screening test to identify grammatical abilities would serve the research, health and education communities, further our understanding of developmental disorders, and identify children who need remediation, many of whom are currently un-diagnosed. A potential realistic screening tool that could be widely administered is the Grammar and Phonology Screening (GAPS) test – a 10 minute test that can be administered by professionals and non-professionals alike. Here we provide a further step in evaluating the validity and accuracy (sensitivity and specificity) of the GAPS test in identifying children who have Specific Language Impairment (SLI). Methods and Findings We tested three groups of children; two groups aged 3;6–6:6, a typically developing (n = 30) group, and a group diagnosed with SLI: (n = 11) (Young (Y)-SLI), and a further group aged 6;9–8;11 with SLI (Older (O)-SLI) (n = 10) who were above the test age norms. We employed a battery of language assessments including the GAPS test to assess the children's language abilities. For Y-SLI children, analyses revealed a sensitivity and specificity at the 5th and 10th percentile of 1.00 and 0.98, respectively, and for O-SLI children at the 10th and 15th percentile .83 and .90, respectively. Conclusions The findings reveal that the GAPS is highly accurate in identifying impaired vs. non-impaired children up to 6;8 years, and has moderate-to-high accuracy up to 9 years. The results indicate that GAPS is a realistic tool for the early identification of grammatical abilities and impairment in young children. A larger

  9. Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure

    Science.gov (United States)

    Nath, Anjali K.; Roberts, Lee D.; Liu, Yan; Mahon, Sari B.; Kim, Sonia; Ryu, Justine H.; Werdich, Andreas; Januzzi, James L.; Boss, Gerry R.; Rockwood, Gary A.; MacRae, Calum A.; Brenner, Matthew; Gerszten, Robert E.; Peterson, Randall T.

    2013-01-01

    Exposure to cyanide causes a spectrum of cardiac, neurological, and metabolic dysfunctions that can be fatal. Improved cyanide antidotes are needed, but the ideal biological pathways to target are not known. To understand better the metabolic effects of cyanide and to discover novel cyanide antidotes, we developed a zebrafish model of cyanide exposure and scaled it for high-throughput chemical screening. In a screen of 3120 small molecules, we discovered 4 novel antidotes that block cyanide toxicity. The most potent antidote was riboflavin. Metabolomic profiling of cyanide-treated zebrafish revealed changes in bile acid and purine metabolism, most notably by an increase in inosine levels. Riboflavin normalizes many of the cyanide-induced neurological and metabolic perturbations in zebrafish. The metabolic effects of cyanide observed in zebrafish were conserved in a rabbit model of cyanide toxicity. Further, humans treated with nitroprusside, a drug that releases nitric oxide and cyanide ions, display increased circulating bile acids and inosine. In summary, riboflavin may be a novel treatment for cyanide toxicity and prophylactic measure during nitroprusside treatment, inosine may serve as a biomarker of cyanide exposure, and metabolites in the bile acid and purine metabolism pathways may shed light on the pathways critical to reversing cyanide toxicity.—Nath, A. K., Roberts, L. D., Liu, Y., Mahon, S. B., Kim, S., Ryu, J. H., Werdich, A., Januzzi, J. L., Boss, G. R., Rockwood, G. A., MacRae, C. A., Brenner, M., Gerszten, R. E., Peterson, R. T. Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure. PMID:23345455

  10. Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity.

    Directory of Open Access Journals (Sweden)

    Natalie G Sanders

    Full Text Available Discovery of transmission blocking compounds is an important intervention strategy necessary to eliminate and eradicate malaria. To date only a small number of drugs that inhibit gametocyte development and thereby transmission from the mosquito to the human host exist. This limitation is largely due to a lack of screening assays easily adaptable to high throughput because of multiple incubation steps or the requirement for high gametocytemia. Here we report the discovery of new compounds with gametocytocidal activity using a simple and robust SYBR Green I- based DNA assay. Our assay utilizes the exflagellation step in male gametocytes and a background suppressor, which masks the staining of dead cells to achieve healthy signal to noise ratio by increasing signal of viable parasites and subtracting signal from dead parasites. By determining the contribution of exflagellation to fluorescent signal and using appropriate cutoff values, we were able to screen for gametocytocidal compounds. After assay validation and optimization, we screened an FDA approved drug library of approximately 1500 compounds, as well as the 400 compound MMV malaria box and identified 44 gametocytocidal compounds with sub to low micromolar IC50s. Major classes of compounds with gametocytocidal activity included quaternary ammonium compounds with structural similarity to choline, acridine-like compounds similar to quinacrine and pyronaridine, as well as antidepressant, antineoplastic, and anthelminthic compounds. Top drug candidates showed near complete transmission blocking in membrane feeding assays. This assay is simple, reproducible and demonstrated robust Z-factor values at low gametocytemia levels, making it amenable to HTS for identification of novel and potent gametocytocidal compounds.

  11. Assistant in design of tissue targeting leads with radio-combinatorial screening vivo

    International Nuclear Information System (INIS)

    Liu Ciyi; Zeng Jun; Xie Wenhui; Hu Silong; Jin Muxiu

    2004-01-01

    The diagnostic and therapeutic efficiency of drug depends highly on the drug distribution in target tissues (tumor for example) both specifically and accumulatively. We report here a powerful approach in design of tissue targeting leads with the assistant of radio-combinatorial screening technique developed in our laboratory. Methods: The C-terminal amide tripeptide libraries were synthesized on Rink Amide-MBHA resin in the OXX aO1OXaO1O2O positional scanning format and iterative protoco. A technetium (V) oxo core[(TcO)3+] was bound to the N4-triligands of tripeptide libraries via four deprotonated anfide nitrogen atoms to form a structure of 99Tcm-tripeptoid libraries. The radio-combinatorial screening (RCS) in vivo was then carried out after SD rats and A549 tumor bearing mice received i.v. with 99Tcm-tripeptoid libraries. Results: Signals of tissue distribution and metabolism of libraries were recorded by g counting or imaging. From library of 8,000 99Tcm-tripeptoid members, the tissue targeting leads had been identified by RCS. Those included 99Tcm-DSG (RES), 99Tcm-VAA, and 99Tcm-VIG that had specific tissue targeting in kidney, stomach, and liver respectively. The percent injected dose per gram tissue (%ID/g) of 99Tcm labeled leads in their target tissues was highly structure-dependent The discovery of 99Tcm-VAA and 99Tcm-VIG indicates that side chain methyl at positionl and 2 are crucial for stomach and liver accumulating 99Tcm-tripeptoids. In the case of kidney targeting, Ser in the position 2 and 3 is crucial for 99Tcm-tripeptoids renal excretion and accumulation characteristics respectively. Conclusion: RCS in vivo is a powerful tool for design of tissue targeting leads. (authors)

  12. Yeast functional screen to identify genes conferring salt stress tolerance in Salicornia europaea.

    Science.gov (United States)

    Nakahara, Yoshiki; Sawabe, Shogo; Kainuma, Kenta; Katsuhara, Maki; Shibasaka, Mineo; Suzuki, Masanori; Yamamoto, Kosuke; Oguri, Suguru; Sakamoto, Hikaru

    2015-01-01

    Salinity is a critical environmental factor that adversely affects crop productivity. Halophytes have evolved various mechanisms to adapt to saline environments. Salicornia europaea L. is one of the most salt-tolerant plant species. It does not have special salt-secreting structures like a salt gland or salt bladder, and is therefore a good model for studying the common mechanisms underlying plant salt tolerance. To identify candidate genes encoding key proteins in the mediation of salt tolerance in S. europaea, we performed a functional screen of a cDNA library in yeast. The library was screened for genes that allowed the yeast to grow in the presence of 1.3 M NaCl. We obtained three full-length S. europaea genes that confer salt tolerance. The genes are predicted to encode (1) a novel protein highly homologous to thaumatin-like proteins, (2) a novel coiled-coil protein of unknown function, and (3) a novel short peptide of 32 residues. Exogenous application of a synthetic peptide corresponding to the 32 residues improved salt tolerance of Arabidopsis. The approach described in this report provides a rapid assay system for large-scale screening of S. europaea genes involved in salt stress tolerance and supports the identification of genes responsible for such mechanisms. These genes may be useful candidates for improving crop salt tolerance by genetic transformation.

  13. Yeast functional screen to identify genes conferring salt stress tolerance in Salicornia europaea

    Directory of Open Access Journals (Sweden)

    Yoshiki eNakahara

    2015-10-01

    Full Text Available Salinity is a critical environmental factor that adversely affects crop productivity. Halophytes have evolved various mechanisms to adapt to saline environments. Salicornia europaea L. is one of the most salt-tolerant plant species. It does not have special salt-secreting structures like a salt gland or salt bladder, and is therefore a good model for studying the common mechanisms underlying plant salt tolerance. To identify candidate genes encoding key proteins in the mediation of salt tolerance in S. europaea, we performed a functional screen of a cDNA library in yeast. The library was screened for genes that allowed the yeast to grow in the presence of 1.3 M NaCl. We obtained three full-length S. europaea genes that confer salt tolerance. The genes are predicted to encode (1 a novel protein highly homologous to thaumatin-like proteins, (2 a novel coiled-coil protein of unknown function, and (3 a novel short peptide of 32 residues. Exogenous application of a synthetic peptide corresponding to the 32 residues improved salt tolerance of Arabidopsis. The approach described in this report provides a rapid assay system for large-scale screening of S. europaea genes involved in salt stress tolerance and supports the identification of genes responsible for such mechanisms. These genes may be useful candidates for improving crop salt tolerance by genetic transformation.

  14. Designing a Visual Factors-Based Screen Display Interface: The New Role of the Graphic Technologist.

    Science.gov (United States)

    Faiola, Tony; DeBloois, Michael L.

    1988-01-01

    Discusses the role of the graphic technologist in preparing computer screen displays for interactive videodisc systems, and suggests screen design guidelines. Topics discussed include the grid system; typography; visual factors research; color; course mobility through branching and software menus; and a model of course integration. (22 references)…

  15. Permanent Childhood Hearing Impairment: Aetiological Evaluation of Infants identified through the Irish Newborn Hearing Screening Programme

    LENUS (Irish Health Repository)

    Smith, A

    2017-11-01

    The Newborn Hearing Screening Programme (NHSP) was established in Cork University Maternity Hospital (CUMH) in April 2011. Between April 2011 and July 2014, 42 infants were identified with a Permanent Childhood Hearing Impairment (PCHI). Following this diagnosis, infants underwent a paediatric assessment according to recognised guidelines with the intention of identifying the underlying aetiology of the PCHI. The aim of this study was to assess the findings of this aetiological workup via retrospective chart review. PCHI data was obtained from the eSP database. This is a web based information system (eSP) used to track each baby through the screening and referral process A retrospective chart review of these patients was performed. Sixteen (38%) infants were diagnosed with a bilateral sensorineural hearing loss. Two infants had congenital CMV infection. A Connexin 26 gene mutation was detected in one infant. Two infants were diagnosed with Waardenburg syndrome, One with Pendred syndrome and one with Pfeiffer syndrome. Five babies underwent cochlear implantation. Through adherence to the recommended protocol a possible cause of PCHI may be determined. This study has identified areas of future improvement for this service in Ireland.

  16. High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

    Science.gov (United States)

    Kaufmann, Markus; Schuffenhauer, Ansgar; Fruh, Isabelle; Klein, Jessica; Thiemeyer, Anke; Rigo, Pierre; Gomez-Mancilla, Baltazar; Heidinger-Millot, Valerie; Bouwmeester, Tewis; Schopfer, Ulrich; Mueller, Matthias; Fodor, Barna D; Cobos-Correa, Amanda

    2015-10-01

    Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention. © 2015 Society for Laboratory Automation and Screening.

  17. A Review of Different Behavior Modification Strategies Designed to Reduce Sedentary Screen Behaviors in Children

    Directory of Open Access Journals (Sweden)

    Jeremy A. Steeves

    2012-01-01

    Full Text Available Previous research suggests that reducing sedentary screen behaviors may be a strategy for preventing and treating obesity in children. This systematic review describes strategies used in interventions designed to either solely target sedentary screen behaviors or multiple health behaviors, including sedentary screen behaviors. Eighteen studies were included in this paper; eight targeting sedentary screen behaviors only, and ten targeting multiple health behaviors. All studies used behavior modification strategies for reducing sedentary screen behaviors in children (aged 1–12 years. Nine studies only used behavior modification strategies, and nine studies supplemented behavior modification strategies with an electronic device to enhance sedentary screen behaviors reductions. Many interventions (50% significantly reduced sedentary screen behaviors; however the magnitude of the significant reductions varied greatly (−0.44 to −3.1 h/day and may have been influenced by the primary focus of the intervention, number of behavior modification strategies used, and other tools used to limit sedentary screen behaviors.

  18. A review of different behavior modification strategies designed to reduce sedentary screen behaviors in children.

    Science.gov (United States)

    Steeves, Jeremy A; Thompson, Dixie L; Bassett, David R; Fitzhugh, Eugene C; Raynor, Hollie A

    2012-01-01

    Previous research suggests that reducing sedentary screen behaviors may be a strategy for preventing and treating obesity in children. This systematic review describes strategies used in interventions designed to either solely target sedentary screen behaviors or multiple health behaviors, including sedentary screen behaviors. Eighteen studies were included in this paper; eight targeting sedentary screen behaviors only, and ten targeting multiple health behaviors. All studies used behavior modification strategies for reducing sedentary screen behaviors in children (aged 1-12 years). Nine studies only used behavior modification strategies, and nine studies supplemented behavior modification strategies with an electronic device to enhance sedentary screen behaviors reductions. Many interventions (50%) significantly reduced sedentary screen behaviors; however the magnitude of the significant reductions varied greatly (-0.44 to -3.1 h/day) and may have been influenced by the primary focus of the intervention, number of behavior modification strategies used, and other tools used to limit sedentary screen behaviors.

  19. A Genome-Wide Screen for Dendritically Localized RNAs Identifies Genes Required for Dendrite Morphogenesis

    Directory of Open Access Journals (Sweden)

    Mala Misra

    2016-08-01

    Full Text Available Localizing messenger RNAs at specific subcellular sites is a conserved mechanism for targeting the synthesis of cytoplasmic proteins to distinct subcellular domains, thereby generating the asymmetric protein distributions necessary for cellular and developmental polarity. However, the full range of transcripts that are asymmetrically distributed in specialized cell types, and the significance of their localization, especially in the nervous system, are not known. We used the EP-MS2 method, which combines EP transposon insertion with the MS2/MCP in vivo fluorescent labeling system, to screen for novel localized transcripts in polarized cells, focusing on the highly branched Drosophila class IV dendritic arborization neurons. Of a total of 541 lines screened, we identified 55 EP-MS2 insertions producing transcripts that were enriched in neuronal processes, particularly in dendrites. The 47 genes identified by these insertions encode molecularly diverse proteins, and are enriched for genes that function in neuronal development and physiology. RNAi-mediated knockdown confirmed roles for many of the candidate genes in dendrite morphogenesis. We propose that the transport of mRNAs encoded by these genes into the dendrites allows their expression to be regulated on a local scale during the dynamic developmental processes of dendrite outgrowth, branching, and/or remodeling.

  20. Design of an off-axis visual display based on a free-form projection screen to realize stereo vision

    Science.gov (United States)

    Zhao, Yuanming; Cui, Qingfeng; Piao, Mingxu; Zhao, Lidong

    2017-10-01

    A free-form projection screen is designed for an off-axis visual display, which shows great potential in applications such as flight training for providing both accommodation and convergence cues for pilots. The method based on point cloud is proposed for the design of the free-form surface, and the design of the point cloud is controlled by a program written in the macro-language. In the visual display based on the free-form projection screen, when the error of the screen along Z-axis is 1 mm, the error of visual distance at each filed is less than 1%. And the resolution of the design for full field is better than 1‧, which meet the requirement of resolution for human eyes.

  1. Induced Polarization Surveying for Acid Rock Screening in Highway Design

    Science.gov (United States)

    Butler, K. E.; Al, T.; Bishop, T.

    2004-05-01

    Highway and pipeline construction agencies have become increasingly vigilant in their efforts to avoid cutting through sulphide-bearing bedrock that has potential to produce acid rock drainage. Blasting and fragmentation of such rock increases the surface area available for sulphide oxidation and hence increases the risk of acid rock drainage unless the rock contains enough natural buffering capacity to neutralize the pH. In December, 2001, the New Brunswick Department of Transportation (NBOT) sponsored a field trial of geophysical surveying in order to assess its suitability as a screening tool for locating near-surface sulphides along proposed highway alignments. The goal was to develop a protocol that would allow existing programs of drilling and geochemical testing to be targeted more effectively, and provide design engineers with the information needed to reduce rock cuts where necessary and dispose of blasted material in a responsible fashion. Induced polarization (IP) was chosen as the primary geophysical method given its ability to detect low-grade disseminated mineralization. The survey was conducted in dipole-dipole mode using an exploration-style time domain IP system, dipoles 8 to 25 m in length, and six potential dipoles for each current dipole location (i.e. n = 1 - 6). Supplementary information was provided by resistivity and VLF-EM surveys sensitive to lateral changes in electrical conductivity, and by magnetic field surveying chosen for its sensitivity to the magnetic susceptibility of pyrrhotite. Geological and geochemical analyses of samples taken from several IP anomalies located along 4.3 line-km of proposed highway confirmed the effectiveness of the screening technique. IP pseudosections from a region of metamorphosed shales and volcaniclastic rocks identified discrete, well-defined mineralized zones. Stronger, overlapping, and more laterally extensive IP anomalies were observed over a section of graphitic and sulphide-bearing metasedimentary

  2. A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Senthilkumar Deivasigamani

    2014-10-01

    Full Text Available Amyotrophic Lateral Sclerosis (ALS is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5–10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions. We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci – TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2 that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt and VAP(P58S, but in a contrasting manner. Reversal of VAP(P58S bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S expression. The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease.

  3. A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Deivasigamani, Senthilkumar; Verma, Hemant Kumar; Ueda, Ryu; Ratnaparkhi, Anuradha; Ratnaparkhi, Girish S

    2014-10-31

    Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5-10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions. We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci - TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt) and VAP(P58S), but in a contrasting manner. Reversal of VAP(P58S) bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S) expression. The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease. © 2014. Published by The Company of Biologists Ltd.

  4. Development and validation of a screening procedure to identify speech-language delay in toddlers with cleft palate

    DEFF Research Database (Denmark)

    Jørgensen, Line Dahl; Willadsen, Elisabeth

    2017-01-01

    condition based on assessment of consonant inventory using a real-time listening procedure in combination with parent-reported expressive vocabulary. These measures allowed evaluation of early speech-language skills found to correlate significantly with later speech-language difficulties in longitudinal......The purpose of this study was to develop and validate a clinically useful speech-language screening procedure for young children with cleft palate +/- cleft lip (CP) to identify those in need of speech-language intervention. Twenty-two children with CP were assigned to a +/- need for intervention...... studies of children with CP. The external validity of this screening procedure was evaluated by comparing the +/- need for intervention assignment determined by the screening procedure to experienced speech-language pathologists’ (SLPs’) clinical judgment of whether or not a child needed early...

  5. Drug discovery for schistosomiasis: hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening.

    Directory of Open Access Journals (Sweden)

    Maha-Hamadien Abdulla

    2009-07-01

    Full Text Available Praziquantel (PZQ is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism screening with adult worms in vitro and/or animal models of disease-tools that limit automation and throughput with modern microtiter plate-formatted compound libraries.A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to 'reposition' (re-profile drugs as anti-schistosomals with potential savings in development timelines and costs.Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of 'hit' drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource.To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that

  6. Ultra-High-Throughput Screening of Natural Product Extracts to Identify Proapoptotic Inhibitors of Bcl-2 Family Proteins.

    Science.gov (United States)

    Hassig, Christian A; Zeng, Fu-Yue; Kung, Paul; Kiankarimi, Mehrak; Kim, Sylvia; Diaz, Paul W; Zhai, Dayong; Welsh, Kate; Morshedian, Shana; Su, Ying; O'Keefe, Barry; Newman, David J; Rusman, Yudi; Kaur, Harneet; Salomon, Christine E; Brown, Susan G; Baire, Beeraiah; Michel, Andrew R; Hoye, Thomas R; Francis, Subhashree; Georg, Gunda I; Walters, Michael A; Divlianska, Daniela B; Roth, Gregory P; Wright, Amy E; Reed, John C

    2014-09-01

    Antiapoptotic Bcl-2 family proteins are validated cancer targets composed of six related proteins. From a drug discovery perspective, these are challenging targets that exert their cellular functions through protein-protein interactions (PPIs). Although several isoform-selective inhibitors have been developed using structure-based design or high-throughput screening (HTS) of synthetic chemical libraries, no large-scale screen of natural product collections has been reported. A competitive displacement fluorescence polarization (FP) screen of nearly 150,000 natural product extracts was conducted against all six antiapoptotic Bcl-2 family proteins using fluorochrome-conjugated peptide ligands that mimic functionally relevant PPIs. The screens were conducted in 1536-well format and displayed satisfactory overall HTS statistics, with Z'-factor values ranging from 0.72 to 0.83 and a hit confirmation rate between 16% and 64%. Confirmed active extracts were orthogonally tested in a luminescent assay for caspase-3/7 activation in tumor cells. Active extracts were resupplied, and effort toward the isolation of pure active components was initiated through iterative bioassay-guided fractionation. Several previously described altertoxins were isolated from a microbial source, and the pure compounds demonstrate activity in both Bcl-2 FP and caspase cellular assays. The studies demonstrate the feasibility of ultra-high-throughput screening using natural product sources and highlight some of the challenges associated with this approach. © 2014 Society for Laboratory Automation and Screening.

  7. Description of 15 DNA-positive and antibody-negative "window-period" blood donations identified during prospective screening for Babesia microti.

    Science.gov (United States)

    Moritz, Erin D; Tonnetti, Laura; Hewins, Mary Ellen; Berardi, Victor P; Dodd, Roger Y; Stramer, Susan L

    2017-07-01

    Blood donation screening detecting only antibodies fails to identify donors in the earliest stage of infection, before a detectable immunologic response, that is, the "window period" (WP). We present data on WP donations identified during prospective screening for Babesia microti, a transfusion-transmissible parasite of increasing concern in the United States. Blood donations collected in Connecticut, Massachusetts, Minnesota, and Wisconsin were screened using polymerase chain reaction (PCR) and arrayed fluorescence immunoassay (AFIA) to detect B. microti DNA and antibodies, respectively. Parasite loads were estimated using quantitative PCR. Red blood cell (RBC) samples were inoculated into hamsters to assess infectivity. Donors screening reactive were indefinitely deferred, tested by supplemental methods, and followed to assess DNA and antibody clearance. Demographic data from WP donors (i.e., those screening PCR positive and AFIA negative) were compared to data from other positive donors. Of 220,479 donations screened from June 2012 to August 2016, a total of 700 were positive, of which 15 (2% of positive donations or 1 per 14,699 screened donations) were confirmed WP donations. The median estimated parasite load in WP donations was 350 parasites/mL, no different than AFIA-positive and PCR-positive donors. Parasite loads in RBC samples from WP units ranged from 14 to 11,022 parasites/mL; RBC samples from three of 10 (30%) WP donations infected hamsters. The mean age of WP donors was 48 years (range, 17-75 years); three (20%) were female. WP donor demographics did not differ significantly from demographics of other donors. We report one per 15,000 B. microti WP infections in blood donors in endemic areas, demonstrating the importance of nucleic acid testing to mitigate the risk of transfusion-transmitted babesiosis. © 2017 AABB.

  8. Advances in genome-wide RNAi cellular screens: a case study using the Drosophila JAK/STAT pathway

    Science.gov (United States)

    2012-01-01

    Background Genome-scale RNA-interference (RNAi) screens are becoming ever more common gene discovery tools. However, whilst every screen identifies interacting genes, less attention has been given to how factors such as library design and post-screening bioinformatics may be effecting the data generated. Results Here we present a new genome-wide RNAi screen of the Drosophila JAK/STAT signalling pathway undertaken in the Sheffield RNAi Screening Facility (SRSF). This screen was carried out using a second-generation, computationally optimised dsRNA library and analysed using current methods and bioinformatic tools. To examine advances in RNAi screening technology, we compare this screen to a biologically very similar screen undertaken in 2005 with a first-generation library. Both screens used the same cell line, reporters and experimental design, with the SRSF screen identifying 42 putative regulators of JAK/STAT signalling, 22 of which verified in a secondary screen and 16 verified with an independent probe design. Following reanalysis of the original screen data, comparisons of the two gene lists allows us to make estimates of false discovery rates in the SRSF data and to conduct an assessment of off-target effects (OTEs) associated with both libraries. We discuss the differences and similarities between the resulting data sets and examine the relative improvements in gene discovery protocols. Conclusions Our work represents one of the first direct comparisons between first- and second-generation libraries and shows that modern library designs together with methodological advances have had a significant influence on genome-scale RNAi screens. PMID:23006893

  9. Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

    Science.gov (United States)

    Duffy, Supipi; Fam, Hok Khim; Wang, Yi Kan; Styles, Erin B.; Kim, Jung-Hyun; Ang, J. Sidney; Singh, Tejomayee; Larionov, Vladimir; Shah, Sohrab P.; Andrews, Brenda; Boerkoel, Cornelius F.; Hieter, Philip

    2016-01-01

    Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors. PMID:27551064

  10. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF-p53 signaling

    NARCIS (Netherlands)

    Shvarts, A.; Brummelkamp, T.; Koh, E.; Daley, G.Q.; Bernards, R.A.

    2002-01-01

    Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify BCL6 as a potent inhibitor of senescence. BCL6 is frequently activated in

  11. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling

    NARCIS (Netherlands)

    Shvarts, Avi; Brummelkamp, Thijn R.; Scheeren, Ferenc; Koh, Eugene; Daley, George Q.; Spits, Hergen; Bernards, René

    2002-01-01

    Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify BCL6 as a potent inhibitor of senescence. BCL6 is frequently activated in

  12. Barriers to Breast and Cervical Cancer Screening in Singapore: a Mixed Methods Analysis.

    Science.gov (United States)

    Malhotra, Chetna; Bilger, Marcel; Liu, Joy; Finkelstein, Eric

    2016-01-01

    In order to increase breast and cervical cancer screening uptake in Singapore, women's perceived barriers to screening need to be identified and overcome. Using data from both focus groups and surveys, we aimed to assess perceived barriers and motivations for breast and cervical cancer screening. We conducted 8 focus groups with 64 women, using thematic analysis to identify overarching themes related to women's attitudes towards screening. Based on recurring themes from focus groups, several hypotheses regarding potential barriers and motivations to screen were generated and tested through a national survey of 801 women aged 25-64. Focus group participants had misconceptions related to screening, believing that the procedures were painful. Cost was an issue, as well as efficacy and fatalism. By identifying barriers to and motivators for screening through a mixed-method design that has both nuance and external validity, this study offers valuable suggestions to policymakers to improve breast and cervical cancer screening uptake in Singapore.

  13. Nickel-resistance determinants in Acidiphilium sp. PM identified by genome-wide functional screening.

    Directory of Open Access Journals (Sweden)

    Patxi San Martin-Uriz

    Full Text Available Acidiphilium spp. are conspicuous dwellers of acidic, metal-rich environments. Indeed, they are among the most metal-resistant organisms; yet little is known about the mechanisms behind the metal tolerance in this genus. Acidiphilium sp. PM is an environmental isolate from Rio Tinto, an acidic, metal-laden river located in southwestern Spain. The characterization of its metal resistance revealed a remarkable ability to tolerate high Ni concentrations. Here we report the screening of a genomic library of Acidiphilium sp. PM to identify genes involved in Ni resistance. This approach revealed seven different genes conferring Ni resistance to E. coli, two of which form an operon encoding the ATP-dependent protease HslVU (ClpQY. This protease was found to enhance resistance to both Ni and Co in E. coli, a function not previously reported. Other Ni-resistance determinants include genes involved in lipopolysaccharide biosynthesis and the synthesis of branched amino acids. The diversity of molecular functions of the genes recovered in the screening suggests that Ni resistance in Acidiphilium sp. PM probably relies on different molecular mechanisms.

  14. Genes Important for Schizosaccharomyces pombe Meiosis Identified Through a Functional Genomics Screen

    Science.gov (United States)

    Blyth, Julie; Makrantoni, Vasso; Barton, Rachael E.; Spanos, Christos; Rappsilber, Juri; Marston, Adele L.

    2018-01-01

    Meiosis is a specialized cell division that generates gametes, such as eggs and sperm. Errors in meiosis result in miscarriages and are the leading cause of birth defects; however, the molecular origins of these defects remain unknown. Studies in model organisms are beginning to identify the genes and pathways important for meiosis, but the parts list is still poorly defined. Here we present a comprehensive catalog of genes important for meiosis in the fission yeast, Schizosaccharomyces pombe. Our genome-wide functional screen surveyed all nonessential genes for roles in chromosome segregation and spore formation. Novel genes important at distinct stages of the meiotic chromosome segregation and differentiation program were identified. Preliminary characterization implicated three of these genes in centrosome/spindle pole body, centromere, and cohesion function. Our findings represent a near-complete parts list of genes important for meiosis in fission yeast, providing a valuable resource to advance our molecular understanding of meiosis. PMID:29259000

  15. An open-access endoscopy screen correctly and safely identifies patients for conscious sedation.

    Science.gov (United States)

    Kothari, Darshan; Feuerstein, Joseph D; Moss, Laureen; D'Souza, Julie; Montanaro, Kerri; Leffler, Daniel A; Sheth, Sunil G

    2016-11-01

    Open-access scheduling is highly utilized for facilitating generally low-risk endoscopies. Preprocedural screening addresses sedation requirements; however, procedural safety may be compromised if screening is inaccurate. We sought to determine the reliability of our open-access scheduling system for appropriate use of conscious sedation. We prospectively and consecutively enrolled outpatient procedures booked at an academic center by open-access using screening after in-office gastroenterology (GI) consultation. We collected the cases inappropriately booked for conscious sedation and compared the characteristics for significant differences. A total of 8063 outpatients were scheduled for procedures with conscious sedation, and 5959 were booked with open-access. Only 78 patients (0.97%, 78/8063) were identified as subsequently needing anesthesiologist-assisted sedation; 44 (56.4%, 44/78) were booked through open-access, of which chronic opioid (47.7%, 21/44) or benzodiazepine use (34.1%, 15/44) were the most common reasons for needing anesthesiologist-assisted sedation. Patients on chronic benzodiazepines required more midazolam than those not on chronic benzodiazepines (P = .03) of those patients who underwent conscious sedation. Similarly, patients with chronic opioid use required more fentanyl than those without chronic opioid use (P = .04). Advanced liver disease and alcohol use were common reasons for patients being booked after in-office consultation and were significantly higher than those booked with open-access (both P open-access scheduling. © The Author(s) 2016. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-Sen University.

  16. CT screening for lung cancer: Frequency of enlarged adrenal glands identified in baseline and annual repeat rounds

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Minxia [Icahn School of Medicine at Mount Sinai, Department of Radiology, New York, NY (United States); Capital Medical University, Department of Diagnostic Ultrasound, Beijing Tongren Hospital, Beijing (China); Yip, Rowena; Yankelevitz, David Y.; Henschke, Claudia I. [Icahn School of Medicine at Mount Sinai, Department of Radiology, New York, NY (United States)

    2016-12-15

    To determine the frequency of adrenal enlargement of participants in a CT-screening program for lung cancer and demonstrate the progression during follow-up, separately for baseline and annual repeat rounds. HIPAA-compliant informed consent was obtained in 4,776 participants. The adrenal gland was defined as enlarged if it measured ≥6 mm at its largest diameter. Logistic regression analyses were performed. At baseline, 202 (4 %) of 4,776 participants had adrenal enlargement. Significant factors were age (OR = 1.4, 95 % CI: 1.2-1.7) and current smoker (OR = 1.8, 95 % CI: 1.3-2.4). Follow-up 7-18 months after baseline for 133 cases with adrenal enlargement <40 mm showed it decreased or was stable in 85 (64 %), and increased by <10 mm in 48 (36 %). Five (0.04 %) cases of adrenal enlargement were newly identified, none increased beyond 40 mm on follow-up. Adrenal enlargement was a significant predictor of a subsequent diagnosis of lung cancer (OR = 2.0, 95 % CI: 1.2-3.4). Participants with adrenal enlargement <40 mm identified at baseline and on repeat screening could be reasonably assessed on subsequent annual screening. Adrenal enlargement increased with increasing pack-years of smoking. Adrenal enlargement was an independent predictor of a subsequent diagnosis of lung cancer. (orig.)

  17. Microfluidic screening and whole-genome sequencing identifies mutations associated with improved protein secretion by yeast

    DEFF Research Database (Denmark)

    Huang, Mingtao; Bai, Yunpeng; Sjostrom, Staffan L.

    2015-01-01

    There is an increasing demand for biotech-based production of recombinant proteins for use as pharmaceuticals in the food and feed industry and in industrial applications. Yeast Saccharomyces cerevisiae is among preferred cell factories for recombinant protein production, and there is increasing...... interest in improving its protein secretion capacity. Due to the complexity of the secretory machinery in eukaryotic cells, it is difficult to apply rational engineering for construction of improved strains. Here we used high-throughput microfluidics for the screening of yeast libraries, generated by UV...... mutagenesis. Several screening and sorting rounds resulted in the selection of eight yeast clones with significantly improved secretion of recombinant a-amylase. Efficient secretion was genetically stable in the selected clones. We performed whole-genome sequencing of the eight clones and identified 330...

  18. A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease.

    Directory of Open Access Journals (Sweden)

    John P Miller

    Full Text Available A genome-scale RNAi screen was performed in a mammalian cell-based assay to identify modifiers of mutant huntingtin toxicity. Ontology analysis of suppressor data identified processes previously implicated in Huntington's disease, including proteolysis, glutamate excitotoxicity, and mitochondrial dysfunction. In addition to established mechanisms, the screen identified multiple components of the RRAS signaling pathway as loss-of-function suppressors of mutant huntingtin toxicity in human and mouse cell models. Loss-of-function in orthologous RRAS pathway members also suppressed motor dysfunction in a Drosophila model of Huntington's disease. Abnormal activation of RRAS and a down-stream effector, RAF1, was observed in cellular models and a mouse model of Huntington's disease. We also observe co-localization of RRAS and mutant huntingtin in cells and in mouse striatum, suggesting that activation of R-Ras may occur through protein interaction. These data indicate that mutant huntingtin exerts a pathogenic effect on this pathway that can be corrected at multiple intervention points including RRAS, FNTA/B, PIN1, and PLK1. Consistent with these results, chemical inhibition of farnesyltransferase can also suppress mutant huntingtin toxicity. These data suggest that pharmacological inhibition of RRAS signaling may confer therapeutic benefit in Huntington's disease.

  19. Novel immune-modulator identified by a rapid, functional screen of the parapoxvirus ovis (Orf virus genome

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    McGuire Michael J

    2012-01-01

    Full Text Available Abstract Background The success of new sequencing technologies and informatic methods for identifying genes has made establishing gene product function a critical rate limiting step in progressing the molecular sciences. We present a method to functionally mine genomes for useful activities in vivo, using an unusual property of a member of the poxvirus family to demonstrate this screening approach. Results The genome of Parapoxvirus ovis (Orf virus was sequenced, annotated, and then used to PCR-amplify its open-reading-frames. Employing a cloning-independent protocol, a viral expression-library was rapidly built and arrayed into sub-library pools. These were directly delivered into mice as expressible cassettes and assayed for an immune-modulating activity associated with parapoxvirus infection. The product of the B2L gene, a homolog of vaccinia F13L, was identified as the factor eliciting immune cell accumulation at sites of skin inoculation. Administration of purified B2 protein also elicited immune cell accumulation activity, and additionally was found to serve as an adjuvant for antigen-specific responses. Co-delivery of the B2L gene with an influenza gene-vaccine significantly improved protection in mice. Furthermore, delivery of the B2L expression construct, without antigen, non-specifically reduced tumor growth in murine models of cancer. Conclusion A streamlined, functional approach to genome-wide screening of a biological activity in vivo is presented. Its application to screening in mice for an immune activity elicited by the pathogen genome of Parapoxvirus ovis yielded a novel immunomodulator. In this inverted discovery method, it was possible to identify the adjuvant responsible for a function of interest prior to a mechanistic study of the adjuvant. The non-specific immune activity of this modulator, B2, is similar to that associated with administration of inactivated particles to a host or to a live viral infection. Administration

  20. indCAPS: A tool for designing screening primers for CRISPR/Cas9 mutagenesis events.

    Science.gov (United States)

    Hodgens, Charles; Nimchuk, Zachary L; Kieber, Joseph J

    2017-01-01

    Genetic manipulation of organisms using CRISPR/Cas9 technology generally produces small insertions/deletions (indels) that can be difficult to detect. Here, we describe a technique to easily and rapidly identify such indels. Sequence-identified mutations that alter a restriction enzyme recognition site can be readily distinguished from wild-type alleles using a cleaved amplified polymorphic sequence (CAPS) technique. If a restriction site is created or altered by the mutation such that only one allele contains the restriction site, a polymerase chain reaction (PCR) followed by a restriction digest can be used to distinguish the two alleles. However, in the case of most CRISPR-induced alleles, no such restriction sites are present in the target sequences. In this case, a derived CAPS (dCAPS) approach can be used in which mismatches are purposefully introduced in the oligonucleotide primers to create a restriction site in one, but not both, of the amplified templates. Web-based tools exist to aid dCAPS primer design, but when supplied sequences that include indels, the current tools often fail to suggest appropriate primers. Here, we report the development of a Python-based, species-agnostic web tool, called indCAPS, suitable for the design of PCR primers used in dCAPS assays that is compatible with indels. This tool should have wide utility for screening editing events following CRISPR/Cas9 mutagenesis as well as for identifying specific editing events in a pool of CRISPR-mediated mutagenesis events. This tool was field-tested in a CRISPR mutagenesis experiment targeting a cytokinin receptor (AHK3) in Arabidopsis thaliana. The tool suggested primers that successfully distinguished between wild-type and edited alleles of a target locus and facilitated the isolation of two novel ahk3 null alleles. Users can access indCAPS and design PCR primers to employ dCAPS to identify CRISPR/Cas9 alleles at http://indcaps.kieber.cloudapps.unc.edu/.

  1. Identifiability in N-mixture models: a large-scale screening test with bird data.

    Science.gov (United States)

    Kéry, Marc

    2018-02-01

    Binomial N-mixture models have proven very useful in ecology, conservation, and monitoring: they allow estimation and modeling of abundance separately from detection probability using simple counts. Recently, doubts about parameter identifiability have been voiced. I conducted a large-scale screening test with 137 bird data sets from 2,037 sites. I found virtually no identifiability problems for Poisson and zero-inflated Poisson (ZIP) binomial N-mixture models, but negative-binomial (NB) models had problems in 25% of all data sets. The corresponding multinomial N-mixture models had no problems. Parameter estimates under Poisson and ZIP binomial and multinomial N-mixture models were extremely similar. Identifiability problems became a little more frequent with smaller sample sizes (267 and 50 sites), but were unaffected by whether the models did or did not include covariates. Hence, binomial N-mixture model parameters with Poisson and ZIP mixtures typically appeared identifiable. In contrast, NB mixtures were often unidentifiable, which is worrying since these were often selected by Akaike's information criterion. Identifiability of binomial N-mixture models should always be checked. If problems are found, simpler models, integrated models that combine different observation models or the use of external information via informative priors or penalized likelihoods, may help. © 2017 by the Ecological Society of America.

  2. Large screen mimic display design research for advanced main control room in nuclear power plant

    International Nuclear Information System (INIS)

    Zheng Mingguang; Yang Yanhua; Xu Jijun; Zhang Qinshun; Ning Zhonghe

    2002-01-01

    Firstly the evolution of mimic diagrams or displays used in the main control room of nuclear power plant was introduced. The active functions of mimic diagrams were analyzed on the release of operator psychological burden and pressure, the assistance of operator for the information searching, status understanding, manual actuation, correct decision making as well as the safe and reliable operation of the nuclear power plant. The importance and necessity to use the (large screen) mimic diagrams in advanced main control room of nuclear power plant, the design principle, design details and verification measures of large screen mimic display are also described

  3. Cellular adhesome screen identifies critical modulators of focal adhesion dynamics, cellular traction forces and cell migration behaviour

    Science.gov (United States)

    Fokkelman, Michiel; Balcıoğlu, Hayri E.; Klip, Janna E.; Yan, Kuan; Verbeek, Fons J.; Danen, Erik H. J.; van de Water, Bob

    2016-01-01

    Cancer cells migrate from the primary tumour into surrounding tissue in order to form metastasis. Cell migration is a highly complex process, which requires continuous remodelling and re-organization of the cytoskeleton and cell-matrix adhesions. Here, we aimed to identify genes controlling aspects of tumour cell migration, including the dynamic organization of cell-matrix adhesions and cellular traction forces. In a siRNA screen targeting most cell adhesion-related genes we identified 200+ genes that regulate size and/or dynamics of cell-matrix adhesions in MCF7 breast cancer cells. In a subsequent secondary screen, the 64 most effective genes were evaluated for growth factor-induced cell migration and validated by tertiary RNAi pool deconvolution experiments. Four validated hits showed significantly enlarged adhesions accompanied by reduced cell migration upon siRNA-mediated knockdown. Furthermore, loss of PPP1R12B, HIPK3 or RAC2 caused cells to exert higher traction forces, as determined by traction force microscopy with elastomeric micropillar post arrays, and led to considerably reduced force turnover. Altogether, we identified genes that co-regulate cell-matrix adhesion dynamics and traction force turnover, thereby modulating overall motility behaviour. PMID:27531518

  4. A Novel High Content Imaging-Based Screen Identifies the Anti-Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion.

    Directory of Open Access Journals (Sweden)

    Magdalena L Circu

    Full Text Available Lysosome trafficking plays a significant role in tumor invasion, a key event for the development of metastasis. Previous studies from our laboratory have demonstrated that the anterograde (outward movement of lysosomes to the cell surface in response to certain tumor microenvironment stimulus, such as hepatocyte growth factor (HGF or acidic extracellular pH (pHe, increases cathepsin B secretion and tumor cell invasion. Anterograde lysosome trafficking depends on sodium-proton exchanger activity and can be reversed by blocking these ion pumps with Troglitazone or EIPA. Since these drugs cannot be advanced into the clinic due to toxicity, we have designed a high-content assay to discover drugs that block peripheral lysosome trafficking with the goal of identifying novel drugs that inhibit tumor cell invasion. An automated high-content imaging system (Cellomics was used to measure the position of lysosomes relative to the nucleus. Among a total of 2210 repurposed and natural product drugs screened, 18 "hits" were identified. One of the compounds identified as an anterograde lysosome trafficking inhibitor was niclosamide, a marketed human anti-helminthic drug. Further studies revealed that niclosamide blocked acidic pHe, HGF, and epidermal growth factor (EGF-induced anterograde lysosome redistribution, protease secretion, motility, and invasion of DU145 castrate resistant prostate cancer cells at clinically relevant concentrations. In an effort to identify the mechanism by which niclosamide prevented anterograde lysosome movement, we found that this drug exhibited no significant effect on the level of ATP, microtubules or actin filaments, and had minimal effect on the PI3K and MAPK pathways. Niclosamide collapsed intralysosomal pH without disruption of the lysosome membrane, while bafilomycin, an agent that impairs lysosome acidification, was also found to induce JLA in our model. Taken together, these data suggest that niclosamide promotes

  5. Engineering aspects of Passavant screening

    International Nuclear Information System (INIS)

    Siddle, K.R.; Sharma, R.K.

    1978-01-01

    The Passavant screen was developed in Europe almost 30 years ago. The Passavant screen is a vertical traveling screen; however, the basic difference between the conventional vertical traveling screen and the Passavant screen is that in the conventional screen water passes through the front screen belt and then the back screen belt, whereas in the Passavant screen the water enters in between the two belts and passes laterally through either of the belts. Thus, theoretically, the screening surface of the Passavant screen is doubled as compared to the same size conventional vertical traveling screen. Various design and operational modifications of the Passavant screen are possible to yield optimum design and performance characteristics which make it amenable to installation at power plants for safe removal of not only fish but also smaller organisms such as fish eggs and larvae. In this paper, details of the screen design and operational characteristics are discussed with notes on how these features can be modified to suit site- and organism-specific requirements

  6. Distributed Persistent Identifiers System Design

    Directory of Open Access Journals (Sweden)

    Pavel Golodoniuc

    2017-06-01

    Full Text Available The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID systems, of which there is a great variety in terms of technical and social implementation, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have, by in large, catered for identifier uniqueness, integrity, and persistence, regardless of the identifier’s application domain. Trustworthiness of these systems has been measured by the criteria first defined by Bütikofer (2009 and further elaborated by Golodoniuc 'et al'. (2016 and Car 'et al'. (2017. Since many PID systems have been largely conceived and developed by a single organisation they faced challenges for widespread adoption and, most importantly, the ability to survive change of technology. We believe that a cause of PID systems that were once successful fading away is the centralisation of support infrastructure – both organisational and computing and data storage systems. In this paper, we propose a PID system design that implements the pillars of a trustworthy system – ensuring identifiers’ independence of any particular technology or organisation, implementation of core PID system functions, separation from data delivery, and enabling the system to adapt for future change. We propose decentralisation at all levels — persistent identifiers and information objects registration, resolution, and data delivery — using Distributed Hash Tables and traditional peer-to-peer networks with information replication and caching mechanisms, thus eliminating the need for a central PID data store. This will increase overall system fault tolerance thus ensuring its trustworthiness. We also discuss important aspects of the distributed system’s governance, such as the notion of the authoritative source and data integrity

  7. A Quantitative RNAi Screen for JNK Modifiers Identifies Pvr as a Novel Regulator of Drosophila Immune Signaling

    Science.gov (United States)

    Bond, David; Foley, Edan

    2009-01-01

    Drosophila melanogaster responds to gram-negative bacterial challenges through the IMD pathway, a signal transduction cassette that is driven by the coordinated activities of JNK, NF-κB and caspase modules. While many modifiers of NF-κB activity were identified in cell culture and in vivo assays, the regulatory apparatus that determines JNK inputs into the IMD pathway is relatively unexplored. In this manuscript, we present the first quantitative screen of the entire genome of Drosophila for novel regulators of JNK activity in the IMD pathway. We identified a large number of gene products that negatively or positively impact on JNK activation in the IMD pathway. In particular, we identified the Pvr receptor tyrosine kinase as a potent inhibitor of JNK activation. In a series of in vivo and cell culture assays, we demonstrated that activation of the IMD pathway drives JNK-dependent expression of the Pvr ligands, Pvf2 and Pvf3, which in turn act through the Pvr/ERK MAP kinase pathway to attenuate the JNK and NF-κB arms of the IMD pathway. Our data illuminate a poorly understood arm of a critical and evolutionarily conserved innate immune response. Furthermore, given the pleiotropic involvement of JNK in eukaryotic cell biology, we believe that many of the novel regulators identified in this screen are of interest beyond immune signaling. PMID:19893628

  8. Mid-upper arm circumference as a screening tool for identifying children with obesity: a 12-country study.

    Science.gov (United States)

    Chaput, J-P; Katzmarzyk, P T; Barnes, J D; Fogelholm, M; Hu, G; Kuriyan, R; Kurpad, A; Lambert, E V; Maher, C; Maia, J; Matsudo, V; Olds, T; Onywera, V; Sarmiento, O L; Standage, M; Tudor-Locke, C; Zhao, P; Tremblay, M S

    2017-12-01

    No studies have examined if mid-upper arm circumference (MUAC) can be an alternative screening tool for obesity in an international sample of children differing widely in levels of human development. Our aim is to determine whether MUAC could be used to identify obesity in children from 12 countries in five major geographic regions of the world. This observational, multinational cross-sectional study included 7337 children aged 9-11 years. Anthropometric measurements were objectively assessed, and obesity was defined according to the World Health Organization reference data. In the total sample, MUAC was strongly correlated with adiposity indicators in both boys and girls (r > 0.86, p obesity was high in both sexes and across study sites (overall area under the curve of 0.97, sensitivity of 95% and specificity of 90%). The MUAC cut-off value to identify obesity was ~25 cm for both boys and girls. In country-specific analyses, the cut-off value to identify obesity ranged from 23.2 cm (boys in South Africa) to 26.2 cm (girls in the UK). Results from this 12-country study suggest that MUAC is a simple and accurate measurement that may be used to identify obesity in children aged 9-11 years. MUAC may be a promising screening tool for obesity in resource-limited settings. © 2016 World Obesity Federation.

  9. A Synthetic Lethality Screen Using a Focused siRNA Library to Identify Sensitizers to Dasatinib Therapy for the Treatment of Epithelial Ovarian Cancer.

    Directory of Open Access Journals (Sweden)

    Harsh B Pathak

    Full Text Available Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC. The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1 was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other

  10. Identifying Disruptive Technologies in Design: Horizon Scanning in the Early Stages of Design

    DEFF Research Database (Denmark)

    Ernstsen, Sidsel Katrine; Thuesen, Christian; Larsen, Laurids Rolighed

    Technology development is accelerating, driving disruption. Design is seen as key differentiator in creating innovative offerings but few design methods consider future technologies explicitly. In this article, we explore how a foresight method, namely horizon scanning, may be applied in a design...... context to anticipate disruption of construction. By means of a 3-step horizon scan, we identify 133 potentially disruptive technologies from across industries. We find that when preparing for disruption, design may benefit from the future-oriented and technology-focused features of horizon scanning....

  11. A Morpholino-based screen to identify novel genes involved in craniofacial morphogenesis

    Science.gov (United States)

    Melvin, Vida Senkus; Feng, Weiguo; Hernandez-Lagunas, Laura; Artinger, Kristin Bruk; Williams, Trevor

    2014-01-01

    BACKGROUND The regulatory mechanisms underpinning facial development are conserved between diverse species. Therefore, results from model systems provide insight into the genetic causes of human craniofacial defects. Previously, we generated a comprehensive dataset examining gene expression during development and fusion of the mouse facial prominences. Here, we used this resource to identify genes that have dynamic expression patterns in the facial prominences, but for which only limited information exists concerning developmental function. RESULTS This set of ~80 genes was used for a high throughput functional analysis in the zebrafish system using Morpholino gene knockdown technology. This screen revealed three classes of cranial cartilage phenotypes depending upon whether knockdown of the gene affected the neurocranium, viscerocranium, or both. The targeted genes that produced consistent phenotypes encoded proteins linked to transcription (meis1, meis2a, tshz2, vgll4l), signaling (pkdcc, vlk, macc1, wu:fb16h09), and extracellular matrix function (smoc2). The majority of these phenotypes were not altered by reduction of p53 levels, demonstrating that both p53 dependent and independent mechanisms were involved in the craniofacial abnormalities. CONCLUSIONS This Morpholino-based screen highlights new genes involved in development of the zebrafish craniofacial skeleton with wider relevance to formation of the face in other species, particularly mouse and human. PMID:23559552

  12. Rationale, design, and results of the first screening round of a comprehensive, register-based, Chlamydia screening implementation programme in the Netherlands

    Directory of Open Access Journals (Sweden)

    Koekenbier Rik H

    2010-10-01

    Full Text Available Abstract Background Implementing Chlamydia trachomatis screening in the Netherlands has been a point of debate for several years. The National Health Council advised against implementing nationwide screening until additional data collected from a pilot project in 2003 suggested that screening by risk profiles could be effective. A continuous increase in infections recorded in the national surveillance database affirmed the need for a more active approach. Here, we describe the rationale, design, and implementation of a Chlamydia screening demonstration programme. Methods A systematic, selective, internet-based Chlamydia screening programme started in April 2008. Letters are sent annually to all 16 to 29-year-old residents of Amsterdam, Rotterdam, and selected municipalities of South Limburg. The letters invite sexually active persons to login to http://www.chlamydiatest.nl with a personal code and to request a test kit. In the lower prevalence area of South Limburg, test kits can only be requested if the internet-based risk assessment exceeds a predefined value. Results We sent invitations to 261,025 people in the first round. One-fifth of the invitees requested a test kit, of whom 80% sent in a sample for testing. The overall positivity rate was 4.2%. Conclusions This programme advances Chlamydia control activities in the Netherlands. Insight into the feasibility, effectiveness, cost-effectiveness, and impact of this large-scale screening programme will determine whether the programme will be implemented nationally.

  13. Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Taddei Kevin

    2010-01-01

    Full Text Available Abstract Background The low-density lipoprotein receptor related protein 1 (LRP1 has been implicated in Alzheimer's disease (AD but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1. Results We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split-ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP, which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b. Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two-hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human APOE4 gene showed significant differences in Nyggf4 expression. Conclusions These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered

  14. High-throughput screening in niche-based assay identifies compounds to target preleukemic stem cells

    Science.gov (United States)

    Gerby, Bastien; Veiga, Diogo F.T.; Krosl, Jana; Nourreddine, Sami; Ouellette, Julianne; Haman, André; Lavoie, Geneviève; Fares, Iman; Tremblay, Mathieu; Litalien, Véronique; Ottoni, Elizabeth; Geoffrion, Dominique; Maddox, Paul S.; Chagraoui, Jalila; Hébert, Josée; Sauvageau, Guy; Kwok, Benjamin H.; Roux, Philippe P.

    2016-01-01

    Current chemotherapies for T cell acute lymphoblastic leukemia (T-ALL) efficiently reduce tumor mass. Nonetheless, disease relapse attributed to survival of preleukemic stem cells (pre-LSCs) is associated with poor prognosis. Herein, we provide direct evidence that pre-LSCs are much less chemosensitive to existing chemotherapy drugs than leukemic blasts because of a distinctive lower proliferative state. Improving therapies for T-ALL requires the development of strategies to target pre-LSCs that are absolutely dependent on their microenvironment. Therefore, we designed a robust protocol for high-throughput screening of compounds that target primary pre-LSCs maintained in a niche-like environment, on stromal cells that were engineered for optimal NOTCH1 activation. The multiparametric readout takes into account the intrinsic complexity of primary cells in order to specifically monitor pre-LSCs, which were induced here by the SCL/TAL1 and LMO1 oncogenes. We screened a targeted library of compounds and determined that the estrogen derivative 2-methoxyestradiol (2-ME2) disrupted both cell-autonomous and non–cell-autonomous pathways. Specifically, 2-ME2 abrogated pre-LSC viability and self-renewal activity in vivo by inhibiting translation of MYC, a downstream effector of NOTCH1, and preventing SCL/TAL1 activity. In contrast, normal hematopoietic stem/progenitor cells remained functional. These results illustrate how recapitulating tissue-like properties of primary cells in high-throughput screening is a promising avenue for innovation in cancer chemotherapy. PMID:27797342

  15. A genetic screen in Myxococcus xanthus identifies mutants that uncouple outer membrane exchange from a downstream cellular response.

    Science.gov (United States)

    Dey, Arup; Wall, Daniel

    2014-12-01

    Upon physical contact with sibling cells, myxobacteria transiently fuse their outer membranes (OMs) and exchange OM proteins and lipids. From previous work, TraA and TraB were identified to be essential factors for OM exchange (OME) in donor and recipient cells. To define the genetic complexity of OME, we carried out a comprehensive forward genetic screen. The screen was based on the observation that Myxococcus xanthus nonmotile cells, by a Tra-dependent mechanism, block swarm expansion of motile cells when mixed. Thus, mutants defective in OME or a downstream responsive pathway were readily identified as escape flares from mixed inocula seeded on agar. This screen was surprisingly powerful, as we found >50 mutants defective in OME. Importantly, all of the mutations mapped to the traAB operon, suggesting that there may be few, if any, proteins besides TraA and TraB directly required for OME. We also found a second and phenotypically different class of mutants that exhibited wild-type OME but were defective in a responsive pathway. This pathway is postulated to control inner membrane homeostasis by covalently attaching amino acids to phospholipids. The identified proteins are homologous to the Staphylococcus aureus MprF protein, which is involved in membrane adaptation and antibiotic resistance. Interestingly, we also found that a small number of nonmotile cells were sufficient to block the swarming behavior of a large gliding-proficient population. This result suggests that an OME-derived signal could be amplified from a few nonmotile producers to act on many responder cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  16. Microclimate evaluation of a new design of insect-proof screens in a Mediterranean greenhouse

    Directory of Open Access Journals (Sweden)

    Alejandro Lopez-Martinez

    2014-05-01

    Full Text Available This work studies natural ventilation in a Mediterranean greenhouse, comparing a new experimental screen of 13×30 threads cm-2 (porosity 39.0% with a commercial control screen of 10×20 threads cm-2 (porosity 33.5%. In addition, both screens were tested in a wind tunnel to determine the discharge coefficients Cd of the greenhouse side and roof vents, which proved to be 0.16 for the commercial control screen and 0.18 for the experimental screen at both vents. These values represent a theoretical increase of 11% (Cd,φ-10×20 /Cd,φ-13×30 = 0.89 in the natural ventilation capacity of the greenhouse when the experimental screen is used. The greenhouse was divided into two separate sections allowing us to analyze natural ventilation in both sectors simultaneously. Air velocity was measured in the lateral and roof vents with two 3D and six 2D sonic anemometers. Using the commercial control screen there was an average reduction of 16% in ventilation rate, and an average increase of 0.5ºC in the average indoor air temperature, compared to the experimental screen. In addition, the ventilation efficiency ηT was higher with the experimental screen (mean value of 0.9 than with the control (mean value 0.6. We have designed an experimental insect-proof screen (13×30 threads cm-2 with smaller thread diameter, higher thread density, smaller pore size and higher porosity than are used in most commercial meshes. All of these factors promote natural ventilation and improve the greenhouse microclimate.

  17. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

    Science.gov (United States)

    Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

    2013-01-01

    Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

  18. A CRISPR-Based Screen Identifies Genes Essential for West-Nile-Virus-Induced Cell Death.

    Science.gov (United States)

    Ma, Hongming; Dang, Ying; Wu, Yonggan; Jia, Gengxiang; Anaya, Edgar; Zhang, Junli; Abraham, Sojan; Choi, Jang-Gi; Shi, Guojun; Qi, Ling; Manjunath, N; Wu, Haoquan

    2015-07-28

    West Nile virus (WNV) causes an acute neurological infection attended by massive neuronal cell death. However, the mechanism(s) behind the virus-induced cell death is poorly understood. Using a library containing 77,406 sgRNAs targeting 20,121 genes, we performed a genome-wide screen followed by a second screen with a sub-library. Among the genes identified, seven genes, EMC2, EMC3, SEL1L, DERL2, UBE2G2, UBE2J1, and HRD1, stood out as having the strongest phenotype, whose knockout conferred strong protection against WNV-induced cell death with two different WNV strains and in three cell lines. Interestingly, knockout of these genes did not block WNV replication. Thus, these appear to be essential genes that link WNV replication to downstream cell death pathway(s). In addition, the fact that all of these genes belong to the ER-associated protein degradation (ERAD) pathway suggests that this might be the primary driver of WNV-induced cell death. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Attitudes toward newborn screening for cytomegalovirus infection.

    Science.gov (United States)

    Din, Erica S; Brown, Cedric J; Grosse, Scott D; Wang, Chengbin; Bialek, Stephanie R; Ross, Danielle S; Cannon, Michael J

    2011-12-01

    Newborns are not routinely screened for cytomegalovirus (CMV), the leading infectious cause of developmental disability. Congenital CMV satisfies a number of criteria for inclusion in newborn screening, and screening potentially offers benefits. Screening could also introduce harms such as anxiety and unnecessary costs for the families of the substantial proportion of CMV-infected children who never develop CMV-related disabilities. Our objective was to assess attitudes toward newborn screening for CMV. We analyzed responses to 5 statements about CMV and newborn screening from 3922 participants in the 2009 HealthStyles survey, a national mail survey designed to include a group similar to the US population with respect to gender, age, race/ethnicity, income, and household size. Two-step cluster analysis was performed to identify clusters of parental attitudes. The majority of respondents strongly or somewhat agreed that they would want to have their newborn tested for CMV even if it was not performed routinely (84%), they had to pay $20 (87%), or CMV-related problems never developed (84%). Nearly half (47%) of them "would worry that the CMV test would lead to unneeded doctor visits and expenses," and 32% "think CMV problems are too rare to worry about." Three clusters of parent respondents were identified on the basis of their attitudes toward CMV screening: "strongly in favor" (31%), "moderately in favor" (49%), and "weakly opposed" (20%). Among most parents, costs, worry, and anxiety associated with newborn screening for CMV would be acceptable. Although attitudes were generally favorable, a minority of the parents were weakly opposed to newborn screening for CMV.

  20. Rationale and design of Mi-CARE: The mile square colorectal cancer screening, awareness and referral and education project.

    Science.gov (United States)

    Buscemi, Joanna; Miguel, Yazmin San; Tussing-Humphreys, Lisa; Watts, Elizabeth A; Fitzgibbon, Marian L; Watson, Karriem; Winn, Robert A; Matthews, Kameron L; Molina, Yamile

    2017-01-01

    Although colorectal cancer (CRC) is largely preventable through identification of pre-cancerous polyps through various screening modalities, morbidity and mortality rates remain a challenge, especially in African-American, Latino, low-income and uninsured/underinsured patients. Barriers to screening include cost, access to health care facilities, lack of recommendation to screen, and psychosocial factors such as embarrassment, fear of the test, anxiety about testing preparation and fear of a cancer diagnosis. Various intervention approaches to improve CRC screening rates have been developed. However, comparative effectiveness research (CER) to investigate the relative performance of different approaches has been understudied, especially across different real-life practice settings. Assessment of differential efficacy across diverse vulnerable populations is also lacking. The current paper describes the rationale and design for the Mile Square Colorectal Cancer Screening, Awareness and Referral and Education Project (Mi-CARE), which aims to increase CRC screening rates in 3 clinics of a large Federally Qualified Health Center (FQHC) by reducing prominent barriers to screening for low-income, minority and underserved patients. Patients attending these clinics will receive one of three interventions to increase screening uptake: lay patient navigator (LPN)-based navigation, provider level navigation, or mailed birthday CRC screening reminders. The design of our program allows for comparison of the effectiveness of the tailored interventions across sites and patient populations. Data from Mi-CARE may help to inform the dissemination of tailored interventions across FQHCs to reduce health disparities in CRC. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Designing a Pediatric Severe Sepsis Screening Tool

    Directory of Open Access Journals (Sweden)

    Robert eSepanski

    2014-06-01

    Full Text Available We sought to create a screening tool with improved predictive value for pediatric severe sepsis and septic shock that can be incorporated into the electronic medical record and actively screen all patients arriving at a pediatric Emergency Department (ED. Gold standard severe sepsis cases were identified using a combination of coded discharge diagnosis and physician chart review from 7,402 children who visited a pediatric ED over two months. The tool’s identification of severe sepsis was initially based on International Consensus Conference on Pediatric Sepsis (ICCPS parameters that were refined by an iterative, virtual process that allowed us to propose successive changes in sepsis detection parameters in order to optimize the tool’s predictive value based on receiver operating curve (ROC characteristics. Age-specific normal and abnormal values for heart rate (HR and respiratory rate (RR were empirically derived from 143,603 children seen in a second pediatric ED over three years. Univariate analyses were performed for each measure in the tool to assess its association with severe sepsis and to characterize it as an early or late indicator of severe sepsis. A split-sample was used to validate the final, optimized tool. The final tool incorporated age-specific thresholds for abnormal HR and RR and employed a linear temperature correction for each category. The final tool’s positive predictive value was 48.7%, a significant, nearly three-fold improvement over the original ICCPS tool. False positive Systemic Inflammatory Response Syndrome (SIRS identifications were nearly six-fold lower.

  2. To twist or poke? A method for identifying usability issues with the rotary controller and touch screen for control of in-vehicle information systems.

    Science.gov (United States)

    Harvey, Catherine; Stanton, Neville A; Pickering, Carl A; McDonald, Mike; Zheng, Pengjun

    2011-07-01

    In-vehicle information systems (IVIS) can be controlled by the user via direct or indirect input devices. In order to develop the next generation of usable IVIS, designers need to be able to evaluate and understand the usability issues associated with these two input types. The aim of this study was to investigate the effectiveness of a set of empirical usability evaluation methods for identifying important usability issues and distinguishing between the IVIS input devices. A number of usability issues were identified and their causal factors have been explored. These were related to the input type, the structure of the menu/tasks and hardware issues. In particular, the translation between inputs and on-screen actions and a lack of visual feedback for menu navigation resulted in lower levels of usability for the indirect device. This information will be useful in informing the design of new IVIS, with improved usability. STATEMENT OF RELEVANCE: This paper examines the use of empirical methods for distinguishing between direct and indirect IVIS input devices and identifying usability issues. Results have shown that the characteristics of indirect input devices produce more serious usability issues, compared with direct devices and can have a negative effect on the driver-vehicle interaction.

  3. High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes in Bacillus subtilis.

    Science.gov (United States)

    Meeske, Alexander J; Rodrigues, Christopher D A; Brady, Jacqueline; Lim, Hoong Chuin; Bernhardt, Thomas G; Rudner, David Z

    2016-01-01

    The differentiation of the bacterium Bacillus subtilis into a dormant spore is among the most well-characterized developmental pathways in biology. Classical genetic screens performed over the past half century identified scores of factors involved in every step of this morphological process. More recently, transcriptional profiling uncovered additional sporulation-induced genes required for successful spore development. Here, we used transposon-sequencing (Tn-seq) to assess whether there were any sporulation genes left to be discovered. Our screen identified 133 out of the 148 genes with known sporulation defects. Surprisingly, we discovered 24 additional genes that had not been previously implicated in spore formation. To investigate their functions, we used fluorescence microscopy to survey early, middle, and late stages of differentiation of null mutants from the B. subtilis ordered knockout collection. This analysis identified mutants that are delayed in the initiation of sporulation, defective in membrane remodeling, and impaired in spore maturation. Several mutants had novel sporulation phenotypes. We performed in-depth characterization of two new factors that participate in cell-cell signaling pathways during sporulation. One (SpoIIT) functions in the activation of σE in the mother cell; the other (SpoIIIL) is required for σG activity in the forespore. Our analysis also revealed that as many as 36 sporulation-induced genes with no previously reported mutant phenotypes are required for timely spore maturation. Finally, we discovered a large set of transposon insertions that trigger premature initiation of sporulation. Our results highlight the power of Tn-seq for the discovery of new genes and novel pathways in sporulation and, combined with the recently completed null mutant collection, open the door for similar screens in other, less well-characterized processes.

  4. High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes in Bacillus subtilis

    Science.gov (United States)

    Brady, Jacqueline; Lim, Hoong Chuin; Bernhardt, Thomas G.; Rudner, David Z.

    2016-01-01

    The differentiation of the bacterium Bacillus subtilis into a dormant spore is among the most well-characterized developmental pathways in biology. Classical genetic screens performed over the past half century identified scores of factors involved in every step of this morphological process. More recently, transcriptional profiling uncovered additional sporulation-induced genes required for successful spore development. Here, we used transposon-sequencing (Tn-seq) to assess whether there were any sporulation genes left to be discovered. Our screen identified 133 out of the 148 genes with known sporulation defects. Surprisingly, we discovered 24 additional genes that had not been previously implicated in spore formation. To investigate their functions, we used fluorescence microscopy to survey early, middle, and late stages of differentiation of null mutants from the B. subtilis ordered knockout collection. This analysis identified mutants that are delayed in the initiation of sporulation, defective in membrane remodeling, and impaired in spore maturation. Several mutants had novel sporulation phenotypes. We performed in-depth characterization of two new factors that participate in cell–cell signaling pathways during sporulation. One (SpoIIT) functions in the activation of σE in the mother cell; the other (SpoIIIL) is required for σG activity in the forespore. Our analysis also revealed that as many as 36 sporulation-induced genes with no previously reported mutant phenotypes are required for timely spore maturation. Finally, we discovered a large set of transposon insertions that trigger premature initiation of sporulation. Our results highlight the power of Tn-seq for the discovery of new genes and novel pathways in sporulation and, combined with the recently completed null mutant collection, open the door for similar screens in other, less well-characterized processes. PMID:26735940

  5. Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

    DEFF Research Database (Denmark)

    Wittig-Blaich, Stephanie; Wittig, Rainer; Schmidt, Steffen

    2017-01-01

    Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technolo......Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few...... technologies are available for the systematic downstream evaluation of these results to identify novel starting points of future cancer therapies. We improved and extended a site-specific recombination-based system for systematic analysis of the individual functions of a large number of candidate genes......, a library of 108 isogenic melanoma cell lines was constructed and 8 genes were identified that significantly reduced viability in a discovery screen and in an independent validation screen. Here, we demonstrate the broad applicability of this recombination-based method and we proved its potential...

  6. An RNAi-mediated screen identifies novel targets for next-generation antiepileptic drugs based on increased expression of the homeostatic regulator pumilio.

    Science.gov (United States)

    Lin, Wei-Hsiang; He, Miaomiao; Fan, Yuen Ngan; Baines, Richard A

    2018-05-02

    Despite availability of a diverse range of anti-epileptic drugs (AEDs), only about two-thirds of epilepsy patients respond well to drug treatment. Thus, novel targets are required to catalyse the design of next-generation AEDs. Manipulation of neuron firing-rate homoeostasis, through enhancing Pumilio (Pum) activity, has been shown to be potently anticonvulsant in Drosophila. In this study, we performed a genome-wide RNAi screen in S2R + cells, using a luciferase-based dPum activity reporter and identified 1166 genes involved in dPum regulation. Of these genes, we focused on 699 genes that, on knock-down, potentiate dPum activity/expression. Of this subgroup, 101 genes are activity-dependent based on comparison with genes previously identified as activity-dependent by RNA-sequencing. Functional cluster analysis shows these genes are enriched in pathways involved in DNA damage, regulation of cell cycle and proteasomal protein catabolism. To test for anticonvulsant activity, we utilised an RNA-interference approach in vivo. RNAi-mediated knockdown showed that 57/101 genes (61%) are sufficient to significantly reduce seizure duration in the characterized seizure mutant, para bss . We further show that chemical inhibitors of protein products of some of the genes targeted are similarly anticonvulsant. Finally, to establish whether the anticonvulsant activity of identified compounds results from increased dpum transcription, we performed a luciferase-based assay to monitor dpum promoter activity. Third instar larvae exposed to sodium fluoride, gemcitabine, metformin, bestatin, WP1066 or valproic acid all showed increased dpum promoter activity. Thus, this study validates Pum as a favourable target for AED design and, moreover, identifies a number of lead compounds capable of increasing the expression of this homeostatic regulator.

  7. Patient-completed or symptom-based screening tools for endometriosis: a scoping review.

    Science.gov (United States)

    Surrey, Eric; Carter, Cathryn M; Soliman, Ahmed M; Khan, Shahnaz; DiBenedetti, Dana B; Snabes, Michael C

    2017-08-01

    The objective of this review was to evaluate existing patient-completed screening questionnaires and/or symptom-based predictive models with respect to their potential for use as screening tools for endometriosis in adult women. Validated instruments were of particular interest. We conducted structured searches of PubMed and targeted searches of the gray literature to identify studies reporting on screening instruments used in endometriosis. Studies were screened according to inclusion and exclusion criteria that followed the PICOS (population, intervention, comparison, outcomes, study design) framework. A total of 16 studies were identified, of which 10 described measures for endometriosis in general, 2 described measures for endometriosis at specific sites, and 4 described measures for deep-infiltrating endometriosis. Only 1 study evaluated a questionnaire that was solely patient-completed. Most measures required physician, imaging, or laboratory assessments in addition to patient-completed questionnaires, and several measures relied on complex scoring. Validation for use as a screening tool in adult women with potential endometriosis was lacking in all studies, as most studies focused on diagnosis versus screening. This literature review did not identify any fully validated, symptom-based, patient-reported questionnaires for endometriosis screening in adult women.

  8. Investigating Effects of Screen Layout Elements on Interface and Screen Design Aesthetics

    Directory of Open Access Journals (Sweden)

    Ahamed Altaboli

    2011-01-01

    Full Text Available A recent study suggested the use of the screen layout elements of balance, unity, and sequence as a part of a computational model of interface aesthetics. It is argued that these three elements are the most contributed terms in the model. In the current study, a controlled experiment was designed and conducted to systematically investigate effects of these three elements (balance, unity, and sequence on the perceived interface aesthetics. Results showed that the three elements have significant effects on the perceived interface aesthetics. Significant interactions were also found among the three elements. A regression model relating the perceived visual aesthetics to the three elements was constructed. When validating the model using standard questionnaire scores of real web pages, high correlations were found between the values computed by the model and scores of questionnaire items related to visual layout of the web pages, indicating that layout-based measures are good at assessing the classical dimension of website aesthetics.

  9. Advances in Predictive Toxicology for Discovery Safety through High Content Screening.

    Science.gov (United States)

    Persson, Mikael; Hornberg, Jorrit J

    2016-12-19

    High content screening enables parallel acquisition of multiple molecular and cellular readouts. In particular the predictive toxicology field has progressed from the advances in high content screening, as more refined end points that report on cellular health can be studied in combination, at the single cell level, and in relatively high throughput. Here, we discuss how high content screening has become an essential tool for Discovery Safety, the discipline that integrates safety and toxicology in the drug discovery process to identify and mitigate safety concerns with the aim to design drug candidates with a superior safety profile. In addition to customized mechanistic assays to evaluate target safety, routine screening assays can be applied to identify risk factors for frequently occurring organ toxicities. We discuss the current state of high content screening assays for hepatotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, and genotoxicity, including recent developments and current advances.

  10. A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance

    DEFF Research Database (Denmark)

    Menzel, Tobias; Nähse-Kumpf, Viola; Kousholt, Arne Nedergaard

    2011-01-01

    To identify key connections between DNA-damage repair and checkpoint pathways, we performed RNA interference screens for regulators of the ionizing radiation-induced G2 checkpoint, and we identified the breast cancer gene BRCA2. The checkpoint was also abrogated following depletion of PALB2......, an interaction partner of BRCA2. BRCA2 and PALB2 depletion led to premature checkpoint abrogation and earlier activation of the AURORA A-PLK1 checkpoint-recovery pathway. These results indicate that the breast cancer tumour suppressors and homologous recombination repair proteins BRCA2 and PALB2 are main...

  11. Efficient high-throughput biological process characterization: Definitive screening design with the ambr250 bioreactor system.

    Science.gov (United States)

    Tai, Mitchell; Ly, Amanda; Leung, Inne; Nayar, Gautam

    2015-01-01

    The burgeoning pipeline for new biologic drugs has increased the need for high-throughput process characterization to efficiently use process development resources. Breakthroughs in highly automated and parallelized upstream process development have led to technologies such as the 250-mL automated mini bioreactor (ambr250™) system. Furthermore, developments in modern design of experiments (DoE) have promoted the use of definitive screening design (DSD) as an efficient method to combine factor screening and characterization. Here we utilize the 24-bioreactor ambr250™ system with 10-factor DSD to demonstrate a systematic experimental workflow to efficiently characterize an Escherichia coli (E. coli) fermentation process for recombinant protein production. The generated process model is further validated by laboratory-scale experiments and shows how the strategy is useful for quality by design (QbD) approaches to control strategies for late-stage characterization. © 2015 American Institute of Chemical Engineers.

  12. Histology Verification Demonstrates That Biospectroscopy Analysis of Cervical Cytology Identifies Underlying Disease More Accurately than Conventional Screening: Removing the Confounder of Discordance

    Science.gov (United States)

    Gajjar, Ketan; Ahmadzai, Abdullah A.; Valasoulis, George; Trevisan, Júlio; Founta, Christina; Nasioutziki, Maria; Loufopoulos, Aristotelis; Kyrgiou, Maria; Stasinou, Sofia Melina; Karakitsos, Petros; Paraskevaidis, Evangelos; Da Gama-Rose, Bianca; Martin-Hirsch, Pierre L.; Martin, Francis L.

    2014-01-01

    Background Subjective visual assessment of cervical cytology is flawed, and this can manifest itself by inter- and intra-observer variability resulting ultimately in the degree of discordance in the grading categorisation of samples in screening vs. representative histology. Biospectroscopy methods have been suggested as sensor-based tools that can deliver objective assessments of cytology. However, studies to date have been apparently flawed by a corresponding lack of diagnostic efficiency when samples have previously been classed using cytology screening. This raises the question as to whether categorisation of cervical cytology based on imperfect conventional screening reduces the diagnostic accuracy of biospectroscopy approaches; are these latter methods more accurate and diagnose underlying disease? The purpose of this study was to compare the objective accuracy of infrared (IR) spectroscopy of cervical cytology samples using conventional cytology vs. histology-based categorisation. Methods Within a typical clinical setting, a total of n = 322 liquid-based cytology samples were collected immediately before biopsy. Of these, it was possible to acquire subsequent histology for n = 154. Cytology samples were categorised according to conventional screening methods and subsequently interrogated employing attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. IR spectra were pre-processed and analysed using linear discriminant analysis. Dunn’s test was applied to identify the differences in spectra. Within the diagnostic categories, histology allowed us to determine the comparative efficiency of conventional screening vs. biospectroscopy to correctly identify either true atypia or underlying disease. Results Conventional cytology-based screening results in poor sensitivity and specificity. IR spectra derived from cervical cytology do not appear to discriminate in a diagnostic fashion when categories were based on conventional screening

  13. Macrophage replication screen identifies a novel Francisella hydroperoxide resistance protein involved in virulence.

    Directory of Open Access Journals (Sweden)

    Anna C Llewellyn

    Full Text Available Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Recently, genome-wide screens have identified Francisella genes required for virulence in mice. However, the mechanisms by which most of the corresponding proteins contribute to pathogenesis are still largely unknown. To further elucidate the roles of these virulence determinants in Francisella pathogenesis, we tested whether each gene was required for replication of the model pathogen F. novicida within macrophages, an important virulence trait. Fifty-three of the 224 genes tested were involved in intracellular replication, including many of those within the Francisella pathogenicity island (FPI, validating our results. Interestingly, over one third of the genes identified are annotated as hypothetical, indicating that F. novicida likely utilizes novel virulence factors for intracellular replication. To further characterize these virulence determinants, we selected two hypothetical genes to study in more detail. As predicted by our screen, deletion mutants of FTN_0096 and FTN_1133 were attenuated for replication in macrophages. The mutants displayed differing levels of attenuation in vivo, with the FTN_1133 mutant being the most attenuated. FTN_1133 has sequence similarity to the organic hydroperoxide resistance protein Ohr, an enzyme involved in the bacterial response to oxidative stress. We show that FTN_1133 is required for F. novicida resistance to, and degradation of, organic hydroperoxides as well as resistance to the action of the NADPH oxidase both in macrophages and mice. Furthermore, we demonstrate that F. holarctica LVS, a strain derived from a highly virulent human pathogenic species of Francisella, also requires this protein for organic hydroperoxide resistance as well as replication in macrophages and mice. This study expands our knowledge of Francisella's largely uncharacterized intracellular lifecycle and

  14. The usefulness and feasibility of a screening instrument to identify psychosocial problems in patients receiving curative radiotherapy: a process evaluation

    International Nuclear Information System (INIS)

    Braeken, Anna PBM; Kempen, Gertrudis IJM; Eekers, Daniëlle; Gils, Francis CJM van; Houben, Ruud MA; Lechner, Lilian

    2011-01-01

    Psychosocial problems in cancer patients are often unrecognized and untreated due to the low awareness of the existence of these problems or pressures of time. The awareness of the need to identify psychosocial problems in cancer patients is growing and has affected the development of screening instruments. This study explored the usefulness and feasibility of using a screening instrument (SIPP: Screening Inventory of Psychosocial Problems) to identify psychosocial problems in cancer patients receiving curative radiotherapy treatment (RT). The study was conducted in a radiation oncology department in the Netherlands. Several methods were used to document the usefulness and feasibility of the SIPP. Data were collected using self-report questionnaires completed by seven radiotherapists and 268 cancer patients. Regarding the screening procedure 33 patients were offered to consult a psychosocial care provider (e.g. social worker, psychologist) during the first consultation with their radiotherapist. Of these patients, 31 patients suffered from at least sub-clinical symptoms and two patients hardly suffered from any symptoms. Patients' acceptance rate 63.6% (21/33) was high. Patients were positive about the content of the SIPP (mean scores vary from 8.00 to 8.88, out of a range between 0 and 10) and about the importance of discussing items of the SIPP with their radiotherapist (mean score = 7.42). Radiotherapists' perspectives about the contribution of the SIPP to discuss the different psychosocial problems were mixed (mean scores varied from 3.17 to 4.67). Patients were more positive about discussing items of the SIPP if the radiotherapists had positive attitudes towards screening and discussing psychosocial problems. The screening procedure appeared to be feasible in a radiotherapy department. In general, patients' perspectives were at least moderate. Radiotherapists considered the usefulness and feasibility of the SIPP generally to be lower, but their

  15. Walkthrough screening evaluation field guide

    International Nuclear Information System (INIS)

    Eder, S.J.; Eli, M.W.; Salmon, M.W.

    1993-11-01

    The US Department of Energy (DOE) has a large inventory of existing facilities. Many of these facilities were not designed and constructed to current natural phenomena hazard (NPH) criteria. The NPH events include earthquakes, extreme winds and tornadoes, and floods. DOE Order 5480.28 establishes policy and requirements for NPH mitigation for DOE facilities. DOE is conducting a multiyear project to develop evaluation guidelines for assessing the condition and determining the need for upgrades at DOE facilities. One element of the NPH evaluation guidelines' development involves the existing systems and components at DOE facilities. This effort is described in detail in a cited reference. In the interim period prior to availability of the final guidelines, DOE facilities are encouraged to implement an NPH walk through screening evaluation process by which systems and components that need attention can be rapidly identified. Guidelines for conducting the walk through screening evaluations are contained herein. The result of the NPH walk through screening evaluation should be a prioritized list of systems and components that need further action. Simple and inexpensive fixes for items identified in the walk through as marginal or inadequate should be implemented without further study. By implementing an NPH walk through screening evaluation, DOE facilities may realize significant reduction in risk from NPH in the short term

  16. Performance-oriented packaging: A guide to identifying and designing. Identifying and designing hazardous materials packaging for compliance with post HM-181 DOT Regulations

    International Nuclear Information System (INIS)

    1994-08-01

    With the initial publication of Docket HM-181 (hereafter referred to as HM-181), the U.S. Department of Energy (DOE), Headquarters, Transportation Management Division decided to produce guidance to help the DOE community transition to performance-oriented packagings (POP). As only a few individuals were familiar with the new requirements, elementary guidance was desirable. The decision was to prepare the guidance at a level easily understood by a novice to regulatory requirements. This document identifies design development strategies for use in obtaining performance-oriented packagings that are not readily available commercially. These design development strategies will be part of the methodologies for compliance with post HM-181 U.S. Department of Transportation (DOT) packaging regulations. This information was prepared for use by the DOE and its contractors. The document provides guidance for making decisions associated with designing performance-oriented packaging, and not for identifying specific material or fabrication design details. It does provide some specific design considerations. Having a copy of the regulations handy when reading this document is recommended to permit a fuller understanding of the requirements impacting the design effort. While this document is not written for the packaging specialist, it does contain guidance important to those not familiar with the new POP requirements

  17. Material characterisation and preliminary mechanical design for the HL-LHC shielded beam screens operating at cryogenic temperatures

    CERN Document Server

    Garion, C; Koettig, T; Machiocha, W; Morrone, M

    2015-01-01

    The High Luminosity LHC project (HL-LHC) aims at increasing the luminosity (rate of collisions) in the Large Hadron Collider (LHC) experiments by a factor of 10 beyond the original design value (from 300 to 3000 fb-1). It relies on new superconducting magnets, installed close to the interaction points, equipped with new beam screen. This component has to ensure the vacuum performance together with shielding the cold mass from physics debris and screening the cold bore cryogenic system from beam induced heating. The beam screen operates in the range 40-60 K whereas the magnet cold bore temperature is 1.9 K. A tungsten-based material is used to absorb the energy of particles. In this paper, measurements of the mechanical and physical properties of such tungsten material are shown at room and cryogenic temperature. In addition, the design and the thermal mechanical behaviour of the beam screen assembly are presented also. They include the heat transfer from the tungsten absorbers to the cooling pipes and the sup...

  18. Two-field photography can identify patients with vision-threatening diabetic retinopathy - A screening approach in the primary care setting

    NARCIS (Netherlands)

    Stellingwerf, C; Hardus, PLLJ; Hooymans, JMM

    2001-01-01

    OBJECTIVE - To compare the effectiveness of two 45 degrees photographic fields per eye in the screening for diabetic retinopathy with the routine ophthalmologist's examination and to study the effectiveness of visual acuity measurement in the detection of diabetic macular edema, RESEARCH DESIGN AND

  19. cDNA Library Screening Identifies Protein Interactors Potentially Involved in Non-telomeric Roles of Arabidopsis Telomerase

    Directory of Open Access Journals (Sweden)

    Ladislav eDokládal

    2015-11-01

    Full Text Available Telomerase-reverse transcriptase (TERT plays an essential catalytic role in maintaining telomeres. However, in animal systems telomerase plays additional non-telomeric functional roles. We previously screened an Arabidopsis cDNA library for proteins that interact with the C-terminal extension (CTE TERT domain and identified a nuclear-localized protein that contains a RNA recognition motif (RRM. This RRM-protein forms homodimers in both plants and yeast. Mutation of the gene encoding the RRM-protein had no detectable effect on plant growth and development, nor did it affect telomerase activity or telomere length in vivo, suggesting a non-telomeric role for TERT/RRM-protein complexes. The gene encoding the RRM-protein is highly expressed in leaf and reproductive tissues. We further screened an Arabidopsis cDNA library for proteins that interact with the RRM-protein and identified five interactors. These proteins are involved in numerous non-telomere-associated cellular activities. In plants, the RRM-protein, both alone and in a complex with its interactors, localizes to nuclear speckles. Transcriptional analyses in wild-type and rrm mutant plants, as well as transcriptional co-analyses, suggest that TERT, the RRM-protein, and the RRM-protein interactors may play important roles in non-telomeric cellular functions.

  20. Can a Risk Factor Based Approach Safely Reduce Screening for Retinopathy of Prematurity?

    Directory of Open Access Journals (Sweden)

    K. M. Friddle

    2017-01-01

    Full Text Available Objective. Current American retinopathy of prematurity (ROP screening guidelines is imprecise for infants ≥ 30 weeks with birth weights between 1500 and 2000 g. Our objective was to evaluate a risk factor based approach for screening premature infants at low risk for severe ROP. Study Design. We performed a 13-year review from Intermountain Health Care (IHC data. All neonates born at ≤32 weeks were reviewed to determine ROP screening and/or development of severe ROP. Severe ROP was defined by stage ≥ 3 or need for laser therapy. Regression analysis was used to identify significant risk factors for severe ROP. Results. We identified 4607 neonates ≤ 32 weeks gestation. Following exclusion for death, with no retinal exam or incomplete data, 2791 (61% were included in the study. Overall, severe ROP occurred in 260 (9.3%, but only 11/1601 ≥ 29 weeks (0.7%. All infants with severe ROP ≥ 29 weeks had at least 2 identified ROP risk factors. Implementation of this risk based screening strategy to the IHC population over the timeline of this study would have eliminated screening in 21% (343/1601 of the screened population. Conclusions. Limiting ROP screening for infants ≥ 29 and ≤ 32 weeks to only those with clinical risk factors could significantly reduce screening exams while identifying all infants with severe ROP.

  1. Combinatorial drug screening identifies Ewing sarcoma-specific sensitivities

    OpenAIRE

    Radic-Sarikas, Branka; Tsafou, Kalliopi P.; Emdal, Kristina B.; Papamarkou, Theodore; Huber, Kilian V.M.; Mutz, Cornelia; Toretsky, Jeffrey A.; Bennett, Keiryn L.; Olsen, Jesper V.; Brunak, Søren; Kovar, Heinrich; Superti-Furga, Giulio

    2017-01-01

    Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three p...

  2. Identifying harmful drinking using a single screening question in a psychiatric consultation-liaison population.

    Science.gov (United States)

    Massey, Suena H; Norris, Lorenzo; Lausin, Melissa; Nwaneri, Chinyere; Lieberman, Daniel Z

    2011-01-01

    Harmful drinking is common in medical inpatients, yet commonly missed due in part to time pressures. A screening question about past year heavy drinking recommended by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has been validated in primary care and emergency room settings. We tested the psychometric properties of a modified single screening question (SSQ) in hospitalized patients referred to a consultation-liaison service. A psychiatry attending (n = 40), a psychiatry resident (n = 30) and a medical student (n = 30) administered the SSQ, followed by a self-report 10-item Alcohol Use Disorders Identification Test (AUDIT) to a sample of 100 consultation-liaison patients who were able to give informed consent for participation. Using the AUDIT as a reference, the sensitivity and specificity of the SSQ to detect harmful drinking in this sample were .96 and .82, respectively. Gender differences in specificity were not found. The single question also had a strong correlation with dependence (r(b) = .457, p past year heavy drinking can rapidly identify harmful drinking in alert nonpsychotic consultation-liaison patients. Copyright © 2011 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

  3. Screening for type 2 diabetes in a multiethnic setting using known risk factors to identify those at high risk

    DEFF Research Database (Denmark)

    Gray, Laura J.; Tringham, Jennifer R.; Davies, Melanie J.

    2010-01-01

    population to identify those with abnormal glucose tolerance. ethods: A sample of individuals aged 25-75 years (40-75 white European) with at least one risk factor for T2DM were invited for screening from 17 Leicestershire (UK) general practices or through a health awareness campaign. All participants...... received a 75 g oral glucose tolerance test, cardiovascular risk assessment, detailed medical and family histories and anthropometric measurements. Results: In the 3,225 participants who were screened. 640 (20%) were found to have some form of abnormal glucose tolerance of whom 4% had T2DM, 3% impaired...

  4. Diabetes-related symptoms and negative mood in participants of a targeted population-screening program for type 2 diabetes: the Hoorn screening study

    NARCIS (Netherlands)

    Adriaanse, M.C.; Dekker, J.M.; Spijkerman, A.M.W.; Twisk, J.W.R.; Nijpels, M.G.A.A.M.; van der Ploeg, H.M.; Heine, R.J.; Snoek, F.J.

    2005-01-01

    Objective: To determine the level of diabetes-related symptom distress and its association with negative mood in subjects participating in a targeted population-screening program, comparing those identified as having type 2 diabetes vs. those who did not. Research design and methods: This study was

  5. Novel curcumin- and emodin-related compounds identified by in silico 2D/3D conformer screening induce apoptosis in tumor cells

    International Nuclear Information System (INIS)

    Füllbeck, Melanie; Huang, Xiaohua; Dumdey, Renate; Frommel, Cornelius; Dubiel, Wolfgang; Preissner, Robert

    2005-01-01

    Inhibition of the COP9 signalosome (CSN) associated kinases CK2 and PKD by curcumin causes stabilization of the tumor suppressor p53. It has been shown that curcumin induces tumor cell death and apoptosis. Curcumin and emodin block the CSN-directed c-Jun signaling pathway, which results in diminished c-Jun steady state levels in HeLa cells. The aim of this work was to search for new CSN kinase inhibitors analogue to curcumin and emodin by means of an in silico screening method. Here we present a novel method to identify efficient inhibitors of CSN-associated kinases. Using curcumin and emodin as lead structures an in silico screening with our in-house database containing more than 10 6 structures was carried out. Thirty-five compounds were identified and further evaluated by the Lipinski's rule-of-five. Two groups of compounds can be clearly discriminated according to their structures: the curcumin-group and the emodin-group. The compounds were evaluated in in vitro kinase assays and in cell culture experiments. The data revealed 3 compounds of the curcumin-group (e.g. piceatannol) and 4 of the emodin-group (e.g. anthrachinone) as potent inhibitors of CSN-associated kinases. Identified agents increased p53 levels and induced apoptosis in tumor cells as determined by annexin V-FITC binding, DNA fragmentation and caspase activity assays. Our data demonstrate that the new in silico screening method is highly efficient for identifying potential anti-tumor drugs

  6. A Systematic Genetic Screen to Dissect the MicroRNA Pathway in Drosophila.

    Science.gov (United States)

    Pressman, Sigal; Reinke, Catherine A; Wang, Xiaohong; Carthew, Richard W

    2012-04-01

    A central goal of microRNA biology is to elucidate the genetic program of miRNA function and regulation. However, relatively few of the effectors that execute miRNA repression have been identified. Because such genes may function in many developmental processes, mutations in them are expected to be pleiotropic and thus are discarded in most standard genetic screens. Here, we describe a systematic screen designed to identify all Drosophila genes in ∼40% of the genome that function in the miRNA pathway. To identify potentially pleiotropic genes, the screen analyzed clones of homozygous mutant cells in heterozygous animals. We identified 45 mutations representing 24 genes, and we molecularly characterized 9 genes. These include 4 previously known genes that encode core components of the miRNA pathway, including Drosha, Pasha, Dicer-1, and Ago1. The rest are new genes that function through chromatin remodeling, signaling, and mRNA decapping. The results suggest genetic screens that use clonal analysis can elucidate the miRNA program and that ∼100 genes are required to execute the miRNA program.

  7. Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.

    Science.gov (United States)

    Tanaka, Takeshi Q; Guiguemde, W Armand; Barnett, David S; Maron, Maxim I; Min, Jaeki; Connelly, Michele C; Suryadevara, Praveen Kumar; Guy, R Kiplin; Williamson, Kim C

    2015-03-01

    Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  8. A Kinome RNAi Screen in Drosophila Identifies Novel Genes Interacting with Lgl, aPKC, and Crb Cell Polarity Genes in Epithelial Tissues.

    Science.gov (United States)

    Parsons, Linda M; Grzeschik, Nicola A; Amaratunga, Kasun; Burke, Peter; Quinn, Leonie M; Richardson, Helena E

    2017-08-07

    In both Drosophila melanogaster and mammalian systems, epithelial structure and underlying cell polarity are essential for proper tissue morphogenesis and organ growth. Cell polarity interfaces with multiple cellular processes that are regulated by the phosphorylation status of large protein networks. To gain insight into the molecular mechanisms that coordinate cell polarity with tissue growth, we screened a boutique collection of RNAi stocks targeting the kinome for their capacity to modify Drosophila "cell polarity" eye and wing phenotypes. Initially, we identified kinase or phosphatase genes whose depletion modified adult eye phenotypes associated with the manipulation of cell polarity complexes (via overexpression of Crb or aPKC). We next conducted a secondary screen to test whether these cell polarity modifiers altered tissue overgrowth associated with depletion of Lgl in the wing. These screens identified Hippo, Jun kinase (JNK), and Notch signaling pathways, previously linked to cell polarity regulation of tissue growth. Furthermore, novel pathways not previously connected to cell polarity regulation of tissue growth were identified, including Wingless (Wg/Wnt), Ras, and lipid/Phospho-inositol-3-kinase (PI3K) signaling pathways. Additionally, we demonstrated that the "nutrient sensing" kinases Salt Inducible Kinase 2 and 3 ( SIK2 and 3 ) are potent modifiers of cell polarity phenotypes and regulators of tissue growth. Overall, our screen has revealed novel cell polarity-interacting kinases and phosphatases that affect tissue growth, providing a platform for investigating molecular mechanisms coordinating cell polarity and tissue growth during development. Copyright © 2017 Parsons et al.

  9. Metabolomic screening using ESI-FT MS identifies potential radiation-responsive molecules in mouse urine

    International Nuclear Information System (INIS)

    Iizuka, Daisuke; Yoshioka, Susumu; Kawai, Hidehiko; Izumi, Shunsuke; Suzuki, Fumio; Kamiya, Kenji

    2017-01-01

    The demand for establishment of high-throughput biodosimetric methods is increasing. Our aim in this study was to identify low-molecular-weight urinary radiation-responsive molecules using electrospray ionization Fourier transform mass spectrometry (ESI-FT MS), and our final goal was to develop a sensitive biodosimetry technique that can be applied in the early triage of a radiation emergency medical system. We identified nine metabolites by statistical comparison of mouse urine before and 8 h after irradiation. Time-course analysis showed that, of these metabolites, thymidine and either thymine or imidazoleacetic acid were significantly increased dose-dependently 8 h after radiation exposure; these molecules have already been reported as potential radiation biomarkers. Phenyl glucuronide was significantly decreased 8 h after radiation exposure, irrespective of the dose. Histamine and 1-methylhistamine were newly identified by MS/MS and showed significant, dose-dependent increases 72 h after irradiation. Quantification of 1-methylhistamine by enzyme-linked immunosorbent assay (ELISA) analysis also showed a significant increase 72 h after 4 Gy irradiation. These results suggest that urinary metabolomics screening using ESI-FT MS can be a powerful tool for identifying promising radiation-responsive molecules, and that urinary 1-methylhistamine is a potential radiation-responsive molecule for acute, high-dose exposure.

  10. A Multi-Center Diabetes Eye Screening Study in Community Settings: Study Design and Methodology.

    Science.gov (United States)

    Murchison, Ann P; Friedman, David S; Gower, Emily W; Haller, Julia A; Lam, Byron L; Lee, David J; McGwin, Gerald; Owsley, Cynthia; Saaddine, Jinan; Insight Study Group

    2016-01-01

    Diabetes is the leading cause of new cases of blindness among adults aged 20-74 years within the United States. The Innovative Network for Sight Research group (INSIGHT) designed the Diabetic Eye Screening Study (DESS) to examine the feasibility and short-term effectiveness of non-mydriatic diabetic retinopathy (DR) screening for adults with diabetes in community-based settings. Study enrollment began in December 2011 at four sites: an internal medicine clinic at a county hospital in Birmingham, Alabama; a Federally-qualified community healthcare center in Miami-Dade County, Florida; a university-affiliated outpatient pharmacy in Philadelphia, Pennsylvania; and a medical home in Winston-Salem, North Carolina. People 18 years or older with previously diagnosed diabetes were offered free DR screening using non-mydriatic retinal photography that was preceded by a brief questionnaire addressing demographic information and previous eye care use. Visual acuity was also measured for each eye. Images were evaluated at a telemedicine reading center by trained evaluators using the National Health System DR grading classification. Participants and their physicians were sent screening report results and telephoned for a follow-up survey 3 months post-screening to determine whether participants had sought follow-up comprehensive eye care and their experiences with the screening process. Target enrollment at each site was a minimum of 500 persons. Three of the four sites met this enrollment goal. The INSIGHT/DESS is intended to establish the feasibility and short-term effectiveness of DR screening using non-mydriatic retinal photography in persons with diabetes who seek services in community-based clinic and pharmacy settings.

  11. Use of a single alcohol screening question to identify other drug use.

    Science.gov (United States)

    Smith, Peter C; Cheng, Debbie M; Allensworth-Davies, Donald; Winter, Michael R; Saitz, Richard

    2014-06-01

    People who consume unhealthy amounts of alcohol are more likely to use illicit drugs. We tested the ability of a screening test for unhealthy alcohol use to simultaneously detect drug use. Adult English speaking patients (n=286) were enrolled from a primary care waiting room. They were asked the screening question for unhealthy alcohol use "How many times in the past year have you had X or more drinks in a day?", where X is 5 for men and 4 for women, and a response of one or more is considered positive. A standard diagnostic interview was used to determine current (past year) drug use or a drug use disorder (abuse or dependence). Oral fluid testing was also used to detect recent use of common drugs of abuse. The single screening question for unhealthy alcohol use was 67.6% sensitive (95% confidence interval [CI], 50.2-82.0%) and 64.7% specific (95% CI, 58.4-70.6%) for the detection of a drug use disorder. It was similarly insensitive for drug use detected by oral fluid testing and/or self-report. Although a patient with a drug use disorder has twice the odds of screening positive for unhealthy alcohol use compared to one without a drug use disorder, suggesting patients who screen positive for alcohol should be asked about drug use, a single screening question for unhealthy alcohol use was not sensitive or specific for the detection of other drug use or drug use disorders in a sample of primary care patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    Science.gov (United States)

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types.

  13. A structured women's preventive health clinic for residents: a quality improvement project designed to meet training needs and improve cervical cancer screening rates.

    Science.gov (United States)

    Singh, Mamta K; Einstadter, Douglas; Lawrence, Renee

    2010-10-01

    Multiple resident-related factors contribute to 'missed opportunities' in providing comprehensive preventive care for female patients, including comfort level, knowledge and experience--all of which are compounded by resident turnover rates. Of particular concern among Internal Medicine (IM) residents is their knowledge and comfort level in performing pelvic exams. To evaluate the impact of a quality improvement project of implementing a Women's Preventive Health Clinic (WPHC) on addressing gaps identified by needs assessments: residents' comfort and knowledge with female preventive care and cervical cancer screening. The WPHC, a multidisciplinary weekly clinic, focused on preventive services for women with chronic conditions. The alternating didactic and clinic sessions emphasised women's preventive health topics for IM residents. Sixty-three IM residents participated in WPHC between 2002 and 2005. Pre- and post-test design was used to assess resident knowledge and comfort levels. Cervical cancer screening rates of residents' patients were assessed pre- and post-WPHC initiation. There was a significant improvement in general knowledge (64% correct at pretest vs 73% at post-test, p=0.0002), resident comfort level in discussing women's health topics and performing gynaecological exams (p<0.0002). Cervical cancer screening rates among IM residents' patients improved from 54% (pre-WPHC initiation) to 65% (post-WPHC initiation period). The results indicate that a focused resident preventive programme can meet gaps identified by education and needs assessments, and simultaneously have a positive impact on cervical cancer screening rates and thus may serve as a model for other residency programmes.

  14. A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM Stem Cells.

    Science.gov (United States)

    Kulkarni, Shreya; Goel-Bhattacharya, Surbhi; Sengupta, Sejuti; Cochran, Brent H

    2018-01-01

    Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11 , and RAN , the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival. Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103-14. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. A Proteomic Screen Identified Stress-Induced Chaperone Proteins as Targets of Akt Phosphorylation in Mesangial Cells

    OpenAIRE

    Barati, Michelle T.; Rane, Madhavi J.; Klein, Jon B.; McLeish, Kenneth R.

    2006-01-01

    The serine-threonine kinase Akt regulates mesangial cell apoptosis, proliferation, and hypertrophy. To define Akt signaling pathways in mesangial cells, we performed a functional proteomic screen for rat mesangial cell proteins phosphorylated by Akt. A group of chaperone proteins, heat shock protein (Hsp) 70, Hsp90α, Hsp90β, Glucose-regulated protein (Grp) Grp78, Grp94, and protein disulfide isomerase (PDI) were identified as potential Akt substrates by two techniques: (a) in vitro phosphoryl...

  16. Genome-wide RNAi Screen Identifies Networks Involved in Intestinal Stem Cell Regulation in Drosophila

    Directory of Open Access Journals (Sweden)

    Xiankun Zeng

    2015-02-01

    Full Text Available The intestinal epithelium is the most rapidly self-renewing tissue in adult animals and maintained by intestinal stem cells (ISCs in both Drosophila and mammals. To comprehensively identify genes and pathways that regulate ISC fates, we performed a genome-wide transgenic RNAi screen in adult Drosophila intestine and identified 405 genes that regulate ISC maintenance and lineage-specific differentiation. By integrating these genes into publicly available interaction databases, we further developed functional networks that regulate ISC self-renewal, ISC proliferation, ISC maintenance of diploid status, ISC survival, ISC-to-enterocyte (EC lineage differentiation, and ISC-to-enteroendocrine (EE lineage differentiation. By comparing regulators among ISCs, female germline stem cells, and neural stem cells, we found that factors related to basic stem cell cellular processes are commonly required in all stem cells, and stem-cell-specific, niche-related signals are required only in the unique stem cell type. Our findings provide valuable insights into stem cell maintenance and lineage-specific differentiation.

  17. Material characterisation and preliminary mechanical design for the HL-LHC shielded beam screens operating at cryogenic temperatures.

    Science.gov (United States)

    Garion, C.; Dufay-Chanat, L.; Koettig, T.; Machiocha, W.; Morrone, M.

    2015-12-01

    The High Luminosity LHC project (HL-LHC) aims at increasing the luminosity (rate of collisions) in the Large Hadron Collider (LHC) experiments by a factor of 10 beyond the original design value (from 300 to 3000 fb-1). It relies on new superconducting magnets, installed close to the interaction points, equipped with new beam screen. This component has to ensure the vacuum performance together with shielding the cold mass from physics debris and screening the cold bore cryogenic system from beam induced heating. The beam screen operates in the range 40-60 K whereas the magnet cold bore temperature is 1.9 K. A tungsten-based material is used to absorb the energy of particles. In this paper, measurements of the mechanical and physical properties of such tungsten material are shown at room and cryogenic temperature. In addition, the design and the thermal mechanical behaviour of the beam screen assembly are presented also. They include the heat transfer from the tungsten absorbers to the cooling pipes and the supporting system that has to minimise the heat inleak into the cold mass. The behaviour during a magnet quench is also presented.

  18. Material characterisation and preliminary mechanical design for the HL-LHC shielded beam screens operating at cryogenic temperatures

    International Nuclear Information System (INIS)

    Garion, C; Dufay-Chanat, L; Koettig, T; Machiocha, W; Morrone, M

    2015-01-01

    The High Luminosity LHC project (HL-LHC) aims at increasing the luminosity (rate of collisions) in the Large Hadron Collider (LHC) experiments by a factor of 10 beyond the original design value (from 300 to 3000 fb -1 ). It relies on new superconducting magnets, installed close to the interaction points, equipped with new beam screen. This component has to ensure the vacuum performance together with shielding the cold mass from physics debris and screening the cold bore cryogenic system from beam induced heating. The beam screen operates in the range 40-60 K whereas the magnet cold bore temperature is 1.9 K. A tungsten-based material is used to absorb the energy of particles. In this paper, measurements of the mechanical and physical properties of such tungsten material are shown at room and cryogenic temperature. In addition, the design and the thermal mechanical behaviour of the beam screen assembly are presented also. They include the heat transfer from the tungsten absorbers to the cooling pipes and the supporting system that has to minimise the heat inleak into the cold mass. The behaviour during a magnet quench is also presented. (paper)

  19. A support vector machine designed to identify breasts at high risk using multi-probe generated REIS signals: a preliminary assessment

    Science.gov (United States)

    Gur, David; Zheng, Bin; Lederman, Dror; Dhurjaty, Sreeram; Sumkin, Jules; Zuley, Margarita

    2010-02-01

    A new resonance-frequency based electronic impedance spectroscopy (REIS) system with multi-probes, including one central probe and six external probes that are designed to contact the breast skin in a circular form with a radius of 60 millimeters to the central ("nipple") probe, has been assembled and installed in our breast imaging facility. We are conducting a prospective clinical study to test the performance of this REIS system in identifying younger women (detection of a highly suspicious breast lesion and 50 were determined negative during mammography screening. REIS output signal sweeps that we used to compute an initial feature included both amplitude and phase information representing differences between corresponding (matched) EIS signal values acquired from the left and right breasts. A genetic algorithm was applied to reduce the feature set and optimize a support vector machine (SVM) to classify the REIS examinations into "biopsy recommended" and "non-biopsy" recommended groups. Using the leave-one-case-out testing method, the classification performance as measured by the area under the receiver operating characteristic (ROC) curve was 0.816 +/- 0.042. This pilot analysis suggests that the new multi-probe-based REIS system could potentially be used as a risk stratification tool to identify pre-screened young women who are at higher risk of having or developing breast cancer.

  20. A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene.

    Science.gov (United States)

    Gobeil, Stephane; Zhu, Xiaochun; Doillon, Charles J; Green, Michael R

    2008-11-01

    Metastasis suppressor genes inhibit one or more steps required for metastasis without affecting primary tumor formation. Due to the complexity of the metastatic process, the development of experimental approaches for identifying genes involved in metastasis prevention has been challenging. Here we describe a genome-wide RNAi screening strategy to identify candidate metastasis suppressor genes. Following expression in weakly metastatic B16-F0 mouse melanoma cells, shRNAs were selected based upon enhanced satellite colony formation in a three-dimensional cell culture system and confirmed in a mouse experimental metastasis assay. Using this approach we discovered 22 genes whose knockdown increased metastasis without affecting primary tumor growth. We focused on one of these genes, Gas1 (Growth arrest-specific 1), because we found that it was substantially down-regulated in highly metastatic B16-F10 melanoma cells, which contributed to the high metastatic potential of this mouse cell line. We further demonstrated that Gas1 has all the expected properties of a melanoma tumor suppressor including: suppression of metastasis in a spontaneous metastasis assay, promotion of apoptosis following dissemination of cells to secondary sites, and frequent down-regulation in human melanoma metastasis-derived cell lines and metastatic tumor samples. Thus, we developed a genome-wide shRNA screening strategy that enables the discovery of new metastasis suppressor genes.

  1. Evaluation of critical materials in five additional advance design photovoltaic cells

    Energy Technology Data Exchange (ETDEWEB)

    Smith, S.A.; Watts, R.L.; Martin, P.; Gurwell, W.E.

    1981-02-01

    The objective of this study is to identify potential material supply constraints due to the large-scale deployment of five advanced photovoltaic (PV) cell designs, and to suggest strategies to reduce the impacts of these production capacity limitations and potential future material shortages. The Critical Materials Assessment Program (CMAP) screens the designs and their supply chains and identifies potential shortages which might preclude large-scale use of the technologies. The results of the screening of five advanced PV cell designs are presented: (1) indium phosphide/cadmium sulfide, (2) zinc phosphide, (3) cadmium telluride/cadmium sulfide, (4) copper indium selenium, and (5) cadmium selenide photoelectrochemical. Each of these five cells is screened individually assuming that they first come online in 1991, and that 25 Gwe of peak capacity is online by the year 2000. A second computer screening assumes that each cell first comes online in 1991 and that each cell has a 5 GWe of peak capacity by the year 2000, so that the total online capacity for the five cells is 25 GWe. Based on a review of the preliminary baseline screening results, suggestions were made for varying such parameters as the layer thickness, cell production processes, etc. The resulting PV cell characterizations were then screened again by the CMAP computer code. The CMAP methodology used to identify critical materials is described; and detailed characterizations of the advanced photovoltaic cell designs under investigation, descriptions of additional cell production processes, and the results are presented. (WHK)

  2. Hearing Screening Follow-Up: Completing the Process to Identify Hearing Health Needs

    Science.gov (United States)

    Eiserman, William; Shisler, Lenore; Hoffman, Jeff

    2015-01-01

    Hearing is at the heart of language development and school readiness; increasing numbers of Early Head Start programs have come to rely on otoacoustic emissions (OAE) technology to screen all infants and toddlers for hearing loss. Successful identification of hearing health needs is dependent not only on an appropriate screening method, but also…

  3. Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci.

    Science.gov (United States)

    Westrick, Randal J; Tomberg, Kärt; Siebert, Amy E; Zhu, Guojing; Winn, Mary E; Dobies, Sarah L; Manning, Sara L; Brake, Marisa A; Cleuren, Audrey C; Hobbs, Linzi M; Mishack, Lena M; Johnston, Alexander J; Kotnik, Emilee; Siemieniak, David R; Xu, Jishu; Li, Jun Z; Saunders, Thomas L; Ginsburg, David

    2017-09-05

    Factor V Leiden ( F5 L ) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized N -ethyl- N -nitrosourea (ENU) mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for F5 L ( F5 L/L ) and haploinsufficient for tissue factor pathway inhibitor ( Tfpi +/- ). F8 deficiency enhanced the survival of F5 L/L Tfpi +/- mice, demonstrating that F5 L/L Tfpi +/- lethality is genetically suppressible. ENU-mutagenized F5 L/L males and F5 L/+ Tfpi +/- females were crossed to generate 6,729 progeny, with 98 F5 L/L Tfpi +/- offspring surviving until weaning. Sixteen lines, referred to as "modifier of Factor 5 Leiden ( MF5L1-16 )," exhibited transmission of a putative thrombosuppressor to subsequent generations. Linkage analysis in MF5L6 identified a chromosome 3 locus containing the tissue factor gene ( F3 ). Although no ENU-induced F3 mutation was identified, haploinsufficiency for F3 ( F3 +/- ) suppressed F5 L/L Tfpi +/- lethality. Whole-exome sequencing in MF5L12 identified an Actr2 gene point mutation (p.R258G) as the sole candidate. Inheritance of this variant is associated with suppression of F5 L/L Tfpi +/- lethality ( P = 1.7 × 10 -6 ), suggesting that Actr2 p.R258G is thrombosuppressive. CRISPR/Cas9 experiments to generate an independent Actr2 knockin/knockout demonstrated that Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism of action for Actr2 p.R258G Our findings identify F8 and the Tfpi/F3 axis as key regulators in determining thrombosis balance in the setting of F5 L and also suggest a role for Actr2 in this process.

  4. A stakeholder co-design approach for developing a community pharmacy service to enhance screening and management of atrial fibrillation.

    Science.gov (United States)

    Sabater-Hernández, Daniel; Tudball, Jacqueline; Ferguson, Caleb; Franco-Trigo, Lucía; Hossain, Lutfun N; Benrimoj, Shalom I

    2018-02-27

    Community pharmacies provide a suitable setting to promote self-screening programs aimed at enhancing the early detection of atrial fibrillation (AF). Developing and implementing novel community pharmacy services (CPSs) is a complex and acknowledged challenge, which requires comprehensive planning and the participation of relevant stakeholders. Co-design processes are participatory research approaches that can enhance the development, evaluation and implementation of health services. The aim of this study was to co-design a pharmacist-led CPS aimed at enhancing self-monitoring/screening of AF. A 3-step co-design process was conducted using qualitative methods: (1) interviews and focus group with potential service users (n = 8) to identify key needs and concerns; (2) focus group with a mixed group of stakeholders (n = 8) to generate a preliminary model of the service; and (3) focus group with community pharmacy owners and managers (n = 4) to explore the feasibility and appropriateness of the model. Data were analysed qualitatively to identify themes and intersections between themes. The JeMa2 model to conceptualize pharmacy-based health programs was used to build a theoretical model of the service. Stakeholders delineated: a clear target population (i.e., individuals ≥65 years old, with hypertension, with or without previous AF or stroke); the components of the service (i.e., patient education; self-monitoring at home; results evaluation, referral and follow-up); and a set of circumstances that may influence the implementation of the service (e.g., quality of the service, competency of the pharmacist, inter-professional relationships, etc.). A number of strategies were recommended to enable implementation (e.g.,. endorsement by leading cardiovascular organizations, appropriate communication methods and channels between the pharmacy and the general medical practice settings, etc.). A novel and preliminary model of a CPS aimed at enhancing the

  5. Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia

    Science.gov (United States)

    Karjalainen, Katja; Pasqualini, Renata; Cortes, Jorge E.; Kornblau, Steven M.; Lichtiger, Benjamin; O'Brien, Susan; Kantarjian, Hagop M.; Sidman, Richard L.; Arap, Wadih; Koivunen, Erkki

    2015-01-01

    Background We introduce an ex vivo methodology to perform drug library screening against human leukemia. Method Our strategy relies on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. We demonstrate several advantages: (I) partial recapitulation of the leukemia microenvironment, (ii) use of native hemoglobin oxygenation as real-time sensor/reporter, (iii) cost-effectiveness, (iv) species-specificity, and (v) format that enables high-throughput screening. Results As a proof-of-concept, we screened a chemical library (size ∼20,000) against human leukemia cells. We identified 70 compounds (“hit” rate=0.35%; Z-factor=0.71) with activity; we examined 20 to find 18 true-positives (90%). Finally, we show that carbonohydraxonic diamide group-containing compounds are potent anti-leukemia agents that induce cell death in leukemia cells and patient-derived samples. Conclusions This unique functional assay can identify novel drug candidates as well as find future applications in personalized drug selection for leukemia patients. PMID:24496871

  6. Screening and Identifying a Novel ssDNA Aptamer against Alpha-fetoprotein Using CE-SELEX

    Science.gov (United States)

    Dong, Lili; Tan, Qiwen; Ye, Wei; Liu, Dongli; Chen, Haifeng; Hu, Hongwei; Wen, Duo; Liu, Yang; Cao, Ya; Kang, Jingwu; Fan, Jia; Guo, Wei; Wu, Weizhong

    2015-01-01

    Alpha-fetoprotein (AFP) is a liver cancer associated protein and has long been utilized as a serum tumor biomarker of disease progression. AFP is usually detected in HCC patients by an antibody based system. Recently, however, aptamers generated from systematic evolution of ligands by exponential enrichment (SELEX) were reported to have an alternative potential in targeted imaging, diagnosis and therapy. In this study, AFP-bound ssDNA aptamers were screened and identified using capillary electrophoresis (CE) SELEX technology. After cloning, sequencing and motif analysis, we successfully confirmed an aptamer, named AP273, specifically targeting AFP. The aptamer could be used as a probe in AFP immunofluorescence imaging in HepG2, one AFP positive cancer cell line, but not in A549, an AFP negative cancer cell line. More interesting, the aptamer efficiently inhibited the migration and invasion of HCC cells after in vivo transfection. Motif analysis revealed that AP273 had several stable secondary motifs in its structure. Our results indicate that CE-SELEX technology is an efficient method to screen specific protein-bound ssDNA, and AP273 could be used as an agent in AFP-based staining, diagnosis and therapy, although more works are still needed. PMID:26497223

  7. Quantitative structure-activity relationship analysis and virtual screening studies for identifying HDAC2 inhibitors from known HDAC bioactive chemical libraries.

    Science.gov (United States)

    Pham-The, H; Casañola-Martin, G; Diéguez-Santana, K; Nguyen-Hai, N; Ngoc, N T; Vu-Duc, L; Le-Thi-Thu, H

    2017-03-01

    Histone deacetylases (HDAC) are emerging as promising targets in cancer, neuronal diseases and immune disorders. Computational modelling approaches have been widely applied for the virtual screening and rational design of novel HDAC inhibitors. In this study, different machine learning (ML) techniques were applied for the development of models that accurately discriminate HDAC2 inhibitors form non-inhibitors. The obtained models showed encouraging results, with the global accuracy in the external set ranging from 0.83 to 0.90. Various aspects related to the comparison of modelling techniques, applicability domain and descriptor interpretations were discussed. Finally, consensus predictions of these models were used for screening HDAC2 inhibitors from four chemical libraries whose bioactivities against HDAC1, HDAC3, HDAC6 and HDAC8 have been known. According to the results of virtual screening assays, structures of some hits with pair-isoform-selective activity (between HDAC2 and other HDACs) were revealed. This study illustrates the power of ML-based QSAR approaches for the screening and discovery of potent, isoform-selective HDACIs.

  8. Virtual screening approach to identifying influenza virus neuraminidase inhibitors using molecular docking combined with machine-learning-based scoring function.

    Science.gov (United States)

    Zhang, Li; Ai, Hai-Xin; Li, Shi-Meng; Qi, Meng-Yuan; Zhao, Jian; Zhao, Qi; Liu, Hong-Sheng

    2017-10-10

    In recent years, an epidemic of the highly pathogenic avian influenza H7N9 virus has persisted in China, with a high mortality rate. To develop novel anti-influenza therapies, we have constructed a machine-learning-based scoring function (RF-NA-Score) for the effective virtual screening of lead compounds targeting the viral neuraminidase (NA) protein. RF-NA-Score is more accurate than RF-Score, with a root-mean-square error of 1.46, Pearson's correlation coefficient of 0.707, and Spearman's rank correlation coefficient of 0.707 in a 5-fold cross-validation study. The performance of RF-NA-Score in a docking-based virtual screening of NA inhibitors was evaluated with a dataset containing 281 NA inhibitors and 322 noninhibitors. Compared with other docking-rescoring virtual screening strategies, rescoring with RF-NA-Score significantly improved the efficiency of virtual screening, and a strategy that averaged the scores given by RF-NA-Score, based on the binding conformations predicted with AutoDock, AutoDock Vina, and LeDock, was shown to be the best strategy. This strategy was then applied to the virtual screening of NA inhibitors in the SPECS database. The 100 selected compounds were tested in an in vitro H7N9 NA inhibition assay, and two compounds with novel scaffolds showed moderate inhibitory activities. These results indicate that RF-NA-Score improves the efficiency of virtual screening for NA inhibitors, and can be used successfully to identify new NA inhibitor scaffolds. Scoring functions specific for other drug targets could also be established with the same method.

  9. A fast, simple method for screening radiation susceptibility genes by RNA interference

    International Nuclear Information System (INIS)

    Tsuji, Atsushi B.; Sudo, Hitomi; Sugyo, Aya; Otsuki, Marika; Miyagishi, Makoto; Taira, Kazunari; Imai, Takashi; Harada, Yoshi-nobu

    2005-01-01

    Radiotherapy can cause unacceptable levels of damage to normal tissues in some cancer patients. To understand the molecular mechanisms underlying radiation-induced physiological responses, and to be able to predict the radiation susceptibility of normal tissues in individual patients, it is important to identify a comprehensive set of genes responsible for radiation susceptibility. We have developed a simple and rapid 96-well screening protocol using cell proliferation assays and RNA interference to identify genes associated with radiation susceptibility. We evaluated the performance of alamarBlue-, BrdU-, and sulforhodamine B-based cell proliferation assays using the 96-well format. Each proliferation assay detected the known radiation susceptibility gene, PRKDC. In a trial screen using 28 shRNA vectors, another known gene, CDKN1A, and one new radiation susceptibility gene, ATP5G3, were identified. Our results indicate that this method may be useful for large-scale screens designed to identify novel radiation susceptibility genes

  10. Screening for skin cancer.

    Science.gov (United States)

    Helfand, M; Mahon, S M; Eden, K B; Frame, P S; Orleans, C T

    2001-04-01

    Malignant melanoma is often lethal, and its incidence in the United States has increased rapidly over the past 2 decades. Nonmelanoma skin cancer is seldom lethal, but, if advanced, can cause severe disfigurement and morbidity. Early detection and treatment of melanoma might reduce mortality, while early detection and treatment of nonmelanoma skin cancer might prevent major disfigurement and to a lesser extent prevent mortality. Current recommendations from professional societies regarding screening for skin cancer vary. To examine published data on the effectiveness of routine screening for skin cancer by a primary care provider, as part of an assessment for the U.S. Preventive Services Task Force. We searched the MEDLINE database for papers published between 1994 and June 1999, using search terms for screening, physical examination, morbidity, and skin neoplasms. For information on accuracy of screening tests, we used the search terms sensitivity and specificity. We identified the most important studies from before 1994 from the Guide to Clinical Preventive Services, second edition, and from high-quality reviews. We used reference lists and expert recommendations to locate additional articles. Two reviewers independently reviewed a subset of 500 abstracts. Once consistency was established, the remainder were reviewed by one reviewer. We included studies if they contained data on yield of screening, screening tests, risk factors, risk assessment, effectiveness of early detection, or cost effectiveness. We abstracted the following descriptive information from full-text published studies of screening and recorded it in an electronic database: type of screening study, study design, setting, population, patient recruitment, screening test description, examiner, advertising targeted at high-risk groups or not targeted, reported risk factors of participants, and procedure for referrals. We also abstracted the yield of screening data including probabilities and numbers

  11. Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

    Science.gov (United States)

    Lejeune, François-Xavier; Mesrob, Lilia; Parmentier, Frédéric; Bicep, Cedric; Vazquez-Manrique, Rafael P; Parker, J Alex; Vert, Jean-Philippe; Tourette, Cendrine; Neri, Christian

    2012-03-13

    A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. © 2012 Lejeune et al; licensee BioMed Central Ltd.

  12. Preliminary Design of the HiLumi-LHC Triplet Area Beam Screen

    CERN Document Server

    Kersevan, R; Kos, N

    2014-01-01

    The so-called beam screen (BS) is a proven solution for intercepting the thermal loads caused by the circulating beams in the cryogenically-cooled sections of the LHC and minimizing dynamic vacuum effects [1]. The new triplet area foreseen for the HiLumi-LHC (HL-LHC) machine upgrade [2] has the additional feature of needing internal tungsten shields to reduce the amount of collision debris which is deflected by the high-gradient triplet magnets towards the superconducting magnets' cold masses and coils. The very aggressive optics design, based on large beam separations, calls for a maximum of physical space to remain available to the counter rotating beams in the common BS. This places severe constraints to the fabrication and installation tolerances of the BS itself, in addition to affecting the design and routing of the cryogenic lines in the area. The latest version of the BS design will be shown and discussed, together with future plans for testing materials, fabrication procedures, and installation.

  13. High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists.

    Science.gov (United States)

    Wu, Bainan; Barile, Elisa; De, Surya K; Wei, Jun; Purves, Angela; Pellecchia, Maurizio

    2015-01-01

    In recent years the ever so complex field of drug discovery has embraced novel design strategies based on biophysical fragment screening (fragment-based drug design; FBDD) using nuclear magnetic resonance spectroscopy (NMR) and/or structure-guided approaches, most often using X-ray crystallography and computer modeling. Experience from recent years unveiled that these methods are more effective and less prone to artifacts compared to biochemical high-throughput screening (HTS) of large collection of compounds in designing protein inhibitors. Hence these strategies are increasingly becoming the most utilized in the modern pharmaceutical industry. Nonetheless, there is still an impending need to develop innovative and effective strategies to tackle other more challenging targets such as those involving protein-protein interactions (PPIs). While HTS strategies notoriously fail to identify viable hits against such targets, few successful examples of PPIs antagonists derived by FBDD strategies exist. Recently, we reported on a new strategy that combines some of the basic principles of fragment-based screening with combinatorial chemistry and NMR-based screening. The approach, termed HTS by NMR, combines the advantages of combinatorial chemistry and NMR-based screening to rapidly and unambiguously identify bona fide inhibitors of PPIs. This review will reiterate the critical aspects of the approach with examples of possible applications.

  14. Instruments to Identify Commercially Sexually Exploited Children: Feasibility of Use in an Emergency Department Setting.

    Science.gov (United States)

    Armstrong, Stephanie

    2017-12-01

    This review examines the screening instruments that are in existence today to identify commercially sexually exploited children. The instruments are compared and evaluated for their feasibility of use in an emergency department setting. Four electronic databases were searched to identify screening instruments that assessed solely for commercial sexual exploitation. Search terms included "commercially sexually exploited children," "CSEC," "domestic minor sex trafficking," "DMST," "juvenile sex trafficking," and "JST." Those terms were then searched in combination with each of the following: "tools," "instruments," "screening," "policies," "procedures," "data collection," "evidence," and "validity." Six screening instruments were found to meet the inclusion criteria. Variation among instruments included number of questions, ease of administration, information sources, scoring methods, and training information provided. Two instruments were determined to be highly feasible for use in the emergency department setting, those being the Asian Health Services and Banteay Srei's CSEC Screening Protocol and Greenbaum et al's CSEC/child sex trafficking 6-item screening tool. A current dearth of screening instruments was confirmed. It is recommended that additional screening instruments be created to include developmentally appropriate instruments for preadolescent children. Numerous positive features were identified within the instruments in this review and are suggested for use in future screening instruments, including succinctness, a simple format, easy administration, training materials, sample questions, multiple information sources, designation of questions requiring mandatory reporting, a straightforward scoring system, and an algorithm format.

  15. The Data Gap in the EHR for Clinical Research Eligibility Screening.

    Science.gov (United States)

    Butler, Alex; Wei, Wei; Yuan, Chi; Kang, Tian; Si, Yuqi; Weng, Chunhua

    2018-01-01

    Much effort has been devoted to leverage EHR data for matching patients into clinical trials. However, EHRs may not contain all important data elements for clinical research eligibility screening. To better design research-friendly EHRs, an important step is to identify data elements frequently used for eligibility screening but not yet available in EHRs. This study fills this knowledge gap. Using the Alzheimer's disease domain as an example, we performed text mining on the eligibility criteria text in Clinicaltrials.gov to identify frequently used eligibility criteria concepts. We compared them to the EHR data elements of a cohort of Alzheimer's Disease patients to assess the data gap by usingthe OMOP Common Data Model to standardize the representations for both criteria concepts and EHR data elements. We identified the most common SNOMED CT concepts used in Alzheimer 's Disease trials, andfound 40% of common eligibility criteria concepts were not even defined in the concept space in the EHR dataset for a cohort of Alzheimer 'sDisease patients, indicating a significant data gap may impede EHR-based eligibility screening. The results of this study can be useful for designing targeted research data collection forms to help fill the data gap in the EHR.

  16. Haploid genetic screens identify an essential role for PLP2 in the downregulation of novel plasma membrane targets by viral E3 ubiquitin ligases.

    Directory of Open Access Journals (Sweden)

    Richard T Timms

    Full Text Available The Kaposi's sarcoma-associated herpesvirus gene products K3 and K5 are viral ubiquitin E3 ligases which downregulate MHC-I and additional cell surface immunoreceptors. To identify novel cellular genes required for K5 function we performed a forward genetic screen in near-haploid human KBM7 cells. The screen identified proteolipid protein 2 (PLP2, a MARVEL domain protein of unknown function, as essential for K5 activity. Genetic loss of PLP2 traps the viral ligase in the endoplasmic reticulum, where it is unable to ubiquitinate and degrade its substrates. Subsequent analysis of the plasma membrane proteome of K5-expressing KBM7 cells in the presence and absence of PLP2 revealed a wide range of novel K5 targets, all of which required PLP2 for their K5-mediated downregulation. This work ascribes a critical function to PLP2 for viral ligase activity and underlines the power of non-lethal haploid genetic screens in human cells to identify the genes involved in pathogen manipulation of the host immune system.

  17. ScreenCube: A 3D Printed System for Rapid and Cost-Effective Chemical Screening in Adult Zebrafish.

    Science.gov (United States)

    Monstad-Rios, Adrian T; Watson, Claire J; Kwon, Ronald Y

    2018-02-01

    Phenotype-based small molecule screens in zebrafish embryos and larvae have been successful in accelerating pathway and therapeutic discovery for diverse biological processes. Yet, the application of chemical screens to adult physiologies has been relatively limited due to additional demands on cost, space, and labor associated with screens in adult animals. In this study, we present a 3D printed system and methods for intermittent drug dosing that enable rapid and cost-effective chemical administration in adult zebrafish. Using prefilled screening plates, the system enables dosing of 96 fish in ∼3 min, with a 10-fold reduction in drug quantity compared to that used in previous chemical screens in adult zebrafish. We characterize water quality kinetics during immersion in the system and use these kinetics to rationally design intermittent dosing regimens that result in 100% fish survival. As a demonstration of system fidelity, we show the potential to identify two known chemical inhibitors of adult tail fin regeneration, cyclopamine and dorsomorphin. By developing methods for rapid and cost-effective chemical administration in adult zebrafish, this study expands the potential for small molecule discovery in postembryonic models of development, disease, and regeneration.

  18. Identifying Disruptive Technologies in Design: Horizon Scanning in the Early Stages of Design

    DEFF Research Database (Denmark)

    Ernstsen, Sidsel Katrine; Thuesen, Christian; Larsen, Laurids Rolighed

    context to anticipate disruption of construction. By means of a 3-step horizon scan, we identify 133 potentially disruptive technologies from across industries. We find that when preparing for disruption, design may benefit from the future-oriented and technology-focused features of horizon scanning....

  19. Computer-aided system of evaluation for population-based all-in-one service screening (CASE-PASS): from study design to outcome analysis with bias adjustment.

    Science.gov (United States)

    Chen, Li-Sheng; Yen, Amy Ming-Fang; Duffy, Stephen W; Tabar, Laszlo; Lin, Wen-Chou; Chen, Hsiu-Hsi

    2010-10-01

    Population-based routine service screening has gained popularity following an era of randomized controlled trials. The evaluation of these service screening programs is subject to study design, data availability, and the precise data analysis for adjusting bias. We developed a computer-aided system that allows the evaluation of population-based service screening to unify these aspects and facilitate and guide the program assessor to efficiently perform an evaluation. This system underpins two experimental designs: the posttest-only non-equivalent design and the one-group pretest-posttest design and demonstrates the type of data required at both the population and individual levels. Three major analyses were developed that included a cumulative mortality analysis, survival analysis with lead-time adjustment, and self-selection bias adjustment. We used SAS AF software to develop a graphic interface system with a pull-down menu style. We demonstrate the application of this system with data obtained from a Swedish population-based service screen and a population-based randomized controlled trial for the screening of breast, colorectal, and prostate cancer, and one service screening program for cervical cancer with Pap smears. The system provided automated descriptive results based on the various sources of available data and cumulative mortality curves corresponding to the study designs. The comparison of cumulative survival between clinically and screen-detected cases without a lead-time adjustment are also demonstrated. The intention-to-treat and noncompliance analysis with self-selection bias adjustments are also shown to assess the effectiveness of the population-based service screening program. Model validation was composed of a comparison between our adjusted self-selection bias estimates and the empirical results on effectiveness reported in the literature. We demonstrate a computer-aided system allowing the evaluation of population-based service screening

  20. A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen

    Directory of Open Access Journals (Sweden)

    Ashlee J. Conway

    2017-08-01

    Full Text Available A genome-wide ethyl-N-nitrosourea (ENU mutagenesis screen in mice was performed to identify novel regulators of erythropoiesis. Here, we describe a mouse line, RBC16, which harbours a dominantly inherited mutation in the Cpox gene, responsible for production of the haem biosynthesis enzyme, coproporphyrinogen III oxidase (CPOX. A premature stop codon in place of a tryptophan at amino acid 373 results in reduced mRNA expression and diminished protein levels, yielding a microcytic red blood cell phenotype in heterozygous mice. Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly elevated compared with that of wild-type littermates, particularly coproporphyrinogen III, whereas males were biochemically normal. Attempts to induce acute porphyric crises were made using fasting and phenobarbital treatment on females. While fasting had no biochemical effect on RBC16 mice, phenobarbital caused significant elevation of faecal coproporphyrinogen III in heterozygous mice. This is the first known investigation of a mutagenesis mouse model with genetic and biochemical parallels to hereditary coproporphyria.

  1. A High-Throughput Cell-Based Screen Identified a 2-[(E)-2-Phenylvinyl]-8-Quinolinol Core Structure That Activates p53.

    Science.gov (United States)

    Bechill, John; Zhong, Rong; Zhang, Chen; Solomaha, Elena; Spiotto, Michael T

    2016-01-01

    p53 function is frequently inhibited in cancer either through mutations or by increased degradation via MDM2 and/or E6AP E3-ubiquitin ligases. Most agents that restore p53 expression act by binding MDM2 or E6AP to prevent p53 degradation. However, fewer compounds directly bind to and activate p53. Here, we identified compounds that shared a core structure that bound p53, caused nuclear localization of p53 and caused cell death. To identify these compounds, we developed a novel cell-based screen to redirect p53 degradation to the Skip-Cullin-F-box (SCF) ubiquitin ligase complex in cells expressing high levels of p53. In a multiplexed assay, we coupled p53 targeted degradation with Rb1 targeted degradation in order to identify compounds that prevented p53 degradation while not inhibiting degradation through the SCF complex or other proteolytic machinery. High-throughput screening identified several leads that shared a common 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that stabilized p53. Surface plasmon resonance analysis indicated that these compounds bound p53 with a KD of 200 ± 52 nM. Furthermore, these compounds increased p53 nuclear localization and transcription of the p53 target genes PUMA, BAX, p21 and FAS in cancer cells. Although p53-null cells had a 2.5±0.5-fold greater viability compared to p53 wild type cells after treatment with core compounds, loss of p53 did not completely rescue cell viability suggesting that compounds may target both p53-dependent and p53-independent pathways to inhibit cell proliferation. Thus, we present a novel, cell-based high-throughput screen to identify a 2-[(E)-2-phenylvinyl]-8-quinolinol core structure that bound to p53 and increased p53 activity in cancer cells. These compounds may serve as anti-neoplastic agents in part by targeting p53 as well as other potential pathways.

  2. Idea Screening in Engineering Design Using Employee-Driven Wisdom of the Crowds

    DEFF Research Database (Denmark)

    Onarheim, Balder; Christensen, Bo Thomas

    /ownership of ideas. The study shows that the crowd wisdom of employees significantly correlates with the preferences of the marketing team: overall, in top 12 selected ideas and in choice of idea categories. This match increases when including only the ratings of the most experienced employees. The experienced......The paper investigates the question of screening ideas in the ‘fuzzy front end’ of engineering design, examining the validity of employee voting schemes and related biases. After an employee-driven innovation project at {Company Name removed for review}, 99 ideas were to be screened for further...... development. Based on the concept of ‘wisdom of the crowds’, all ideas were individually rated by a broad selection of employees, and their choices of ideas and idea categories compared to those of a small team of senior marketers. The study also tested for two biases: visual complexity and endowment effect...

  3. Systems of support to increase colorectal cancer screening and follow-up rates (SOS): design, challenges, and baseline characteristics of trial participants.

    Science.gov (United States)

    Green, Beverly B; Wang, C Y; Horner, Kathryn; Catz, Sheryl; Meenan, Richard T; Vernon, Sally W; Carrell, David; Chubak, Jessica; Ko, Cynthia; Laing, Sharon; Bogart, Andy

    2010-11-01

    Screening decreases colorectal cancer (CRC) morbidity and mortality, yet remains underutilized. Screening breakdowns arise from lack of uptake and failure to follow-up after a positive screening test. Systems of support to increase colorectal cancer screening and follow-up (SOS) is a randomized trial designed to increase: (1) CRC screening and (2) follow-up of positive screening tests. The Chronic Care Model and the Preventive Health Model inform study design. The setting is a large nonprofit healthcare organization. In part-1 study, patients age 50-75 due for CRC screening are randomized to one of 4 study conditions. Arm 1 receives usual care. Arm 2 receives automated support (mailed information about screening choices and fecal occult blood tests (FOBT)). Arm 3 receives automated and assisted support (a medical assistant telephone call). Arm 4 receives automated, assisted, and care management support (a registered nurse provides behavioral activation and coordination of care). In part-2, study patients with a positive FOBT or adenomas on flexible sigmoidoscopy are randomized to receive either usual care or nurse care management. Primary outcomes are: 1) the proportion with CRC screening, 2) the proportion with a complete diagnostic evaluation after a positive screening test. We sent recruitment letters to 15,414 patients and 4675 were randomized. Randomly assigned treatment groups were similar in age, sex, race, education, self-reported health, and CRC screening history. We will determine the effectiveness and cost effectiveness of stepped increases in systems of support to increase CRC screening and follow-up after a positive screening test over 2years. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Screening of Natural Product Derivatives Identifies Two Structurally Related Flavonoids as Potent Quorum Sensing Inhibitors against Gram-Negative Bacteria

    Directory of Open Access Journals (Sweden)

    Suvi Manner

    2018-05-01

    Full Text Available Owing to the failure of conventional antibiotics in biofilm control, alternative approaches are urgently needed. Inhibition of quorum sensing (QS represents an attractive target since it is involved in several processes essential for biofilm formation. In this study, a compound library of natural product derivatives (n = 3040 was screened for anti-quorum sensing activity using Chromobacterium violaceum as reporter bacteria. Screening assays, based on QS-mediated violacein production and viability, were performed in parallel to identify non-bactericidal QS inhibitors (QSIs. Nine highly active QSIs were identified, while 328 compounds were classified as moderately actives and 2062 compounds as inactives. Re-testing of the highly actives at a lower concentration against C. violaceum, complemented by a literature search, led to the identification of two flavonoid derivatives as the most potent QSIs, and their impact on biofilm maturation in Escherichia coli and Pseudomonas aeruginosa was further investigated. Finally, effects of these leads on swimming and swarming motility of P. aeruginosa were quantified. The identified flavonoids affected all the studied QS-related functions at micromolar concentrations. These compounds can serve as starting points for further optimization and development of more potent QSIs as adjunctive agents used with antibiotics in the treatment of biofilms.

  5. Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Kirsi Ketola

    Full Text Available Current treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.In this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.Taken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram

  6. Identifying the trauma recovery needs of maltreated children: An examination of child welfare workers' effectiveness in screening for traumatic stress.

    Science.gov (United States)

    Whitt-Woosley, Adrienne; Sprang, Ginny; Royse, David G

    2018-07-01

    Children in the child welfare system comprise a group characterized by exposure to trauma via experiences of maltreatment, under circumstances presenting multiple risk factors for traumatic stress. High rates of posttraumatic stress have been observed in this population. However, there is currently no standard for the universal screening of children in child welfare for trauma exposure and traumatic stress. This study examined the trauma experiences of a sample of maltreated children and whether their child welfare workers were effective screeners of traumatic stress symptoms. Descriptive and correlational analyses were conducted regarding a sample of children (N = 131) with trauma screenings completed by their child welfare workers and clinical measures of traumatic stress symptoms. Four hierarchical regression models were also examined to determine whether workers' screening information regarding child age, trauma exposure history and symptoms of traumatic stress were predictive of outcomes on clinical measures. The analyses revealed complex trauma exposure histories and high rates of traumatic stress symptoms among this generally younger sample of maltreated children. Additionally, the models supported workers' efficacy in screening for symptoms of total posttraumatic stress and specific trauma symptoms of intrusion and avoidance. Workers were less effective in screening for the symptoms of arousal. These findings support the importance of identifying the trauma recovery needs of maltreated children and the utility of child protection workers in assisting with the trauma screening process. Implications are provided for related practice, policy and training efforts in child welfare. Published by Elsevier Ltd.

  7. Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

    Science.gov (United States)

    Lau, Wan F.; Withka, Jane M.; Hepworth, David; Magee, Thomas V.; Du, Yuhua J.; Bakken, Gregory A.; Miller, Michael D.; Hendsch, Zachary S.; Thanabal, Venkataraman; Kolodziej, Steve A.; Xing, Li; Hu, Qiyue; Narasimhan, Lakshmi S.; Love, Robert; Charlton, Maura E.; Hughes, Samantha; van Hoorn, Willem P.; Mills, James E.

    2011-07-01

    Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.

  8. A genome-wide screen identifies conserved protein hubs required for cadherin-mediated cell–cell adhesion

    Science.gov (United States)

    Toret, Christopher P.; D’Ambrosio, Michael V.; Vale, Ronald D.; Simon, Michael A.

    2014-01-01

    Cadherins and associated catenins provide an important structural interface between neighboring cells, the actin cytoskeleton, and intracellular signaling pathways in a variety of cell types throughout the Metazoa. However, the full inventory of the proteins and pathways required for cadherin-mediated adhesion has not been established. To this end, we completed a genome-wide (∼14,000 genes) ribonucleic acid interference (RNAi) screen that targeted Ca2+-dependent adhesion in DE-cadherin–expressing Drosophila melanogaster S2 cells in suspension culture. This novel screen eliminated Ca2+-independent cell–cell adhesion, integrin-based adhesion, cell spreading, and cell migration. We identified 17 interconnected regulatory hubs, based on protein functions and protein–protein interactions that regulate the levels of the core cadherin–catenin complex and coordinate cadherin-mediated cell–cell adhesion. Representative proteins from these hubs were analyzed further in Drosophila oogenesis, using targeted germline RNAi, and adhesion was analyzed in Madin–Darby canine kidney mammalian epithelial cell–cell adhesion. These experiments reveal roles for a diversity of cellular pathways that are required for cadherin function in Metazoa, including cytoskeleton organization, cell–substrate interactions, and nuclear and cytoplasmic signaling. PMID:24446484

  9. Preliminary design of the beam screen cooling for the Future Circular Collider of hadron beams

    CERN Document Server

    Kotnig, C

    2015-01-01

    Following recommendations of the recent update of the European strategy in particle physics, CERN has undertaken an international study of possible future circular colliders beyond the LHC. This study considers an option for a very high energy (100 TeV) hadron-hadron collider located in a quasi-circular underground tunnel having a circumference of 80 to 100 km. The synchrotron radiation emitted by the high-energy hadron beam increases by more than two orders of magnitude compared to the LHC. To reduce the entropic load on the superconducting magnets' refrigeration system, beam screens are indispensable to extract the heat load at a higher temperature level. After illustrating the decisive constraints of the beam screen's refrigeration design, this paper presents a preliminary design of the length of a continuous cooling loop comparing helium and neon, for different cooling channel geometries with emphasis on the cooling length limitations and the exergetic efficiency.

  10. Preliminary design of the beam screen cooling for the Future Circular Collider of hadron beams

    Science.gov (United States)

    Kotnig, C.; Tavian, L.

    2015-12-01

    Following recommendations of the recent update of the European strategy in particle physics, CERN has undertaken an international study of possible future circular colliders beyond the LHC. This study considers an option for a very high energy (100 TeV) hadron-hadron collider located in a quasi-circular underground tunnel having a circumference of 80 to 100 km. The synchrotron radiation emitted by the high-energy hadron beam increases by more than two orders of magnitude compared to the LHC. To reduce the entropic load on the superconducting magnets’ refrigeration system, beam screens are indispensable to extract the heat load at a higher temperature level. After illustrating the decisive constraints of the beam screen's refrigeration design, this paper presents a preliminary design of the length of a continuous cooling loop comparing helium and neon, for different cooling channel geometries with emphasis on the cooling length limitations and the exergetic efficiency.

  11. Control system design of the CERN/CMS tracker thermal screen

    CERN Document Server

    Carrone, E

    2003-01-01

    The Tracker is one of the CMS (Compact Muon Solenoid experiment) subdetectors to be installed at the LHC (Large Hadron Collider) accelerator, scheduled to start data taking in 2007 at CERN (European Organization for Nuclear Research). The tracker will be operated at a temperature of -10 degree C in order to reduce the radiation damage on the silicon detectors; hence, an insulated environment has to be provided by means of a screen that introduces a thermal separation between the Tracker and the neighboring detection systems. The control system design includes a formal description of the process by means of a thermodynamic model; then, the electrical equivalence is derived. The transfer function is inferred by the ratio of the voltage on the outer skin and the voltage input, i.e. the ratio of the temperature outside the tracker and the heat generated (which is the controlled variable). A PID (Proportional Integral Derivative) controller has been designed using MatLab. The results achieved so far prove that thi...

  12. A Clinical Drug Library Screen Identifies Tosufloxacin as Being Highly Active against Staphylococcus aureus Persisters

    Directory of Open Access Journals (Sweden)

    Hongxia Niu

    2015-07-01

    Full Text Available To identify effective compounds that are active against Staphylococcus aureus (S. aureus persisters, we screened a clinical drug library consisting of 1524 compounds and identified six drug candidates that had anti-persister activity: tosufloxacin, clinafloxacin, sarafloxacin, doxycycline, thiostrepton, and chlorosalicylanilide. Among them, tosufloxacin had the highest anti-persister activity, which could completely eradicate S. aureus persisters within 2 days in vitro. Clinafloxacin ranked the second with very few persisters surviving the drug exposure. Interestingly, we found that both tosufloxacin and trovafloxacin that had high activity against persisters contained at the N-1 position the 2,4-difluorophenyl group, which is absent in other less active quinolones and may be associated with the high anti-persister activity. Further studies are needed to evaluate tosufloxacin in animal models and to explain its unique activity against bacterial persisters. Our findings may have implications for improved treatment of persistent bacterial infections.

  13. A comparison of two psychological screening methods currently used for inpatients in a UK burns service.

    Science.gov (United States)

    Shepherd, Laura; Tew, Victoria; Rai, Lovedeep

    2017-12-01

    Various types of psychological screening are currently used in the UK to identify burn patients who are experiencing psychological distress and may need additional support and intervention during their hospital admission. This audit compared two types of psychological screening in 40 burn inpatients. One screening method was an unpublished questionnaire designed to explore multiple areas of potential distress for those who have experienced burns. The other method was an indirect psychological screen via discussions within multi-disciplinary team (MDT) meetings where a Clinical Psychologist was present to guide and prompt psychological discussions. Data was collected between November 2012 and September 2016. Results suggested that both screening methods were similar in identifying patients who benefit from more formal psychological assessment. Indeed, statistical analysis reported no difference between the two screening methods (N=40, p=.424, two-tailed). In conclusion, measuring distress in burns inpatients using a burns-specific questionnaire and psychological discussions within MDT meetings are similar in their ability to identify patients in need of more thorough psychological assessment. However, both screening methods identified patients who were in need of psychological input when the other did not. This suggests that psychological screening of burns inpatients, and the psychological difficulties that they can present with, is complex. The advantages and disadvantages of both methods of screening are discussed. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  14. Target based screening of small molecule library identifies pregnelonene, a Nrf2 agonist, as a potential radioprotector in zebrafish

    International Nuclear Information System (INIS)

    Joshi, Jayadev; Ghosh, Subhajit; Dimri, Manali; Shrivastava, Nitisha; Indracanti, Prem Kumar; Ray, Jharna

    2014-01-01

    Reactive oxygen species, cellular oxidative stress, tissue inflammation and cell death are the downstream consequences of radiation exposures which ultimately could lead to organism death. Present study aims at identifying potential targets and screening of small molecule compound library for identifying novel and effective radioprotectors. In-silco analysis of known radioprotectors revealed three main function, antioxidant, anti-inflammation and antiapoptosis. In this study, a collection of small molecules (John Hopkins Clinical Compound Library, JHCCL) were screened for these different functions using the biological activity database of NCBI with the help of in-house developed python script. Further, filtering of the JHCCL was done by searching for molecules which are known to be active against target of radiobiological significance, Nrf-2. Close observation of potential hits identified, pregnenolone, as an Nrf-2 agonist which was further evaluated for radioprotection in zebrafish model. Pregnenolone rendered significant protection (at 40 μM; added 1 hour prior to 20 Gy gamma radiation) in terms of damage manifestations (pericardial edema, microcephaly, micropthalmia, yolk sac resorption, curvature of spine, blood flow, body length, heart-beat, blood clot, roughness of skin) and survival advantage (60%) when compared to irradiated control. Further, the ability of pregnenolone to act as a neuroprotectant was also carried out using in-house developed software for assessing neuromotor functions. In comparison to radiation alone group, pregnenolone was found to possess significant neuroactive functions and diminished radiation induced neuronal impairment. Over all these results suggests that pregnenolone is an effective radioprotector which warrants further investigation for validation of its radioprotective action in higher vertebrates. Apart from that the utility of approach to screen out bioactivity data base of various chemical compound libraries for possible

  15. Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells

    Directory of Open Access Journals (Sweden)

    Thomas D. B. MacVicar

    2015-06-01

    Full Text Available Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial autophagy (mitophagy, mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1, as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT and the IP3-receptors (IP3Rs as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R-mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R-mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis.

  16. Resolution V fractional factorial Design for Screening of factors affecting weakly basic drugs liposomal systems.

    Science.gov (United States)

    El-Helaly, Sara Nageeb; Habib, Basant A; Abd El-Rahman, Mohamed K

    2018-04-21

    This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2 V 5-1 ) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2 V 5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies. Copyright © 2017. Published by Elsevier B.V.

  17. Teaching focused echocardiography for rheumatic heart disease screening

    Directory of Open Access Journals (Sweden)

    Daniel Engelman

    2015-01-01

    Full Text Available Screening for rheumatic heart disease (RHD requires workers skilled in echocardiography, which typically involves prolonged, specialized training. Task shifting echocardiographic screening to nonexpert health workers may be a solution in settings with limited human resources. An 8-week training program was designed to train health workers without any prior experience in focused echocardiography for RHD screening. Seven health workers participated. At the completion of training, the health workers performed unsupervised echocardiography on 16 volunteer children with known RHD status. A pediatric cardiologist assessed image quality. Participants provided qualitative feedback. The quality of echocardiograms were high at completion of training (55 of 56 were adequate for diagnosis and all cases of RHD were identified. Feedback was strongly positive. Training health workers to perform focused echocardiography for RHD screening is feasible. After systematic testing for accuracy, this training program could be adapted in other settings seeking to expand echocardiographic capabilities.

  18. Teaching focused echocardiography for rheumatic heart disease screening

    International Nuclear Information System (INIS)

    Engelman, Daniel; Kado, Joseph H; Reményi, Bo; Colquhoun, Samantha M; Watson, Caroline; Rayasidamu, Sera C; Steer, Andrew C

    2005-01-01

    Screening for rheumatic heart disease (RHD) requires workers skilled in echocardiography, which typically involves prolonged, specialized training. Task shifting echocardiographic screening to nonexpert health workers may be a solution in settings with limited human resources. An 8-week training program was designed to train health workers without any prior experience in focused echocardiography for RHD screening. Seven health workers participated. At the completion of training, the health workers performed unsupervised echocardiography on 16 volunteer children with known RHD status. A pediatric cardiologist assessed image quality. Participants provided qualitative feedback. The quality of echocardiograms were high at completion of training (55 of 56 were adequate for diagnosis) and all cases of RHD were identified. Feedback was strongly positive. Training health workers to perform focused echocardiography for RHD screening is feasible. After systematic testing for accuracy, this training program could be adapted in other settings seeking to expand echocardiographic capabilities

  19. Efficient logistic regression designs under an imperfect population identifier.

    Science.gov (United States)

    Albert, Paul S; Liu, Aiyi; Nansel, Tonja

    2014-03-01

    Motivated by actual study designs, this article considers efficient logistic regression designs where the population is identified with a binary test that is subject to diagnostic error. We consider the case where the imperfect test is obtained on all participants, while the gold standard test is measured on a small chosen subsample. Under maximum-likelihood estimation, we evaluate the optimal design in terms of sample selection as well as verification. We show that there may be substantial efficiency gains by choosing a small percentage of individuals who test negative on the imperfect test for inclusion in the sample (e.g., verifying 90% test-positive cases). We also show that a two-stage design may be a good practical alternative to a fixed design in some situations. Under optimal and nearly optimal designs, we compare maximum-likelihood and semi-parametric efficient estimators under correct and misspecified models with simulations. The methodology is illustrated with an analysis from a diabetes behavioral intervention trial. © 2013, The International Biometric Society.

  20. Implementing a screening tool for identifying patients at risk for hereditary breast and ovarian cancer: a statewide initiative.

    Science.gov (United States)

    Brannon Traxler, L; Martin, Monique L; Kerber, Alice S; Bellcross, Cecelia A; Crane, Barbara E; Green, Victoria; Matthews, Roland; Paris, Nancy M; Gabram, Sheryl G A

    2014-10-01

    The Georgia Breast Cancer Genomic Health Consortium is a partnership created with funding from the Centers for Disease Control and Prevention (CDC) to the Georgia Department of Public Health to reduce cancer disparities among high-risk minority women. The project addresses young women at increased risk for hereditary breast and ovarian cancer (HBOC) syndrome through outreach efforts. The consortium provides education and collects surveillance data using the breast cancer genetics referral screening tool (B-RST) available at www.BreastCancerGeneScreen.org . The HBOC educational protocol was presented to 73 staff in 6 public health centers. Staff used the tool during the collection of medical history. Further family history assessments and testing for mutations in the BRCA1/2 genes were facilitated if appropriate. Data was collected from November 2012 through December 2013, including 2,159 screened women. The majority of patients identified as black/African American and were 18-49 years old. Also, 6.0 % (n = 130) had positive screens, and 60.9 % (n = 67) of the 110 patients who agreed to be contacted provided a detailed family history. A total of 47 patients (42.7 %) met National Comprehensive Cancer Network guidelines when family history was clarified. Fourteen (12.7 %) underwent genetic testing; 1 patient was positive for a BRCA2 mutation, and 1 patient was found to carry a variant of uncertain significance. The introduction of genomics practice within public health departments has provided access to comprehensive cancer care for uninsured individuals. The successful implementation of the B-RST into public health centers demonstrates the opportunity for integration of HBOC screening into primary care practices.

  1. shRNA screening identifies JMJD1C as being required for leukemia maintenance

    DEFF Research Database (Denmark)

    Sroczynska, Patrycja; Cruickshank, V Adam; Bukowski, John-Paul

    2014-01-01

    Epigenetic regulatory mechanisms are implicated in the pathogenesis of acute myeloid and lymphoid leukemia (AML and ALL). Recent progress suggests that proteins involved in epigenetic control are amenable to drug intervention, but little is known about the cancer-specific dependency on epigenetic...... candidate drug targets identified in these screens was Jmjd1c. Depletion of Jmjd1c impairs growth and colony formation of mouse MLL-AF9 cells in vitro, as well as establishment of leukemia after transplantation. Depletion of JMJD1C impairs expansion and colony formation of human leukemic cell lines......, with the strongest effect observed in the MLL-rearranged ALL cell line, SEM. In both mouse and human leukemic cells, the growth defect upon JMJD1C depletion appears to be primarily due to increased apoptosis, which implicates JMJD1C as a potential therapeutic target in leukemia....

  2. Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening.

    Science.gov (United States)

    Xing, Li; McDonald, Joseph J; Kolodziej, Steve A; Kurumbail, Ravi G; Williams, Jennifer M; Warren, Chad J; O'Neal, Janet M; Skepner, Jill E; Roberds, Steven L

    2011-03-10

    Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.

  3. Design and preliminary analysis of a vaginal inserter for speculum-free cervical cancer screening.

    Directory of Open Access Journals (Sweden)

    Mercy Nyamewaa Asiedu

    Full Text Available Cervical cancer screening usually requires use of a speculum to provide a clear view of the cervix. The speculum is one potential barrier to screening due to fear of pain, discomfort and embarrassment. The aim of this paper is to present and demonstrate the feasibility of a tampon-sized inserter and the POCkeT Colposcope, a miniature pen sized-colposcope, for comfortable, speculum-free and potentially self-colposcopy.We explored different designs using 3D computer-aided design (CAD software and performed mechanical testing simulations on each. Designs were rapid prototyped and tested using a custom vaginal phantom across a range of vaginal pressures and uterine tilts to select an optimal design. Two final designs were tested with fifteen volunteers to assess cervix visualization, comfort and usability compared to the speculum and the optimal design, the curved-tip inserter, was selected for testing in volunteers.We present a vaginal inserter as an alternative to the standard speculum for use with the POCkeT Colposcope. The device has a slim tubular body with a funnel-like curved tip measuring approximately 2.5 cm in diameter. The inserter has a channel through which a 2 megapixel (MP mini camera with LED illumination fits to enable image capture. Mechanical finite element testing simulations with an applied pressure of 15 cm H2O indicated a high factor of safety (90.9 for the inserter. Testing of the device with a custom vaginal phantom, across a range of supine vaginal pressures and uterine tilts (retroverted, anteverted and sideverted, demonstrated image capture with a visual area comparable to the speculum for a normal/axial positioned uteri and significantly better than the speculum for anteverted and sideverted uteri (p<0.00001. Volunteer studies with self-insertion and physician-assisted cervix image capture showed adequate cervix visualization for 83% of patients. In addition, questionnaire responses from volunteers indicated a 92

  4. Hypersexual Disorder According to the Hypersexual Disorder Screening Inventory in Help-Seeking Swedish Men and Women With Self-Identified Hypersexual Behavior

    Directory of Open Access Journals (Sweden)

    Katarina Görts Öberg, PhD

    2017-12-01

    Öberg KG, Hallberg J, Kaldo V, et al. Hypersexual Disorder According to the Hypersexual Disorder Screening Inventory in Help-Seeking Swedish Men and Women With Self-Identified Hypersexual Behavior. Sex Med 2017;5:e229–e236.

  5. Cancer Screening Among Patients Who Self-Identify as Muslim: Combining Self-Reported Data with Medical Records in a Family Practice Setting.

    Science.gov (United States)

    Lofters, A K; Slater, M; Vahabi, M

    2018-02-01

    Cancer screening is a core component of family medicine but screening inequalities are well documented in Canada for foreign-born persons. Although people of Muslim faith and culture are the fastest growing immigrant population in Canada, there is little information in the literature about their cancer screening practices. Determining screening gaps could inform practice-based quality improvement initiatives. We conducted a retrospective chart review combining patient-level medical record data with self-reported religious affiliation to examine the relationship between religion and cancer screening in a large multi-site urban family practice. Religious affiliation was classified as Muslim, other affiliation, or atheist/no religious affiliation. 5311 patients were included in the study sample. Muslim patients were significantly less likely to prefer English for spoken communication than the other two groups, less likely to be Canadian-born, more likely to have a female family physician, and were over-represented in the lowest income quintile. Muslim women were most likely to be up-to-date on breast cancer screening (85.2 vs. 77.5 % for those with other religions vs. 69.5 % for those with no religious affiliation). There were no significant differences in cancer screening by physician sex. In this pilot study conducted within a primary care practice, we used self-reported data on religious affiliation to examine possible inequities in cancer screening and observed intriguing variations in screening by self-identified religious affiliation. Future efforts to collect and use similar patient-level data should incorporate non-official languages and intensively outreach to patients with less health system contact. Regardless, the family medicine context may be the ideal setting to collect and act on patient-level sociodemographic data such as religious affiliation.

  6. The impact of HPV vaccination on future cervical screening

    DEFF Research Database (Denmark)

    Hestbech, Mie Sara; Lynge, Elsebeth; Kragstrup, Jakob

    2015-01-01

    intraepithelial neoplasia (CIN) grade 2+ and 3+ as cut-off values. RESULTS: The proportion of positive screening tests was reduced from 8.7% before vaccination to 6.5% after vaccination, and the proportion of false-positive screening tests using CIN2+ as a cut-off was reduced from 5.5% pre-vaccination to 4......OBJECTIVES: To explore the interplay between primary and secondary prevention of cervical cancer by estimating future screening outcomes in women offered human papillomavirus (HPV) vaccination when they were sexually naïve. DESIGN: Estimation of outcome of liquid-based cytology screening for a post...... vaccinated for HPV before sexual debut. All identified studies were reviewed by two authors, and weighted pooled estimates of vaccine efficacies were used. MAIN OUTCOME MEASURES: Proportions of positive and false-positive cervical cytologies and positive predictive value (PPV) were calculated using cervical...

  7. The HLJ1-targeting drug screening identified Chinese herb andrographolide that can suppress tumour growth and invasion in non-small-cell lung cancer.

    Science.gov (United States)

    Lai, Yi-Hua; Yu, Sung-Liang; Chen, Hsuan-Yu; Wang, Chi-Chung; Chen, Huei-Wen; Chen, Jeremy J W

    2013-05-01

    HLJ1 is a novel tumour suppressor and is a potential druggable target for non-small-cell lung cancer (NSCLC). In this report, using a promoter-containing enhancer region as the HLJ1-targeting drug-screening platform, we identified several herbal compounds from a Chinese herbal bank with the capacity to enhance HLJ1 promoter activity and suppress tumour growth and invasion of NSCLC. Among the herbal drugs identified, the andrographolide (from Andrographis paniculata [Burm. f.] Nees.) most significantly induced HLJ1 expression and suppressed tumorigenesis both in vitro and in vivo. The andrographolide upregulates HLJ1 via JunB activation, which modulates AP-2α binding at the MMP-2 promoter and represses the expression of MMP-2. In addition, silencing of HLJ1 partially reverses the inhibition of cancer-cell invasion by andrographolide. Microarray transcriptomic analysis was performed to comprehensively depict the andrographolide-regulated signalling pathways. We showed that andrographolide can affect 939 genes (analysis of variance, false discovery rate andrographolide on anticancer invasion and proliferation. In conclusion, the HLJ1-targeting drug-screening platform is useful for screening of novel anticancer compounds. Using this platform, we identified andrographolide is a promising new anticancer agent that could suppress tumour growth and invasion in NSCLC.

  8. Food Insecurity Screening in Pediatric Primary Care: Can Offering Referrals Help Identify Families in Need?

    Science.gov (United States)

    Bottino, Clement J; Rhodes, Erinn T; Kreatsoulas, Catherine; Cox, Joanne E; Fleegler, Eric W

    2017-07-01

    To describe a clinical approach for food insecurity screening incorporating a menu offering food-assistance referrals, and to examine relationships between food insecurity and referral selection. Caregivers of 3- to 10-year-old children presenting for well-child care completed a self-administered questionnaire on a laptop computer. Items included the US Household Food Security Survey Module: 6-Item Short Form (food insecurity screen) and a referral menu offering assistance with: 1) finding a food pantry, 2) getting hot meals, 3) applying for Supplemental Nutrition Assistance Program (SNAP), and 4) applying for Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Referrals were offered independent of food insecurity status or eligibility. We examined associations between food insecurity and referral selection using multiple logistic regression while adjusting for covariates. A total of 340 caregivers participated; 106 (31.2%) reported food insecurity, and 107 (31.5%) selected one or more referrals. Forty-nine caregivers (14.4%) reported food insecurity but selected no referrals; 50 caregivers (14.7%) selected one or more referrals but did not report food insecurity; and 57 caregivers (16.8%) both reported food insecurity and selected one or more referrals. After adjustment, caregivers who selected one or more referrals had greater odds of food insecurity compared to caregivers who selected no referrals (adjusted odds ratio 4.0; 95% confidence interval 2.4-7.0). In this sample, there was incomplete overlap between food insecurity and referral selection. Offering referrals may be a helpful adjunct to standard screening for eliciting family preferences and identifying unmet social needs. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

  9. Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations.

    Science.gov (United States)

    Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj

    2016-08-01

    Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed.

  10. Inter-rater reliability and stability of diagnoses of autism spectrum disorder in children identified through screening at a very young age.

    Science.gov (United States)

    van Daalen, Emma; Kemner, Chantal; Dietz, Claudine; Swinkels, Sophie H N; Buitelaar, Jan K; van Engeland, Herman

    2009-11-01

    To examine the inter-rater reliability and stability of autism spectrum disorder (ASD) diagnoses made at a very early age in children identified through a screening procedure around 14 months of age. In a prospective design, preschoolers were recruited from a screening study for ASD. The inter-rater reliability of the diagnosis of ASD was measured through an independent assessment of a randomly selected subsample of 38 patients by two other psychiatrists. The diagnoses at 23 months and 42 months of 131 patients, based on the clinical assessment and the diagnostic classifications of standardised instruments, were compared to evaluate stability of the diagnosis of ASD. Inter-rater reliability on a diagnosis of ASD versus non-ASD at 23 months was 87% with a weighted kappa of 0.74 (SE 0.11). The stability of the different diagnoses in the autism spectrum was 63% for autistic disorder, 54% for pervasive developmental disorder, not otherwise specified (PDD-NOS), and 91% for the whole category of ASD. Most diagnostic changes at 42 months were within the autism spectrum from autistic disorder to PDD-NOS and were mainly due to diminished symptom severity. Children who moved outside the ASD category at 42 months made significantly larger gains in cognitive and language skills than children with a stable ASD diagnosis. In conclusion, the inter-rater reliability and stability of the diagnoses of ASD established at 23 months in this population-based sample of very young children are good.

  11. Evaluation of a new website design for iwantthekit for chlamydia, gonorrhea, and trichomonas screening.

    Science.gov (United States)

    Kuder, Margaret; Goheen, Mary Jett; Dize, Laura; Barnes, Mathilda; Gaydos, Charlotte A

    2015-05-01

    The www.iwantthekit.org provides Internet-based, at-home sexually transmitted infection screening. The Web site implemented an automated test result access system. To evaluate potential deleterious effects of the new system, we analyzed demographics, Web site usage, and treatment. The post-Web site design captured more participant information and no decrease in requests, kit return, or treatment adherence.

  12. INJECTION TECHNOLOGY RESEARCH OF THE PROTECTIVE SCREEN

    Directory of Open Access Journals (Sweden)

    MENEJLYUK A. I.

    2016-12-01

    Full Text Available Formulation of the problem. This article contains information about the methods and the planning principles used in experimental research study of the injection technology of impervious screen. Today, there are ways to create impervious screens and curtains solve soil protection issues in the field impermeable layer arrangement at a shallow depth. However, for Ukraine, in the burial sites of radiation and other wastes is urgent issue of protection of underground space in places with deep impermeable layer. Classical methods can not fully solve such problems. To solve them, you need to develop innovative technology to create such a screen, which will lie authentic sole object to be protected, at the project depth. For the experiments, it is necessary to choose the most important indicator, and technological factors affecting it. This is due to the fact that the proposed technology provides for lesser known technical solutions, the use of which should ultimately result in impervious screens with desired properties. Goal. The aim of this study is the selection of technological parameters of injection, design of experiments and the selection of indicators characterizing the efficient operation of the screen. Such constructs must first have almost zero permeability. In this paper, it was of interest to study the influence of process parameters on the filtration rate of the protective screen. Conclusion. As a result of the design of experiments, the basic technological factors that have a significant effect on the studied parameters. varying levels of these factors are also identified, which in turn makes it possible to determine the optimum process parameters creating a screen that meets all the desired properties and characteristics. Based on a series of experiments it is possible to obtain optimal formulations for different types of soils.

  13. Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity

    Science.gov (United States)

    Marjanovic, Jasmina; Chalupska, Dominika; Patenode, Caroline; Coster, Adam; Arnold, Evan; Ye, Alice; Anesi, George; Lu, Ying; Okun, Ilya; Tkachenko, Sergey; Haselkorn, Robert; Gornicki, Piotr

    2010-01-01

    Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In “proof of concept” experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 μM IC50 and having no effect on human ACC1 at 100 μM. PMID:20439761

  14. Optimal screening of children with acute malnutrition requires a change in current WHO guidelines as MUAC and WHZ identify different patient groups

    DEFF Research Database (Denmark)

    Laillou, Arnaud; Prak, Sophonneary; de Groot, Richard

    2014-01-01

    BACKGROUND: Timely treatment of acute malnutrition in children 500,000 deaths annually. Screening at community level is essential to identify children with malnutrition. Current WHO guidelines for community screening for malnutrition recommend a Mid Upper Arm...... Circumference (MUAC) of malnutrition (SAM). However, it is currently unclear how MUAC relates to the other indicator used to define acute malnutrition: weight-for-height Z-score (WHZ). METHODS: Secondary data from >11,000 Cambodian children, obtained by different surveys between...... 2010 and 2012, was used to calculate sensitivity and ROC curves for MUAC and WHZ. FINDINGS: The secondary analysis showed that using the current WHO cut-off of 115 mm for screening for severe acute malnutrition over 90% of children with a weight-for-height z-score (WHZ)

  15. Newborn blood spot screening for sickle cell disease by using tandem mass spectrometry: implementation of a protocol to identify only the disease states of sickle cell disease.

    Science.gov (United States)

    Moat, Stuart J; Rees, Derek; King, Lawrence; Ifederu, Adeboye; Harvey, Katie; Hall, Kate; Lloyd, Geoff; Morrell, Christine; Hillier, Sharon

    2014-02-01

    The currently recommended technologies of HPLC and isoelectric focusing for newborn blood spot screening for sickle cell disease (SCD) identify both the disease and carrier states, resulting in large numbers of infants being followed up unnecessarily. Analysis of blood spot tryptic peptides performed by using tandem mass spectrometry (MS/MS) is an alternative technology to detect hemoglobin (Hb) variant disorders. We analyzed 2154 residual newborn blood spots and 675 newborn blood spots from infants with Hb variants by using MS/MS after trypsin digestion. Screening cutoffs were developed by using the ratio between the variant peptide-to-wild-type peptide abundance for HbS, C, D(Punjab), O(Arab), Lepore, and E peptides. A postanalytical data analysis protocol was developed using these cutoffs to detect only the disease states of SCD and not to identify carrier states. A parallel study of 13 249 newborn blood spots from a high-prevalence SCD area were analyzed by both MS/MS and HPLC. Screening cutoffs developed distinguished the infants with the disease states of SCD, infants who were carriers of SCD, and infants with normal Hb. In the parallel study no false-negative results were identified, and all clinically relevant cases were correctly identified using the MS/MS protocol. Unblinding the data revealed a total of 328 carrier infants that were successfully excluded by the protocol. The screening protocol developed correctly identified infants with the disease states of SCD. Furthermore, large numbers of sickle cell carrier infants were successfully not identified, thereby avoiding unnecessary follow-up testing and referral for genetic counseling.

  16. A multicopy suppressor screening approach as a means to identify antibiotic resistance determinant candidates in Yersinia pestis

    Directory of Open Access Journals (Sweden)

    Moy Richard L

    2008-07-01

    Full Text Available Abstract Background Yersinia pestis is the causative agent of plague and a potential agent of bioterrorism and biowarfare. The plague biothreat and the emergence of multidrug-resistant plague underscore the need to increase our understanding of the intrinsic potential of Y. pestis for developing antimicrobial resistance and to anticipate the mechanisms of resistance that may emerge in Y. pestis. Identification of Y. pestis genes that, when overexpressed, are capable of reducing antibiotic susceptibility is a useful strategy to expose genes that this pathogen may rely upon to evolve antibiotic resistance via a vertical modality. In this study, we explored the use of a multicopy suppressor, Escherichia coli host-based screening approach as a means to expose antibiotic resistance determinant candidates in Y. pestis. Results We constructed a multicopy plasmid-based, Y. pestis genome-wide expression library of nearly 16,000 clones in E. coli and screened the library for suppressors of the antimicrobial activity of ofloxacin, a fluoroquinolone antibiotic. The screen permitted the identification of a transcriptional regulator-encoding gene (robAYp that increased the MIC99 of ofloxacin by 23-fold when overexpressed from a multicopy plasmid in Y. pestis. Additionally, we found that robAYp overexpression in Y. pestis conferred low-level resistance to many other antibiotics and increased organic solvent tolerance. Overexpression of robAYp also upregulated the expression of several efflux pumps in Y. pestis. Conclusion Our study provides proof of principle for the use of multicopy suppressor screening based on the tractable and easy-to-manipulate E. coli host as a means to identify antibiotic resistance determinant candidates of Y. pestis.

  17. Optical pre-screening in breast screening programs: Can we identify women who benefit most from limited mammography resources?

    Science.gov (United States)

    Walter, Jane; Loshchenov, Maxim; Zhilkin, Vladimir; Peake, Rachel; Stone, Jennifer; Lilge, Lothar

    2017-04-01

    Background: In excess of 60% of all cancers are detected in low and middle-income countries, with breast cancer (BC) the dominant malignancy for women. Incidence rates continue to climb, most noticeably in the less than 50-year-old population. Expansion of mammography infrastructure and resources is lacking, resulting in over 60% of women diagnosed with stage III/IV BC in the majority of these countries. Optical Breast Spectroscopy (OBS) was shown to correlate well with mammographic breast density (MBD). OBS could aid breast screening programs in low- and middle-income countries by lowering the number of mammographs required for complete population coverage. However, its performance needs to be tested in large population trails to ensure high sensitivity and acceptable specificity. Methods: For the planned studies in low- and middle-income countries in different continents, online methods need to be implemented to monitor the performance and data collection by these devices, operated by trained nurses. Based on existing datasets, procedures were developed to validate an individual woman's data integrity and to identify operator errors versus system malfunctions. Results: Using a dataset comprising spectra from 360 women collected by 2 instruments in different locations and with 3 different trained operators, automated methods were developed to identify 100% of the source or photodetector malfunctions as well as incorrect calibrations and 96% of instances of insufficient tissue contact. Conclusions: Implementing the dataset validation locally in each instrument and tethered to a cloud database will allow the planned clinical trials to proceed.

  18. Thyroid Peroxidase Antibody and Screening for Postpartum Thyroid Dysfunction

    Directory of Open Access Journals (Sweden)

    Mohamed A. Adlan

    2011-01-01

    Full Text Available Postpartum thyroid dysfunction (PPTD is a common disorder which causes considerable morbidity in affected women. The availability of effective treatment for hypothyroid PPTD, the occurrence of the disease in subsequent pregnancies and the need to identify subjects who develop long term hypothyroidism, has prompted discussion about screening for this disorder. There is currently no consensus about screening as investigations hitherto have been variable in their design, definitions and assay frequency and methodology. There is also a lack of consensus about a suitable screening tool although thyroid peroxidase antibody (TPOAb is a leading contender. We present data about the use of TPOAb in early pregnancy and its value as a screening tool. Although its positive predictive value is moderate, its sensitivity and specificity when used in early pregnancy are comparable or better compared to other times during pregnancy and the postpartum period. Recent studies have also confirmed this strategy to be cost effective and to compare favourably with other screening strategies. We also explore the advantages of universal screening.

  19. Rational approach to identify newer caspase-1 inhibitors using pharmacophore based virtual screening, docking and molecular dynamic simulation studies.

    Science.gov (United States)

    Patel, Shivani; Modi, Palmi; Chhabria, Mahesh

    2018-05-01

    Caspase-1 is a key endoprotease responsible for the post-translational processing of pro-inflammatory cytokines IL-1β, 18 & 33. Excessive secretion of IL-1β leads to numerous inflammatory and autoimmune diseases. Thus caspase-1 inhibition would be considered as an important therapeutic strategy for development of newer anti-inflammatory agents. Here we have employed an integrated virtual screening by combining pharmacophore mapping and docking to identify small molecules as caspase-1 inhibitors. The ligand based 3D pharmacophore model was generated having the essential structural features of (HBA, HY & RA) using a data set of 27 compounds. A validated pharmacophore hypothesis (Hypo 1) was used to screen ZINC and Minimaybridge chemical databases. The retrieved virtual hits were filtered by ADMET properties and molecular docking analysis. Subsequently, the cross-docking study was also carried out using crystal structure of caspase-1, 3, 7 and 8 to identify the key residual interaction for specific caspase-1 inhibition. Finally, the best mapped and top scored (ZINC00885612, ZINC72003647, BTB04175 and BTB04410) molecules were subjected to molecular dynamics simulation for accessing the dynamic structure of protein after ligand binding. This study identifies the most promising hits, which can be leads for the development of novel caspase-1 inhibitors as anti-inflammatory agents. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Early screening for dyslexia--a collaborative pilot project.

    Science.gov (United States)

    Ball, S; Becker, T; Boys, M; Davies, S; Noton, H

    2001-01-01

    An ongoing collaborative project, currently being piloted in 12 Wiltshire primary schools, is described. The aim is to provide a means of identifying potentially dyslexic children by the end of Key Stage 1 (Year 2) with a view to early intervention. The causal links identified by research between phonological skills and literacy development are taken as the theoretical basis of an initial screening procedure, and an intervention package is implemented for identified children. Those demonstrating persistent difficulties one year later are further assessed over a school term using an assessment package designed to identify those children showing a dyslexic profile. Further intervention is then planned and implemented.

  1. Barriers and strategies for identifying and managing risk factors of cardiovascular diseases in levels of preventing, screening, and treating

    Directory of Open Access Journals (Sweden)

    Saber Azami Aghdash

    2015-11-01

    Full Text Available Introduction: Cardiovascular diseases (CVD are of the main causes of mortality in the world and impose a heavy economic, social, and health burden on society. Therefore, the objective of this study was to determine the barriers and strategies for identifying and managing risk factors of CVD in levels of preventing, screening, and treating. Methods: During present qualitative study with phenomenological approach, 60 subjects of cardiologists, nurses, patients, and their relatives were selected based on purposive sampling from educational-medical cardiothoracic subspecialty centers. Data were collected using an open-ended questionnaire and was extracted and analyzed with content analysis method. Results: Barriers were divided into three groups of individual barriers (low awareness, delay in referring for treatment and screening, incorrect beliefs, and not caring about health, socio-economic barriers (high costs, lack of resources, mental and psychological pressures, and health care barriers (non-alignment of doctors, being therapy-oriented, managerial and planning weaknesses, and lack of health care facilities. The most important presenting strategies are: providing public educations, improving family physician program, reduction of costs, cooperation of patients, and using functional indices to evaluate and improve the quality of services. Conclusion: Low awareness of people, high costs of services, lack of health care facilities, socio-cultural problems of people, and delay in referring of people, for treatment and screening are of the most important barriers of proper identifying and managing risk factors of CVD. Strategies provided in this study to overcome these barriers could be used.

  2. Screening and Identifying Antioxidative Components in Ginkgo biloba Pollen by DPPH-HPLC-PAD Coupled with HPLC-ESI-MS2

    Science.gov (United States)

    Netrusov, A. I.; Zhou, Qingxin; Guo, Danyang; Liu, Xiaoyong; He, Hailun; Xin, Xue; Wang, Yifen; Chen, Leilei

    2017-01-01

    The Ginkgo biloba is one of ancient trees that exists from billions of years ago, its leaf and nut are used as herbs and foods in China, while so far its pollen does not have any application except pollination. In order to evaluate the antioxidant activity of Ginkgo biloba pollen, and rapidly screen its antioxidative components, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging ability, total flavonoid, total phenol, and proanthocyanidin of Ginkgo biloba pollen were determined and compared with those of Ginkgo biloba leaf and nut, and the off-line DPPH-HPLC-PAD and HPLC-ESI-MS2 were applied for screening and identifying the antioxidant flavonoids in Ginkgo biloba pollen. The results showed that the DPPH scavenging ability of Ginkgo biloba pollen was much higher than Ginkgo biloba nut, but lower than Ginkgo biloba leaf, while the total content of flavonoid in Ginkgo biloba pollen was approximately 4.37 times higher than in Ginkgo biloba leaf. Further studies found that the major flavonol aglycone in Ginkgo biloba pollen was kaempferol, which accounted for 96.71% of the total aglycones (includes quercetin, kaempferol and isorhamnetin), and the main flavonoid components in Ginkgo biloba pollen were flavonoid glycosides. Finally, ten antioxidant peaks were screened and identified to be flavonoids (including kaempferol and nine flavonoid glycosides), so flavonoids were likely to be the main antioxidant components in GP, and among them, three novel kaempferol glycosides (peaks 1, 2, and 3) were found in Ginkgo biloba pollen for the first time, which had never been found in Ginkgo biloba. PMID:28095510

  3. Identifying lubricant options for compressor bearing designs

    Science.gov (United States)

    Karnaz, J.; Seeton, C.; Dixon, L.

    2017-08-01

    Today’s refrigeration and air conditioning market is not only driven by the environmental aspects of the refrigerants, but also by the energy efficiency and reliability of system operation. Numerous types of compressor designs are used in refrigeration and air conditioning applications which means that different bearings are used; and in some cases, multiple bearing types within a single compressor. Since only one lubricant is used, it is important to try to optimize the lubricant to meet the various demands and requirements for operation. This optimization entails investigating different types of lubricant chemistries, viscosities, and various formulation options. What makes evaluating these options more challenging is the refrigerant which changes the properties of the lubricant delivered to the bearing. Once the lubricant and refrigerant interaction are understood, through various test methods, then work can start on collaborating with compressor engineers on identifying the lubricant chemistry and formulation options. These interaction properties are important to the design engineer to make decisions on the adequacy of the lubricant before compressor tests are started. This paper will discuss the process to evaluate lubricants for various types of compressors and bearing design with focus on what’s needed for current refrigerant trends. In addition, the paper will show how the lubricant chemistry choice can be manipulated through understanding of the bearing design and knowledge of interaction with the refrigerant to maximize performance. Emphasis will be placed on evaluation of synthetic lubricants for both natural and synthetic low GWP refrigerants.

  4. Strategies to design clinical studies to identify predictive biomarkers in cancer research.

    Science.gov (United States)

    Perez-Gracia, Jose Luis; Sanmamed, Miguel F; Bosch, Ana; Patiño-Garcia, Ana; Schalper, Kurt A; Segura, Victor; Bellmunt, Joaquim; Tabernero, Josep; Sweeney, Christopher J; Choueiri, Toni K; Martín, Miguel; Fusco, Juan Pablo; Rodriguez-Ruiz, Maria Esperanza; Calvo, Alfonso; Prior, Celia; Paz-Ares, Luis; Pio, Ruben; Gonzalez-Billalabeitia, Enrique; Gonzalez Hernandez, Alvaro; Páez, David; Piulats, Jose María; Gurpide, Alfonso; Andueza, Mapi; de Velasco, Guillermo; Pazo, Roberto; Grande, Enrique; Nicolas, Pilar; Abad-Santos, Francisco; Garcia-Donas, Jesus; Castellano, Daniel; Pajares, María J; Suarez, Cristina; Colomer, Ramon; Montuenga, Luis M; Melero, Ignacio

    2017-02-01

    The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Gestational diabetes mellitus in Europe: prevalence, current screening practice and barriers to screening.

    LENUS (Irish Health Repository)

    Buckley, B S

    2011-12-12

    Background:  Gestational diabetes mellitus is a potentially serious condition that affects many pregnancies and its prevalence is increasing. Evidence suggests early detection and treatment improves outcomes, but this is hampered by continued disagreement and inconsistency regarding many aspects of its diagnosis. Methods:  The Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention (DALI) research programme aims to promote pan-European standards in the detection and diagnosis of gestational diabetes and to develop effective preventive interventions. To provide an overview of the context within which the programme will be conducted and its findings interpreted, systematic searching and narrative synthesis have been used to identify and review the best available European evidence relating to the prevalence of gestational diabetes, current screening practices and barriers to screening. Results:  Prevalence is most often reported as 2-6% of pregnancies. Prevalence may be lower towards the Northern Atlantic seaboard of Europe and higher in the Southern Mediterranean seaboard. Screening practice and policy is inconsistent across Europe, hampered by lack of consensus on testing methods, diagnostic glycaemic thresholds and the value of routine screening. Poor clinician awareness of gestational diabetes, its diagnosis and local clinical guidelines further undermine detection of gestational diabetes. Conclusions:  Europe-wide agreement on screening approaches and diagnostic standards for gestational diabetes could lead to better detection and treatment, improved outcomes for women and children and a strengthened evidence base. There is an urgent need for well-designed research that can inform decisions on best practice in gestational diabetes mellitus screening and diagnosis. © 2011 The Authors. Diabetic Medicine© 2011 Diabetes UK.

  6. Randomized controlled dissemination study of community-to-clinic navigation to promote CRC screening: Study design and implications.

    Science.gov (United States)

    Larkey, Linda; Szalacha, Laura; Herman, Patricia; Gonzalez, Julie; Menon, Usha

    2017-02-01

    Regular screening facilitates early diagnosis of colorectal cancer (CRC) and reduction of CRC morbidity and mortality. Screening rates for minorities and low-income populations remain suboptimal. Provider referral for CRC screening is one of the strongest predictors of adherence, but referrals are unlikely among those who have no clinic home (common among poor and minority populations). This group randomized controlled study will test the effectiveness of an evidence based tailored messaging intervention in a community-to-clinic navigation context compared to no navigation. Multicultural, underinsured individuals from community sites will be randomized (by site) to receive CRC screening education only, or education plus navigation. In Phase I, those randomized to education plus navigation will be guided to make a clinic appointment to receive a provider referral for CRC screening. Patients attending clinic appointments will continue to receive navigation until screened (Phase II) regardless of initial arm assignment. We hypothesize that those receiving education plus navigation will be more likely to attend clinic appointments (H1) and show higher rates of screening (H2) compared to those receiving education only. Phase I group assignment will be used as a control variable in analysis of screening follow-through in Phase II. Costs per screening achieved will be evaluated for each condition and the RE-AIM framework will be used to examine dissemination results. The novelty of our study design is the translational dissemination model that will allow us to assess the real-world application of an efficacious intervention previously tested in a randomized controlled trial. Copyright © 2016. Published by Elsevier Inc.

  7. Distributed design approach in persistent identifiers systems

    Science.gov (United States)

    Golodoniuc, Pavel; Car, Nicholas; Klump, Jens

    2017-04-01

    The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID) systems, of which there is a great variety in terms of technical and social implementations, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have catered for identifier uniqueness, integrity, persistence, and trustworthiness, regardless of the identifier's application domain, the scope of which has expanded significantly in the past two decades. Since many PID systems have been largely conceived and developed by small communities, or even a single organisation, they have faced challenges in gaining widespread adoption and, most importantly, the ability to survive change of technology. This has left a legacy of identifiers that still exist and are being used but which have lost their resolution service. We believe that one of the causes of once successful PID systems fading is their reliance on a centralised technical infrastructure or a governing authority. Golodoniuc et al. (2016) proposed an approach to the development of PID systems that combines the use of (a) the Handle system, as a distributed system for the registration and first-degree resolution of persistent identifiers, and (b) the PID Service (Golodoniuc et al., 2015), to enable fine-grained resolution to different information object representations. The proposed approach solved the problem of guaranteed first-degree resolution of identifiers, but left fine-grained resolution and information delivery under the control of a single authoritative source, posing risk to the long-term availability of information resources. Herein, we develop these approaches further and explore the potential of large-scale decentralisation at all levels: (i) persistent identifiers and information resources registration; (ii) identifier resolution; and (iii) data delivery. To achieve large-scale decentralisation

  8. Screening for Intimate Partner Violence in Orthopedic Patients: A Comparison of Three Screening Tools

    Science.gov (United States)

    Sprague, Sheila; Madden, Kim; Dosanjh, Sonia; Petrisor, Brad; Schemitsch, Emil H.; Bhandari, Mohit

    2012-01-01

    Accurately identifying victims of intimate partner violence (IPV) can be a challenge for clinicians and clinical researchers. Multiple instruments have been developed and validated to identify IPV in patients presenting to health care practitioners, including the Woman Abuse Screening Tool (WAST) and the Partner Violence Screen (PVS). The purpose…

  9. Triazole incorporated thiazoles as a new class of anticonvulsants: design, synthesis and in vivo screening.

    Science.gov (United States)

    Siddiqui, Nadeem; Ahsan, Waquar

    2010-04-01

    Various 3-[4-(substituted phenyl)-1,3-thiazol-2-ylamino]-4-(substituted phenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones (7a-t) were designed keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity. Thiazole and triazole moieties being anticonvulsants were clubbed together to get the titled compounds and their in vivo anticonvulsant screening were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Two compounds 7d and 7f showed significant anticonvulsant activity in both the screens with ED(50) values 23.9 mg/kg and 13.4 mg/kg respectively in MES screen and 178.6 mg/kg and 81.6 mg/kg respectively in scPTZ test. They displayed a wide margin of safety with Protective index (PI), median hypnotic dose (HD(50)) and median lethal dose (LD(50)) much higher than the standard drugs. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  10. A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay.

    Directory of Open Access Journals (Sweden)

    Jing Lu

    Full Text Available Polo-like kinase 1 (PLK1, one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.

  11. Virtual screening filters for the design of type II p38 MAP kinase inhibitors: a fragment based library generation approach.

    Science.gov (United States)

    Badrinarayan, Preethi; Sastry, G Narahari

    2012-04-01

    In this work, we introduce the development and application of a three-step scoring and filtering procedure for the design of type II p38 MAP kinase leads using allosteric fragments extracted from virtual screening hits. The design of the virtual screening filters is based on a thorough evaluation of docking methods, DFG-loop conformation, binding interactions and chemotype specificity of the 138 p38 MAP kinase inhibitors from Protein Data Bank bound to DFG-in and DFG-out conformations using Glide, GOLD and CDOCKER. A 40 ns molecular dynamics simulation with the apo, type I with DFG-in and type II with DFG-out forms was carried out to delineate the effects of structural variations on inhibitor binding. The designed docking-score and sub-structure filters were first tested on a dataset of 249 potent p38 MAP kinase inhibitors from seven diverse series and 18,842 kinase inhibitors from PDB, to gauge their capacity to discriminate between kinase and non-kinase inhibitors and likewise to selectively filter-in target-specific inhibitors. The designed filters were then applied in the virtual screening of a database of ten million (10⁷) compounds resulting in the identification of 100 hits. Based on their binding modes, 98 allosteric fragments were extracted from the hits and a fragment library was generated. New type II p38 MAP kinase leads were designed by tailoring the existing type I ATP site binders with allosteric fragments using a common urea linker. Target specific virtual screening filters can thus be easily developed for other kinases based on this strategy to retrieve target selective compounds. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. HCS-Neurons: identifying phenotypic changes in multi-neuron images upon drug treatments of high-content screening.

    Science.gov (United States)

    Charoenkwan, Phasit; Hwang, Eric; Cutler, Robert W; Lee, Hua-Chin; Ko, Li-Wei; Huang, Hui-Ling; Ho, Shinn-Ying

    2013-01-01

    High-content screening (HCS) has become a powerful tool for drug discovery. However, the discovery of drugs targeting neurons is still hampered by the inability to accurately identify and quantify the phenotypic changes of multiple neurons in a single image (named multi-neuron image) of a high-content screen. Therefore, it is desirable to develop an automated image analysis method for analyzing multi-neuron images. We propose an automated analysis method with novel descriptors of neuromorphology features for analyzing HCS-based multi-neuron images, called HCS-neurons. To observe multiple phenotypic changes of neurons, we propose two kinds of descriptors which are neuron feature descriptor (NFD) of 13 neuromorphology features, e.g., neurite length, and generic feature descriptors (GFDs), e.g., Haralick texture. HCS-neurons can 1) automatically extract all quantitative phenotype features in both NFD and GFDs, 2) identify statistically significant phenotypic changes upon drug treatments using ANOVA and regression analysis, and 3) generate an accurate classifier to group neurons treated by different drug concentrations using support vector machine and an intelligent feature selection method. To evaluate HCS-neurons, we treated P19 neurons with nocodazole (a microtubule depolymerizing drug which has been shown to impair neurite development) at six concentrations ranging from 0 to 1000 ng/mL. The experimental results show that all the 13 features of NFD have statistically significant difference with respect to changes in various levels of nocodazole drug concentrations (NDC) and the phenotypic changes of neurites were consistent to the known effect of nocodazole in promoting neurite retraction. Three identified features, total neurite length, average neurite length, and average neurite area were able to achieve an independent test accuracy of 90.28% for the six-dosage classification problem. This NFD module and neuron image datasets are provided as a freely downloadable

  13. A genome-wide RNAi screen identifies regulators of cholesterol-modified hedgehog secretion in Drosophila.

    Directory of Open Access Journals (Sweden)

    Reid Aikin

    Full Text Available Hedgehog (Hh proteins are secreted molecules that function as organizers in animal development. In addition to being palmitoylated, Hh is the only metazoan protein known to possess a covalently-linked cholesterol moiety. The absence of either modification severely disrupts the organization of numerous tissues during development. It is currently not known how lipid-modified Hh is secreted and released from producing cells. We have performed a genome-wide RNAi screen in Drosophila melanogaster cells to identify regulators of Hh secretion. We found that cholesterol-modified Hh secretion is strongly dependent on coat protein complex I (COPI but not COPII vesicles, suggesting that cholesterol modification alters the movement of Hh through the early secretory pathway. We provide evidence that both proteolysis and cholesterol modification are necessary for the efficient trafficking of Hh through the ER and Golgi. Finally, we identified several putative regulators of protein secretion and demonstrate a role for some of these genes in Hh and Wingless (Wg morphogen secretion in vivo. These data open new perspectives for studying how morphogen secretion is regulated, as well as provide insight into regulation of lipid-modified protein secretion.

  14. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

    Science.gov (United States)

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R; Herrmann, Harald; Sison, Edward A; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J; Johns, Christopher; Chicas, Agustin; Mulloy, James C; Kogan, Scott C; Brown, Patrick; Valent, Peter; Bradner, James E; Lowe, Scott W; Vakoc, Christopher R

    2011-08-03

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

  15. Thermodynamic Studies for Drug Design and Screening

    Science.gov (United States)

    Garbett, Nichola C.; Chaires, Jonathan B.

    2012-01-01

    Introduction A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. Areas covered This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 – 2011 using the Science Citation Index and PUBMED and the keywords listed below. Expert opinion The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically-driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development towards an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. PMID:22458502

  16. Thermodynamic studies for drug design and screening.

    Science.gov (United States)

    Garbett, Nichola C; Chaires, Jonathan B

    2012-04-01

    A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 - 2011 using the Science Citation Index and PUBMED and the keywords listed below. The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development toward an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in the design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. © 2012 Informa UK, Ltd.

  17. High throughput Screening to Identify Natural Human Monoamine Oxidase B Inhibitors

    Science.gov (United States)

    Mazzio, E; Deiab, S; Park, K; Soliman, KFA

    2012-01-01

    Age-related increase in monoamine oxidase B (MAO-B) may contribute to CNS neurodegenerative diseases. Moreover, MAO-B inhibitors are used in the treatment of idiopathic Parkinson disease as preliminary monotherapy or adjunct therapy with L-dopa. To date, meager natural sources of MAO-B inhibitors have been identified, and the relative strength, potency and rank of many plants relative to standard drugs such as Selegiline (L-deprenyl, Eldepryl) are not known. In this work, we developed and utilized a high throughput enzyme microarray format to screen and evaluate 905 natural product extracts (0.025–.7 mg/ml) to inhibit human MAO-B derived from BTI-TN-5B1-4 cells infected with recombinant baculovirus. The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis-matrix assisted laser desorption ionization-time-of-flight-tandem mass spectroscopy, and enzyme activity was confirmed by [1] substrate conversion (3-mM benzylamine) to H202 and [2] benzaldehyde. Of the 905 natural extracts tested, the lowest IC50s [Comfrey, Bringraj, Skullcap, Kava-kava, Wild Indigo, Gentian and Green Tea. In conclusion, the data reflect relative potency information by rank of commonly used herbs and plants that contain human MAO-B inhibitory properties in their natural form. PMID:22887993

  18. Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

    Science.gov (United States)

    Ryall, Karen A; Shin, Jimin; Yoo, Minjae; Hinz, Trista K; Kim, Jihye; Kang, Jaewoo; Heasley, Lynn E; Tan, Aik Choon

    2015-12-01

    Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/. aikchoon.tan@ucdenver.edu. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. A comparative genomics screen identifies a Sinorhizobium meliloti 1021 sodM-like gene strongly expressed within host plant nodules

    Directory of Open Access Journals (Sweden)

    Queiroux Clothilde

    2012-05-01

    Full Text Available Abstract Background We have used the genomic data in the Integrated Microbial Genomes system of the Department of Energy’s Joint Genome Institute to make predictions about rhizobial open reading frames that play a role in nodulation of host plants. The genomic data was screened by searching for ORFs conserved in α-proteobacterial rhizobia, but not conserved in closely-related non-nitrogen-fixing α-proteobacteria. Results Using this approach, we identified many genes known to be involved in nodulation or nitrogen fixation, as well as several new candidate genes. We knocked out selected new genes and assayed for the presence of nodulation phenotypes and/or nodule-specific expression. One of these genes, SMc00911, is strongly expressed by bacterial cells within host plant nodules, but is expressed minimally by free-living bacterial cells. A strain carrying an insertion mutation in SMc00911 is not defective in the symbiosis with host plants, but in contrast to expectations, this mutant strain is able to out-compete the S. meliloti 1021 wild type strain for nodule occupancy in co-inoculation experiments. The SMc00911 ORF is predicted to encode a “SodM-like” (superoxide dismutase-like protein containing a rhodanese sulfurtransferase domain at the N-terminus and a chromate-resistance superfamily domain at the C-terminus. Several other ORFs (SMb20360, SMc01562, SMc01266, SMc03964, and the SMc01424-22 operon identified in the screen are expressed at a moderate level by bacteria within nodules, but not by free-living bacteria. Conclusions Based on the analysis of ORFs identified in this study, we conclude that this comparative genomics approach can identify rhizobial genes involved in the nitrogen-fixing symbiosis with host plants, although none of the newly identified genes were found to be essential for this process.

  20. Older Adults’ Views and Communication Preferences About Cancer Screening Cessation

    Science.gov (United States)

    Schoenborn, Nancy L.; Lee, Kimberley; Pollack, Craig E.; Armacost, Karen; Dy, Sydney M.; Bridges, John F. P.; Xue, Qian-Li; Wolff, Antonio C.; Boyd, Cynthia

    2017-01-01

    IMPORTANCE Older adults with limited life expectancy are frequently screened for cancer even though it exposes them to risks of screening with minimal benefit. Patient preferences may be an important contributor to continued screening. OBJECTIVE To examine older adults’ views on the decision to stop cancer screening when life expectancy is limited and to identify older adults’ preferences for how clinicians should communicate recommendations to cease cancer screening. DESIGN, SETTING, AND PARTICIPANTS In this semistructured interview study, we interviewed 40 community-dwelling older adults (≥ 65 years) recruited at 4 clinical programs affiliated with an urban academic medical center. MAIN OUTCOMES AND MEASURE We transcribed the audio recorded discussions and analyzed the transcripts using standard techniques of qualitative content analysis to identify major themes and subthemes. RESULTS The participants’ average age was 75.7 years. Twenty-three participants (57.5%) were female; 25 (62.5%) were white. Estimated life expectancy was less than 10 years for 19 participants (47.5%). We identified 3 key themes. First, participants were amenable to stopping cancer screening, especially in the context of a trusting relationship with their clinician. Second, although many participants supported using age and health status to individualize the screening decision, they did not often understand the role of life expectancy. All except 2 participants objected to a Choosing Wisely statement about not recommending cancer screening in those with limited life expectancy, often believing that clinicians cannot accurately predict life expectancy. Third, participants preferred that clinicians explain a recommendation to stop screening by incorporating individual health status but were divided on whether life expectancy should be mentioned. Specific wording of life expectancy was important; many felt the language of “you may not live long enough to benefit from this test” was

  1. A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening.

    Science.gov (United States)

    Fowler, Karen B; McCollister, Faye P; Sabo, Diane L; Shoup, Angela G; Owen, Kris E; Woodruff, Julie L; Cox, Edith; Mohamed, Lisa S; Choo, Daniel I; Boppana, Suresh B

    2017-02-01

    Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL). Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss. Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period. A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS. Copyright © 2017 by the American Academy of Pediatrics.

  2. A Screen Identifies the Oncogenic Micro-RNA miR-378a-5p as a Negative Regulator of Oncogene-Induced Senescence

    DEFF Research Database (Denmark)

    Kooistra, Susanne Marije; Rudkjær, Lise Christine; Lees, Michael James

    2014-01-01

    Oncogene-induced senescence (OIS) can occur in response to hyperactive oncogenic signals and is believed to be a fail-safe mechanism protecting against tumorigenesis. To identify new factors involved in OIS, we performed a screen for microRNAs that can overcome or inhibit OIS in human diploid fib...

  3. A novel case-control design to estimate the extent of over-diagnosis of breast cancer due to organised population-based mammography screening.

    Science.gov (United States)

    Beckmann, Kerri R; Lynch, John W; Hiller, Janet E; Farshid, Gelareh; Houssami, Nehmat; Duffy, Stephen W; Roder, David M

    2015-03-15

    Debate about the extent of breast cancer over-diagnosis due to mammography screening has continued for over a decade, without consensus. Estimates range from 0 to 54%, but many studies have been criticized for having flawed methodology. In this study we used a novel study design to estimate over-diagnosis due to organised mammography screening in South Australia (SA). To estimate breast cancer incidence at and following screening we used a population-based, age-matched case-control design involving 4,931 breast cancer cases and 22,914 controls to obtain OR for yearly time intervals since women's last screening mammogram. The level of over-diagnosis was estimated by comparing the cumulative breast cancer incidence with and without screening. The former was derived by applying ORs for each time window to incidence rates in the absence of screening, and the latter, by projecting pre-screening incidence rates. Sensitivity analyses were undertaken to assess potential biases. Over-diagnosis was estimated to be 8% (95%CI 2-14%) and 14% (95%CI 8-19%) among SA women aged 45 to 85 years from 2006-2010, for invasive breast cancer and all breast cancer respectively. These estimates were robust when applying various sensitivity analyses, except for adjustment for potential confounding assuming higher risk among screened than non-screened women, which reduced levels of over-diagnosis to 1% (95%CI 5-7%) and 8% (95%CI 2-14%) respectively when incidence rates for screening participants were adjusted by 10%. Our results indicate that the level of over-diagnosis due to mammography screening is modest and considerably lower than many previous estimates, including others for Australia. © 2014 UICC.

  4. Small molecule screening with laser cytometry can be used to identify pro-survival molecules in human embryonic stem cells.

    Science.gov (United States)

    Sherman, Sean P; Pyle, April D

    2013-01-01

    Differentiated cells from human embryonic stem cells (hESCs) provide an unlimited source of cells for use in regenerative medicine. The recent derivation of human induced pluripotent cells (hiPSCs) provides a potential supply of pluripotent cells that avoid immune rejection and could provide patient-tailored therapy. In addition, the use of pluripotent cells for drug screening could enable routine toxicity testing and evaluation of underlying disease mechanisms. However, prior to establishment of patient specific cells for cell therapy it is important to understand the basic regulation of cell fate decisions in hESCs. One critical issue that hinders the use of these cells is the fact that hESCs survive poorly upon dissociation, which limits genetic manipulation because of poor cloning efficiency of individual hESCs, and hampers production of large-scale culture of hESCs. To address the problems associated with poor growth in culture and our lack of understanding of what regulates hESC signaling, we successfully developed a screening platform that allows for large scale screening for small molecules that regulate survival. In this work we developed the first large scale platform for hESC screening using laser scanning cytometry and were able to validate this platform by identifying the pro-survival molecule HA-1077. These small molecules provide targets for both improving our basic understanding of hESC survival as well as a tool to improve our ability to expand and genetically manipulate hESCs for use in regenerative applications.

  5. Using lessons from breast, cervical, and colorectal cancer screening to inform the development of lung cancer screening programs.

    Science.gov (United States)

    Armstrong, Katrina; Kim, Jane J; Halm, Ethan A; Ballard, Rachel M; Schnall, Mitchell D

    2016-05-01

    Multiple advisory groups now recommend that high-risk smokers be screened for lung cancer by low-dose computed tomography. Given that the development of lung cancer screening programs will face many of the same issues that have challenged other cancer screening programs, the National Cancer Institute-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium was used to identify lessons learned from the implementation of breast, cervical, and colorectal cancer screening that should inform the introduction of lung cancer screening. These lessons include the importance of developing systems for identifying and recruiting eligible individuals in primary care, ensuring that screening centers are qualified and performance is monitored, creating clear communication standards for reporting screening results to referring physicians and patients, ensuring follow-up is available for individuals with abnormal test results, avoiding overscreening, remembering primary prevention, and leveraging advances in cancer genetics and immunology. Overall, this experience emphasizes that effective cancer screening is a multistep activity that requires robust strategies to initiate, report, follow up, and track each step as well as a dynamic and ongoing oversight process to revise current screening practices as new evidence regarding screening is created, new screening technologies are developed, new biological markers are identified, and new approaches to health care delivery are disseminated. Cancer 2016;122:1338-1342. © 2016 American Cancer Society. © 2016 American Cancer Society.

  6. Construct validity of the Heart Failure Screening Tool (Heart-FaST) to identify heart failure patients at risk of poor self-care: Rasch analysis.

    Science.gov (United States)

    Reynolds, Nicholas A; Ski, Chantal F; McEvedy, Samantha M; Thompson, David R; Cameron, Jan

    2018-02-14

    The aim of this study was to psychometrically evaluate the Heart Failure Screening Tool (Heart-FaST) via: (1) examination of internal construct validity; (2) testing of scale function in accordance with design; and (3) recommendation for change/s, if items are not well adjusted, to improve psychometric credential. Self-care is vital to the management of heart failure. The Heart-FaST may provide a prospective assessment of risk, regarding the likelihood that patients with heart failure will engage in self-care. Psychometric validation of the Heart-FaST using Rasch analysis. The Heart-FaST was administered to 135 patients (median age = 68, IQR = 59-78 years; 105 males) enrolled in a multidisciplinary heart failure management program. The Heart-FaST is a nurse-administered tool for screening patients with HF at risk of poor self-care. A Rasch analysis of responses was conducted which tested data against Rasch model expectations, including whether items serve as unbiased, non-redundant indicators of risk and measure a single construct and that rating scales operate as intended. The results showed that data met Rasch model expectations after rescoring or deleting items due to poor discrimination, disordered thresholds, differential item functioning, or response dependence. There was no evidence of multidimensionality which supports the use of total scores from Heart-FaST as indicators of risk. Aggregate scores from this modified screening tool rank heart failure patients according to their "risk of poor self-care" demonstrating that the Heart-FaST items constitute a meaningful scale to identify heart failure patients at risk of poor engagement in heart failure self-care. © 2018 John Wiley & Sons Ltd.

  7. Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

    Science.gov (United States)

    Huang, Duo; Cheng, Yang-Yang; Chan, Pak-Hei; Hai, Jojo; Yiu, Kai-Hang; Tse, Hung-Fat; Wong, Ka-Lam; Fan, Katherine; Li, Ying Wah; Ng, Woon-Leung; Yim, Cheuk-Wan; Wong, Cheuk-Hon John; Tam, Lai-Shan; Wong, Priscilla C H; Wong, Chi-Yuen; Ho, Chup-Hei; Leung, Alexander M H; Mok, Chi-Chiu; Lam, Ho; Lau, Chak-Sing; Cheung, Tommy; Ho, Carmen; Law, Sharon W Y; Chan, Esther W; Yin, Li-Xue; Yue, Wen-Sheng; Mok, Toi Meng; Evora, Mario Alberto; Siu, Chung-Wah

    2018-01-01

    Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross-sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participating centres will undergo an echocardiography- and biomarker-based pulmonary hypertension screening procedure as in the DETECT study. Standard right heart catheterisation will be provided to patients with intermediate or high echocardiographic probability of pulmonary hypertension. Those with low echocardiographic probability will rescreen within 1 year. The primary measure will be the diagnosis and types of pulmonary hypertension and prevalence of pulmonary hypertension in SLE patients. The secondary measures will be the predictors and prediction models for pulmonary hypertension in SLE patients. The estimated sample size is approximately 895 participants. The results of the SOPHIE study will be an important contribution to the literature of SLE-related pulmonary hypertension and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for screening of pulmonary hypertension in SLE patients.

  8. Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

    Science.gov (United States)

    Kwan, Antonia; Abraham, Roshini S.; Currier, Robert; Brower, Amy; Andruszewski, Karen; Abbott, Jordan K.; Baker, Mei; Ballow, Mark; Bartoshesky, Louis E.; Bonagura, Vincent R.; Bonilla, Francisco A.; Brokopp, Charles; Brooks, Edward; Caggana, Michele; Celestin, Jocelyn; Church, Joseph A.; Comeau, Anne Marie; Connelly, James A.; Cowan, Morton J.; Cunningham-Rundles, Charlotte; Dasu, Trivikram; Dave, Nina; De La Morena, Maria T.; Duffner, Ulrich; Fong, Chin-To; Forbes, Lisa; Freedenberg, Debra; Gelfand, Erwin W.; Hale, Jaime E.; Celine Hanson, I.; Hay, Beverly N.; Hu, Diana; Infante, Anthony; Johnson, Daisy; Kapoor, Neena; Kay, Denise M.; Kohn, Donald B.; Lee, Rachel; Lehman, Heather; Lin, Zhili; Lorey, Fred; Abdel-Mageed, Aly; Manning, Adrienne; McGhee, Sean; Moore, Theodore B.; Naides, Stanley J.; Notarangelo, Luigi D.; Orange, Jordan S.; Pai, Sung-Yun; Porteus, Matthew; Rodriguez, Ray; Romberg, Neil; Routes, John; Ruehle, Mary; Rubenstein, Arye; Saavedra-Matiz, Carlos A.; Scott, Ginger; Scott, Patricia M.; Secord, Elizabeth; Seroogy, Christine; Shearer, William T.; Siegel, Subhadra; Silvers, Stacy K.; Stiehm, E. Richard; Sugerman, Robert W.; Sullivan, John L.; Tanksley, Susan; Tierce, Millard L.; Verbsky, James; Vogel, Beth; Walker, Rosalyn; Walkovich, Kelly; Walter, Jolan E.; Wasserman, Richard L.; Watson, Michael S.; Weinberg, Geoffrey A.; Weiner, Leonard B.; Wood, Heather; Yates, Anne B.; Puck, Jennifer M.

    2015-01-01

    IMPORTANCE Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100 000 births. OBJECTIVES To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN Epidemiological and retrospective observational study. SETTING Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3 030 083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58 000 infants (95%CI, 1/46 000-1/80 000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87%(45/52), 92%(45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in

  9. Identifying Indicators Related to Constructs for Engineering Design Outcome

    Science.gov (United States)

    Wilhelmsen, Cheryl A.; Dixon, Raymond A.

    2016-01-01

    This study ranked constructs articulated by Childress and Rhodes (2008) and identified the key indicators for each construct as a starting point to explore what should be included on an instrument to measure the engineering design process and outcomes of students in high schools that use the PLTW and EbDTM curricula in Idaho. A case-study design…

  10. Rationale and design of the HOME trial: A pragmatic randomized controlled trial of home-based human papillomavirus (HPV) self-sampling for increasing cervical cancer screening uptake and effectiveness in a U.S. healthcare system.

    Science.gov (United States)

    Winer, Rachel L; Tiro, Jasmin A; Miglioretti, Diana L; Thayer, Chris; Beatty, Tara; Lin, John; Gao, Hongyuan; Kimbel, Kilian; Buist, Diana S M

    2018-01-01

    Women who delay or do not attend Papanicolaou (Pap) screening are at increased risk for cervical cancer. Trials in countries with organized screening programs have demonstrated that mailing high-risk (hr) human papillomavirus (HPV) self-sampling kits to under-screened women increases participation, but U.S. data are lacking. HOME is a pragmatic randomized controlled trial set within a U.S. integrated healthcare delivery system to compare two programmatic approaches for increasing cervical cancer screening uptake and effectiveness in under-screened women (≥3.4years since last Pap) aged 30-64years: 1) usual care (annual patient reminders and ad hoc outreach by clinics) and 2) usual care plus mailed hrHPV self-screening kits. Over 2.5years, eligible women were identified through electronic medical record (EMR) data and randomized 1:1 to the intervention or control arm. Women in the intervention arm were mailed kits with pre-paid envelopes to return samples to the central clinical laboratory for hrHPV testing. Results were documented in the EMR to notify women's primary care providers of appropriate follow-up. Primary outcomes are detection and treatment of cervical neoplasia. Secondary outcomes are cervical cancer screening uptake, abnormal screening results, and women's experiences and attitudes towards hrHPV self-sampling and follow-up of hrHPV-positive results (measured through surveys and interviews). The trial was designed to evaluate whether a programmatic strategy incorporating hrHPV self-sampling is effective in promoting adherence to the complete screening process (including follow-up of abnormal screening results and treatment). The objective of this report is to describe the rationale and design of this pragmatic trial. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Barriers to cancer screening among Orthodox Jewish women.

    Science.gov (United States)

    Tkatch, Rifky; Hudson, Janella; Katz, Anne; Berry-Bobovski, Lisa; Vichich, Jennifer; Eggly, Susan; Penner, Louis A; Albrecht, Terrance L

    2014-12-01

    The increased risk of genetic cancer mutations for Ashkenazi Jews is well known. However, little is known about the cancer-related health behaviors of a subset of Ashkenazi Jews, Orthodox Jews, who are a very religious and insular group. This study partnered with Rabbinical leadership and community members in an Orthodox Jewish community to investigate barriers to cancer screening in this community. Orthodox Jewish women were recruited to participate in focus groups designed to elicit their perspectives on barriers to cancer screening. A total of five focus groups were conducted, consisting of 3-5 members per group, stratified by age and family history of cancer. Focus groups were audio recorded and transcribed. Transcripts were coded using conventional content analysis. The resulting themes identified as barriers to cancer screening were: preservation of hidden miracles, fate, cost, competing priorities, lack of culturally relevant programming, lack of information, and fear. These results provide a unique perspective on barriers to cancer screening in a high risk but understudied population. Findings from this study may serve to inform culturally appropriate cancer education programs to overcome barriers to screening in this and other similar communities.

  12. Prostate and Colon Cancer Screening Messages in Popular Magazines

    Science.gov (United States)

    Katz, Mira L; Sheridan, Stacey; Pignone, Michael; Lewis, Carmen; Battle, Jamila; Gollop, Claudia; O'Malley, Michael

    2004-01-01

    OBJECTIVES To 1) compare the number of articles published about prostate, colon, and breast cancer in popular magazines during the past 2 decades, and 2) evaluate the content of in-depth prostate and colon cancer screening articles identified from 1996 to 2001. DESIGN We used a searchable database to identify the number of prostate, colon, and breast cancer articles published in three magazines with the highest circulation from six categories. In addition, we performed a systematic review on the in-depth (≥2 pages) articles on prostate and colon cancer screening that appeared from 1996 through 2001. RESULTS Although the number of magazine articles on prostate and colon cancer published in the 1990s increased compared to the 1980s, the number of articles is approximately one third of breast cancer articles. There were 36 in-depth articles from 1996 to 2001 in which prostate or colon cancer screening were mentioned. Over 90% of the articles recommended screening. However, of those articles, only 76% (25/33; 95% confidence interval [CI], 58% to 89%) cited screening guidelines. The benefits of screening were mentioned in 89% (32/36; 95% CI, 74% to 97%) but the harms were only found in 58% (21/36; 95% CI, 41% to 75%). Only 28% (10/36; 95% CI, 14% to 45%) of the articles provided all the necessary information needed for the reader to make an informed decision. CONCLUSIONS In-depth articles about prostate and colon cancer in popular magazines do not appear as frequently as articles about breast cancer. The available articles on prostate and colon cancer screening often do not provide the information necessary for the reader to make an informed decision about screening. PMID:15242469

  13. Application of chemical arrays in screening elastase inhibitors.

    Science.gov (United States)

    Gao, Feng; Du, Guan-Hua

    2006-06-01

    Protein chip technology provides a new and useful tool for high-throughput screening of drugs because of its high performance and low sample consumption. In order to screen elastase inhibitors on a large scale, we designed a composite microarray integrating enzyme chip containing chemical arrays on glass slides to screen for enzymatic inhibitors. The composite microarray includes an active proteinase film, screened chemical arrays distributed on the film, and substrate microarrays to demonstrate change of color. The detection principle is that elastase hydrolyzes synthetic colorless substrates and turns them into yellow products. Because yellow is difficult to detect, bromochlorophenol blue (BPB) was added into substrate solutions to facilitate the detection process. After the enzyme had catalyzed reactions for 2 h, effects of samples on enzymatic activity could be determined by detecting color change of the spots. When chemical samples inhibited enzymatic activity, substrates were blue instead of yellow products. If the enzyme retained its activity, the yellow color of the products combined with blue of BPB to make the spots green. Chromogenic differences demonstrated whether chemicals inhibited enzymatic activity or not. In this assay, 11,680 compounds were screened, and two valuable chemical hits were identified, which demonstrates that this assay is effective, sensitive and applicable for high-throughput screening (HTS).

  14. Vision Screening

    Science.gov (United States)

    ... an efficient and cost-effective method to identify children with visual impairment or eye conditions that are likely to lead ... main goal of vision screening is to identify children who have or are at ... visual impairment unless treated in early childhood. Other problems that ...

  15. The dynamic modeling and design improvement of a piezoelectric exciter of a touch screen device for efficient tactile feedback

    International Nuclear Information System (INIS)

    Park, Young-Min; Kim, Kwang-Joon

    2011-01-01

    Piezoelectric exciters have been receiving greater attention recently as a vibration source for tactile feedback in devices with touch screens, such as a mobile phones, in place of DC motors due to lower energy consumption and smaller volume. Their insufficient excitation level, however, still remains a problem. In this paper, dynamic modeling and design improvement of a piezoelectric exciter are presented. The excitation performance is defined as the acceleration response at the center of a touch screen per electric power and to be maximized around 250 Hz where the index finger is most sensitive. The piezoelectric exciter consists of a z-shaped metal beam, a piezoelectric layer on the long horizontal segment and an adhesive layer between the short horizontal segment and the touch screen. Assuming that the piezoelectric exciter is attached onto a rigid ground due to its low mechanical impedance compared with that of the touch screen, the piezoelectric exciter is dynamically modeled by applying Hamilton's principle, where the adhesive layer is treated as a distributed stiffness. The touch screen is modeled approximately as a simply supported beam such that it may have the same fundamental natural frequency and bending stiffness as the screen based on measurements. The performance improvement is focused on the change of five geometric parameters of the piezoelectric exciter: length of the long horizontal segment, thickness of the piezoelectric layer, thickness of the elastic metal layer, width of the beams and tip mass. The procedure to improve the performance of the piezoelectric exciter via dynamic modeling is presented together with experimental results on a prototype. Effectiveness of the design modification and limitations in practice are further discussed as well

  16. Genome-wide RNAi screen identifies novel host proteins required for alphavirus entry.

    Directory of Open Access Journals (Sweden)

    Yaw Shin Ooi

    Full Text Available The enveloped alphaviruses include important and emerging human pathogens such as Chikungunya virus and Eastern equine encephalitis virus. Alphaviruses enter cells by clathrin-mediated endocytosis, and exit by budding from the plasma membrane. While there has been considerable progress in defining the structure and function of the viral proteins, relatively little is known about the host factors involved in alphavirus infection. We used a genome-wide siRNA screen to identify host factors that promote or inhibit alphavirus infection in human cells. Fuzzy homologue (FUZ, a protein with reported roles in planar cell polarity and cilia biogenesis, was required for the clathrin-dependent internalization of both alphaviruses and the classical endocytic ligand transferrin. The tetraspanin membrane protein TSPAN9 was critical for the efficient fusion of low pH-triggered virus with the endosome membrane. FUZ and TSPAN9 were broadly required for infection by the alphaviruses Sindbis virus, Semliki Forest virus, and Chikungunya virus, but were not required by the structurally-related flavivirus Dengue virus. Our results highlight the unanticipated functions of FUZ and TSPAN9 in distinct steps of alphavirus entry and suggest novel host proteins that may serve as targets for antiviral therapy.

  17. Screening for hearing, visual and dual sensory impairment in older adults using behavioural cues : A validation study

    NARCIS (Netherlands)

    Roets-Merken, Lieve M.; Zuidema, Sytse U.; Vernooij-Dassen, Myrra J. F. J.; Kempen, Gertrudis I. J. M.

    2014-01-01

    Objective: This study investigated the psychometric properties of the Severe Dual Sensory Loss screening tool, a tool designed to help nurses and care assistants to identify hearing, visual and dual sensory impairment in older adults. Design: Construct validity of the Severe Dual Sensory Loss

  18. Health Literacy Screening Instruments for eHealth Applications: A Systematic Review

    Science.gov (United States)

    Collins, Sarah A.; Currie, Leanne M.; Bakken, Suzanne; Vawdrey, David K.; Stone, Patricia W.

    2012-01-01

    Objective To systematically review current health literacy (HL) instruments for use in consumer-facing and mobile health information technology screening and evaluation tools. Design The databases, PubMed, OVID, Google Scholar, Cochrane Library and Science Citation Index, were searched for health literacy assessment instruments using the terms “health”, “literacy”, “computer-based,” and “psychometrics”. All instruments identified by this method were critically appraised according to their reported psychometric properties and clinical feasibility. Results Eleven different health literacy instruments were found. Screening questions, such as asking a patient about his/her need for assistance in navigating health information, were evaluated in 7 different studies and are promising for use as a valid, reliable, and feasible computer-based approach to identify patients that struggle with low health literacy. However, there was a lack of consistency in the types of screening questions proposed. There is also a lack of information regarding the psychometric properties of computer-based health literacy instruments. Limitations Only English language health literacy assessment instruments were reviewed and analyzed. Conclusions Current health literacy screening tools demonstrate varying benefits depending on the context of their use. In many cases, it seems that a single screening question may be a reliable, valid, and feasible means for establishing health literacy. A combination of screening questions that assess health literacy and technological literacy may enable tailoring eHealth applications to user needs. Further research should determine the best screening question(s) and the best synthesis of various instruments’ content and methodologies for computer-based health literacy screening and assessment. PMID:22521719

  19. Prognostic factors for specific lower extremity and spinal musculoskeletal injuries identified through medical screening and training load monitoring in professional football (soccer): a systematic review

    Science.gov (United States)

    Sergeant, Jamie C; Parkes, Matthew J; Callaghan, Michael J

    2017-01-01

    Background Medical screening and load monitoring procedures are commonly used in professional football to assess factors perceived to be associated with injury. Objectives To identify prognostic factors (PFs) and models for lower extremity and spinal musculoskeletal injuries in professional/elite football players from medical screening and training load monitoring processes. Methods The MEDLINE, AMED, EMBASE, CINAHL Plus, SPORTDiscus and PubMed electronic bibliographic databases were searched (from inception to January 2017). Prospective and retrospective cohort studies of lower extremity and spinal musculoskeletal injury incidence in professional/elite football players aged between 16 and 40 years were included. The Quality in Prognostic Studies appraisal tool and the modified Grading of Recommendations Assessment, Development and Evaluation synthesis approach was used to assess the quality of the evidence. Results Fourteen studies were included. 16 specific lower extremity injury outcomes were identified. No spinal injury outcomes were identified. Meta-analysis was not possible due to heterogeneity and study quality. All evidence related to PFs and specific lower extremity injury outcomes was of very low to low quality. On the few occasions where multiple studies could be used to compare PFs and outcomes, only two factors demonstrated consensus. A history of previous hamstring injuries (HSI) and increasing age may be prognostic for future HSI in male players. Conclusions The assumed ability of medical screening tests to predict specific musculoskeletal injuries is not supported by the current evidence. Screening procedures should currently be considered as benchmarks of function or performance only. The prognostic value of load monitoring modalities is unknown. PMID:29177074

  20. Breast cancer screening in older women.

    Science.gov (United States)

    Caplan, L S; Haynes, S G

    1996-01-01

    There is currently an epidemic of breast cancer in women 65 years of age and older. The purposes of this paper are to explore the breast cancer screening behaviors of older women and to identify some of the determinants of screening in these women. Data were analyzed from the 1987 National Health Interview Survey, a continuous nationwide household interview survey of the U.S. civilian, noninstitutionalized population. As in other studies, the utilization of breast cancer screening by older women was less in older women than in younger women. This was true for both mammography and clinical breast examination. A number of determinants of screening in older women were identified here. Women with a usual source of care and/or no activity limitation, as well as high school graduates, were the ones most likely to have received a screening mammogram and/or a screening clinical breast exam during the past year. The failure of older women to receive adequate breast cancer screening is an important concern which should be reevaluated, given the breast cancer epidemic in this population. This study identified a number of determinants of breast cancer screening in older women. For the most part, these determinants point to the primary care physician as the key to breast cancer screening in these women. Therefore, the primary care physician must be informed of, and encouraged to follow, the recommendations for periodic breast cancer screening in older women.

  1. Identification and screening of hazards for the external event PRA - External hazard identification, screening and studies for a new plant site

    International Nuclear Information System (INIS)

    Hellander, Juho

    2014-01-01

    Fennovoima is constructing a new nuclear power plant on a greenfield site in Northern Finland. Various evaluations for site-specific hazards are needed to ensure sufficient plant design basis values, proper design solutions and to provide input for the PRA model. This paper presents the general process used in identifying the relevant site-specific external hazards. The applicable legislative requirements, guides and standards regarding external hazards and external event PRA shall be identified. Based on these, an initial comprehensive list of events should be compiled. The initial list shall be filtered to exclude irrelevant events. Events can be screened out if the probability is very low or if the consequences are only mild. Events with similar consequences should be combined. Events can be grouped in several ways, and in this paper the risks are categorized into events related to air, water bodies, ground and human behaviour. In addition, the simultaneously occurring combinations of events should be identified. The paper also summarizes some hazard studies already performed and required in the future in Fennovoima's project. A comprehensive study is ongoing related to earthquake risks. The study aims at identifying all relevant seismic sources and taking into account various expert opinions in seismic modelling. Also frazil ice and anchor ice studies are being performed to eliminate the risk of cooling water intake blockage due to ice. In addition, some other study areas are mentioned. This paper presented a list of Finnish and international guides and standards useful in evaluating external hazards. Also a methodology was presented to identify and screen site-specific hazards in a new nuclear power plant project. The screened list of relevant events for the Hanhikivi site requiring further studies was presented. Also the studies needed in different phases of a new nuclear power plant project were discussed. Some specific studies regarding earthquakes and

  2. Barriers and Facilitators of Prostate Cancer Screening among Filipino Men in Hawai’i

    Science.gov (United States)

    Conde, Francisco A.; Landier, Wendy; Ishida, Dianne; Bell, Rose; Cuaresma, Charlene F.; Misola, Jane

    2013-01-01

    Purpose/Objectives To examine perceptions, attitudes, and beliefs regarding barriers and facilitators to prostate cancer screening, and to identify potential interventional strategies to promote prostate cancer screening among Filipino men in Hawai’i. Design Exploratory, qualitative. Setting Community-based settings in Hawai’i. Sample 20 Filipino men, 40 years old or older Methods Focus group discussions were tape-recorded, transcribed, and content analysis performed for emergent themes. Main Research Variables Perceptions regarding prostate cancer, barriers and facilitators to prostate cancer screening, and culturally-relevant interventional strategies Findings Perceptions of prostate cancer included fatalism, hopelessness, and dread. Misconceptions regarding causes of prostate cancer, such as frequency of sexual activity, were identified. Barriers to prostate cancer screening included lack of awareness of the need for screening, reticence to seek healthcare when feeling well, fear of cancer diagnosis, financial issues, time constraints, and embarrassment. Presence of urinary symptoms, personal experience with family or friend who had cancer, and receiving recommendations from a healthcare provider regarding screening were facilitators for screening. Potential culturally-relevant interventional strategies to promote prostate cancer screening included screening recommendations from health professionals and cancer survivors; radio/television commercials and newspaper articles targeted to the Filipino community; informational brochures in Tagalog, Ilocano and/or English; and interactive, educational forums facilitated by Filipino multilingual, male healthcare professionals. Conclusions Culturally-relevant interventions are needed that address barriers to prostate cancer screening participation and misconceptions about causes of prostate cancer. Implications for Nursing Findings provide a foundation for future research regarding development of interventional

  3. Random small interfering RNA library screen identifies siRNAs that induce human erythroleukemia cell differentiation.

    Science.gov (United States)

    Fan, Cuiqing; Xiong, Yuan; Zhu, Ning; Lu, Yabin; Zhang, Jiewen; Wang, Song; Liang, Zicai; Shen, Yan; Chen, Meihong

    2011-03-01

    Cancers are characterized by poor differentiation. Differentiation therapy is a strategy to alleviate malignant phenotypes by inducing cancer cell differentiation. Here we carried out a combinatorial high-throughput screen with a random siRNA library on human erythroleukemia K-562 cell differentiation. Two siRNAs screened from the library were validated to be able to induce erythroid differentiation to varying degrees, determined by CD235 and globin up-regulation, GATA-2 down-regulation, and cell growth inhibition. The screen we performed here is the first trial of screening cancer differentiation-inducing agents from a random siRNA library, demonstrating that a random siRNA library can be considered as a new resource in efforts to seek new therapeutic agents for cancers. As a random siRNA library has a broad coverage for the entire genome, including known/unknown genes and protein coding/non-coding sequences, screening using a random siRNA library can be expected to greatly augment the repertoire of therapeutic siRNAs for cancers.

  4. Evaluating the effects of buffer conditions and extremolytes on thermostability of granulocyte colony-stimulating factor using high-throughput screening combined with design of experiments.

    Science.gov (United States)

    Ablinger, Elisabeth; Hellweger, Monika; Leitgeb, Stefan; Zimmer, Andreas

    2012-10-15

    In this study, we combined a high-throughput screening method, differential scanning fluorimetry (DSF), with design of experiments (DoE) methodology to evaluate the effects of several formulation components on the thermostability of granulocyte colony stimulating factor (G-CSF). First we performed a primary buffer screening where we tested thermal stability of G-CSF in different buffers, pH values and buffer concentrations. The significance of each factor and the two-way interactions between them were studied by multivariable regression analysis. pH was identified as most critical factor regarding thermal stability. The most stabilizing buffer, sodium glutamate, and sodium acetate were determined for further investigations. Second we tested the effect of 6 naturally occurring extremolytes (trehalose, sucrose, ectoine, hydroxyectoine, sorbitol, mannitol) on the thermal stability of G-CSF, using a central composite circumscribed design. At low pH (3.8) and low buffer concentration (5 mM) all extremolytes led to a significant increase in thermal stability except the addition of ectoine which resulted in a strong destabilization of G-CSF. Increasing pH and buffer concentration led to an increase in thermal stability with all investigated extremolytes. The described systematic approach allowed to create a ranking of stabilizing extremolytes at different buffer conditions. Copyright © 2012. Published by Elsevier B.V.

  5. Small molecule screening with laser cytometry can be used to identify pro-survival molecules in human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Sean P Sherman

    Full Text Available Differentiated cells from human embryonic stem cells (hESCs provide an unlimited source of cells for use in regenerative medicine. The recent derivation of human induced pluripotent cells (hiPSCs provides a potential supply of pluripotent cells that avoid immune rejection and could provide patient-tailored therapy. In addition, the use of pluripotent cells for drug screening could enable routine toxicity testing and evaluation of underlying disease mechanisms. However, prior to establishment of patient specific cells for cell therapy it is important to understand the basic regulation of cell fate decisions in hESCs. One critical issue that hinders the use of these cells is the fact that hESCs survive poorly upon dissociation, which limits genetic manipulation because of poor cloning efficiency of individual hESCs, and hampers production of large-scale culture of hESCs. To address the problems associated with poor growth in culture and our lack of understanding of what regulates hESC signaling, we successfully developed a screening platform that allows for large scale screening for small molecules that regulate survival. In this work we developed the first large scale platform for hESC screening using laser scanning cytometry and were able to validate this platform by identifying the pro-survival molecule HA-1077. These small molecules provide targets for both improving our basic understanding of hESC survival as well as a tool to improve our ability to expand and genetically manipulate hESCs for use in regenerative applications.

  6. Inhibitors of MyD88-dependent proinflammatory cytokine production identified utilizing a novel RNA interference screening approach.

    Directory of Open Access Journals (Sweden)

    John S Cho

    2009-09-01

    Full Text Available The events required to initiate host defenses against invading pathogens involve complex signaling cascades comprised of numerous adaptor molecules, kinases, and transcriptional elements, ultimately leading to the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha. How these signaling cascades are regulated, and the proteins and regulatory elements participating are still poorly understood.We report here the development a completely random short-hairpin RNA (shRNA library coupled with a novel forward genetic screening strategy to identify inhibitors of Toll-like receptor (TLR dependent proinflammatory responses. We developed a murine macrophage reporter cell line stably transfected with a construct expressing diphtheria toxin-A (DT-A under the control of the TNF-alpha-promoter. Stimulation of the reporter cell line with the TLR ligand lipopolysaccharide (LPS resulted in DT-A induced cell death, which could be prevented by the addition of an shRNA targeting the TLR adaptor molecule MyD88. Utilizing this cell line, we screened a completely random lentiviral short hairpin RNA (shRNA library for sequences that inhibited TLR-mediated TNF-alpha production. Recovery of shRNA sequences from surviving cells led to the identification of unique shRNA sequences that significantly inhibited TLR4-dependent TNF-alpha gene expression. Furthermore, these shRNA sequences specifically blocked TLR2 but not TLR3-dependent TNF-alpha production.Thus, we describe the generation of novel tools to facilitate large-scale forward genetic screens in mammalian cells and the identification of potent shRNA inhibitors of TLR2 and TLR4- dependent proinflammatory responses.

  7. Nutrition screening: science behind simplicity

    African Journals Online (AJOL)

    Nutrition screening triggers entry into the nutrition care process.1 Screening has informally been described as simple, quick or low-intensity proxy for more complex procedures. More formal definitions for the nutrition setting have been proposed, describing nutrition screening as a process of identifying patients, clients, or ...

  8. Systematic screening methodology and energy efficient design of ionic liquid-based separation processes

    DEFF Research Database (Denmark)

    Kulajanpeng, Kusuma; Suriyapraphadilok, Uthaiporn; Gani, Rafiqul

    2016-01-01

    in size of the target solute was investigated using the same separation process and IL entrainer to obtain the same product purity. The proposed methodology has been evaluated through a case study of binary alcoholic aqueous azeotropic separation: water+ethanol and water+isopropanol.......A systematic methodology for the screening of ionic liquids (ILs) as entrainers and for the design of ILs-based separation processes in various homogeneous binary azeotropic mixtures has been developed. The methodology focuses on the homogeneous binary aqueous azeotropic systems (for example, water...

  9. An experience of qualified preventive screening: shiraz smart screening software.

    Science.gov (United States)

    Islami Parkoohi, Parisa; Zare, Hashem; Abdollahifard, Gholamreza

    2015-01-01

    Computerized preventive screening software is a cost effective intervention tool to address non-communicable chronic diseases. Shiraz Smart Screening Software (SSSS) was developed as an innovative tool for qualified screening. It allows simultaneous smart screening of several high-burden chronic diseases and supports reminder notification functionality. The extent in which SSSS affects screening quality is also described. Following software development, preventive screening and annual health examinations of 261 school staff (Medical School of Shiraz, Iran) was carried out in a software-assisted manner. To evaluate the quality of the software-assisted screening, we used quasi-experimental study design and determined coverage, irregular attendance and inappropriateness proportions in relation with the manual and software-assisted screening as well as the corresponding number of requested tests. In manual screening method, 27% of employees were covered (with 94% irregular attendance) while by software-assisted screening, the coverage proportion was 79% (attendance status will clear after the specified time). The frequency of inappropriate screening test requests, before the software implementation, was 41.37% for fasting plasma glucose, 41.37% for lipid profile, 0.84% for occult blood, 0.19% for flexible sigmoidoscopy/colonoscopy, 35.29% for Pap smear, 19.20% for mammography and 11.2% for prostate specific antigen. All of the above were corrected by the software application. In total, 366 manual screening and 334 software-assisted screening tests were requested. SSSS is an innovative tool to improve the quality of preventive screening plans in terms of increased screening coverage, reduction in inappropriateness and the total number of requested tests.

  10. In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

    Science.gov (United States)

    Miller, Peter G.; Al-Shahrour, Fatima; Hartwell, Kimberly A.; Chu, Lisa P.; Järås, Marcus; Puram, Rishi V.; Puissant, Alexandre; Callahan, Kevin P.; Ashton, John; McConkey, Marie E.; Poveromo, Luke P.; Cowley, Glenn S.; Kharas, Michael G.; Labelle, Myriam; Shterental, Sebastian; Fujisaki, Joji; Silberstein, Lev; Alexe, Gabriela; Al-Hajj, Muhammad A.; Shelton, Christopher A.; Armstrong, Scott A.; Root, David E.; Scadden, David T.; Hynes, Richard O.; Mukherjee, Siddhartha; Stegmaier, Kimberly; Jordan, Craig T.; Ebert, Benjamin L.

    2013-01-01

    SUMMARY We used an in vivo short hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo, and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase, Syk. In contrast, loss of Itgb3 in normal HSPCs did not affect engraftment, reconstitution, or differentiation. Finally, we confirmed that Itgb3 is dispensable for normal hematopoiesis and required for leukemogenesis using an Itgb3 knockout mouse model. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. PMID:23770013

  11. Implementing an organised cervical screening programme in the Republic of Moldova-Stakeholder identification and engagement.

    Science.gov (United States)

    Davies, Philip; Valuta, Diana; Cojohari, Natalia; Sancho-Garnier, Helene

    2017-10-01

    Successfully implementing cervical screening programmes requires them to be adapted to the local context and have broad stakeholder support. This can be achieved by actively engaging local stakeholders in planning as well as implementing the programmes. The Moldovan government started implementing an organised cervical screening programme in 2010 with the first step being stakeholder identification and engagement. This process started by contacting easily identified stakeholders with each asked to recommend others and the process continued until no new ones were identified. Stakeholders were then involved in a series of individual and group meetings over a 2-year period to build confidence and encourage progressively greater engagement. In total, 87 individuals from 46 organisations were identified. Over the 2-year process, the individual and group meetings facilitated a change in stakeholder attitudes from disinterest, to acceptance and finally to active cooperation in designing the screening programme and preparing an implementation plan that were both well adapted to the Moldovan context. Developing the broad support needed to implement cervical screening programmes required ongoing interaction with stakeholders over an extended period. This interaction allowed stakeholder concerns to be identified and addressed, progress to be demonstrated, and stakeholders to be educated about organised screening programmes so they had the knowledge to progressively take greater responsibility and ownership. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. RNA interference screen to identify pathways that enhance or reduce nonviral gene transfer during lipofection.

    Science.gov (United States)

    Barker, Gregory A; Diamond, Scott L

    2008-09-01

    Some barriers to DNA lipofection are well characterized; however, there is as yet no method of finding unknown pathways that impact the process. A druggable genome small-interfering RNA (siRNA) screen against 5,520 genes was tested for its effect on lipofection of human aortic endothelial cells (HAECs). We found 130 gene targets which, when silenced by pooled siRNAs (three siRNAs per gene), resulted in enhanced luminescence after lipofection (86 gene targets showed reduced expression). In confirmation tests with single siRNAs, 18 of the 130 hits showed enhanced lipofection with two or more individual siRNAs in the absence of cytotoxicity. Of these confirmed gene targets, we identified five leading candidates, two of which are isoforms of the regulatory subunit of protein phosphatase 2A (PP2A). The best candidate siRNA targeted the PPP2R2C gene and produced a 65% increase in luminescence from lipofection, with a quantitative PCR-validated knockdown of approximately 76%. Flow cytometric analysis confirmed that the silencing of the PPP2R2C gene resulted in an improvement of 10% in transfection efficiency, thereby demonstrating an increase in the number of transfected cells. These results show that an RNA interference (RNAi) high-throughput screen (HTS) can be applied to nonviral gene transfer. We have also demonstrated that siRNAs can be co-delivered with lipofected DNA to increase the transfection efficiency in vitro.

  13. Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

    Science.gov (United States)

    Shaginian, Alex; Whitby, Landon R; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K; Boger, Dale L

    2009-04-22

    The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

  14. Screening novel candidates and exploring design strategies for organic dye sensitizers with rigid π-linker: A theoretical study

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Kai-Li [Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Key Laboratory of Eco-environment-related Polymer Materials, Ministry of Education, Northwest Normal University, Lanzhou, 730070 Gansu (China); College of Chemistry and Life Science, Gansu Normal University for Nationalities, Hezuo, 747000 Gansu (China); Liu, Le-Yan [College of Chemistry and Life Science, Gansu Normal University for Nationalities, Hezuo, 747000 Gansu (China); Geng, Zhi-Yuan, E-mail: zhiyuangeng@126.com [Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Key Laboratory of Eco-environment-related Polymer Materials, Ministry of Education, Northwest Normal University, Lanzhou, 730070 Gansu (China); Yan, Pen-Ji; Lu, Yan-Hong; Liu, Rui-Rui [Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Key Laboratory of Eco-environment-related Polymer Materials, Ministry of Education, Northwest Normal University, Lanzhou, 730070 Gansu (China)

    2015-07-15

    Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations have been carried out to explore the underlying origin of merits for rigid π-spacer based on reference dyes C255 and C254. The results demonstrate that higher short-circuit current density (J{sub SC}) of C255 is primarily ascribed to the lower EBE, while the biggish short-circuit current density (V{sub OC}) mainly originates from the larger μ{sub normal} compared to C254. Besides, a novel index integral of overlap between hole and electron (S) is firstly introduced to quantitatively estimate the facility of intramolecular charge transfer (ICT) and preliminarily confirmed to be effective for the research target of this work. Furthermore, three series of dyes (C-series, A-series, AC-series) have been designed and characterized to screen promising sensitizer candidates and design strategies, while delightful results have been achieved including 6 promising candidates, design stratagem on efficiently reducing the charge recombination and combinational tactics on screening new dyes with excellent spectral properties or outstanding DSSC performance. - Graphical abstract: Display Omitted - Highlights: • Novel S index was introduced in and confirmed to be effective to estimate ICT. • The merits of rigid π bridge have been theoretically revealed. • Six promising candidates have been screened out. • New strategy on reduce charge recombination was reported. • Novel combinational tactics were acquired and justified to be feasible.

  15. CT screening for lung cancer. Update 2008

    International Nuclear Information System (INIS)

    Henschke, C.I.; Yip, R.; Yankelevitz, D.F.

    2009-01-01

    Screening for a cancer should be considered when the cancer is significant in terms of incidence and mortality, treatment of early stage disease is better than treatment of late stage disease, and there is a screening regimen that provides for earlier diagnosis rather than later, symptom-prompted diagnosis. Lung cancer qualifies as it kills more people than any other cancer worldwide. In the United States it kills more people than colon, breast, and prostate cancer combined and more women than breast cancer. The fundamental concepts of screening are presented. Screening for a cancer is a repetitive process, starting with the baseline round followed by repeat rounds of screening at set intervals. The regimen of screening defines the initial diagnostic test and the sequence of tests to be performed leading to a rule-in diagnosis of the cancer. The regimen should provide lead time of the diagnosis of the cancer. The regimen for the first, baseline round may be different from the regimen for the repeat rounds as the former is inherently different from the subsequent repeat rounds. Baseline screening identifies a greater proportion of cancers with a longer latent (asymptomatic) phase than repeat screening, called length bias. Length bias exists for any screening program, regardless of the design of the study or the cancer. Repeat rounds of screening identify the same proportion of cancer diagnoses found in absence of screening for people having the same risk of the cancer and these repeat rounds of screening can be pooled. It is also a consequence of length bias that cancers found in repeat rounds are earlier in their latent phase than those of the baseline round, a less frequently mentioned consequence. Overdiagnosis bias, another bias of screening, can occur in two ways: a cancer' detected by the screening, pathologically proven, that is not life-threatening even when not resected and a genuine life-threatening cancer that is diagnosed and treated but the person dies

  16. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

    2011-01-01

    Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

  17. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  18. WWER-type NPP spray ponds screen

    International Nuclear Information System (INIS)

    Nikolova, M.; Jordanov, M.; Denev, J.; Markov, D.

    2003-01-01

    The objective of this study is to develop a protection screen of WWER-type NPP spray ponds. The screen design is to ensure reduction of the water droplets blown by the wind and, if possible, their return back to the spray ponds. The cooling capacity of the ponds is not to be changed below the design level for safety reasons. Computational fluid dynamics analysis is used to assess the influence of each design variant on the behavior of the water droplets distribution. Two variants are presented here. The one with plants is found not feasible. The second variant, with steel screen and terrain profile modification is selected for implementation. (author)

  19. Design of stepwise screening for prediabetes and type 2 diabetes based on costs and cases detected.

    Science.gov (United States)

    de Graaf, Gimon; Postmus, Douwe; Bakker, Stephan J L; Buskens, Erik

    2015-09-01

    To provide insight into the trade-off between cost per case detected (CPCD) and the detection rate in questionnaire-based stepwise screening for impaired fasting glucose and undiagnosed type 2 diabetes. We considered a stepwise screening in which individuals whose risk score exceeds a predetermined cutoff value are invited for further blood glucose testing. Using individual patient data to determine questionnaire sensitivity and specificity and external sources to determine screening costs and patient response rates, we rolled back a decision tree to estimate the CPCD and the detection rate for all possible cutoffs on the questionnaire. We found a U-shaped relation between CPCD and detection rate, with high costs per case detected at very low and very high detection rates. Changes in patient response rates had a large impact on both the detection rate and the CPCD, whereas screening costs and questionnaire accuracy mainly impacted the CPCD. Our applied method makes it possible to identify a range of efficient cutoffs where higher detection rates can be achieved at an additional cost per detected patient. This enables decision makers to choose an optimal cutoff based on their willingness to pay for additional detected patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics

    Directory of Open Access Journals (Sweden)

    Kirsten Tschapalda

    2016-06-01

    Full Text Available Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened >320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1, a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.

  1. Manipulation of signaling thresholds in "engineered stem cell niches" identifies design criteria for pluripotent stem cell screens.

    Directory of Open Access Journals (Sweden)

    Raheem Peerani

    Full Text Available In vivo, stem cell fate is regulated by local microenvironmental parameters. Governing parameters in this stem cell niche include soluble factors, extra-cellular matrix, and cell-cell interactions. The complexity of this in vivo niche limits analyses into how individual niche parameters regulate stem cell fate. Herein we use mouse embryonic stem cells (mESC and micro-contact printing (microCP to investigate how niche size controls endogenous signaling thresholds. microCP is used to restrict colony diameter, separation, and degree of clustering. We show, for the first time, spatial control over the activation of the Janus kinase/signal transducer and activator of transcription pathway (Jak-Stat. The functional consequences of this niche-size-dependent signaling control are confirmed by demonstrating that direct and indirect transcriptional targets of Stat3, including members of the Jak-Stat pathway and pluripotency-associated genes, are regulated by colony size. Modeling results and empirical observations demonstrate that colonies less than 100 microm in diameter are too small to maximize endogenous Stat3 activation and that colonies separated by more than 400 microm can be considered independent from each other. These results define parameter boundaries for the use of ESCs in screening studies, demonstrate the importance of context in stem cell responsiveness to exogenous cues, and suggest that niche size is an important parameter in stem cell fate control.

  2. Symptom screening rules to identify active pulmonary tuberculosis: Findings from the Zambian South African Tuberculosis and HIV/AIDS Reduction (ZAMSTAR trial prevalence surveys.

    Directory of Open Access Journals (Sweden)

    M M Claassens

    Full Text Available High tuberculosis (TB burden countries should consider systematic screening among adults in the general population. We identified symptom screening rules to be used in addition to cough ≥2 weeks, in a context where X-ray screening is not feasible, aiming to increase the sensitivity of screening while achieving a specificity of ≥85%.We used 2010 Zambia South Africa Tuberculosis and HIV/AIDS Reduction (ZAMSTAR survey data: a South African (SA training dataset, a SA testing dataset for internal validation and a Zambian dataset for external validation. Regression analyses investigated relationships between symptoms or combinations of symptoms and active disease. Sensitivity and specificity were calculated for candidate rules.Among all participants, the sensitivity of using only cough ≥2 weeks as a screening rule was less than 25% in both SA and Zambia. The addition of any three of six TB symptoms (cough <2 weeks, night sweats, weight loss, fever, chest pain, shortness of breath, or 2 or more of cough <2 weeks, night sweats, and weight loss, increased the sensitivity to ~38%, while reducing specificity from ~95% to ~85% in SA and ~97% to ~92% in Zambia. Among HIV-negative adults, findings were similar in SA, whereas in Zambia the increase in sensitivity was relatively small (15% to 22%.High TB burden countries should investigate cost-effective strategies for systematic screening: one such strategy could be to use our rule in addition to cough ≥2 weeks.

  3. Identifying and Managing Engineering Design Requirements for Emerging Markets

    DEFF Research Database (Denmark)

    Li, Xuemeng

    , especially for those companies originally from developed markets, to acquire an in-depth understanding of particular design requirements in emerging markets in order to adapt both company products and approaches in such contexts. Prior studies on the identification and management of design requirements have...... predominantly been conducted in the context of developed countries and relatively affluent markets. Emerging markets are distinct from developed markets in terms of numerous contextual factors, e.g., regulatory environments and competitive landscapes. These factors influence the requirement identification...... attention. There is a need for an overview of different perspectives in requirement identification for manufacturing companies and their corresponding assessments in the context of emerging markets. Therefore, this research project is motivated to 1) investigate the process of identifying and managing...

  4. Screening for autistic spectrum disorder in children aged 14-15 months. II: population screening with the Early Screening of Autistic Traits Questionnaire (ESAT). Design and general findings.

    NARCIS (Netherlands)

    Dietz, C.; Swinkels, S.H.N.; Daalen, E. van; Engeland, H.M. van; Buitelaar, J.K.

    2006-01-01

    A two-stage protocol for screening for autistic spectrum disorders (ASD) was evaluated in a random population of 31,724 children aged 14-15 months. Children were first pre-screened by physicians at well-baby clinics using a 4-item screening instrument. Infants that screened positive were then

  5. HPPD: ligand- and target-based virtual screening on a herbicide target.

    Science.gov (United States)

    López-Ramos, Miriam; Perruccio, Francesca

    2010-05-24

    Hydroxyphenylpyruvate dioxygenase (HPPD) has proven to be a very successful target for the development of herbicides with bleaching properties, and today HPPD inhibitors are well established in the agrochemical market. Syngenta has a long history of HPPD-inhibitor research, and HPPD was chosen as a case study for the validation of diverse ligand- and target-based virtual screening approaches to identify compounds with inhibitory properties. Two-dimensional extended connectivity fingerprints, three-dimensional shape-based tools (ROCS, EON, and Phase-shape) and a pharmacophore approach (Phase) were used as ligand-based methods; Glide and Gold were used as target-based. Both the virtual screening utility and the scaffold-hopping ability of the screening tools were assessed. Particular emphasis was put on the specific pitfalls to take into account for the design of a virtual screening campaign in an agrochemical context, as compared to a pharmaceutical environment.

  6. LANL seismic screening method for existing buildings

    International Nuclear Information System (INIS)

    Dickson, S.L.; Feller, K.C.; Fritz de la Orta, G.O.

    1997-01-01

    The purpose of the Los Alamos National Laboratory (LANL) Seismic Screening Method is to provide a comprehensive, rational, and inexpensive method for evaluating the relative seismic integrity of a large building inventory using substantial life-safety as the minimum goal. The substantial life-safety goal is deemed to be satisfied if the extent of structural damage or nonstructural component damage does not pose a significant risk to human life. The screening is limited to Performance Category (PC) -0, -1, and -2 buildings and structures. Because of their higher performance objectives, PC-3 and PC-4 buildings automatically fail the LANL Seismic Screening Method and will be subject to a more detailed seismic analysis. The Laboratory has also designated that PC-0, PC-1, and PC-2 unreinforced masonry bearing wall and masonry infill shear wall buildings fail the LANL Seismic Screening Method because of their historically poor seismic performance or complex behavior. These building types are also recommended for a more detailed seismic analysis. The results of the LANL Seismic Screening Method are expressed in terms of separate scores for potential configuration or physical hazards (Phase One) and calculated capacity/demand ratios (Phase Two). This two-phase method allows the user to quickly identify buildings that have adequate seismic characteristics and structural capacity and screen them out from further evaluation. The resulting scores also provide a ranking of those buildings found to be inadequate. Thus, buildings not passing the screening can be rationally prioritized for further evaluation. For the purpose of complying with Executive Order 12941, the buildings failing the LANL Seismic Screening Method are deemed to have seismic deficiencies, and cost estimates for mitigation must be prepared. Mitigation techniques and cost-estimate guidelines are not included in the LANL Seismic Screening Method

  7. Universal screening for alcohol misuse in acute medical admissions is feasible and identifies patients at high risk of liver disease.

    Science.gov (United States)

    Westwood, Greta; Meredith, Paul; Atkins, Susan; Greengross, Peter; Schmidt, Paul E; Aspinall, Richard J

    2017-09-01

    Many people who die from alcohol related liver disease (ARLD) have a history of recurrent admissions to hospital, representing potential missed opportunities for intervention. Universal screening for alcohol misuse has been advocated but it is not known if this is achievable or effective at detecting individuals at high risk of ARLD. We systematically screened all admissions to the Acute Medical Unit (AMU) of a large acute hospital using an electronic data capture system in real time. Patients at an increasing risk of alcohol harm were referred for either brief intervention (BI) or further assessment by an Alcohol Specialist Nursing Service (ASNS). Additional data were recorded on admission diagnoses, alcohol unit consumption, previous attendances, previous admissions, length of stay and mortality. Between July 2011 and March 2014, there were 53,165 admissions and 48,211 (90.68%) completed screening. Of these, 1,122 (2.3%) were classified as "increasing", and 1,921 (4.0%) as "high" risk of alcohol harm. High risk patients had more hospital admissions in the three previous years (average 4.74) than the low (3.00) and increasing (2.92) risk groups (prisk patients also had more frequent emergency department (ED) attendances (7.68) than the lower (2.64) and increasing (3.81) groups (prisk group were seen by the ASNS and 1,135 (81.2%) had an Alcohol Use Disorders Identification Test (AUDIT) score over 20 with 527 (37.8%) recording the maximum value of 40. Compared to the other groups, high risk patients had a distinct profile of admissions with the most common diagnoses being mental health disorders, gastro-intestinal bleeding, poisoning and liver disease. Universal screening of admissions for alcohol misuse is feasible and identifies a cohort with frequent ED attendances, recurrent admissions and an elevated risk of ARLD. An additional group of patients at an increasing risk of alcohol harm can be identified in a range of common presentations. These patients can be

  8. Diagnostic accuracy of an integrated respiratory guideline in identifying patients with respiratory symptoms requiring screening for pulmonary tuberculosis: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Majara Bosielo P

    2006-08-01

    Full Text Available Abstract Background To evaluate the diagnostic accuracy of the integrated Practical Approach to Lung Health in South Africa (PALSA guideline in identifying patients requiring bacteriological screening for tuberculosis (TB, and to determine which clinical features best predict suspected and bacteriologically-confirmed tuberculosis among patients with respiratory symptoms. Methods A prospective, cross-sectional study in which 1392 adult patients with cough and/or difficult breathing, attending a primary care facility in Cape Town, South Africa, were evaluated by a nurse using the guideline. The accuracy of a nurse using the guideline to identify TB suspects was compared to that of primary care physicians' diagnoses of (1 suspected TB, and (2 proven TB supported by clinical information and chest radiographs. Results The nurse using the guideline identified 516 patients as TB suspects compared with 365 by the primary care physicians, representing a sensitivity of 76% (95% confidence interval (CI 71%–79%, specificity of 77% (95% CI 74%–79%, positive predictive value of 53% (95% CI 49%–58%, negative predictive value of 90% (95% CI 88%–92%, and area under the receiver operating characteristic curve (ARUC of 0.76 (95% CI 0.74–0.79. Sputum results were obtained in 320 of the 365 primary care physicians TB suspects (88%; 40 (13% of these were positive for TB. Only 4 cases were not identified by the nurse using the guideline. The primary care physicians diagnostic accuracy in diagnosing bacteriologically-confirmed TB (n = 320 was as follows: sensitivity 90% (95% CI 76%–97%, specificity 65% (95% CI 63%–68%, negative predictive value 7% (95% CI 5%–10%, positive predictive value 99.5% (95% CI 98.8%–99.8%, and ARUC 0.78 (95% CI 0.73–0.82. Weight loss, pleuritic pain, and night sweats were independently associated with the diagnosis of bacteriologically-confirmed tuberculosis (positive likelihood ratio if all three present = 16.7, 95% CI 5

  9. Integrated Review of Barriers to Cervical Cancer Screening in Sub-Saharan Africa.

    Science.gov (United States)

    McFarland, Ditsapelo M; Gueldner, Sarah M; Mogobe, Keitshokile D

    2016-09-01

    The aim of this study was to review published studies to identify and describe barriers to Papanicolaou (Pap) smear screening among women in sub-Saharan Africa. Guided by Cooper's integrative review methodology, studies published between 2006 and 2015 were identified by searching electronic databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, MEDLINE, ProQuest, and PsycINFO using specified search terms. Using this strategy, 224 articles were identified and screened for duplication and by reading titles, abstracts, and full texts. Seventeen articles met the inclusion criteria and were appraised using relevant tools for qualitative and quantitative designs. No relevant articles published in 2006, 2007, and 2014 were found. All 17 articles had good methodological quality and were included in the review. The studies were from 10 sub-Saharan countries and from different settings. Content analysis of the data revealed three major themes coded as client, provider, and system barriers. The most common client barriers were lack of knowledge and awareness about Pap smear screening, fear of cancer, belief of not being at risk for cervical cancer, and that a Pap smear is not important unless one is ill and cultural or religious factors. Provider barriers were failure to inform or encourage women to screen. Major system barriers were unavailability and inaccessibility of the Pap test. The review provided evidence of barriers to Pap smear screening among sub-Saharan women. Although there were some variations from country to country, sub-Saharan countries share similar constraints to Pap smear screening. These findings have important implications for practice and policy. Understanding the client, provider, and system barriers to cervical cancer screening could guide development of effective interventions. © 2016 Sigma Theta Tau International.

  10. A Screening Tool for Assessing Alcohol Use Risk among Medically Vulnerable Youth.

    Science.gov (United States)

    Levy, Sharon; Dedeoglu, Fatma; Gaffin, Jonathan M; Garvey, Katharine C; Harstad, Elizabeth; MacGinnitie, Andrew; Rufo, Paul A; Huang, Qian; Ziemnik, Rosemary E; Wisk, Lauren E; Weitzman, Elissa R

    2016-01-01

    In an effort to reduce barriers to screening for alcohol use in pediatric primary care, the National Institute on Alcoholism and Alcohol Abuse (NIAAA) developed a two-question Youth Alcohol Screening Tool derived from population-based survey data. It is unknown whether this screening tool, designed for use with general populations, accurately identifies risk among youth with chronic medical conditions (YCMC). This growing population, which comprises nearly one in four youth in the US, faces a unique constellation of drinking-related risks. To validate the NIAAA Youth Alcohol Screening Tool in a population of YCMC, we performed a cross-sectional validation study with a sample of 388 youth ages 9-18 years presenting for routine subspecialty care at a large children's hospital for type 1 diabetes, persistent asthma, cystic fibrosis, inflammatory bowel disease, or juvenile idiopathic arthritis. Participants self-administered the NIAAA Youth Alcohol Screening Tool and the Diagnostic Interview Schedule for Children as a criterion standard measure of alcohol use disorders (AUD). Receiver operating curve analysis was used to determine cut points for identifying youth at moderate and highest risk for an AUD. Nearly one third of participants (n = 118; 30.4%) reported alcohol use in the past year; 86.4% (106) of past year drinkers did not endorse any AUD criteria, 6.8% (n = 8) of drinkers endorsed a single criterion, and 6.8% of drinkers met criteria for an AUD. Using the NIAAA tool, optimal cut points found to identify youth at moderate and highest risk for an AUD were ≥ 6 and ≥12 drinking days in the past year, respectively. The NIAAA Youth Alcohol Screening Tool is highly efficient for detecting alcohol use and discriminating disordered use among YCMC. This brief screen appears feasible for use in specialty care to ascertain alcohol-related risk that may impact adversely on health status and disease management.

  11. Intimate partner and sexual violence screening practices of college health care providers.

    Science.gov (United States)

    Sutherland, Melissa A; Hutchinson, M Katherine

    2018-02-01

    Female college students experience higher rates of intimate partner violence (IPV) and sexual violence (SV) compared to men of all ages, older women and young women who are not attending college. Experts and medical organizations have issued recommendations that health care providers should routinely screen women for IPV and SV. However, most female college students report they are not being screened for IPV and SV at college health centers. This exploratory study sought to examine the IPV and SV screening practices of college health care providers and identify individual and organizational influences using a cross-sectional, quantitative survey design. Sixty-four health care providers (physicians, nurse practitioners and registered nurses) from five colleges and universities in the northeastern U.S. were invited to participate in an anonymous, web-based survey about their IPV/SV-related screening practices and beliefs, and organizational characteristics of their college health centers. Twenty-six health care providers completed surveys (56% response rate). The median reported IPV/SV screening rate was 15%. More IPV/SV screening was reported by nurse practitioners, providers at state colleges, and by those in health centers that prioritized IPV/SV screening and had greater organizational capacity for change. College health centers represent unique, yet often missed, opportunities to screen for IPV/SV in a high-risk population. Provider- and organization-level influences should be incorporated into future interventions to improve IPV/SV screening in college health centers. Future studies with larger numbers of colleges and providers are needed to better understand organizational influences and identify mediators and moderators of effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Nutritional Risk Screening 2002, Short Nutritional Assessment Questionnaire, Malnutrition Screening Tool, and Malnutrition Universal Screening Tool Are Good Predictors of Nutrition Risk in an Emergency Service.

    Science.gov (United States)

    Rabito, Estela Iraci; Marcadenti, Aline; da Silva Fink, Jaqueline; Figueira, Luciane; Silva, Flávia Moraes

    2017-08-01

    There is an international consensus that nutrition screening be performed at the hospital; however, there is no "best tool" for screening of malnutrition risk in hospitalized patients. To evaluate (1) the accuracy of the MUST (Malnutrition Universal Screening Tool), MST (Malnutrition Screening Tool), and SNAQ (Short Nutritional Assessment Questionnaire) in comparison with the NRS-2002 (Nutritional Risk Screening 2002) to identify patients at risk of malnutrition and (2) the ability of these nutrition screening tools to predict morbidity and mortality. A specific questionnaire was administered to complete the 4 screening tools. Outcomes measures included length of hospital stay, transfer to the intensive care unit, presence of infection, and incidence of death. A total of 752 patients were included. The nutrition risk was 29.3%, 37.1%, 33.6%, and 31.3% according to the NRS-2002, MUST, MST, and SNAQ, respectively. All screening tools showed satisfactory performance to identify patients at nutrition risk (area under the receiver operating characteristic curve between 0.765-0.808). Patients at nutrition risk showed higher risk of very long length of hospital stay as compared with those not at nutrition risk, independent of the tool applied (relative risk, 1.35-1.78). Increased risk of mortality (2.34 times) was detected by the MUST. The MUST, MST, and SNAQ share similar accuracy to the NRS-2002 in identifying risk of malnutrition, and all instruments were positively associated with very long hospital stay. In clinical practice, the 4 tools could be applied, and the choice for one of them should be made per the particularities of the service.

  13. Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome.

    Science.gov (United States)

    Kang, Hyun Tae; Park, Joon Tae; Choi, Kobong; Choi, Hyo Jei Claudia; Jung, Chul Won; Kim, Gyu Ree; Lee, Young-Sam; Park, Sang Chul

    2017-06-01

    Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two-hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y-27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y-27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double-strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  14. Down syndrome screening in assisted conception twins: an iatrogenic medical challenge.

    Science.gov (United States)

    Ben-Ami, Ido; Maymon, Ron; Svirsky, Ran; Cuckle, Howard; Jauniaux, Eric

    2013-11-01

    The objective of this study was to provide a critical analysis of the impact of assisted conception on prenatal screening for Down syndrome (DS) in twin pregnancies and the value of various screening modalities for early detection of anomalies. The literature was searched using PubMed and the Cochrane Library focusing on prenatal screening and antenatal care of assisted-conception twin pregnancies. Serum screening alone is of limited value in detecting aneuploid twins, because the unaffected cotwin can "mask" the abnormal serum results of an affected one. In addition, this test can designate the pregnancy as at high risk but not identify the affected fetus. Nuchal translucency (NT) screening is the best available modality and a highly effective screening method for twin pregnancies. Among twins, NT alone has a 69% DS detection rate, first-trimester combined NT and serum biochemistry has a 72% DS detection rate, and an integrated screen will have an 80% DS detection rate at a 5% FPR. The data in the literature concerning the effect of assisted conception on maternal serum screening markers in twin pregnancies are scarce. Down syndrome screening in assisted-conception twins presents clinical and technical challenges. Therefore, assisted-conception twins need close monitoring from conception to delivery, by a practitioner familiar with the available screening modalities and their relative accuracy.

  15. Optimal screening of children with acute malnutrition requires a change in current WHO guidelines as MUAC and WHZ identify different patient groups.

    Science.gov (United States)

    Laillou, Arnaud; Prak, Sophonneary; de Groot, Richard; Whitney, Sophie; Conkle, Joel; Horton, Lindsey; Un, Sam Oeurn; Dijkhuizen, Marjoleine A; Wieringa, Frank T

    2014-01-01

    Timely treatment of acute malnutrition in children 500,000 deaths annually. Screening at community level is essential to identify children with malnutrition. Current WHO guidelines for community screening for malnutrition recommend a Mid Upper Arm Circumference (MUAC) of malnutrition (SAM). However, it is currently unclear how MUAC relates to the other indicator used to define acute malnutrition: weight-for-height Z-score (WHZ). Secondary data from >11,000 Cambodian children, obtained by different surveys between 2010 and 2012, was used to calculate sensitivity and ROC curves for MUAC and WHZ. The secondary analysis showed that using the current WHO cut-off of 115 mm for screening for severe acute malnutrition over 90% of children with a weight-for-height z-score (WHZ) children with a MUAC65% of children with a WHZchildren with acute malnutrition, therefore these 2 indicators should be regarded as independent from each other. We suggest a 2-step model with MUAC used a screening at community level, followed by MUAC and WHZ measured at a primary health care unit, with both indicators used independently to diagnose severe acute malnutrition. Current guidelines should be changed to reflect this, with treatment initiated when either MUAC <115 mm or WHZ<-3.

  16. Optimal Screening of Children with Acute Malnutrition Requires a Change in Current WHO Guidelines as MUAC and WHZ Identify Different Patient Groups

    Science.gov (United States)

    Laillou, Arnaud; Prak, Sophonneary; de Groot, Richard; Whitney, Sophie; Conkle, Joel; Horton, Lindsey; Un, Sam Oeurn; Dijkhuizen, Marjoleine A.; Wieringa, Frank T.

    2014-01-01

    Background Timely treatment of acute malnutrition in children 500,000 deaths annually. Screening at community level is essential to identify children with malnutrition. Current WHO guidelines for community screening for malnutrition recommend a Mid Upper Arm Circumference (MUAC) of malnutrition (SAM). However, it is currently unclear how MUAC relates to the other indicator used to define acute malnutrition: weight-for-height Z-score (WHZ). Methods Secondary data from >11,000 Cambodian children, obtained by different surveys between 2010 and 2012, was used to calculate sensitivity and ROC curves for MUAC and WHZ. Findings The secondary analysis showed that using the current WHO cut-off of 115 mm for screening for severe acute malnutrition over 90% of children with a weight-for-height z-score (WHZ) 65% of children with a WHZmalnutrition, therefore these 2 indicators should be regarded as independent from each other. We suggest a 2-step model with MUAC used a screening at community level, followed by MUAC and WHZ measured at a primary health care unit, with both indicators used independently to diagnose severe acute malnutrition. Current guidelines should be changed to reflect this, with treatment initiated when either MUAC <115 mm or WHZ<−3. PMID:24983995

  17. The Evonik-Mainz-Eye-Care-Study (EMECS: design and execution of the screening investigation.

    Directory of Open Access Journals (Sweden)

    Lorenz Barleon

    Full Text Available To determine if screening for major ophthalmological diseases is feasible within the frame of routine occupational medicine examinations in a large working population.13037 employees of Evonik Industries aged 40 to 65 years were invited to be screened for major ophthalmological diseases (glaucoma, age related macular degeneration and diabetic retinopathy between June 2007 and March 2008 within an extended setting of occupational medicine. Ophthalmological examinations consisted of visual acuity, objective refraction, pachymetry, tonometry, perimetry (frequency doubling technology, confocal scanning laser ophthalmoscopy and digital fundus photography. Participants responded to a questionnaire addressing history of ocular and general diseases and social history.4183 participants (961 female and 3222 male were examined at 13 different sites. Response rates for eligible persons at those sites ranged from 17.9 to 60.5% but were in part limited by availability of examination slots. Average age of participants was 48.4 ± 5.4 years (mean ± SD. 4147 out of 4183 subjects (99.1% had a visual acuity ≥ 0.5 in the better eye and 3665 out of 4183 (87.6% subjects had a visual acuity ≥ 0.8 in the better eye. 1629 participants (38.9% had previously not been seen by an ophthalmologist at all or not within the last three years.This article describes the study design and basic characteristics of study participants within a large occupational medicine based screening study for ophthalmological diseases. Response rates exceeded expectations and were limiting examination capacity. Meaningful data could be obtained for almost all participants. We reached participants who previously had not received ophthalmic care. Thus, ophthalmological screening appears to be feasible within the frame of routine occupational medicine examinations.

  18. Panoramic, large-screen, 3-D flight display system design

    Science.gov (United States)

    Franklin, Henry; Larson, Brent; Johnson, Michael; Droessler, Justin; Reinhart, William F.

    1995-01-01

    The report documents and summarizes the results of the required evaluations specified in the SOW and the design specifications for the selected display system hardware. Also included are the proposed development plan and schedule as well as the estimated rough order of magnitude (ROM) cost to design, fabricate, and demonstrate a flyable prototype research flight display system. The thrust of the effort was development of a complete understanding of the user/system requirements for a panoramic, collimated, 3-D flyable avionic display system and the translation of the requirements into an acceptable system design for fabrication and demonstration of a prototype display in the early 1997 time frame. Eleven display system design concepts were presented to NASA LaRC during the program, one of which was down-selected to a preferred display system concept. A set of preliminary display requirements was formulated. The state of the art in image source technology, 3-D methods, collimation methods, and interaction methods for a panoramic, 3-D flight display system were reviewed in depth and evaluated. Display technology improvements and risk reductions associated with maturity of the technologies for the preferred display system design concept were identified.

  19. On various metrics used for validation of predictive QSAR models with applications in virtual screening and focused library design.

    Science.gov (United States)

    Roy, Kunal; Mitra, Indrani

    2011-07-01

    Quantitative structure-activity relationships (QSARs) have important applications in drug discovery research, environmental fate modeling, property prediction, etc. Validation has been recognized as a very important step for QSAR model development. As one of the important objectives of QSAR modeling is to predict activity/property/toxicity of new chemicals falling within the domain of applicability of the developed models and QSARs are being used for regulatory decisions, checking reliability of the models and confidence of their predictions is a very important aspect, which can be judged during the validation process. One prime application of a statistically significant QSAR model is virtual screening for molecules with improved potency based on the pharmacophoric features and the descriptors appearing in the QSAR model. Validated QSAR models may also be utilized for design of focused libraries which may be subsequently screened for the selection of hits. The present review focuses on various metrics used for validation of predictive QSAR models together with an overview of the application of QSAR models in the fields of virtual screening and focused library design for diverse series of compounds with citation of some recent examples.

  20. Designing airport checked-baggage-screening strategies considering system capability and reliability

    International Nuclear Information System (INIS)

    Feng Qianmei; Sahin, Hande; Kapur, Kailash C.

    2009-01-01

    Emerging image-based technologies are critical components of airport security for screening checked baggage. Since these new technologies differ widely in cost and accuracy, a comprehensive mathematical framework should be developed for selecting technology or combination of technologies for efficient 100% baggage screening. This paper addresses the problem of setting threshold values of these screening technologies and determining the optimal combination of technologies in a two-level screening system by considering system capability and human reliability. Probability and optimization techniques are used to quantify and evaluate the cost- and risk-effectiveness of various deployment configurations, which is captured by using a system life-cycle cost model that incorporates the deployment cost, operating cost, and costs associated with system decisions. Two system decision rules are studied for a two-level screening system. For each decision rule, two different optimization approaches are formulated and investigated from practitioner's perspective. Numerical examples for different decision rules, optimization approaches and system arrangements are demonstrated

  1. RNA interference screen identifies Abl kinase and PDGFR signaling in Chlamydia trachomatis entry.

    Directory of Open Access Journals (Sweden)

    Cherilyn A Elwell

    2008-03-01

    Full Text Available The strain designated Chlamydia trachomatis serovar L2 that was used for experiments in this paper is Chlamydia muridarum, a species closely related to C. trachomatis (and formerly termed the Mouse Pneumonitis strain of C. trachomatis. This conclusion was verified by deep sequencing and by PCR using species-specific primers. All data presented in the results section that refer to C. trachomatis should be interpreted as referring to C. muridarum. Since C. muridarum TARP lacks the consensus tyrosine repeats present in C. trachomatis TARP, we cannot make any conclusions about the role of TARP phosphorylation and C. muridarum entry. However, the conclusion that C. trachomatis L2 TARP is a target of Abl kinase is still valid as these experiments were performed with C. trachomatis L2 TARP [corrected]. To elucidate the mechanisms involved in early events in Chlamydia trachomatis infection, we conducted a large scale unbiased RNA interference screen in Drosophila melanogaster S2 cells. This allowed identification of candidate host factors in a simple non-redundant, genetically tractable system. From a library of 7,216 double stranded RNAs (dsRNA, we identified approximately 226 host genes, including two tyrosine kinases, Abelson (Abl kinase and PDGF- and VEGF-receptor related (Pvr, a homolog of the Platelet-derived growth factor receptor (PDGFR. We further examined the role of these two kinases in C. trachomatis binding and internalization into mammalian cells. Both kinases are phosphorylated upon infection and recruited to the site of bacterial attachment, but their roles in the infectious process are distinct. We provide evidence that PDGFRbeta may function as a receptor, as inhibition of PDGFRbeta by RNA interference or by PDGFRbeta neutralizing antibodies significantly reduces bacterial binding, whereas depletion of Abl kinase has no effect on binding. Bacterial internalization can occur through activation of PDGFRbeta or through independent

  2. Domestic violence screening in a military setting: provider screening and attitudes.

    Science.gov (United States)

    Lutgendorf, Monica; Busch, Jeanne; Magann, Everett F; Morrison, John C

    2010-06-01

    Domestic violence is an important healthcare problem, and it appears more prevalent in military patient populations although no one has demonstrated the cause behind this phenomenon. The purpose of this observational study was to assess data regarding domestic violence screening from practitioners at one military training center. This study used an anonymous questionnaire for physicians, nurses and nurse midwives, which surveyed current methods, attitudes toward screening, and barriers for such assessment. Fifty-seven surveys were distributed, and 26 were returned for a response rate of 45.6%. Only about a third (38.5%) of the practitioners screened all obstetric patients while the remainder screened selected patients for domestic violence. Even less (19%) screened gynecology patients routinely, whereas 69% reported they screened selected women with chronic or somatic complaints. A history of prior abuse in the respondents led practitioners to try to identify such patients within their practice. Lack of education or training was the most common barrier to universal screening followed by time constraints and frustration about not being able to address adequately the problem when noted. These results emphasized the importance of an educational program to increase domestic violence awareness and routine screening.

  3. Screening children for elevated blood lead - Learnings from the literature

    International Nuclear Information System (INIS)

    Boreland, Frances; Lyle, David

    2008-01-01

    Introduction: Although it is important that children at risk of developing elevated blood lead receive regular screening, attendance at screening programs is variable. A literature review was undertaken to better understand the factors that affect carers' decisions about whether or not to take their children for blood lead screening. Method: Electronic databases (Medline, EMBASE, CINAHL, Psychinfo) were searched to identify relevant publications, supported by reviewing reference lists of identified articles and searching with internet-based search engines. Results: Thirty-four published studies dealing with blood lead screening rates were identified, of which only seven papers focused specifically on parent's attitudes to blood lead screening. The barriers to and enablers of screening for elevated blood lead levels appear to be similar to those identified for other screening programs. Discussion: It is recommended that attendance at screening be routinely monitored, and that where participation is suboptimal further research be undertaken, in close co-operation with affected communities or sub-groups, to determine how best to encourage screening and to protect children from lead. It is important to minimize stigma and to ensure, as far as possible, that practical barriers such as lack of transport do not restrict access to screening programs

  4. Selective anti-proliferation of HER2-positive breast cancer cells by anthocyanins identified by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Weihua Liu

    Full Text Available Overexpressed Human epidermal growth factor receptor 2 (HER2 drives the biology of 20% breast cancer and is a prediction of a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients. Traditional Chinese herbs/medicines have been used to treat breast cancer patients including HER2-positive patients in Asia for decades. Although the traditional medicines demonstrate efficacy in clinics for HER2-positive patients, the mechanism is largely unknown. In this article, we screened a 10,000 natural product library in 6 different cell lines representing breast cancer, and assessed the ability of each drug to cause cytotoxicity through a high-throughput screening approach. We have identified eight natural compounds that selectively inhibit the proliferation of HER2-positive cells. Two of the hit compounds, peonidin-3-glucoside and cyaniding-3-glucoside, are both extracts from black rice. They inhibit the phospho-HER2 and phospho-AKT and were confirmed to induce HER2-psotive breast cancer cells apoptosis both in vitro and in vivo. Peonidin-3-glucoside and cyaniding-3-glucoside treatments significantly reduced the tumor size and volume in vivo compared to the control group. There is no significant difference of antitumorgenic effects between peonidin-3-glucoside and cyaniding-3-glucoside treatments.

  5. Fish screens at hydroelectric diversions

    International Nuclear Information System (INIS)

    Ott, R.F.

    1994-01-01

    Preventing downstream migrating fish from entering the turbines at hydroelectric projects is a standard mitigation goal of state and federal fishery management agencies. The object is to minimize the adverse impacts to the fish associated with the exclusion and passage through the bypass water conveyance facilities. In the western United States, most of the fishery management agencies have fish screen design criteria that focus on the approach and transportational velocities, maximum opening dimensions of the screen material, and the cleaning standards. Recently, more attention has been given to fish behavioral traits such as attraction and sustained and darting swimming speed, which has resulted in more attention to the position of the screens to the flow and the length of time the downstream migrants are exposed to the screens. Criteria for length of time of exposure, size and position of bypass, flow and velocities in the bypass entrances, discharge requirements back into the receiving water, and exposure to predation have created unique challenges to the fish screen designer. This paper discusses some of the more recent types of fixed fish screens that are being installed at hydroelectric plants that meet these challenges

  6. Virtual screening of electron acceptor materials for organic photovoltaic applications

    International Nuclear Information System (INIS)

    D Halls, Mathew; Giesen, David J; Goldberg, Alexander; Djurovich, Peter J; Sommer, Jonathan; McAnally, Eric; Thompson, Mark E

    2013-01-01

    Virtual screening involves the generation of structure libraries, automated analysis to predict properties related to application performance and subsequent screening to identify lead systems and estimate critical structure–property limits across a targeted chemical design space. This approach holds great promise for informing experimental discovery and development efforts for next-generation materials, such as organic semiconductors. In this work, the virtual screening approach is illustrated for nitrogen-substituted pentacene molecules to identify systems for development as electron acceptor materials for use in organic photovoltaic (OPV) devices. A structure library of tetra-azapentacenes (TAPs) was generated by substituting four nitrogens for CH at 12 sites on the pentacene molecular framework. Molecular properties (e.g. E LUMO , E g and μ) were computed for each candidate structure using hybrid DFT at the B3LYP/6-311G** level of theory. The resulting TAPs library was then analyzed with respect to intrinsic properties associated with OPV acceptor performance. Marcus reorganization energies for charge transport for the most favorable TAP candidates were then calculated to further determine suitability as OPV electron acceptors. The synthesis, characterization and OPV device testing of TAP materials is underway, guided by these results. (paper)

  7. The comparison of the performance of two screening strategies identifying newly-diagnosed HIV during pregnancy

    NARCIS (Netherlands)

    Boer, K.; Smit, C.; Flier, M. van der; Wolf, F. de; Koopmans †, P.P.; Crevel, R. van; Eggink, A.J.; Groot, R. de; Keuter, M.; Post, F.; Ven, A.J.A.M. van der; Warris, A.; et al.,

    2011-01-01

    BACKGROUND: In the Netherlands, a non-selective opt-out instead of a selective opt-in antenatal HIV screening strategy was implemented in 2004. In case of infection, screening was followed by prevention of mother-to-child-transmission (PMTCT). We compared the performance of the two strategies in

  8. Biological Evaluations of an Off-Stream Channel, Horizontal Flat-Plate Fish Screen-The Farmers Screen

    Science.gov (United States)

    Mesa, Matthew G.; Rose, Brien P.; Copeland, Elizabeth S.

    2010-01-01

    Screens are commonly installed at water diversion sites to reduce entrainment of fish. Recently, the Farmers Irrigation District in Hood River, Oregon, developed a new flat-plate screen design that offers passive operation and may result in reduced operation and installation costs to irrigators. To evaluate the performance (its biological effect on fish) of this type of screen, two size classes of juvenile coho salmon (Oncorhynchus kistuch) were released over a small version of this screen in the field-the Herman Creek screen. The performance of the screen was evaluated over a range of inflow [0.02 to 0.42 m3/s (cubic meters per second)] and diversion flows (0.02 to 0.34 m3/s) at different weir wall heights. The mean approach velocities for the screen ranged from 0 to 5 cm/s (centimeters per second) and mean sweeping velocities ranged from 36 to 178 cm/s. Water depths over the screen surface ranged from 1 to 25 centimeters and were directly related to weir wall height and inflow. Passage of juvenile coho salmon over the screen under a variety of hydraulic conditions did not severely injure them or cause delayed mortality. For all fish, the mean percentage of body surface area that was injured after passage over the screen ranged from about 0.4 to 3.0%. This occurred even though many fish contacted the screen surface during passage. No fish were observed becoming impinged on the screen surface (greater than 1 second contact with the screen). When operated within its design criteria (diversion flows of about 0.28 m3/s), the screen provided safe and effective downstream passage of juvenile salmonids under a variety of hydraulic conditions. However, we do not recommend operating the screen at inflows less than 0.14 m3/s (5 ft3/s) because water depth can get quite shallow and the screen can completely dewater, particularly at very low flows.

  9. ROS-activated ATM-dependent phosphorylation of cytoplasmic substrates identified by large scale phosphoproteomics screen

    DEFF Research Database (Denmark)

    Kozlov, Sergei V; Waardenberg, Ashley J; Engholm-Keller, Kasper

    2016-01-01

    ATM (ataxia-telangiectasia, mutated) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signalling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoi......ATM (ataxia-telangiectasia, mutated) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signalling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle...... checkpoints, initiating DNA repair and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress. Here we confirmed activation of cytoplasmic ATM by autophosphorylation at multiple sites. Then we employed a global quantitative phosphoproteomics approach...... to identify cytoplasmic proteins altered in their phosphorylation state in control and A-T (ataxia-telangiectasia) cells in response to oxidative damage. We demonstrated that ATM was activated by oxidative damage in the cytoplasm as well as in the nucleus and identified a total of 9,833 phosphorylation sites...

  10. Molecular HIV screening.

    Science.gov (United States)

    Bourlet, Thomas; Memmi, Meriam; Saoudin, Henia; Pozzetto, Bruno

    2013-09-01

    Nuclear acid testing is more and more used for the diagnosis of infectious diseases. This paper focuses on the use of molecular tools for HIV screening. The term 'screening' will be used under the meaning of first-line HIV molecular techniques performed on a routine basis, which excludes HIV molecular tests designed to confirm or infirm a newly discovered HIV-seropositive patient or other molecular tests performed for the follow-up of HIV-infected patients. The following items are developed successively: i) presentation of the variety of molecular tools used for molecular HIV screening, ii) use of HIV molecular tools for the screening of blood products, iii) use of HIV molecular tools for the screening of organs and tissue from human origin, iv) use of HIV molecular tools in medically assisted procreation and v) use of HIV molecular tools in neonates from HIV-infected mothers.

  11. Transcriptional Profiling of Biofilm Regulators Identified by an Overexpression Screen in Saccharomyces cerevisiae

    Science.gov (United States)

    Cromie, Gareth A.; Tan, Zhihao; Hays, Michelle; Sirr, Amy; Jeffery, Eric W.; Dudley, Aimée M.

    2017-01-01

    Biofilm formation by microorganisms is a major cause of recurring infections and removal of biofilms has proven to be extremely difficult given their inherent drug resistance . Understanding the biological processes that underlie biofilm formation is thus extremely important and could lead to the development of more effective drug therapies, resulting in better infection outcomes. Using the yeast Saccharomyces cerevisiae as a biofilm model, overexpression screens identified DIG1, SFL1, HEK2, TOS8, SAN1, and ROF1/YHR177W as regulators of biofilm formation. Subsequent RNA-seq analysis of biofilm and nonbiofilm-forming strains revealed that all of the overexpression strains, other than DIG1 and TOS8, were adopting a single differential expression profile, although induced to varying degrees. TOS8 adopted a separate profile, while the expression profile of DIG1 reflected the common pattern seen in most of the strains, plus substantial DIG1-specific expression changes. We interpret the existence of the common transcriptional pattern seen across multiple, unrelated overexpression strains as reflecting a transcriptional state, that the yeast cell can access through regulatory signaling mechanisms, allowing an adaptive morphological change between biofilm-forming and nonbiofilm states. PMID:28673928

  12. Identifying obstructive sleep apnea after stroke/TIA: evaluating four simple screening tools.

    Science.gov (United States)

    Boulos, Mark I; Wan, Anthony; Im, James; Elias, Sara; Frankul, Fadi; Atalla, Mina; Black, Sandra E; Basile, Vincenzo S; Sundaram, Arun; Hopyan, Julia J; Boyle, Karl; Gladstone, David J; Murray, Brian J; Swartz, Richard H

    2016-05-01

    Despite its high prevalence and unfavorable clinical consequences, obstructive sleep apnea (OSA) often remains underappreciated after cerebrovascular events. The purpose of our study was to evaluate the clinical utility of four simple paper-based screening tools for excluding OSA after stroke or transient ischemic attack (TIA). Sixty-nine inpatients and outpatients with stroke or TIA during the past 180 days completed the 4-Variable screening tool (4V), STOP-BAG questionnaire (ie, STOP-BANG questionnaire without the neck circumference measurement), Berlin questionnaire, and the Sleep Obstructive apnea score optimized for Stroke (SOS). They subsequently underwent objective testing using a portable sleep monitoring device. Cutoffs were selected to maximize sensitivity and exclude OSA (AHI ≥ 10) in ≥10% of the cohort. The mean age was 68.3 ± 14.2 years and 47.8% were male. Thirty-two patients (46.4%) were found to have OSA. Male sex, body mass index (BMI), and atrial fibrillation were independent predictors of OSA. Among the screening tools, the 4V had the greatest area under the curve (AUC) of 0.688 (p = 0.007); the sensitivity was 96.9% for a cutoff of stroke/TIA. Due to the atypical presentation of poststroke/TIA OSA, these tools are only moderately predictive; objective testing should still be used for OSA diagnosis in this population. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Screening and prioritisation of chemical risks from metal mining operations, identifying exposure media of concern.

    Science.gov (United States)

    Pan, Jilang; Oates, Christopher J; Ihlenfeld, Christian; Plant, Jane A; Voulvoulis, Nikolaos

    2010-04-01

    Metals have been central to the development of human civilisation from the Bronze Age to modern times, although in the past, metal mining and smelting have been the cause of serious environmental pollution with the potential to harm human health. Despite problems from artisanal mining in some developing countries, modern mining to Western standards now uses the best available mining technology combined with environmental monitoring, mitigation and remediation measures to limit emissions to the environment. This paper develops risk screening and prioritisation methods previously used for contaminated land on military and civilian sites and engineering systems for the analysis and prioritisation of chemical risks from modern metal mining operations. It uses hierarchical holographic modelling and multi-criteria decision making to analyse and prioritise the risks from potentially hazardous inorganic chemical substances released by mining operations. A case study of an active platinum group metals mine in South Africa is used to demonstrate the potential of the method. This risk-based methodology for identifying, filtering and ranking mining-related environmental and human health risks can be used to identify exposure media of greatest concern to inform risk management. It also provides a practical decision-making tool for mine acquisition and helps to communicate risk to all members of mining operation teams.

  14. Increasingly strong reduction in breast cancer mortality due to screening

    Science.gov (United States)

    van Schoor, G; Moss, S M; Otten, J D M; Donders, R; Paap, E; den Heeten, G J; Holland, R; Broeders, M J M; Verbeek, A L M

    2011-01-01

    Background: Favourable outcomes of breast cancer screening trials in the 1970s and 1980s resulted in the launch of population-based service screening programmes in many Western countries. We investigated whether improvements in mammography and treatment modalities have had an influence on the effectiveness of breast cancer screening from 1975 to 2008. Methods: In Nijmegen, the Netherlands, 55 529 women received an invitation for screening between 1975 and 2008. We designed a case–referent study to evaluate the impact of mammographic screening on breast cancer mortality over time from 1975 to 2008. A total number of 282 breast cancer deaths were identified, and 1410 referents aged 50–69 were sampled from the population invited for screening. We estimated the effectiveness by calculating the odds ratio (OR) indicating the breast cancer death rate for screened vs unscreened women. Results: The breast cancer death rate in the screened group over the complete period was 35% lower than in the unscreened group (OR=0.65; 95% CI=0.49–0.87). Analysis by calendar year showed an increasing effectiveness from a 28% reduction in breast cancer mortality in the period 1975–1991 (OR=0.72; 95% CI=0.47–1.09) to 65% in the period 1992–2008 (OR=0.35; 95% CI=0.19–0.64). Conclusion: Our results show an increasingly strong reduction in breast cancer mortality over time because of mammographic screening. PMID:21343930

  15. Adding biological meaning to human protein-protein interactions identified by yeast two-hybrid screenings: A guide through bioinformatics tools.

    Science.gov (United States)

    Felgueiras, Juliana; Silva, Joana Vieira; Fardilha, Margarida

    2018-01-16

    "A man is known by the company he keeps" is a popular expression that perfectly fits proteins. A common approach to characterize the function of a target protein is to identify its interacting partners and thus infer its roles based on the known functions of the interactors. Protein-protein interaction networks (PPINs) have been created for several organisms, including humans, primarily as results of high-throughput screenings, such as yeast two-hybrid (Y2H). Their unequivocal use to understand events underlying human pathophysiology is promising in identifying genes and proteins associated with diseases. Therefore, numerous opportunities have emerged for PPINs as tools for clinical management of diseases: network-based disease classification systems, discovery of biomarkers and identification of therapeutic targets. Despite the great advantages of PPINs, their use is still unrecognised by several researchers who generate high-throughput data to generally characterize interactions in a certain model or to select an interaction to study in detail. We strongly believe that both approaches are not exclusive and that we can use PPINs as a complementary methodology and rich-source of information to the initial study proposal. Here, we suggest a pipeline to deal with Y2H results using bioinformatics tools freely available for academics. Yeast two-hybrid is widely-used to identify protein-protein interactions. Conventionally, the positive clones that result from a yeast two-hybrid screening are sequenced to identify the interactors of the protein of interest (also known as bait protein), and few interactions, thought as potentially relevant for the model in study, are selected for further validation using biochemical methods (e.g. co-immunoprecipitation and co-localization). The huge amount of data that is potentially lost during this conservative approach motivated us to write this tutorial-like review, so that researchers feel encouraged to take advantage of

  16. The Clinical Validation of the Athlete Sleep Screening Questionnaire: an Instrument to Identify Athletes that Need Further Sleep Assessment.

    Science.gov (United States)

    Bender, Amy M; Lawson, Doug; Werthner, Penny; Samuels, Charles H

    2018-06-04

    Previous research has established that general sleep screening questionnaires are not valid and reliable in an athlete population. The Athlete Sleep Screening Questionnaire (ASSQ) was developed to address this need. While the initial validation of the ASSQ has been established, the clinical validity of the ASSQ has yet to be determined. The main objective of the current study was to evaluate the clinical validity of the ASSQ. Canadian National Team athletes (N = 199; mean age 24.0 ± 4.2 years, 62% females; from 23 sports) completed the ASSQ. A subset of athletes (N = 46) were randomized to the clinical validation sub-study which required subjects to complete an ASSQ at times 2 and 3 and to have a clinical sleep interview by a sleep medicine physician (SMP) who rated each subjects' category of clinical sleep problem and provided recommendations to improve sleep. To assess clinical validity, the SMP category of clinical sleep problem was compared to the ASSQ. The internal consistency (Cronbach's alpha = 0.74) and test-retest reliability (r = 0.86) of the ASSQ were acceptable. The ASSQ demonstrated good agreement with the SMP (Cohen's kappa = 0.84) which yielded a diagnostic sensitivity of 81%, specificity of 93%, positive predictive value of 87%, and negative predictive value of 90%. There were 25.1% of athletes identified to have clinically relevant sleep disturbances that required further clinical sleep assessment. Sleep improved from time 1 at baseline to after the recommendations at time 3. Sleep screening athletes with the ASSQ provides a method of accurately determining which athletes would benefit from preventative measures and which athletes suffer from clinically significant sleep problems. The process of sleep screening athletes and providing recommendations improves sleep and offers a clinical intervention output that is simple and efficient for teams and athletes to implement.

  17. Yeast screens identify the RNA polymerase II CTD and SPT5 as relevant targets of BRCA1 interaction.

    Directory of Open Access Journals (Sweden)

    Craig B Bennett

    2008-01-01

    Full Text Available BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1 to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34 and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1. Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII carboxy terminal domain (P-CTD, phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1

  18. The comparison of the performance of two screening strategies identifying newly-diagnosed HIV during pregnancy

    NARCIS (Netherlands)

    Boer, Kees; Smit, Colette; van der Flier, Michiel; de Wolf, Frank; Bezemer, D. O.; Gras, L. A. J.; Kesselring, A. M.; van Sighem, A. I.; Smit, C.; Zhang, S.; Zaheri, S.; Bronsveld, W.; Hillebrand-Haverkort, M. E.; Prins, J. M.; Branger, J.; Eeftinck Schattenkerk, J. K. M.; Gisolf, J.; Godfried, M. H.; Lange, J. M. A.; Lettinga, K. D.; van der Meer, J. T. M.; Nellen, F. J. B.; van der Poll, T.; Reiss, P.; Ruys, Th A.; Steingrover, R.; van Twillert, G.; Vermeulen, J. N.; Vrouenraets, S. M. E.; van Vugt, M.; Wit, F. W. M. N.; Kuijpers, T. W.; Pajkrt, D.; Scherpbier, H. J.; van Eeden, A.; Brinkman, K.; van den Berk, G. E. L.; Blok, W. L.; Frissen, P. H. J.; Roos, J. C.; Schouten, W. E. M.; Bekendam, D. J.; Weigel, H. M.; Mulder, J. W.; van Gorp, E. C. M.; Wagenaar, J.; Veenstra, J.; Danner, S. A.; van Agtmael, M. A.; Claessen, F. A. P.

    2011-01-01

    In the Netherlands, a non-selective opt-out instead of a selective opt-in antenatal HIV screening strategy was implemented in 2004. In case of infection, screening was followed by prevention of mother-to-child-transmission (PMTCT). We compared the performance of the two strategies in terms of

  19. Characterization of the Raf kinase inhibitory protein (RKIP) binding pocket: NMR-based screening identifies small-molecule ligands.

    Science.gov (United States)

    Shemon, Anne N; Heil, Gary L; Granovsky, Alexey E; Clark, Mathew M; McElheny, Dan; Chimon, Alexander; Rosner, Marsha R; Koide, Shohei

    2010-05-05

    Raf kinase inhibitory protein (RKIP), also known as phoshaptidylethanolamine binding protein (PEBP), has been shown to inhibit Raf and thereby negatively regulate growth factor signaling by the Raf/MAP kinase pathway. RKIP has also been shown to suppress metastasis. We have previously demonstrated that RKIP/Raf interaction is regulated by two mechanisms: phosphorylation of RKIP at Ser-153, and occupation of RKIP's conserved ligand binding domain with a phospholipid (2-dihexanoyl-sn-glycero-3-phosphoethanolamine; DHPE). In addition to phospholipids, other ligands have been reported to bind this domain; however their binding properties remain uncharacterized. In this study, we used high-resolution heteronuclear NMR spectroscopy to screen a chemical library and assay a number of potential RKIP ligands for binding to the protein. Surprisingly, many compounds previously postulated as RKIP ligands showed no detectable binding in near-physiological solution conditions even at millimolar concentrations. In contrast, we found three novel ligands for RKIP that specifically bind to the RKIP pocket. Interestingly, unlike the phospholipid, DHPE, these newly identified ligands did not affect RKIP binding to Raf-1 or RKIP phosphorylation. One out of the three ligands displayed off target biological effects, impairing EGF-induced MAPK and metabolic activity. This work defines the binding properties of RKIP ligands under near physiological conditions, establishing RKIP's affinity for hydrophobic ligands and the importance of bulky aliphatic chains for inhibiting its function. The common structural elements of these compounds defines a minimal requirement for RKIP binding and thus they can be used as lead compounds for future design of RKIP ligands with therapeutic potential.

  20. Characterization of the Raf kinase inhibitory protein (RKIP binding pocket: NMR-based screening identifies small-molecule ligands.

    Directory of Open Access Journals (Sweden)

    Anne N Shemon

    2010-05-01

    Full Text Available Raf kinase inhibitory protein (RKIP, also known as phoshaptidylethanolamine binding protein (PEBP, has been shown to inhibit Raf and thereby negatively regulate growth factor signaling by the Raf/MAP kinase pathway. RKIP has also been shown to suppress metastasis. We have previously demonstrated that RKIP/Raf interaction is regulated by two mechanisms: phosphorylation of RKIP at Ser-153, and occupation of RKIP's conserved ligand binding domain with a phospholipid (2-dihexanoyl-sn-glycero-3-phosphoethanolamine; DHPE. In addition to phospholipids, other ligands have been reported to bind this domain; however their binding properties remain uncharacterized.In this study, we used high-resolution heteronuclear NMR spectroscopy to screen a chemical library and assay a number of potential RKIP ligands for binding to the protein. Surprisingly, many compounds previously postulated as RKIP ligands showed no detectable binding in near-physiological solution conditions even at millimolar concentrations. In contrast, we found three novel ligands for RKIP that specifically bind to the RKIP pocket. Interestingly, unlike the phospholipid, DHPE, these newly identified ligands did not affect RKIP binding to Raf-1 or RKIP phosphorylation. One out of the three ligands displayed off target biological effects, impairing EGF-induced MAPK and metabolic activity.This work defines the binding properties of RKIP ligands under near physiological conditions, establishing RKIP's affinity for hydrophobic ligands and the importance of bulky aliphatic chains for inhibiting its function. The common structural elements of these compounds defines a minimal requirement for RKIP binding and thus they can be used as lead compounds for future design of RKIP ligands with therapeutic potential.

  1. Screening, intervention and outcome in autism and other developmental disorders: the role of randomized controlled trials.

    Science.gov (United States)

    Fernell, Elisabeth; Wilson, Philip; Hadjikhani, Nouchine; Bourgeron, Thomas; Neville, Brian; Taylor, David; Minnis, Helen; Gillberg, Christopher

    2014-08-01

    We draw attention to a number of important considerations in the arguments about screening and outcome of intervention in children with autism and other developmental disorders. Autism screening in itself never provides a final clinical diagnosis, but may well identify developmental deviations indicative of autism-or of other developmental disorders-that should lead to referral for further clinical assessment. Decisions regarding population or clinic screening cannot be allowed to be based on the fact that prospective longitudinal RCT designs over decades could never be performed in complex developmental disorders. We propose an alternative approach. Early screening for autism and other developmental disorders is likely to be of high societal importance and should be promoted and rigorously evaluated.

  2. MSBIS: A Multi-Step Biomedical Informatics Screening Approach for Identifying Medications that Mitigate the Risks of Metoclopramide-Induced Tardive Dyskinesia

    OpenAIRE

    Dong Xu; Alexandrea G. Ham; Rickey D. Tivis; Matthew L. Caylor; Aoxiang Tao; Steve T. Flynn; Peter J. Economen; Hung K. Dang; Royal W. Johnson; Vaughn L. Culbertson

    2017-01-01

    In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anti...

  3. Screening for diabetes in unconventional locations: resource implications and economics of screening in optometry practices.

    Science.gov (United States)

    Howse, Jennifer H; Jones, Steve; Hungin, A Pali S

    2011-10-01

    Unconventional locations outwith general medical practice may prove opportunities for screening. The aim was to determine the resource implications and economics of a screening service using random capillary blood glucose (rCBG) tests to detect raised blood glucose levels in the "at risk" population attending high street optometry practices. A screening service was implemented in optometry practices in North East England: the cost of the service and the implication of different screening strategies was estimated. The cost of a screening test was £5.53-£11.20, depending on the screening strategy employed and who carried out the testing. Refining the screening strategy to target those ≥40 years with BMI of ≥25 kg/m(2) and/or family history of diabetes resulted in a cost per case referred to the GP of £14.38-£26.36. Implementing this strategy in half of optometric practices in England would have the potential to identify up to 150,000 new cases of diabetes and prediabetes a year. Optometry practices provide an effective way of identifying people who would benefit from further investigation for diabetes. Effectiveness could be improved further by improving cooperation and communication between optometrists and medical practitioners. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  4. Identifying model pollutants to investigate biodegradation of hazardous XOCs in WWTPs

    Energy Technology Data Exchange (ETDEWEB)

    Press-Kristensen, Kaare; Ledin, Anna; Schmidt, Jens Ejbye; Henze, Mogens [Department of Environment and Resources, Technical University of Denmark Building 115, 2800 Lyngby (Denmark)

    2007-02-01

    Xenobiotic organic compounds (XOCs) in wastewater treatment plant (WWTP) effluents might cause toxic effects in ecosystems. Several investigations have emphasized biodegradation as an important removal mechanism to reduce pollution with XOCs from WWTP effluents. The aim of the study was to design a screening tool to identify and select hazardous model pollutants for the further investigation of biodegradation in WWTPs. The screening tool consists of three criteria: The XOC is present in WWTP effluents, the XOC constitutes an intolerable risk in drinking water or the environment, and the XOC is expected to be biodegradable in WWTPs. The screening tool was tested on bisphenol A (BPA), carbamazepine (CBZ), di(2ethylhexyl)-phthalate (DEHP), 17{beta}-estradiol (E2), estrone (E1), 17{alpha}-ethinyloetradiol (EE2), ibuprofen, naproxen, nonylphenol (NP), and octylphenol (OP). BPA, DEHP, E2, E1, EE2, and NP passed all criteria in the screening tool and were selected as model pollutants. OP did not pass the filter and was rejected as model pollutant. CBZ, ibuprofen, and naproxen were not finally evaluated due to insufficient data. (author)

  5. Screening efficacy of a simplified logMAR chart

    Directory of Open Access Journals (Sweden)

    Naganathan Muthuramalingam

    2016-04-01

    Aim: This study evaluates the efficacy of a simplified logMAR chart, designed for VA testing over the conventional Snellen chart, in a school-based vision-screening programme. Methods: We designed a simplified logMAR chart by employing the principles of the Early Treatment Diabetic Retinopathy Study (ETDRS chart in terms of logarithmic letter size progression, inter-letter spacing, and inter-line spacing. Once the simplified logMAR chart was validated by students in the Elite school vision-screening programme, we set out to test the chart in 88 primary and middle schools in the Tiruporur block of Kancheepuram district in Tamil Nadu. One school teacher in each school was trained to screen a cross-sectional population of 10 354 primary and secondary school children (girls: 5488; boys: 4866 for VA deficits using a new, simplified logMAR algorithm. An experienced paediatric optometrist was recruited to validate the screening methods and technique used by the teachers to collect the data. Results: The optometrist screened a subset of 1300 school children from the total sample. The optometrist provided the professional insights needed to validate the clinical efficacy of the simplified logMAR algorithm and verified the reliability of the data collected by the teachers. The mean age of children sampled for validation was 8.6 years (range: 9–14 years. The sensitivity and the specificity of the simplified logMAR chart when compared to the standard logMAR chart were found to be 95% and 98%, respectively. Kappa value was 0.97. Sensitivity of the teachers’ screening was 66.63% (95% confidence interval [CI]: 52.73–77.02 and the specificity was 98.33% (95% CI: 97.49–98.95. Testing of VA was done under substandard illumination levels in 87% of the population. A total of 10 354 children were screened, 425 of whom were found to have some form of visual and/or ocular defect that was identified by the teacher or optometrist. Conclusion: The simplified logMAR testing algorithm

  6. Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis.

    Science.gov (United States)

    Fazly, Ahmed; Jain, Charu; Dehner, Amie C; Issi, Luca; Lilly, Elizabeth A; Ali, Akbar; Cao, Hong; Fidel, Paul L; Rao, Reeta P; Kaufman, Paul D

    2013-08-13

    Infection by pathogenic fungi, such as Candida albicans, begins with adhesion to host cells or implanted medical devices followed by biofilm formation. By high-throughput phenotypic screening of small molecules, we identified compounds that inhibit adhesion of C. albicans to polystyrene. Our lead candidate compound also inhibits binding of C. albicans to cultured human epithelial cells, the yeast-to-hyphal morphological transition, induction of the hyphal-specific HWP1 promoter, biofilm formation on silicone elastomers, and pathogenesis in a nematode infection model as well as alters fungal morphology in a mouse mucosal infection assay. We term this compound filastatin based on its strong inhibition of filamentation, and we use chemical genetic experiments to show that it acts downstream of multiple signaling pathways. These studies show that high-throughput functional assays targeting fungal adhesion can provide chemical probes for study of multiple aspects of fungal pathogenesis.

  7. Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40-49 (J-START). Research design

    International Nuclear Information System (INIS)

    Ohuchi, Noriaki; Ishida, Takanori; Kawai, Masaaki; Narikawa, Yoko; Yamamoto, Seiichiro; Sobue, Tomotaka

    2011-01-01

    In cancer screening, it is essential to undertake effective screening with appropriate methodology, which should be supported by evidence of a reduced mortality rate. At present, mammography is the only method for breast cancer screening with such evidence. However, mammography does not achieve sufficient accuracy in breasts with high density at ages below 50. Although ultrasonography achieves better accuracy in Breast Cancer detection even in dense breasts, the effectiveness has not been verified. We have planned a randomized controlled trial to assess the effectiveness of ultrasonography in women aged 40-49, with a design to study 50,000 women with mammography and ultrasonography (intervention group), and 50,000 controls with mammography only (control group). The participants are scheduled to take second round screening with the same modality 2 years on. The primary endpoints are sensitivity and specificity, and the secondary endpoint is the rate of advanced breast cancers. (author)

  8. Application of ToxCast High-Throughput Screening and ...

    Science.gov (United States)

    Slide presentation at the SETAC annual meeting on High-Throughput Screening and Modeling Approaches to Identify Steroidogenesis Distruptors Slide presentation at the SETAC annual meeting on High-Throughput Screening and Modeling Approaches to Identify Steroidogenssis Distruptors

  9. Social Health Insurance-Based Simultaneous Screening for 154 Mutations in 19 Deafness Genes Efficiently Identified Causative Mutations in Japanese Hearing Loss Patients.

    Directory of Open Access Journals (Sweden)

    Kentaro Mori

    Full Text Available Sensorineural hearing loss is one of the most common neurosensory disorders in humans. The incidence of SNHL is estimated to be 1 in 500-1000 newborns. In more than half of these patients, the hearing loss is associated with genetic causes. In Japan, genetic testing for the patients with SNHL using the Invader assay to screen for 46 mutations in 13 deafness genes was approved by the Ministry of Health, Labour and Welfare for inclusion in social health insurance coverage in 2012. Furthermore, from August 2015, this genetic testing has been expanded to screen for 154 mutations in 19 deafness genes using targeted genomic enrichment with massively parallel DNA sequencing combined with the Invader assay and TaqMan genotyping. For this study we analyzed 717 unrelated Japanese hearing loss patients. The total allele frequency of 154 mutations in 19 deafness genes was 32.64% (468/1434 and the total numbers of cases associated with at least one mutation was 44.07% (316/717. Among these, we were able to diagnose 212 (30% patients, indicating that the present screening could efficiently identify causative mutations in hearing loss patients. It is noteworthy that 27 patients (3.8% had coexistent multiple mutations in different genes. Five of these 27 patients (0.7%, 5/717 overall were diagnosed with genetic hearing loss affected by concomitant with responsible mutations in more than two different genes. For patients identified with multiple mutations in different genes, it is necessary to consider that several genes might have an impact on their phenotypes.

  10. Screening cotton genotypes for seedling drought tolerance

    Directory of Open Access Journals (Sweden)

    Penna Julio C. Viglioni

    1998-01-01

    Full Text Available The objectives of this study were to adapt a screening method previously used to assess seedling drought tolerance in cereals for use in cotton (Gossypium hirsutum L. and to identify tolerant accessions among a wide range of genotypes. Ninety genotypes were screened in seven growth chamber experiments. Fifteen-day-old seedlings were subjected to four 4-day drought cycles, and plant survival was evaluated after each cycle. Three cycles are probably the minimum required in cotton work. Significant differences (at the 0.05 level or lower among entries were obtained in four of the seven experiments. A "confirmation test" with entries previously evaluated as "tolerant" (high survival and "susceptible" (low survival was run. A number of entries duplicated their earlier performance, but others did not, which indicates the need to reevaluate selections. Germplasms considered tolerant included: `IAC-13-1', `IAC-RM4-SM5', `Minas Sertaneja', `Acala 1517E-1' and `4521'. In general, the technique is simple, though time-consuming, with practical value for screening a large number of genotypes. Results from the screening tests generally agreed with field information. The screening procedure is suitable to select tolerant accessions from among a large number of entries in germplasm collections as a preliminary step in breeding for drought tolerance. This research also demonstrated the need to characterize the internal lack of uniformity in growth chambers to allow for adequate designs of experiments.

  11. Evaluation of a prospective scoring system designed for a multicenter breast MR imaging screening study.

    Science.gov (United States)

    Warren, Ruth M L; Thompson, Deborah; Pointon, Linda J; Hoff, Rebecca; Gilbert, Fiona J; Padhani, Anwar R; Easton, Douglas F; Lakhani, Sunil R; Leach, Martin O

    2006-06-01

    To evaluate prospectively the accuracy of a lesion classification system designed for use in a magnetic resonance (MR) imaging high-breast-cancer-risk screening study. All participating patients provided written informed consent. Ethics committee approval was obtained. The results of 1541 contrast material-enhanced breast MR imaging examinations were analyzed; 1441 screening examinations were performed in 638 women aged 24-51 years at high risk for breast cancer, and 100 examinations were performed in 100 women aged 23-81 years. Lesion analysis was performed in 991 breasts, which were divided into design (491 breasts) and testing (500 breasts) sets. The reference standard was histologic analysis of biopsy samples, fine-needle aspiration cytology, or minimal follow-up of 24 months. The scoring system involved the use of five features: morphology (MOR), pattern of enhancement (POE), percentage of maximal focal enhancement (PMFE), maximal signal intensity-time ratio (MITR), and pattern of contrast material washout (POCW). The system was evaluated by means of (a) assessment of interreader agreement, as expressed in kappa statistics, for 315 breasts in which both readers analyzed the same lesion, (b) assessment of the diagnostic accuracy of the scored components with receiver operating characteristic curve analysis, and (c) logistic regression analysis to determine which components of the scoring system were critical to the final score. A new simplified scoring system developed with the design set was applied to the testing set. There was moderate reader agreement regarding overall lesion outcome (ie, malignant, suspicious, or benign) (kappa=0.58) and less agreement regarding the scored components. The area under the receiver operating characteristic curve (AUC) for the overall lesion score, 0.88, was higher than the AUC for any one component. The components MOR, POE, and POCW yielded the best overall result. PMFE and MITR did not contribute to diagnostic utility

  12. A novel screening method for cell wall mutants in Aspergillus niger identifies UDP-galactopyranose mutase as an important protein in fungal cell wall biosynthesis

    NARCIS (Netherlands)

    Damveld, R.A.; Franken, A.; Arentshorst, M.; Punt, P.J.; Klis, F.M.; van den Hondel, C.A.M.J.J.; Ram, A.F.J.

    2008-01-01

    To identify cell wall biosynthetic genes in filamentous fungi and thus potential targets for the discovery of new antifungals, we developed a novel screening method for cell wall mutants. It is based on our earlier observation that the Aspergillus niger agsA gene, which encodes a putative

  13. Validation of the TAPS-1: A Four-Item Screening Tool to Identify Unhealthy Substance Use in Primary Care.

    Science.gov (United States)

    Gryczynski, Jan; McNeely, Jennifer; Wu, Li-Tzy; Subramaniam, Geetha A; Svikis, Dace S; Cathers, Lauretta A; Sharma, Gaurav; King, Jacqueline; Jelstrom, Eve; Nordeck, Courtney D; Sharma, Anjalee; Mitchell, Shannon G; O'Grady, Kevin E; Schwartz, Robert P

    2017-09-01

    The Tobacco, Alcohol, Prescription Medication, and Other Substance use (TAPS) tool is a combined two-part screening and brief assessment developed for adult primary care patients. The tool's first-stage screening component (TAPS-1) consists of four items asking about past 12-month use for four substance categories, with response options of never, less than monthly, monthly, weekly, and daily or almost daily. To validate the TAPS-1 in primary care patients. Participants completed the TAPS tool in self- and interviewer-administered formats, in random order. In this secondary analysis, the TAPS-1 was evaluated against DSM-5 substance use disorder (SUD) criteria to determine optimal cut-points for identifying unhealthy substance use at three severity levels (problem use, mild SUD, and moderate-to-severe SUD). Two thousand adult patients at five primary care sites. DSM-5 SUD criteria were determined via the modified Composite International Diagnostic Interview. Oral fluid was used as a biomarker of recent drug use. Optimal frequency-of-use cut-points on the self-administered TAPS-1 for identifying SUDs were ≥ monthly use for tobacco and alcohol (sensitivity = 0.92 and 0.71, specificity = 0.80 and 0.85, AUC = 0.86 and 0.78, respectively) and any reported use for illicit drugs and prescription medication misuse (sensitivity = 0.93 and 0.89, specificity = 0.85 and 0.91, AUC = 0.89 and 0.90, respectively). The performance of the interviewer-administered format was similar. When administered first, the self-administered format yielded higher disclosure rates for past 12-month alcohol use, illicit drug use, and prescription medication misuse. Frequency of use alone did not provide sufficient information to discriminate between gradations of substance use problem severity. Among those who denied drug use on the TAPS-1, less than 4% had a drug-positive biomarker. The TAPS-1 can identify unhealthy substance use in primary care patients with a high level of accuracy

  14. RNAi Screen in Drosophila melanogastor Identifies Regulators of Steroidogenesis and Developmental Maturation

    DEFF Research Database (Denmark)

    Danielsen, Erik Thomas

    and duration required for juvenile-adult transition. This PhD project demonstrates the power of Drosophila genetics by taking an in vivo genome-wide RNAi screening approach to uncover genes required for the function of steroid producing tissue and developmental maturation. In total, 1909 genes were found...... to be required for the prothoracic gland function and affected the developmental timing for the juvenile-adult transition. Among the screen hits, we focused on an uncharacterized gene, sit (CG5278), which is highly expressed in the gland and is required for ecdysone production. Sit is a homolog of mammalian very...... flux of cholesterol uptake in the gland cells and affected the endosomal trafficking. Therefore this gene was suggested to be named stuck in traffic (sit). Sit’s role in cholesterol uptake was also supported by the observation that the developmental delayed phenotype from loss of sit expression...

  15. Screening children for elevated blood lead - Learnings from the literature

    Energy Technology Data Exchange (ETDEWEB)

    Boreland, Frances [Broken Hill Centre for Remote Health Research, Broken Hill University Department of Rural Health, University of Sydney, Corrindah Court, PO Box 457, Broken Hill, NSW 2880 (Australia)], E-mail: fboreland@gwahs.health.nsw.gov.au; Lyle, David [Broken Hill Centre for Remote Health Research, Broken Hill University Department of Rural Health, University of Sydney, Corrindah Court, PO Box 457, Broken Hill, NSW 2880 (Australia)], E-mail: dlyle@gwahs.health.nsw.gov.au

    2008-02-01

    Introduction: Although it is important that children at risk of developing elevated blood lead receive regular screening, attendance at screening programs is variable. A literature review was undertaken to better understand the factors that affect carers' decisions about whether or not to take their children for blood lead screening. Method: Electronic databases (Medline, EMBASE, CINAHL, Psychinfo) were searched to identify relevant publications, supported by reviewing reference lists of identified articles and searching with internet-based search engines. Results: Thirty-four published studies dealing with blood lead screening rates were identified, of which only seven papers focused specifically on parent's attitudes to blood lead screening. The barriers to and enablers of screening for elevated blood lead levels appear to be similar to those identified for other screening programs. Discussion: It is recommended that attendance at screening be routinely monitored, and that where participation is suboptimal further research be undertaken, in close co-operation with affected communities or sub-groups, to determine how best to encourage screening and to protect children from lead. It is important to minimize stigma and to ensure, as far as possible, that practical barriers such as lack of transport do not restrict access to screening programs.

  16. How do new dams impact downstream countries? - A screening approach to identify the best compromise assets and negotiate their designs

    Science.gov (United States)

    Geressu, Robel; Harou, Julien

    2015-04-01

    Water use rights are disputed in many transboundary basins. Even when water projects can benefit all, agreeing on cost and benefit sharing can be difficult where stakeholders have conflicting preferences on the designs and use of proposed water infrastructures. This study suggests a combination of many objective optimization and multi-criteria ranking methods to support negotiations regarding designs of new assets. The method allows competing users to assess development options based on their individual perspectives and agree on designs by incorporating coordination strategies into multi-reservoir system designs. We demonstrate a hypothetical negotiation on proposed Blue Nile reservoirs. The result form a set of Pareto-optimal designs i.e., reservoirs, storage capacity and their operating rules, and power trade, cost sharing and/or financing coordination strategies, which maximize benefit to all countries and show which trade-offs are implied by which designs. The approach fulfils decision-maker's desire to understand a) the critical design parameters that affect various objectives and b) how coordination mechanisms would enable them to incur benefits from proposed new dams.

  17. Newborn screening for galactosaemia.

    Science.gov (United States)

    Lak, Rohollah; Yazdizadeh, Bahareh; Davari, Majid; Nouhi, Mojtaba; Kelishadi, Roya

    2017-12-23

    Classical galactosaemia is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase. This is a rare and potentially lethal condition that classically presents in the first week of life once milk feeds have commenced. Affected babies may present with any or all of the following: cataracts; fulminant liver failure; prolonged jaundice; or Escherichia coli sepsis. Once the diagnosis is suspected, feeds containing galactose must be stopped immediately and replaced with a soya-based formula. The majority of babies will recover, however a number will not survive. There are long-term complications of galactosaemia, despite treatment, including learning disabilities and female infertility. It has been postulated that galactosaemia could be detected on newborn screening and this would prevent the immediate severe liver dysfunction and sepsis. To assess whether there is evidence that newborn screening for galactosaemia prevents or reduces mortality and morbidity and improves clinical outcomes in affected neonates and the quality of life in older children. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from electronic database searches, handsearches of relevant journals and conference abstract books. We also searched online trials registries and the reference lists of relevant articles and reviews.Date of the most recent search of Cochrane Cystic Fibrosis Group's Trials Register: 18 December 2017.Date of the most recent search of additional resources: 11 October 2017. Randomised controlled studies and controlled clinical studies, published or unpublished comparing the use of any newborn screening test to diagnose infants with galactosaemia and presenting a comparison between a screened population versus a non-screened population. No studies of newborn screening for galactosaemia were found. No studies were identified for inclusion in the

  18. The cumulative risk of false-positive screening results across screening centres in the Norwegian Breast Cancer Screening Program

    Energy Technology Data Exchange (ETDEWEB)

    Roman, M., E-mail: Marta.Roman@kreftregisteret.no [Cancer Registry of Norway, Oslo (Norway); Department of Women and Children’s Health, Oslo University Hospital, Oslo (Norway); Skaane, P., E-mail: PERSK@ous-hf.no [Department of Radiology, Oslo University Hospital Ullevaal, University of Oslo, Oslo (Norway); Hofvind, S., E-mail: Solveig.Hofvind@kreftregisteret.no [Cancer Registry of Norway, Oslo (Norway); Oslo and Akershus University College of Applied Sciences, Faculty of Health Science, Oslo (Norway)

    2014-09-15

    Highlights: • We found variation in early performance measures across screening centres. • Radiologists’ performance may play a key role in the variability. • Potential to improve the effectiveness of breast cancer screening programs. • Continuous surveillance of screening centres and radiologists is essential. - Abstract: Background: Recall for assessment in mammographic screening entails an inevitable number of false-positive screening results. This study aimed to investigate the variation in the cumulative risk of a false positive screening result and the positive predictive value across the screening centres in the Norwegian Breast Cancer Screening Program. Methods: We studied 618,636 women aged 50–69 years who underwent 2,090,575 screening exams (1996–2010. Recall rate, positive predictive value, rate of screen-detected cancer, and the cumulative risk of a false positive screening result, without and with invasive procedures across the screening centres were calculated. Generalized linear models were used to estimate the probability of a false positive screening result and to compute the cumulative false-positive risk for up to ten biennial screening examinations. Results: The cumulative risk of a false-positive screening exam varied from 10.7% (95% CI: 9.4–12.0%) to 41.5% (95% CI: 34.1–48.9%) across screening centres, with a highest to lowest ratio of 3.9 (95% CI: 3.7–4.0). The highest to lowest ratio for the cumulative risk of undergoing an invasive procedure with a benign outcome was 4.3 (95% CI: 4.0–4.6). The positive predictive value of recall varied between 12.0% (95% CI: 11.0–12.9%) and 19.9% (95% CI: 18.3–21.5%), with a highest to lowest ratio of 1.7 (95% CI: 1.5–1.9). Conclusions: A substantial variation in the performance measures across the screening centres in the Norwegian Breast Cancer Screening Program was identified, despite of similar administration, procedures, and quality assurance requirements. Differences in the

  19. The cumulative risk of false-positive screening results across screening centres in the Norwegian Breast Cancer Screening Program

    International Nuclear Information System (INIS)

    Roman, M.; Skaane, P.; Hofvind, S.

    2014-01-01

    Highlights: • We found variation in early performance measures across screening centres. • Radiologists’ performance may play a key role in the variability. • Potential to improve the effectiveness of breast cancer screening programs. • Continuous surveillance of screening centres and radiologists is essential. - Abstract: Background: Recall for assessment in mammographic screening entails an inevitable number of false-positive screening results. This study aimed to investigate the variation in the cumulative risk of a false positive screening result and the positive predictive value across the screening centres in the Norwegian Breast Cancer Screening Program. Methods: We studied 618,636 women aged 50–69 years who underwent 2,090,575 screening exams (1996–2010. Recall rate, positive predictive value, rate of screen-detected cancer, and the cumulative risk of a false positive screening result, without and with invasive procedures across the screening centres were calculated. Generalized linear models were used to estimate the probability of a false positive screening result and to compute the cumulative false-positive risk for up to ten biennial screening examinations. Results: The cumulative risk of a false-positive screening exam varied from 10.7% (95% CI: 9.4–12.0%) to 41.5% (95% CI: 34.1–48.9%) across screening centres, with a highest to lowest ratio of 3.9 (95% CI: 3.7–4.0). The highest to lowest ratio for the cumulative risk of undergoing an invasive procedure with a benign outcome was 4.3 (95% CI: 4.0–4.6). The positive predictive value of recall varied between 12.0% (95% CI: 11.0–12.9%) and 19.9% (95% CI: 18.3–21.5%), with a highest to lowest ratio of 1.7 (95% CI: 1.5–1.9). Conclusions: A substantial variation in the performance measures across the screening centres in the Norwegian Breast Cancer Screening Program was identified, despite of similar administration, procedures, and quality assurance requirements. Differences in the

  20. A screen for kinase inhibitors identifies antimicrobial imidazopyridine aminofurazans as specific inhibitors of the Listeria monocytogenes PASTA kinase PrkA.

    Science.gov (United States)

    Schaenzer, Adam J; Wlodarchak, Nathan; Drewry, David H; Zuercher, William J; Rose, Warren E; Striker, Rob; Sauer, John-Demian

    2017-10-13

    Bacterial signaling systems such as protein kinases and quorum sensing have become increasingly attractive targets for the development of novel antimicrobial agents in a time of rising antibiotic resistance. The family of bacterial P enicillin-binding-protein A nd S erine/ T hreonine kinase- A ssociated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to β-lactam antibiotics. As such, small-molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to β-lactam therapy. Despite this interest, only limited progress has been made in identifying functional inhibitors of the PASTA kinases that have both activity against the intact microbe and high kinase specificity. Here, we report the results of a small-molecule screen that identified GSK690693, an imidazopyridine aminofurazan-type kinase inhibitor that increases the sensitivity of the intracellular pathogen Listeria monocytogenes to various β-lactams by inhibiting the PASTA kinase PrkA. GSK690693 potently inhibited PrkA kinase activity biochemically and exhibited significant selectivity for PrkA relative to the Staphylococcus aureus PASTA kinase Stk1. Furthermore, other imidazopyridine aminofurazans could effectively inhibit PrkA and potentiate β-lactam antibiotic activity to varying degrees. The presence of the 2-methyl-3-butyn-2-ol (alkynol) moiety was important for both biochemical and antimicrobial activity. Finally, mutagenesis studies demonstrated residues in the back pocket of the active site are important for GSK690693 selectivity. These data suggest that targeted screens can successfully identify PASTA kinase inhibitors with both biochemical and antimicrobial specificity. Moreover, the imidazopyridine aminofurazans represent a family of PASTA kinase inhibitors that have the potential to be optimized for selective PASTA kinase inhibition.

  1. High-throughput screening using the differential radial capillary action of ligand assay identifies ebselen as an inhibitor of diguanylate cyclases.

    Science.gov (United States)

    Lieberman, Ori J; Orr, Mona W; Wang, Yan; Lee, Vincent T

    2014-01-17

    The rise of bacterial resistance to traditional antibiotics has motivated recent efforts to identify new drug candidates that target virulence factors or their regulatory pathways. One such antivirulence target is the cyclic-di-GMP (cdiGMP) signaling pathway, which regulates biofilm formation, motility, and pathogenesis. Pseudomonas aeruginosa is an important opportunistic pathogen that utilizes cdiGMP-regulated polysaccharides, including alginate and pellicle polysaccharide (PEL), to mediate virulence and antibiotic resistance. CdiGMP activates PEL and alginate biosynthesis by binding to specific receptors including PelD and Alg44. Mutations that abrogate cdiGMP binding to these receptors prevent polysaccharide production. Identification of small molecules that can inhibit cdiGMP binding to the allosteric sites on these proteins could mimic binding defective mutants and potentially reduce biofilm formation or alginate secretion. Here, we report the development of a rapid and quantitative high-throughput screen for inhibitors of protein-cdiGMP interactions based on the differential radial capillary action of ligand assay (DRaCALA). Using this approach, we identified ebselen as an inhibitor of cdiGMP binding to receptors containing an RxxD domain including PelD and diguanylate cyclases (DGC). Ebselen reduces diguanylate cyclase activity by covalently modifying cysteine residues. Ebselen oxide, the selenone analogue of ebselen, also inhibits cdiGMP binding through the same covalent mechanism. Ebselen and ebselen oxide inhibit cdiGMP regulation of biofilm formation and flagella-mediated motility in P. aeruginosa through inhibition of diguanylate cyclases. The identification of ebselen provides a proof-of-principle that a DRaCALA high-throughput screening approach can be used to identify bioactive agents that reverse regulation of cdiGMP signaling by targeting cdiGMP-binding domains.

  2. Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes.

    Science.gov (United States)

    Goldberg, Alexander A; Richard, Vincent R; Kyryakov, Pavlo; Bourque, Simon D; Beach, Adam; Burstein, Michelle T; Glebov, Anastasia; Koupaki, Olivia; Boukh-Viner, Tatiana; Gregg, Christopher; Juneau, Mylène; English, Ann M; Thomas, David Y; Titorenko, Vladimir I

    2010-07-01

    In chronologically aging yeast, longevity can be extended by administering a caloric restriction (CR) diet or some small molecules. These life-extending interventions target the adaptable target of rapamycin (TOR) and cAMP/protein kinase A (cAMP/PKA) signaling pathways that are under the stringent control of calorie availability. We designed a chemical genetic screen for small molecules that increase the chronological life span of yeast under CR by targeting lipid metabolism and modulating housekeeping longevity pathways that regulate longevity irrespective of the number of available calories. Our screen identifies lithocholic acid (LCA) as one of such molecules. We reveal two mechanisms underlying the life-extending effect of LCA in chronologically aging yeast. One mechanism operates in a calorie availability-independent fashion and involves the LCA-governed modulation of housekeeping longevity assurance pathways that do not overlap with the adaptable TOR and cAMP/PKA pathways. The other mechanism extends yeast longevity under non-CR conditions and consists in LCA-driven unmasking of the previously unknown anti-aging potential of PKA. We provide evidence that LCA modulates housekeeping longevity assurance pathways by suppressing lipid-induced necrosis, attenuating mitochondrial fragmentation, altering oxidation-reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria-controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA.

  3. Effect of the LHC Beam Screen Baffle on the Electron Cloud Buildup

    CERN Document Server

    Romano, Annalisa; Li, Kevin; Rumolo, Giovanni

    2016-01-01

    Electron Cloud (EC) has been identified as one of the major intensity-limiting factors in the CERN Large Hadron Collider (LHC). Due to the EC, an additional heat load is deposited on the perforated LHC beam screen, for which only a small cooling capacity is available. In order to preserve the superconducting state of the magnets, pumping slots shields were added on the outer side of the beam screens. In the framework of the design of the beam screens of the new HL-LHC triplets, the impact of these shields on the multipacting process was studied with macroparticle simulations. For this purpose multiple new features had to be introduced in the PyECLOUD code. This contribution will describe the implemented simulation model and summarize the outcome of this study.

  4. Automated Screening for Three Inborn Metabolic Disorders: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Kavitha S

    2006-12-01

    Full Text Available Background: Inborn metabolic disorders (IMDs form a large group of rare, but often serious, metabolic disorders. Aims: Our objective was to construct a decision tree, based on classification algorithm for the data on three metabolic disorders, enabling us to take decisions on the screening and clinical diagnosis of a patient. Settings and Design: A non-incremental concept learning classification algorithm was applied to a set of patient data and the procedure followed to obtain a decision on a patient’s disorder. Materials and Methods: Initially a training set containing 13 cases was investigated for three inborn errors of metabolism. Results: A total of thirty test cases were investigated for the three inborn errors of metabolism. The program identified 10 cases with galactosemia, another 10 cases with fructosemia and the remaining 10 with propionic acidemia. The program successfully identified all the 30 cases. Conclusions: This kind of decision support systems can help the healthcare delivery personnel immensely for early screening of IMDs.

  5. A novel screening method for cell wall mutants in Aspergillus niger identifies UDP-galactopyranose mutase as an important protein in fungal cell wall biosynthesis

    NARCIS (Netherlands)

    Damveld, R.A.; Franken, A.; Arentshorst, M.; Punt, P.J.; Klis, F.M.; Hondel, C.A.M.J.J. van den; Ram, A.F.J.

    2008-01-01

    To identify cell wall biosynthetic genes in filamentous fungi and thus potential targets for the discovery of new antifungals, we developed a novel screening method for cell wall mutants. It is based on our earlier observation that the Aspergillus niger agsA gene, which encodes a putative a-glucan

  6. Masculinity, Racism, Social Support, and Colorectal Cancer Screening Uptake Among African American Men: A Systematic Review.

    Science.gov (United States)

    Rogers, Charles R; Mitchell, Jamie A; Franta, Gabriel J; Foster, Margaret J; Shires, Deirdre

    2017-09-01

    Colorectal cancer (CRC) is highly preventable when CRC screening is utilized, yet CRC screening completion among African American men is relatively low and their mortality rates remain 50% higher juxtaposed to their White counterparts. Since a growing body of literature indicates masculinity, racism, and social support each have strong influences on CRC screening uptake, this systematic review examined the connections between these three sociocultural factors and CRC screening uptake among African American men. Potential studies were retrieved from MEDLINE, CINAHL, EMBASE, and PsycINFO. Cited reference searching for the final sample was employed to identify and assess additional studies for inclusion using Scopus. The methodological quality of the reviewed evidence was also evaluated. Nineteen studies met inclusion/exclusion criteria. Thirteen studies employed nonexperimental research designs; a quasi-experimental design was present in four, and two utilized experimental designs. Studies were published between 2000 and 2014; the majority between 2009 and 2013. Social support was most frequently addressed (84%) while masculinity and racism were equally studied with paucity (11%) for their influence on CRC screening. After evaluating conceptual and methodological characteristics of the studies, 42% fell below average in quality and rigor. The need for increased attention to the sociocultural correlates of CRC screening for African American men are highlighted in this systematic review, and important recommendations for research and practice are provided. Alongside a call for more rigorous research, further research examining the influence of masculinity and racism on CRC screening completion among African American men is warranted.

  7. Screening physical health? Yes! But...: nurses' views on physical health screening in mental health care.

    Science.gov (United States)

    Happell, Brenda; Scott, David; Nankivell, Janette; Platania-Phung, Chris

    2013-08-01

    To explore nurses' views on the role of nurses in screening and monitoring for physical care of consumers with serious mental illness, at a regional mental health care service. People with serious mental illness experience heightened incidence of preventable and treatable physical illnesses such as cardiovascular disease and diabetes. Screening and monitoring are considered universal clinical safeguards. Nurses can potentially facilitate systematic screening, but their views on physical health care practices are rarely investigated. Qualitative exploratory study. Focus group interviews with 38 nurses of a regional mental health care service district of Australia. To facilitate discussion, participants were presented with a screening system, called the Health Improvement Profile (HIP), as an exemplar of screening of physical health risks by nurses. Inductive data analysis and theme development were guided by a thematic analysis framework. Nurses argued that treatable and preventable physical health problems were common. Four main themes were identified: screening - essential for good practice; the policy-practice gap; 'screening then what?' and, is HIP the answer? Screening and monitoring were considered crucial to proper diagnosis and treatment, however, were not performed systematically or consistently. Nurse readiness for an enhanced role in screening was shaped by: role and responsibility issues, legal liability concerns, funding and staff shortages. Participants were concerned that lack of follow up would limit effectiveness of these interventions. Screening was considered an important clinical step in effective diagnosis and treatment; however, identified barriers need to be addressed to ensure screening is part of a systemic approach to improve physical health of consumers with serious mental illness. Nurses have potential to influence improvement in physical health outcomes for consumers of mental health services. Such potential can only be realised if a

  8. Validation of a Type 2 Diabetes Screening Tool in Rural Honduras

    Science.gov (United States)

    Milton, Evan C.; Herman, William H.; Aiello, Allison E.; Danielson, Kris R.; Mendoza-Avelarez, Milton O.; Piette, John D.

    2010-01-01

    OBJECTIVE To validate a low-cost tool for identifying diabetic patients in rural areas of Latin America. RESEARCH DESIGN AND METHODS A regression equation incorporating postprandial time and a random plasma glucose was used to screen 800 adults in Honduras. Patients with a probability of diabetes of ≥20% were asked to return for a fasting plasma glucose (FPG). A random fifth of those with a screener-based probability of diabetes Honduras and could be used to identify diabetic patients in poor clinics in Latin America. PMID:19918008

  9. Psychometric properties and reliability of the Assessment Screen to Identify Survivors Toolkit for Gender Based Violence (ASIST-GBV): results from humanitarian settings in Ethiopia and Colombia.

    Science.gov (United States)

    Vu, Alexander; Wirtz, Andrea; Pham, Kiemanh; Singh, Sonal; Rubenstein, Leonard; Glass, Nancy; Perrin, Nancy

    2016-01-01

    Refugees and internally displaced persons who are affected by armed-conflict are at increased vulnerability to some forms of sexual violence or other types of gender-based violence. A validated, brief and easy-to-administer screening tool will help service providers identify GBV survivors and refer them to appropriate GBV services. To date, no such GBV screening tool exists. We developed the 7-item ASIST-GBV screening tool from qualitative research that included individual interviews and focus groups with GBV refugee and IDP survivors. This study presents the psychometric properties of the ASIST-GBV with female refugees living in Ethiopia and IDPs in Colombia. Several strategies were used to validate ASIST-GBV, including a 3 month implementation to validate the brief screening tool with women/girls seeking health services, aged ≥15 years in Ethiopia (N = 487) and female IDPs aged ≥ 18 years in Colombia (N = 511). High proportions of women screened positive for past-year GBV according to the ASIST-GBV: 50.6 % in Ethiopia and 63.4 % in Colombia. The factor analysis identified a single dimension, meaning that all items loaded on the single factor. Cronbach's α = 0.77. A 2-parameter logistic IRT model was used for estimating the precision and discriminating power of each item. Item difficulty varied across the continuum of GBV experiences in the following order (lowest to highest): threats of violence (0.690), physical violence (1.28), forced sex (2.49), coercive sex for survival (2.25), forced marriage (3.51), and forced pregnancy (6.33). Discrimination results showed that forced pregnancy was the item with the strongest ability to discriminate between different levels of GBV. Physical violence and forced sex also have higher levels of discrimination with threats of violence discriminating among women at the low end of the GBV continuum and coercive sex for survival among women at the mid-range of the continuum. The findings demonstrate that

  10. Hypersexual Disorder According to the Hypersexual Disorder Screening Inventory in Help-Seeking Swedish Men and Women With Self-Identified Hypersexual Behavior.

    Science.gov (United States)

    Öberg, Katarina Görts; Hallberg, Jonas; Kaldo, Viktor; Dhejne, Cecilia; Arver, Stefan

    2017-12-01

    The Hypersexual Disorder Screening Inventory (HDSI) was developed by the American Psychiatric Association for clinical screening of hypersexual disorder (HD). To examine the distribution of the proposed diagnostic entity HD according to the HDSI in a sample of men and women seeking help for problematic hypersexuality and evaluate some psychometric properties. Data on sociodemographics, the HDSI, the Sexual Compulsivity Scale (SCS), and the Cognitive and Behavioral Outcomes of Sexual Behavior were collected online from 16 women and 64 men who self-identified as hypersexual. Respondents were recruited by advertisements offering psychological treatment for hypersexual behavior. The HDSI, covering the proposed criteria for HD. Of the entire sample, 50% fulfilled the criteria for HD. Compared with men, women scored higher on the HDSI, engaged more often in risky sexual behavior, and worried more about physical injuries and pain. Men primarily used pornography, whereas women had sexual encounters. The HD group reported a larger number of sexual specifiers, higher scores on the SCS, more negative effects of sexual behavior, and more concerns about consequences compared with the non-HD group. Sociodemographics had no influence on HD. The HDSI's core diagnostic criteria showed high internal reliability for men (α = 0.80) and women (α = 0.81). A moderate correlation between the HDSI and the SCS was found (0.51). The vast majority of the entire sample (76 of 80, 95%) fulfilled the criteria for sexual compulsivity according to the SCS. The HDSI could be used as a screening tool for HD, although further explorations of the empirical implications regarding criteria are needed, as are refinements of cutoff scores and specific sexual behaviors. Hypersexual problematic behavior causes distress and impairment and, although not included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, HD should be endorsed as a diagnosis to develop evidence

  11. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers.

    Science.gov (United States)

    Linhoff, Michael W; Laurén, Juha; Cassidy, Robert M; Dobie, Frederick A; Takahashi, Hideto; Nygaard, Haakon B; Airaksinen, Matti S; Strittmatter, Stephen M; Craig, Ann Marie

    2009-03-12

    Delineating the molecular basis of synapse development is crucial for understanding brain function. Cocultures of neurons with transfected fibroblasts have demonstrated the synapse-promoting activity of candidate molecules. Here, we performed an unbiased expression screen for synaptogenic proteins in the coculture assay using custom-made cDNA libraries. Reisolation of NGL-3/LRRC4B and neuroligin-2 accounts for a minority of positive clones, indicating that current understanding of mammalian synaptogenic proteins is incomplete. We identify LRRTM1 as a transmembrane protein that induces presynaptic differentiation in contacting axons. All four LRRTM family members exhibit synaptogenic activity, LRRTMs localize to excitatory synapses, and artificially induced clustering of LRRTMs mediates postsynaptic differentiation. We generate LRRTM1(-/-) mice and reveal altered distribution of the vesicular glutamate transporter VGLUT1, confirming an in vivo synaptic function. These results suggest a prevalence of LRR domain proteins in trans-synaptic signaling and provide a cellular basis for the reported linkage of LRRTM1 to handedness and schizophrenia.

  12. Evaluating usability of the Halden Reactor Large Screen Display. Is the Information Rich Design concept suitable for real-world installations?

    International Nuclear Information System (INIS)

    Braseth, Alf Ove

    2013-01-01

    Large Screen Displays (LSDs) are beginning to supplement desktop displays in modern control rooms, having the potential to display the big picture of complex processes. Information Rich Design (IRD) is a LSD concept used in many real-life installations in the petroleum domain, and more recently in nuclear research applications. The objectives of IRD are to provide the big picture, avoiding keyhole related problems while supporting fast visual perception of larger data sets. Two LSDs based on the IRD concept have been developed for large-scale nuclear simulators for research purposes; they have however suffered from unsatisfying user experience. The new Halden Reactor LSD, used to monitor a nuclear research reactor, was designed according to recent proposed Design Principles compiled in this paper to mitigate previously experienced problems. This paper evaluates the usability of the Halden Reactor LSD, comparing usability data with the replaced analogue panel, and data for an older IRD large screen display. The results suggest that the IRD concept is suitable for use in real-life applications from a user experience point of view, and that the recently proposed Design Principles have had a positive effect on usability. (author)

  13. Screening College Students for Hypercholesterolemia.

    Science.gov (United States)

    Faigel, Harris C.

    1992-01-01

    Describes one college's mandatory mass cholesterol screening for new students. Each year, over 30 beginning students with unknown hypercholesterolemia were detected. The program suggests that mass screening efficiently and economically identifies students who would benefit from cholesterol reduction, a modifiable risk in coronary artery disease.…

  14. Gentamicin Sulfate PEG-PLGA/PLGA-H Nanoparticles: Screening Design and Antimicrobial Effect Evaluation toward Clinic Bacterial Isolates

    Science.gov (United States)

    Dorati, Rossella; DeTrizio, Antonella; Spalla, Melissa; Migliavacca, Roberta; Pagani, Laura; Pisani, Silvia; Chiesa, Enrica; Modena, Tiziana; Genta, Ida

    2018-01-01

    Nanotechnology is a promising approach both for restoring or enhancing activity of old and conventional antimicrobial agents and for treating intracellular infections by providing intracellular targeting and sustained release of drug inside infected cells. The present paper introduces a formulation study of gentamicin loaded biodegradable nanoparticles (Nps). Solid-oil-in water technique was studied for gentamicin sulfate nanoencapsulation using uncapped Polylactide-co-glycolide (PLGA-H) and Polylactide-co-glycolide-co-Polyethylenglycol (PLGA-PEG) blends. Screening design was applied to optimize: drug payload, Nps size and size distribution, stability and resuspendability after freeze-drying. PLGA-PEG concentration resulted most significant factor influencing particles size and drug content (DC): 8 w/w% DC and 200 nm Nps were obtained. Stirring rate resulted most influencing factor for size distribution (PDI): 700 rpm permitted to obtain homogeneous Nps dispersion (PDI = 1). Further experimental parameters investigated, by 23 screening design, were: polymer blend composition (PLGA-PEG and PLGA-H), Polyvinylalcohol (PVA) and methanol concentrations into aqueous phase. Drug content was increased to 10.5 w/w%. Nanoparticle lyophilization was studied adding cryoprotectants, polyvinypirrolidone K17 and K32, and sodiumcarboxymetylcellulose. Freeze-drying protocol was optimized by a mixture design. A freeze-dried Nps powder free resuspendable with stable Nps size and payload, was developed. The powder was tested on clinic bacterial isolates demonstrating that after encapsulation, gentamicin sulfate kept its activity. PMID:29329209

  15. Automatic detection of anomalies in screening mammograms

    Science.gov (United States)

    2013-01-01

    Background Diagnostic performance in breast screening programs may be influenced by the prior probability of disease. Since breast cancer incidence is roughly half a percent in the general population there is a large probability that the screening exam will be normal. That factor may contribute to false negatives. Screening programs typically exhibit about 83% sensitivity and 91% specificity. This investigation was undertaken to determine if a system could be developed to pre-sort screening-images into normal and suspicious bins based on their likelihood to contain disease. Wavelets were investigated as a method to parse the image data, potentially removing confounding information. The development of a classification system based on features extracted from wavelet transformed mammograms is reported. Methods In the multi-step procedure images were processed using 2D discrete wavelet transforms to create a set of maps at different size scales. Next, statistical features were computed from each map, and a subset of these features was the input for a concerted-effort set of naïve Bayesian classifiers. The classifier network was constructed to calculate the probability that the parent mammography image contained an abnormality. The abnormalities were not identified, nor were they regionalized. The algorithm was tested on two publicly available databases: the Digital Database for Screening Mammography (DDSM) and the Mammographic Images Analysis Society’s database (MIAS). These databases contain radiologist-verified images and feature common abnormalities including: spiculations, masses, geometric deformations and fibroid tissues. Results The classifier-network designs tested achieved sensitivities and specificities sufficient to be potentially useful in a clinical setting. This first series of tests identified networks with 100% sensitivity and up to 79% specificity for abnormalities. This performance significantly exceeds the mean sensitivity reported in literature

  16. A Yeast/Drosophila Screen to Identify New Compounds Overcoming Frataxin Deficiency

    Directory of Open Access Journals (Sweden)

    Alexandra Seguin

    2015-01-01

    Full Text Available Friedreich’s ataxia (FA is a rare neurodegenerative disease which is very debilitating for the patients who progressively lose their autonomy. The lack of efficient therapeutic treatment of the disease strongly argues for urgent need to search for new active compounds that may stop the progression of the disease or prevent the appearance of the symptoms when the genetic defect is diagnosed early enough. In the present study, we used a yeast strain with a deletion of the frataxin homologue gene as a model of FA cells in a primary screen of two chemical libraries, a fraction of the French National Chemical Library (5500 compounds and the Prestwick collection (880 compounds. We ran a secondary screen on Drosophila melanogaster flies expressing reduced levels of frataxin during larval development. Half of the compounds selected in yeast appeared to be active in flies in this developmental paradigm, and one of the two compounds with highest activities in this assay partially rescued the heart dilatation phenotype resulting from heart specific depletion of frataxin. The unique complementarity of these two frataxin-deficient models, unicellular and multicellular, appears to be very efficient to select new compounds with improved selectivity, bringing significant perspectives towards improvements in FA therapy.

  17. In vivo phage display screening for tumor vascular targets in glioblastoma identifies a llama nanobody against dynactin-1-p150Glued.

    Science.gov (United States)

    van Lith, Sanne A M; Roodink, Ilse; Verhoeff, Joost J C; Mäkinen, Petri I; Lappalainen, Jari P; Ylä-Herttuala, Seppo; Raats, Jos; van Wijk, Erwin; Roepman, Ronald; Letteboer, Stef J; Verrijp, Kiek; Leenders, William P J

    2016-11-01

    Diffuse gliomas are primary brain cancers that are characterised by infiltrative growth. Whereas high-grade glioma characteristically presents with perinecrotic neovascularisation, large tumor areas thrive on pre-existent vasculature as well. Clinical studies have revealed that pharmacological inhibition of the angiogenic process does not improve survival of glioblastoma patients. Direct targeting of tumor vessels may however still be an interesting therapeutic approach as it allows pinching off the blood supply to tumor cells. Such tumor vessel targeting requires the identification of tumor-specific vascular targeting agents (TVTAs).Here we describe a novel TVTA, C-C7, which we identified via in vivo biopanning of a llama nanobody phage display library in an orthotopic mouse model of diffuse glioma. We show that C-C7 recognizes a subpopulation of tumor blood vessels in glioma xenografts and clinical glioma samples. Additionally, C-C7 recognizes macrophages and activated endothelial cells in atherosclerotic lesions. By using C-C7 as bait in yeast-2-hybrid (Y2H) screens we identified dynactin-1-p150Glued as its binding partner. The interaction was confirmed by co-immunostainings with C-C7 and a commercial anti-dynactin-1-p150Glued antibody, and via co-immunoprecipitation/western blot studies. Normal brain vessels do not express dynactin-1-p150Glued and its expression is reduced under anti-VEGF therapy, suggesting that dynactin-1-p150Glued is a marker for activated endothelial cells.In conclusion, we show that in vivo phage display combined with Y2H screenings provides a powerful approach to identify tumor-targeting nanobodies and their binding partners. Using this combination of methods we identify dynactin-1-p150Glued as a novel targetable protein on activated endothelial cells and macrophages.

  18. Protective factor screening for prevention practice: Sensitivity and specificity of the DESSA-Mini.

    Science.gov (United States)

    Shapiro, Valerie B; Kim, B K Elizabeth; Robitaille, Jennifer L; LeBuffe, Paul A

    2017-12-01

    The Devereux Student Strengths Assessment Mini (DESSA-Mini; Naglieri, LeBuffe, & Shapiro, 2011/2014) was designed to overcome practical obstacles to universal prevention screening. This article seeks to determine whether an entirely strength-based, 8-item screening instrument achieves technical accuracy in routine practice. Data come from a district-wide implementation of a new social emotional learning (SEL) initiative designed to promote students' social-emotional competence. All students, kindergarten through Grade 8, were screened using the DESSA-Mini. A random 5 students per classroom received additional assessment. Concurrent and predictive criterion studies were conducted using the full DESSA as well as administrative records of serious disciplinary infraction. The DESSA-Mini showed excellent internal reliability, exceeding .90. Negligible to small differences were found between scores on the DESSA-Mini screen and the DESSA full assessment. Classification consistency between the DESSA-Mini and the DESSA was high (87%-94%) in routine practice, with sensitivity and specificity estimates exceeding Glascoe's (2005) standards. Finally, predictive validity of the DESSA-Mini was reliable; students screened as having a Need for SEL Instruction at the beginning of the year were 4.5 times more likely to have a record of serious disciplinary infraction at the end of the school year compared with those who were not identified (p mental, emotional, and behavioral problems. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  19. Hygiene-therapists could be used to screen for dental caries and periodontal disease.

    Science.gov (United States)

    Richards, Derek

    2015-12-01

    patients with at least one pocket exceeding 3.5 mm in depth. Of these 935 were correctly identified by the H-Ts. For the 825 screened as negative by the dentist H-Ts correctly identified 621. The results suggest that hygiene-therapists could be used to screen for dental caries and periodontal disease. This has important ramifications for service design in public-funded health systems.

  20. Screen or not to screen for peripheral arterial disease: guidance from a decision model.

    Science.gov (United States)

    Vaidya, Anil; Joore, Manuela A; Ten Cate-Hoek, Arina J; Ten Cate, Hugo; Severens, Johan L

    2014-01-29

    Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Years, 28,052 Euros), these results indicate that PAD screening and treatment is a dominant strategy. The cost effectiveness acceptability curves show 88% probability of PAD screening being cost effective at the Willingness To Pay (WTP) threshold of 40000 Euros. In a scenario analysis using clopidogrel as an alternative anti-platelet drug, PAD screening strategy remained dominant. This decision analysis suggests that targeted ABI screening and consequent secondary prevention of cardiovascular events using low dose aspirin or

  1. Testing Precision Screening for Breast Cancer

    Science.gov (United States)

    An NCI research article about individualized approaches that could help identify those at risk of breast cancer who need to be screened and testing screening intervals that are appropriate for each person’s level of risk.

  2. Thermomechanical study of complex structures in the aperture of superconducting magnets: Application to the design of the High-Luminosity LHC shielded beam screen

    CERN Document Server

    AUTHOR|(CDS)2086332; Aurisicchio, Marco

    In the framework of the High-Luminosity Large Hadron Collider (HL-LHC) project, a complex structure, known as the beam screen, will be installed by 2024 in the aperture of the inner triplet superconducting magnets nearby the ATLAS and CMS experiments. The beam screen is an octagonal shaped pipe that shields the 1.9 K magnet cryogenic system from the heat loads and damage to the magnet coils that would be otherwise induced by the highly penetrating collision debris. It also ensures that the vacuum conditions, required for the stability of the beam, are met. This thesis describes the design of the beam screen and proposes extensions to important components and features. The unknown physical properties of the beam screen materials have been characterised. The thermal behaviour of the beam screen during normal working conditions has been optimised by simulations and validated by measurements. The behaviour of the beam screen during a magnet quench, a resistive transition of the superconducting magnet, has been st...

  3. Influence of qualitative research on women's health screening guidelines.

    Science.gov (United States)

    Abadir, Anna Maria; Lang, Ariella; Klein, Talia; Abenhaim, Haim Arie

    2014-01-01

    Considerable time and resources are allocated to carry out qualitative research. The purpose of our study was to evaluate the availability of qualitative research on women's health screening and assess its influence on screening practice guidelines in the United States, Canada, and the United Kingdom. Medline, CINHAL, and WEB of Science databases were used to identify the availability of qualitative research conducted in the past 15 years on 3 different women's health screening topics: cervical cancer screening, breast cancer screening, and prenatal first-trimester screening. Key national practice guidelines on women's health screening were selected using the National Guideline Clearinghouse web site. Bibliometric analysis was used to determine the frequency of qualitative references cited in the guidelines. A total of 272 qualitative research papers on women's health screening was identified: 109 on cervical cancer screening, 104 on breast cancer screening, and 59 on prenatal first-trimester screening. The qualitative studies focused on health care provider perspectives as well as ethical, ethnographic, psychological, and social issues surrounding screening. Fifteen national clinical practice guidelines on women's health screening were identified. A total of 943 references was cited, only 2 of which comprised of qualitative research cited by only 1 clinical practice guideline. Although there is considerable qualitative research that has been carried out on women's health screening, its incorporation into clinical practice guidelines is minimal. Further exploration of the disconnect between the two is important for enhancing knowledge translation of qualitative research within clinical practice. Copyright © 2014 Mosby, Inc. All rights reserved.

  4. A Screening Tool for Assessing Alcohol Use Risk among Medically Vulnerable Youth.

    Directory of Open Access Journals (Sweden)

    Sharon Levy

    Full Text Available In an effort to reduce barriers to screening for alcohol use in pediatric primary care, the National Institute on Alcoholism and Alcohol Abuse (NIAAA developed a two-question Youth Alcohol Screening Tool derived from population-based survey data. It is unknown whether this screening tool, designed for use with general populations, accurately identifies risk among youth with chronic medical conditions (YCMC. This growing population, which comprises nearly one in four youth in the US, faces a unique constellation of drinking-related risks.To validate the NIAAA Youth Alcohol Screening Tool in a population of YCMC, we performed a cross-sectional validation study with a sample of 388 youth ages 9-18 years presenting for routine subspecialty care at a large children's hospital for type 1 diabetes, persistent asthma, cystic fibrosis, inflammatory bowel disease, or juvenile idiopathic arthritis. Participants self-administered the NIAAA Youth Alcohol Screening Tool and the Diagnostic Interview Schedule for Children as a criterion standard measure of alcohol use disorders (AUD. Receiver operating curve analysis was used to determine cut points for identifying youth at moderate and highest risk for an AUD.Nearly one third of participants (n = 118; 30.4% reported alcohol use in the past year; 86.4% (106 of past year drinkers did not endorse any AUD criteria, 6.8% (n = 8 of drinkers endorsed a single criterion, and 6.8% of drinkers met criteria for an AUD. Using the NIAAA tool, optimal cut points found to identify youth at moderate and highest risk for an AUD were ≥ 6 and ≥12 drinking days in the past year, respectively.The NIAAA Youth Alcohol Screening Tool is highly efficient for detecting alcohol use and discriminating disordered use among YCMC. This brief screen appears feasible for use in specialty care to ascertain alcohol-related risk that may impact adversely on health status and disease management.

  5. Evaluating radiographers' diagnostic accuracy in screen-reading mammograms: what constitutes a quality study?

    International Nuclear Information System (INIS)

    Debono, Josephine C; Poulos, Ann E

    2015-01-01

    The aim of this study was to first evaluate the quality of studies investigating the diagnostic accuracy of radiographers as mammogram screen-readers and then to develop an adapted tool for determining the quality of screen-reading studies. A literature search was used to identify relevant studies and a quality evaluation tool constructed by combining the criteria for quality of Whiting, Rutjes, Dinnes et al. and Brealey and Westwood. This constructed tool was then applied to the studies and subsequently adapted specifically for use in evaluating quality in studies investigating diagnostic accuracy of screen-readers. Eleven studies were identified and the constructed tool applied to evaluate quality. This evaluation resulted in the identification of quality issues with the studies such as potential for bias, applicability of results, study conduct, reporting of the study and observer characteristics. An assessment of the applicability and relevance of the tool for this area of research resulted in adaptations to the criteria and the development of a tool specifically for evaluating diagnostic accuracy in screen-reading. This tool, with further refinement and rigorous validation can make a significant contribution to promoting well-designed studies in this important area of research and practice

  6. NSC23925, identified in a high-throughput cell-based screen, reverses multidrug resistance.

    Directory of Open Access Journals (Sweden)

    Zhenfeng Duan

    2009-10-01

    Full Text Available Multidrug resistance (MDR is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically.To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1 but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 microM NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors.The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients.

  7. Experience with simplified inelastic analysis of piping designed for elevated temperature service

    International Nuclear Information System (INIS)

    Severud, L.K.

    1980-03-01

    Screening rules and preliminary design of FFTF piping were developed in 1974 based on expected behavior and engineering judgment, approximate calculations, and a few detailed inelastic analyses of pipelines. This paper provides findings from six additional detailed inelastic analyses with correlations to the simplified analysis screening rules. In addition, simplified analysis methods for treating weldment local stresses and strains as well as fabrication induced flaws are described. Based on the FFTF experience, recommendations for future Code and technology work to reduce design analysis costs are identified

  8. Beyond Screening for Risk Factors Objective Detection of Strabismus and Amblyopia

    Science.gov (United States)

    Jost, Reed M.; Yanni, Susan E.; Beauchamp, Cynthia L.; Stager, David R.; Stager, David; Dao, Lori; Birch, Eileen E.

    2015-01-01

    IMPORTANCE Commercially available automated vision screening devices assess refractive risk factors, not amblyopia or strabismus, underreferring affected children and overreferring healthy children. Nearly half of affected children are not identified until after age 5 years, when treatment is less effective. OBJECTIVES To determine the diagnostic accuracy of the Pediatric Vision Scanner (PVS), a binocular retinal birefringence scanner, to objectively identify strabismus and amblyopia, and to compare retinal birefringence screening with a widely used automated pediatric screening device. DESIGN, SETTING, AND PARTICIPANTS Three hundred consecutive preschool children (aged 2-6 years) were screened using the PVS and the SureSight Autorefractor at 2 pediatric ophthalmology private practices. A masked comprehensive pediatric ophthalmic examination provided the gold standard for determining sensitivity and specificity for each screening device. MAIN OUTCOMES AND MEASURES The primary outcome was sensitivity and specificity of the PVS for detecting the targeted conditions, strabismus and amblyopia, in children aged 2 to 6 years. Secondary outcomes included the positive and negative likelihood ratios of the PVS for identifying the targeted conditions. In addition, sensitivity, specificity, and positive and negative likelihood ratios of the SureSight Autorefractor for the targeted conditions were assessed in the same cohort of children. RESULTS Of the 300 patients, 188 had strabismus only, amblyopia only, or both, and 112 had no strabismus or amblyopia. The sensitivity of the PVS to detect strabismus and amblyopia (0.97; 95% CI, 0.94-1.00) was significantly higher than that of the SureSight Autorefractor (0.74; 95% CI, 0.66-0.83). Specificity of the PVS for strabismus and amblyopia (0.87; 95% CI, 0.80-0.95) was significantly higher than that of the SureSight Autorefractor (0.62; 95% CI, 0.50-0.73). CONCLUSIONS AND RELEVANCE The PVS identified children with strabismus and

  9. Forward genetics screen coupled with whole-genome resequencing identifies novel gene targets for improving heterologous enzyme production in Aspergillus niger.

    Science.gov (United States)

    Reilly, Morgann C; Kim, Joonhoon; Lynn, Jed; Simmons, Blake A; Gladden, John M; Magnuson, Jon K; Baker, Scott E

    2018-02-01

    Plant biomass, once reduced to its composite sugars, can be converted to fuel substitutes. One means of overcoming the recalcitrance of lignocellulose is pretreatment followed by enzymatic hydrolysis. However, currently available commercial enzyme cocktails are inhibited in the presence of residual pretreatment chemicals. Recent studies have identified a number of cellulolytic enzymes from bacteria that are tolerant to pretreatment chemicals such as ionic liquids. The challenge now is generation of these enzymes in copious amounts, an arena where fungal organisms such as Aspergillus niger have proven efficient. Fungal host strains still need to be engineered to increase production titers of heterologous protein over native enzymes, which has been a difficult task. Here, we developed a forward genetics screen coupled with whole-genome resequencing to identify specific lesions responsible for a protein hyper-production phenotype in A. niger. This strategy successfully identified novel targets, including a low-affinity glucose transporter, MstC, whose deletion significantly improved secretion of recombinant proteins driven by a glucoamylase promoter.

  10. Forward genetics screen coupled with whole-genome resequencing identifies novel gene targets for improving heterologous enzyme production in Aspergillus niger

    Energy Technology Data Exchange (ETDEWEB)

    Reilly, Morgann C. [Joint BioEnergy Institute, Emeryville, CA (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kim, Joonhoon [Joint BioEnergy Institute, Emeryville, CA (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lynn, Jed [Joint BioEnergy Institute, Emeryville, CA (United States); Wright-Patterson Air Force Base, Dayton, OH (United States); Simmons, Blake A. [Joint BioEnergy Institute, Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Gladden, John M. [Joint BioEnergy Institute, Emeryville, CA (United States); Sandia National Lab. (SNL-CA), Livermore, CA (United States); Magnuson, Jon K. [Joint BioEnergy Institute, Emeryville, CA (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Baker, Scott E. [Joint BioEnergy Institute, Emeryville, CA (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2018-01-06

    Plant biomass, once reduced to its composite sugars, can be converted to fuel substitutes. One means of overcoming the recalcitrance of lignocellulose is pretreatment followed by enzymatic hydrolysis. However, currently available commercial enzyme cocktails are inhibited in the presence of residual pretreatment chemicals. Recent studies have identified a number of cellulolytic enzymes from bacteria that are tolerant to pretreatment chemicals such as ionic liquids. The challenge now is generation of these enzymes in copious amounts, an arena where fungal organisms such as Aspergillus niger have proven efficient. Fungal host strains still need to be engineered to increase production titers of heterologous protein over native enzymes, which has been a difficult task. Here, we developed a forward genetics screen coupled with whole-genome resequencing to identify specific lesions responsible for a protein hyper-production phenotype in A. niger. This strategy successfully identified novel targets, including a low-affinity glucose transporter, MstC, whose deletion significantly improved secretion of recombinant proteins driven by a glucoamylase promoter.

  11. Nutrition screening tools: does one size fit all? A systematic review of screening tools for the hospital setting.

    Science.gov (United States)

    van Bokhorst-de van der Schueren, Marian A E; Guaitoli, Patrícia Realino; Jansma, Elise P; de Vet, Henrica C W

    2014-02-01

    Numerous nutrition screening tools for the hospital setting have been developed. The aim of this systematic review is to study construct or criterion validity and predictive validity of nutrition screening tools for the general hospital setting. A systematic review of English, French, German, Spanish, Portuguese and Dutch articles identified via MEDLINE, Cinahl and EMBASE (from inception to the 2nd of February 2012). Additional studies were identified by checking reference lists of identified manuscripts. Search terms included key words for malnutrition, screening or assessment instruments, and terms for hospital setting and adults. Data were extracted independently by 2 authors. Only studies expressing the (construct, criterion or predictive) validity of a tool were included. 83 studies (32 screening tools) were identified: 42 studies on construct or criterion validity versus a reference method and 51 studies on predictive validity on outcome (i.e. length of stay, mortality or complications). None of the tools performed consistently well to establish the patients' nutritional status. For the elderly, MNA performed fair to good, for the adults MUST performed fair to good. SGA, NRS-2002 and MUST performed well in predicting outcome in approximately half of the studies reviewed in adults, but not in older patients. Not one single screening or assessment tool is capable of adequate nutrition screening as well as predicting poor nutrition related outcome. Development of new tools seems redundant and will most probably not lead to new insights. New studies comparing different tools within one patient population are required. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  12. Tuberculosis screening in patients with HIV

    DEFF Research Database (Denmark)

    Bjerrum, Stephanie Mia Katrine; Bonsu, Frank; Hanson-Nortey, Nii Nortey

    2016-01-01

    BACKGROUND: Tuberculosis screening of people living with HIV (PLHIV) can contribute to early tuberculosis diagnosis and improved patient outcomes. Evidence-based guidelines for tuberculosis screening are available, but literature assessing their implementation and the quality of clinical practice...... is scarce. OBJECTIVES: To assess tuberculosis screening practices and the effectiveness of audit and performance feedback to improve quality of tuberculosis screening at HIV care clinics in Ghana. DESIGN: Healthcare providers at 10 large HIV care clinics prospectively registered patient consultations during...

  13. High-content screening of yeast mutant libraries by shotgun lipidomics

    DEFF Research Database (Denmark)

    Tarasov, Kirill; Stefanko, Adam; Casanovas, Albert

    2014-01-01

    To identify proteins with a functional role in lipid metabolism and homeostasis we designed a high-throughput platform for high-content lipidomic screening of yeast mutant libraries. To this end, we combined culturing and lipid extraction in 96-well format, automated direct infusion...... factor KAR4 precipitated distinct lipid metabolic phenotypes. These results demonstrate that the high-throughput shotgun lipidomics platform is a valid and complementary proxy for high-content screening of yeast mutant libraries....... nanoelectrospray ionization, high-resolution Orbitrap mass spectrometry, and a dedicated data processing framework to support lipid phenotyping across hundreds of Saccharomyces cerevisiae mutants. Our novel approach revealed that the absence of genes with unknown function YBR141C and YJR015W, and the transcription...

  14. A study looking at the effectiveness of developmental screening in identifying learning disabilities in early childhood.

    Science.gov (United States)

    Flanagan, O; Nualláin, S O

    2001-05-01

    This is a retrospective study of children under six years of age referred to the Brothers of Charity Early Intervention Services in County Galway, a service that caters for children under 6 years with learning disabilities. The aim in doing this study was to assess the value of routine developmental screening in identifying children with learning difficulties. This study also investigates the patterns and sources of referral to the remedial services provided by the Brothers of Charity and highlights possible avoidable delays in referral. The results showed that many children were referred for remedial services late. The reasons for late referral included late identification of some children with problems, insufficient co-ordination of community-based services and a lack of awareness of the importance of early intervention in some cases. As some communication disorders such as autism, autistic spectrum disorders and specific language delay may not express themselves until the later part of the second year of life, the 18-24 month developmental assessment is of vital importance. However identification of these disorders can present difficulties and may call for additional training for professionals involved in the developmental screening of children in that age group. The interval between initial identification and referral for remedial care in many cases was more than twelve months. We propose that, in order to minimize this time, children requiring a more in-depth assessment should be assessed by a community-based multidisciplinary team, enabling integrated assessment by the different disciplines and thus speedier referral to remedial services.

  15. Industrial screening programs for workers

    International Nuclear Information System (INIS)

    Lavine, M.P.

    1982-01-01

    Industrial screening efforts to identify classes of workers who are more susceptible to workplace hazards, by virtue of their fertility, genetic, or lifestyle characteristics, represent a relatively new approach to reducing workplace risks. Screening has already raised some important economic, legal, social, medical, and moral questions. Employers, employees, administrative agencies, and the courts are offering different, often conflicting answers. Ultimately the acceptability of various screening schemes rests upon judgments about how a society justifies the distribution of risk. The questions that industrial screening programs raise are only partially answered by empirical evidence; the rest is a matter of values

  16. Gas Reactor International Cooperative program. Pebble bed reactor plant: screening evaluation. Volume 2. Conceptual balance of plant design

    Energy Technology Data Exchange (ETDEWEB)

    1979-11-01

    This report consists of three volumes which describe the design concepts and screening evaluation for a 3000 MW(t) Pebble Bed Reactor Multiplex Plant (PBR-MX). The Multiplex plant produces both electricity and transportable chemical energy via the thermochemical pipeline (TCP). The evaluation was limited to a direct cycle plant which has the steam generators and steam reformers in the primary circuit. This volume describes the conceptual balance-of-plant (BOP) design and was prepared by United Engineers and Constructors, Inc. of Philadelphia, Pennsylvania. The major emphasis of the BOP study was a preliminary design of an overall plant to provide a basis for future studies.

  17. Gas Reactor International Cooperative program. Pebble bed reactor plant: screening evaluation. Volume 2. Conceptual balance of plant design

    International Nuclear Information System (INIS)

    1979-11-01

    This report consists of three volumes which describe the design concepts and screening evaluation for a 3000 MW(t) Pebble Bed Reactor Multiplex Plant (PBR-MX). The Multiplex plant produces both electricity and transportable chemical energy via the thermochemical pipeline (TCP). The evaluation was limited to a direct cycle plant which has the steam generators and steam reformers in the primary circuit. This volume describes the conceptual balance-of-plant (BOP) design and was prepared by United Engineers and Constructors, Inc. of Philadelphia, Pennsylvania. The major emphasis of the BOP study was a preliminary design of an overall plant to provide a basis for future studies

  18. Identifying the emergence of design ideas

    DEFF Research Database (Denmark)

    Inie, Nanna

    This position paper outlines four types of design idea indicators that provide four starting points for exploration of the emergence of design ideas from a micro perspective. The results are derived from two empirical studies of design processes. The research builds on the assumption that we need...... better understanding and definition of design idea emergence and transformation in order to systematically explore the creative process....

  19. An analysis of normalization methods for Drosophila RNAi genomic screens and development of a robust validation scheme

    Science.gov (United States)

    Wiles, Amy M.; Ravi, Dashnamoorthy; Bhavani, Selvaraj; Bishop, Alexander J.R.

    2010-01-01

    Genome-wide RNAi screening is a powerful, yet relatively immature technology that allows investigation into the role of individual genes in a process of choice. Most RNAi screens identify a large number of genes with a continuous gradient in the assessed phenotype. Screeners must then decide whether to examine just those genes with the most robust phenotype or to examine the full gradient of genes that cause an effect and how to identify the candidate genes to be validated. We have used RNAi in Drosophila cells to examine viability in a 384-well plate format and compare two screens, untreated control and treatment. We compare multiple normalization methods, which take advantage of different features within the data, including quantile normalization, background subtraction, scaling, cellHTS2 1, and interquartile range measurement. Considering the false-positive potential that arises from RNAi technology, a robust validation method was designed for the purpose of gene selection for future investigations. In a retrospective analysis, we describe the use of validation data to evaluate each normalization method. While no normalization method worked ideally, we found that a combination of two methods, background subtraction followed by quantile normalization and cellHTS2, at different thresholds, captures the most dependable and diverse candidate genes. Thresholds are suggested depending on whether a few candidate genes are desired or a more extensive systems level analysis is sought. In summary, our normalization approaches and experimental design to perform validation experiments are likely to apply to those high-throughput screening systems attempting to identify genes for systems level analysis. PMID:18753689

  20. Overdiagnosis in breast cancer screening: The impact of study design and calculations.

    Science.gov (United States)

    Lynge, Elsebeth; Beau, Anna-Belle; Christiansen, Peer; von Euler-Chelpin, My; Kroman, Niels; Njor, Sisse; Vejborg, Ilse

    2017-07-01

    Overdiagnosis in breast cancer screening is an important issue. A recent study from Denmark concluded that one in three breast cancers diagnosed in screening areas in women aged 50-69 years were overdiagnosed. The purpose of this short communication was to disentangle the study's methodology in order to evaluate the soundness of this conclusion. We found that both the use of absolute differences as opposed to ratios; the sole focus on non-advanced tumours and the crude allocation of tumours and person-years by screening history for women aged 70-84 years, all contributed to the very high estimate of overdiagnosis. Screening affects cohorts of screened women. Danish registers allow very accurate mapping of the fate of every woman. We should be past the phase where studies of overdiagnosis are based on the fixed age groups from routine statistics. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  1. Yield and Efficiency of Mental Health Screening: A Comparison of Screening Protocols at Intake to Prison.

    Science.gov (United States)

    Martin, Michael S; Potter, Beth K; Crocker, Anne G; Wells, George A; Colman, Ian

    2016-01-01

    The value of screening for mental illness has increasingly been questioned in low prevalence settings due to high false positive rates. However, since false positive rates are related to prevalence, screening may be more effective in higher prevalence settings, including correctional institutions. We compared the yield (i.e. newly detected cases) and efficiency (i.e. false positives) of five screening protocols to detect mental illness in prisons against the use of mental health history taking (the prior approach to detecting mental illness). We estimated the accuracy of the six approaches to detect an Axis I disorder among a sample of 467 newly admitted male inmates (83.1% participation rate). Mental health history taking identified only 41.0% (95% CI 32.1, 50.6) of all inmates with mental illness. Screening protocols identified between 61.9 and 85.7% of all cases, but referred between 2 and 3 additional individuals who did not have a mental illness for every additional case detected compared to the mental health history taking approach. In low prevalence settings (i.e. 10% or less) the screening protocols would have had between 4.6 and 16.2 false positives per true positive. While screening may not be practical in low prevalence settings, it may be beneficial in jails and prisons where the prevalence of mental illness is higher. Further consideration of the context in which screening is being implemented, and of the impacts of policies and clinical practices on the benefits and harms of screening is needed to determine the effectiveness of screening in these settings.

  2. Yield and Efficiency of Mental Health Screening: A Comparison of Screening Protocols at Intake to Prison.

    Directory of Open Access Journals (Sweden)

    Michael S Martin

    Full Text Available The value of screening for mental illness has increasingly been questioned in low prevalence settings due to high false positive rates. However, since false positive rates are related to prevalence, screening may be more effective in higher prevalence settings, including correctional institutions. We compared the yield (i.e. newly detected cases and efficiency (i.e. false positives of five screening protocols to detect mental illness in prisons against the use of mental health history taking (the prior approach to detecting mental illness.We estimated the accuracy of the six approaches to detect an Axis I disorder among a sample of 467 newly admitted male inmates (83.1% participation rate. Mental health history taking identified only 41.0% (95% CI 32.1, 50.6 of all inmates with mental illness. Screening protocols identified between 61.9 and 85.7% of all cases, but referred between 2 and 3 additional individuals who did not have a mental illness for every additional case detected compared to the mental health history taking approach. In low prevalence settings (i.e. 10% or less the screening protocols would have had between 4.6 and 16.2 false positives per true positive.While screening may not be practical in low prevalence settings, it may be beneficial in jails and prisons where the prevalence of mental illness is higher. Further consideration of the context in which screening is being implemented, and of the impacts of policies and clinical practices on the benefits and harms of screening is needed to determine the effectiveness of screening in these settings.

  3. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

    Chevalier, Aaron

    2017-09-26

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

  4. Massively parallel de novo protein design for targeted therapeutics

    KAUST Repository

    Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Ferná ndez-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

    2017-01-01

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

  5. Massively parallel de novo protein design for targeted therapeutics

    Science.gov (United States)

    Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

    2018-01-01

    De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. PMID:28953867

  6. Screening mammography among nursing home residents in the United States: Current guidelines and practice.

    Science.gov (United States)

    Mack, Deborah S; Epstein, Mara M; Dubé, Catherine; Clark, Robin E; Lapane, Kate L

    2018-06-04

    United States (US) guidelines regarding when to stop routine breast cancer screening remain unclear. No national studies to-date have evaluated the use of screening mammography among US long-stay nursing home residents. This cross-sectional study was designed to identify prevalence, predictors, and geographic variation of screening mammography among that population in the context of current US guidelines. Screening mammography prevalence, identified with Physician/Supplier Part B claims and stratified by guideline age classification (65-74, ≥75 years), was estimated for all women aged ≥65 years residing in US Medicare- and Medicaid- certified nursing homes (≥1 year) with an annual Minimum Data Set (MDS) 3.0 assessment, continuous Medicare Part B enrollment, and no clinical indication for screening mammography as of 2011 (n = 389,821). The associations between resident- and regional- level factors, and screening mammography, were estimated by crude and adjusted prevalence ratios from robust Poisson regressions clustered by facility. Women on average were 85.4 (standard deviation ±8.1) years old, 77.9% were disabled, and 76.3% cognitively impaired. Screening mammography prevalence was 7.1% among those aged 65-74 years (95% Confidence Interval (CI): 6.8%-7.3%) and 1.7% among those ≥75 years (95% CI, 1.7%-1.8%), with geographic variation observed. Predictors of screening in both age groups included race, cognitive impairment, frailty, hospice, and some comorbidities. These results shed light on the current screening mammography practices in US nursing homes. Thoughtful consideration about individual screening recommendations and the implementation of more clear guidelines for this special population are warranted to prevent overscreening. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. One more hurdle to increasing mammography screening: pubescent, adolescent, and prior mammography screening experiences.

    Science.gov (United States)

    Thomas, Eileen; Usher, LaToya

    2009-01-01

    Approximately $8.1 billion dollars is spent each year in the United States alone on the treatment of breast cancer. Survival rates are dependent on access to, and utilization of, early detection services. The primary reason for disparity in breast cancer mortality is the delay in time to diagnosis, resulting in poor prognosis. Despite ongoing research to understand barriers to mammography screening, recent studies report a decrease in mammography screening among all racial groups. A qualitative approach was used to elicit information from 36 White non- Hispanic, African-American, Hispanic, and Native American women without a history of breast cancer. Women were invited to share written or audiotape-recorded narratives about experiences pertaining to their breasts and their mammography screening experiences. Major categories identified were: teasing, family norms and values, media/societal influence, body image, and mammography screening experiences. The resulting effects of these experiences left these women with feelings of shame and "conflict" regarding their breasts. The major theme identified was breast conflict. Findings suggest that breast conflict may persist throughout the lifespan and can have a negative influence on a woman's decision to participate in mammography screening. The authors hypothesize that experiences that occur during adolescence pertaining to young girls' breasts can influence a women's body image, which in turn can later in life affect health-seeking behaviors related to mammography screening. These findings have implications for public health practice in planning for breast cancer screening, education, and interventions for women from diverse racial/ethnics groups.

  8. Using network screening methods to determine locations with specific safety issues: A design consistency case study.

    Science.gov (United States)

    Butsick, Andrew J; Wood, Jonathan S; Jovanis, Paul P

    2017-09-01

    The Highway Safety Manual provides multiple methods that can be used to identify sites with promise (SWiPs) for safety improvement. However, most of these methods cannot be used to identify sites with specific problems. Furthermore, given that infrastructure funding is often specified for use related to specific problems/programs, a method for identifying SWiPs related to those programs would be very useful. This research establishes a method for Identifying SWiPs with specific issues. This is accomplished using two safety performance functions (SPFs). This method is applied to identifying SWiPs with geometric design consistency issues. Mixed effects negative binomial regression was used to develop two SPFs using 5 years of crash data and over 8754km of two-lane rural roadway. The first SPF contained typical roadway elements while the second contained additional geometric design consistency parameters. After empirical Bayes adjustments, sites with promise (SWiPs) were identified. The disparity between SWiPs identified by the two SPFs was evident; 40 unique sites were identified by each model out of the top 220 segments. By comparing sites across the two models, candidate road segments can be identified where a lack design consistency may be contributing to an increase in expected crashes. Practitioners can use this method to more effectively identify roadway segments suffering from reduced safety performance due to geometric design inconsistency, with detailed engineering studies of identified sites required to confirm the initial assessment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Suicide risk in youth with intellectual disabilities: the challenges of screening.

    Science.gov (United States)

    Ludi, Erica; Ballard, Elizabeth D; Greenbaum, Rachel; Pao, Maryland; Bridge, Jeffrey; Reynolds, William; Horowitz, Lisa

    2012-06-01

    Children and adolescents with intellectual disabilities (IDs), often diagnosed with comorbid psychiatric disorders, are a vulnerable population who may be at risk for developing suicidal thoughts and behaviors. Previous research has demonstrated that direct suicide screening can rapidly and effectively detect suicide risk and facilitate further clinical evaluation and management. Currently, there are no measures that screen for suicide risk designed specifically for individuals with ID. A review of the literature was conducted to (1) estimate the prevalence of suicidal thoughts, behaviors, and deaths by suicide in children and adolescents with ID; (2) describe associations between youth with ID and suicide risk; and (3) identify the limitations of commonly used suicide screening measures developed for non-ID youth. The literature review confirms that suicide risk exists in this population; youth with ID think about, attempt, and die by suicide. Standardized suicide risk screening is challenged by the lack of measures developed for this population. A summary of the findings is followed by a discussion of the practical clinical considerations surrounding the assessment of suicide risk in youth with ID.

  10. Suicide Risk in Youth with Intellectual Disability: The Challenges of Screening

    Science.gov (United States)

    Ludi, Erica; Ballard, Elizabeth D.; Greenbaum, Rachel; Pao, Maryland; Bridge, Jeffrey; Reynolds, William; Horowitz, Lisa

    2012-01-01

    Children and adolescents with intellectual disabilities (ID), often diagnosed with co-morbid psychiatric disorders, are a vulnerable population who may be at risk for developing suicidal thoughts and behaviors. Previous research has demonstrated that direct suicide screening can rapidly and effectively detect suicide risk and facilitate further clinical evaluation and management. Currently, there are no measures that screen for suicide risk designed specifically for individuals with ID. A review of the literature was conducted: 1) to estimate the prevalence of suicidal thoughts, behaviors and deaths by suicide in children and adolescents with ID; 2) to describe associations between youth with ID and suicide risk; 3) to identify the limitations of commonly used suicide screening measures developed for non-ID youth. The literature review confirms that suicide risk exists in this population; youth with ID think about, attempt and die by suicide. Standardized suicide risk screening is challenged by the lack of measures developed for this population. A summary of the findings is followed by a discussion of the practical clinical considerations surrounding the assessment of suicide risk in youth with ID. PMID:22668827

  11. Monitored retrievable storage facility site screening and evaluation report

    International Nuclear Information System (INIS)

    1985-05-01

    The Nuclear Waste Policy Act of 1982 directs the Department of Energy to ''complete a detailed study of the need for and feasibility of, and to submit to the Congress a proposal for, the construction of one or more monitored retrievable storage facilities for high level radioactive waste and spent nuclear fuel.'' The Act directs that the proposal includes site specific designs. Further, the proposal is to include, ''for the first such facility, at least three alternative sites and at least five alternative combinations of such proposed site and facility designs...'' as well as a recommendation of ''the combination among the alternatives that the Secretary deems preferable.'' An MRS Site Screening Task Force has been formed to help identify and evaluated potential MRS facility sites within a preferred region and with the application of a siting process and criteria developed by the DOE. The activities of the task force presented in this report includes: site screening (Sections 3, 4, and 5), the MRS facilities which are to be sited are described; the criteria, process and outcome of the screening process is presented; and descriptions of the candidate MRS facility sites are given, and site evaluations (Sections 6 through 9) where the rational for the site evaluations are presented, along with each evaluation and findings of the Task Force

  12. Monitored retrievable storage facility site screening and evaluation report

    Energy Technology Data Exchange (ETDEWEB)

    none,

    1985-05-01

    The Nuclear Waste Policy Act of 1982 directs the Department of Energy to complete a detailed study of the need for and feasibility of, and to submit to the Congress a proposal for, the construction of one or more monitored retrievable storage facilities for high level radioactive waste and spent nuclear fuel.'' The Act directs that the proposal includes site specific designs. Further, the proposal is to include, for the first such facility, at least three alternative sites and at least five alternative combinations of such proposed site and facility designs...'' as well as a recommendation of the combination among the alternatives that the Secretary deems preferable.'' An MRS Site Screening Task Force has been formed to help identify and evaluated potential MRS facility sites within a preferred region and with the application of a siting process and criteria developed by the DOE. The activities of the task force presented in this report includes: site screening (Sections 3, 4, and 5), the MRS facilities which are to be sited are described; the criteria, process and outcome of the screening process is presented; and descriptions of the candidate MRS facility sites are given, and site evaluations (Sections 6 through 9) where the rational for the site evaluations are presented, along with each evaluation and findings of the Task Force.

  13. Q Sepharose micro-column chromatography: A simple screening method for identifying beta thalassemia traits and hemoglobin E carriers.

    Science.gov (United States)

    Wong, Peerapon; Sritippayawan, Suchila; Suwannakhon, Narutchala; Tapprom, Akamon; Deoisares, Rawisut; Sanguansermsri, Torpong

    2016-11-01

    For beta thalassemia control program in pregnancy, mass screening of the carrier state by determination of the hemoglobin (Hb) A 2 and Hb E proportions and mutation analysis is a preferred method for making prenatal diagnoses. Q Sepharose micro-column chromatography, developed for the determination of Hb A 2 and Hb E for screening purposes, was compared with high performance liquid chromatography (HPLC) to ascertain its relative accuracy and reliability. Results using Q Sepharose micro-column chromatography in 350 blood specimens, including 50 samples genetically proven to be beta thalassemia heterozygotes, were compared to HPLC for validation. An additional study was conducted to test a clinical application on a large-scale survey for beta thalassemia in 1581 pregnant women and their spouses. The mean (±SD) Hb A 2 proportions in the normal and genetically proven beta thalassemia heterozygotes were 2.70±0.40% and 6.30±1.23%, respectively, as determined by Q-Sepharose micro-column chromatography, and 2.65±0.31% and 5.37±0.96%, respectively, as determined by HPLC. The mean Hb E proportions in the Hb E heterozygotes were 23.25±4.13% and 24.72±3.5% as determined by Q Sepharose micro-column chromatography and HPLC, respectively. In the large-scale survey for beta thalassemia, 23 at risk couples were detected. Seven affected fetuses were identified by prenatal diagnosis. Q Sepharose micro-column chromatography was found to be reliable, reproducible and well-suited for large-scale surveys. Additionally, by being reusable and convenient, this simple and economical chromatography method may be an alternative means to screen for beta thalassemia and Hb E carriers in the mass population. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  14. Liposomal solubilization of new 3-hydroxy-quinolinone derivatives with promising anticancer activity: a screening method to identify maximum incorporation capacity

    DEFF Research Database (Denmark)

    Di Cagno, Massimiliano; Styskala, Jakub; Hlaváč, Jan

    2011-01-01

    Four new 3-hydroxy-quinolinone derivatives with promising anticancer activity could be solubilized using liposomes as vehicle to an extent that allows their in vitro and in vivo testing without use of toxic solvent(s). A screening method to identify the maximum incorporation capacity of hydrophobic......, resulting in a 200-500-fold increase in apparent solubility. Drug-to-lipid ratios in the range of 2-5 µg/mg were obtained. Interestingly, the four quinolinone derivatives have shown different association tendencies with liposomes, probably due to the physicochemical properties of the different group bonded...

  15. Solid-phase synthesis and screening of N-acylated polyamine (NAPA) combinatorial libraries for protein binding.

    Science.gov (United States)

    Iera, Jaclyn A; Jenkins, Lisa M Miller; Kajiyama, Hiroshi; Kopp, Jeffrey B; Appella, Daniel H

    2010-11-15

    Inhibitors for protein-protein interactions are challenging to design, in part due to the unique and complex architectures of each protein's interaction domain. Most approaches to develop inhibitors for these interactions rely on rational design, which requires prior structural knowledge of the target and its ligands. In the absence of structural information, a combinatorial approach may be the best alternative to finding inhibitors of a protein-protein interaction. Current chemical libraries, however, consist mostly of molecules designed to inhibit enzymes. In this manuscript, we report the synthesis and screening of a library based on an N-acylated polyamine (NAPA) scaffold that we designed to have specific molecular features necessary to inhibit protein-protein interactions. Screens of the library identified a member with favorable binding properties to the HIV viral protein R (Vpr), a regulatory protein from HIV, that is involved in numerous interactions with other proteins critical for viral replication. Published by Elsevier Ltd.

  16. Screening for colorectal cancer.

    Science.gov (United States)

    He, Jin; Efron, Jonathan E

    2011-01-01

    March is national colorectal cancer awareness month. It is estimated that as many as 60% of colorectal cancer deaths could be prevented if all men and women aged 50 years or older were screened routinely. In 2000, Katie Couric's televised colonoscopy led to a 20% increase in screening colonoscopies across America, a stunning rise called the "Katie Couric Effect". This event demonstrated how celebrity endorsement affects health behavior. Currently, discussion is ongoing about the optimal strategy for CRC screening, particularly the costs of screening colonoscopy. The current CRC screening guidelines are summarized in Table 2. Debates over the optimum CRC screening test continue in the face of evidence that 22 million Americans aged 50 to 75 years are not screened for CRC by any modality and 25,000 of those lives may have been saved if they had been screened for CRC. It is clear that improving screening rates and reducing disparities in underscreened communities and population subgroups could further reduce colorectal cancer morbidity and mortality. National Institutes of Health consensus identified the following priority areas to enhance the use and quality of colorectal cancer screening: Eliminate financial barriers to colorectal cancer screening and appropriate follow-up of positive results of colorectal cancer screening. Develop systems to ensure the high quality of colorectal cancer screening programs. Conduct studies to determine the comparative effectiveness of the various colorectal cancer screening methods in usual practice settings. Encouraging population adherence to screening tests and allowing patients to select the tests they prefer may do more good (as long as they choose something) than whatever procedure is chosen by the medical profession as the preferred test.

  17. Provider Perspectives on Promoting Cervical Cancer Screening Among Refugee Women.

    Science.gov (United States)

    Zhang, Ying; Ornelas, India J; Do, H Hoai; Magarati, Maya; Jackson, J Carey; Taylor, Victoria M

    2017-06-01

    Many refugees in the United States emigrated from countries where the incidence of cervical cancer is high. Refugee women are unlikely to have been screened for cervical cancer prior to resettlement in the U.S. National organizations recommend cervical cancer screening for refugee women soon after resettlement. We sought to identify health and social service providers' perspectives on promoting cervical cancer screening in order to inform the development of effective programs to increase screening among recently resettled refugees. This study consisted of 21 in-depth key informant interviews with staff from voluntary refugee resettlement agencies, community based organizations, and healthcare clinics serving refugees in King County, Washington. Interview transcripts were analyzed to identify themes. We identified the following themes: (1) refugee women are unfamiliar with preventive care and cancer screening; (2) providers have concerns about the timing of cervical cancer education and screening; (3) linguistic and cultural barriers impact screening uptake; (4) provider factors and clinic systems facilitate promotion of screening; and (5) strategies for educating refugee women about screening. Our findings suggest that refugee women are in need of health education on cervical cancer screening during early resettlement. Frequent messaging about screening could help ensure that women receive screening within the early resettlement period. Health education videos may be effective for providing simple, low literacy messages in women's native languages. Appointments with female clinicians and interpreters, as well as clinic systems that remind clinicians to offer screening at each appointment could increase screening among refugee women.

  18. Epigenetic Library Screen Identifies Abexinostat as Novel Regulator of Adipocytic and Osteoblastic Differentiation of Human Skeletal (Mesenchymal) Stem Cells

    Science.gov (United States)

    Ali, Dalia; Hamam, Rimi; Alfayez, Musaed; Kassem, Moustapha; Aldahmash, Abdullah

    2016-01-01

    The epigenetic mechanisms promoting lineage-specific commitment of human skeletal (mesenchymal or stromal) stem cells (hMSCs) into adipocytes or osteoblasts are still not fully understood. Herein, we performed an epigenetic library functional screen and identified several novel compounds, including abexinostat, which promoted adipocytic and osteoblastic differentiation of hMSCs. Using gene expression microarrays, chromatin immunoprecipitation for H3K9Ac combined with high-throughput DNA sequencing (ChIP-seq), and bioinformatics, we identified several key genes involved in regulating stem cell proliferation and differentiation that were targeted by abexinostat. Concordantly, ChIP-quantitative polymerase chain reaction revealed marked increase in H3K9Ac epigenetic mark on the promoter region of AdipoQ, FABP4, PPARγ, KLF15, CEBPA, SP7, and ALPL in abexinostat-treated hMSCs. Pharmacological inhibition of focal adhesion kinase (PF-573228) or insulin-like growth factor-1R/insulin receptor (NVP-AEW51) signaling exhibited significant inhibition of abexinostat-mediated adipocytic differentiation, whereas inhibition of WNT (XAV939) or transforming growth factor-β (SB505124) signaling abrogated abexinostat-mediated osteogenic differentiation of hMSCs. Our findings provide insight into the understanding of the relationship between the epigenetic effect of histone deacetylase inhibitors, transcription factors, and differentiation pathways governing adipocyte and osteoblast differentiation. Manipulating such pathways allows a novel use for epigenetic compounds in hMSC-based therapies and tissue engineering. Significance This unbiased epigenetic library functional screen identified several novel compounds, including abexinostat, that promoted adipocytic and osteoblastic differentiation of human skeletal (mesenchymal or stromal) stem cells (hMSCs). These data provide new insight into the understanding of the relationship between the epigenetic effect of histone deacetylase

  19. Effect of screening of immigrants on tuberculosis transmission

    NARCIS (Netherlands)

    Verver, S.; van Soolingen, D.; Borgdorff, M. W.

    2002-01-01

    SETTING: In The Netherlands all immigrants from highly endemic countries undergo obligatory entry screening by X-ray, followed by voluntary half-yearly screening for 2 years. OBJECTIVE: To estimate the contribution of screening of immigrants to reductions in tuberculosis transmission. DESIGN: All

  20. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

    Directory of Open Access Journals (Sweden)

    Jie eFeng

    2016-05-01

    Full Text Available Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. While some drug candidates such as daptomycin and clofazimine overlapped with a previous screen against stationary phase B. burgdorferi persisters, additional drug candidates active against round bodies we identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even if pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

  1. A roadmap to directed enzyme evolution and screening systems for biotechnological applications

    Directory of Open Access Journals (Sweden)

    Ronny Martínez

    2013-01-01

    Full Text Available Enzymes have been long used in man-made biochemical processes, from brewing and fermentation to current industrial production of fine chemicals. The ever-growing demand for enzymes in increasingly specific applications requires tailoring naturally occurring enzymes to the non-natural conditions found in industrial processes. Relationships between enzyme sequence, structure and activity are far from understood, thus hindering the capacity to design tailored biocatalysts. In the field of protein engineering, directed enzyme evolution is a powerful algorithm to generate and identify novel and improved enzymes through iterative rounds of mutagenesis and screening applying a specific evolutive pressure. In practice, critical checkpoints in directed evolution are: selection of the starting point, generation of the mutant library, development of the screening assay and analysis of the output of the screening campaign. Each step in directed evolution can be performed using conceptually and technically different approaches, all having inherent advantages and challenges. In this article, we present and discuss in a general overview, challenges of designing and performing a directed enzyme evolution campaign, current advances in methods, as well as highlighting some examples of its applications in industrially relevant enzymes.

  2. A Pathway to Freedom: An Evaluation of Screening Tools for the Identification of Trafficking Victims.

    Science.gov (United States)

    Bespalova, Nadejda; Morgan, Juliet; Coverdale, John

    2016-02-01

    Because training residents and faculty to identify human trafficking victims is a major public health priority, the authors review existing assessment tools. PubMed and Google were searched using combinations of search terms including human, trafficking, sex, labor, screening, identification, and tool. Nine screening tools that met the inclusion criteria were found. They varied greatly in length, format, target demographic, supporting resources, and other parameters. Only two tools were designed specifically for healthcare providers. Only one tool was formally assessed to be valid and reliable in a pilot project in trafficking victim service organizations, although it has not been validated in the healthcare setting. This toolbox should facilitate the education of resident physicians and faculty in screening for trafficking victims, assist educators in assessing screening skills, and promote future research on the identification of trafficking victims.

  3. Diabetes screening in the workplace.

    Science.gov (United States)

    Gulley, Tauna; Boggs, Dusta; Mullins, Rebecca; Brock, Emily

    2014-11-01

    The prevalence of diabetes has increased worldwide and the pathophysiological problems associated with diabetes increase the potential for employees' physical disabilities. These complications, including neuropathy, nephropathy, and visual impairment, negatively impact the job performance of employees and compromise workplace safety. Occupational health nurses can provide diabetes screening programs to employees and identify chronic disease risk factors early. This article describes an occupational diabetes screening program at a major corporation in Belize, Central America, defines diabetes, outlines the diabetes teaching plan, and presents the demographics of the participants and results of the screening. Cultural considerations and recommendations for future occupational diabetes screenings are proposed. Copyright 2014, SLACK Incorporated.

  4. Using probabilistic record linkage methods to identify Australian Indigenous women on the Queensland Pap Smear Register: the National Indigenous Cervical Screening Project.

    Science.gov (United States)

    Whop, Lisa J; Diaz, Abbey; Baade, Peter; Garvey, Gail; Cunningham, Joan; Brotherton, Julia M L; Canfell, Karen; Valery, Patricia C; O'Connell, Dianne L; Taylor, Catherine; Moore, Suzanne P; Condon, John R

    2016-02-12

    To evaluate the feasibility and reliability of record linkage of existing population-based data sets to determine Indigenous status among women receiving Pap smears. This method may allow for the first ever population measure of Australian Indigenous women's cervical screening participation rates. A linked data set of women aged 20-69 in the Queensland Pap Smear Register (PSR; 1999-2011) and Queensland Cancer Registry (QCR; 1997-2010) formed the Initial Study Cohort. Two extracts (1995-2011) were taken from Queensland public hospitals data (Queensland Hospital Admitted Patient Data Collection, QHAPDC) for women, aged 20-69, who had ever been identified as Indigenous (extract 1) and had a diagnosis or procedure code relating to cervical cancer (extract 2). The Initial Study Cohort was linked to extract 1, and women with cervical cancer in the initial cohort were linked to extract 2. The proportion of women in the Initial Cohort who linked with the extracts (true -pairs) is reported, as well as the proportion of potential pairs that required clerical review. After assigning Indigenous status from QHAPDC to the PSR, the proportion of women identified as Indigenous was calculated using 4 algorithms, and compared. There were 28,872 women (2.1%) from the Initial Study Cohort who matched to an ever Indigenous record in extract 1 (n=76,831). Women with cervical cancer in the Initial Study Cohort linked to 1385 (71%) records in extract 2. The proportion of Indigenous women ranged from 2.00% to 2.08% when using different algorithms to define Indigenous status. The Final Study Cohort included 1,372,823 women (PSR n=1,374,401; QCR n=1955), and 5,062,118 records. Indigenous status in Queensland cervical screening data was successfully ascertained through record linkage, allowing for the crucial assessment of the current cervical screening programme for Indigenous women. Our study highlights the need to include Indigenous status on Pap smear request and report forms in any

  5. Designing a diverse high-quality library for crystallography-based FBDD screening.

    Science.gov (United States)

    Tounge, Brett A; Parker, Michael H

    2011-01-01

    A well-chosen set of fragments is able to cover a large chemical space using a small number of compounds. The actual size and makeup of the fragment set is dependent on the screening method since each technique has its own practical limits in terms of the number of compounds that can be screened and requirements for compound solubility. In this chapter, an overview of the general requirements for a fragment library is presented for different screening platforms. In the case of the FBDD work at Johnson & Johnson Pharmaceutical Research and Development, L.L.C., our main screening technology is X-ray crystallography. Since every soaked protein crystal needs to be diffracted and a protein structure determined to delineate if a fragment binds, the size of our initial screening library cannot be a rate-limiting factor. For this reason, we have chosen 900 as the appropriate primary fragment library size. To choose the best set, we have developed our own mix of simple property ("Rule of 3") and "bad" substructure filtering. While this gets one a long way in terms of limiting the fragment pool, there are still tens of thousands of compounds to choose from after this initial step. Many of the choices left at this stage are not drug-like, so we have developed an FBDD Score to help select a 900-compound set. The details of this score and the filtering are presented. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. Breast cancer screening implementation and reassurance

    DEFF Research Database (Denmark)

    Østerø, J; Siersma, Volkert Dirk; Brodersen, John

    2013-01-01

    difference in reported psychosocial aspects had disappeared or been reduced because of the nationwide screening implementation. METHODS: The 1000 women included in the previous survey were posted part I of the questionnaire Consequences of Screening in Breast Cancer (COS-BC1) in August 2011, nearly 5 years......BACKGROUND: Women not offered screening mammography reported higher levels of negative psychosocial aspects than women offered screening. This was demonstrated in a questionnaire survey where 1000 women were included: 500 women living in areas where the public authorities had never offered...... screening mammography and 500 women living in areas where women had been invited to screening mammography for >10 years. After this baseline survey, nationwide screening mammography was implemented. The aim of this follow-up study was to resurvey the 1000 women and to investigate if the identified...

  7. A Nutrition Screening Form for Female Infertility Patients.

    Science.gov (United States)

    Langley, Susie

    2014-12-01

    A Nutrition Screening Form (NSF) was designed to identify lifestyle risk factors that negatively impact fertility and to provide a descriptive profile of 300 female infertility patients in a private urban infertility clinic. The NSF was mailed to all new patients prior to the initial physician's visit and self-reported data were assessed using specific criteria to determine if a nutrition referral was warranted. This observational study revealed that 43% of the women had a body mass index (BMI) nutrition-related lifestyle factors that may negatively impact fertility and identified weight, BMI, diet, exercise, and stress as modifiable risk factors deserving future research. NSF information can help increase awareness among health professionals and patients about the important link between nutrition, fertility, and successful reproductive outcomes.

  8. Design of a randomized controlled trial for genomic carrier screening in healthy patients seeking preconception genetic testing.

    Science.gov (United States)

    Kauffman, Tia L; Wilfond, Benjamin S; Jarvik, Gail P; Leo, Michael C; Lynch, Frances L; Reiss, Jacob A; Richards, C Sue; McMullen, Carmit; Nickerson, Deborah; Dorschner, Michael O; Goddard, Katrina A B

    2017-02-01

    Population-based carrier screening is limited to well-studied or high-impact genetic conditions for which the benefits may outweigh the associated harms and costs. As the cost of genome sequencing declines and availability increases, the balance of risks and benefits may change for a much larger number of genetic conditions, including medically actionable additional findings. We designed an RCT to evaluate genomic clinical sequencing for women and partners considering a pregnancy. All results are placed into the medical record for use by healthcare providers. Through quantitative and qualitative measures, including baseline and post result disclosure surveys, post result disclosure interviews, 1-2year follow-up interviews, and team journaling, we are obtaining data about the clinical and personal utility of genomic carrier screening in this population. Key outcomes include the number of reportable carrier and additional findings, and the comparative cost, utilization, and psychosocial impacts of usual care vs. genomic carrier screening. As the study progresses, we will compare the costs of genome sequencing and usual care as well as the cost of screening, pattern of use of genetic or mental health counseling services, number of outpatient visits, and total healthcare costs. This project includes novel investigation into human reactions and responses from would-be parents who are learning information that could both affect a future pregnancy and their own health. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Finding needles in a haystack: a methodology for identifying and sampling community-based youth smoking cessation programs.

    Science.gov (United States)

    Emery, Sherry; Lee, Jungwha; Curry, Susan J; Johnson, Tim; Sporer, Amy K; Mermelstein, Robin; Flay, Brian; Warnecke, Richard

    2010-02-01

    Surveys of community-based programs are difficult to conduct when there is virtually no information about the number or locations of the programs of interest. This article describes the methodology used by the Helping Young Smokers Quit (HYSQ) initiative to identify and profile community-based youth smoking cessation programs in the absence of a defined sample frame. We developed a two-stage sampling design, with counties as the first-stage probability sampling units. The second stage used snowball sampling to saturation, to identify individuals who administered youth smoking cessation programs across three economic sectors in each county. Multivariate analyses modeled the relationship between program screening, eligibility, and response rates and economic sector and stratification criteria. Cumulative logit models analyzed the relationship between the number of contacts in a county and the number of programs screened, eligible, or profiled in a county. The snowball process yielded 9,983 unique and traceable contacts. Urban and high-income counties yielded significantly more screened program administrators; urban counties produced significantly more eligible programs, but there was no significant association between the county characteristics and program response rate. There is a positive relationship between the number of informants initially located and the number of programs screened, eligible, and profiled in a county. Our strategy to identify youth tobacco cessation programs could be used to create a sample frame for other nonprofit organizations that are difficult to identify due to a lack of existing directories, lists, or other traditional sample frames.

  10. Metabolic Toxicity Screening Using Electrochemiluminescence Arrays Coupled with Enzyme-DNA Biocolloid Reactors and Liquid Chromatography–Mass Spectrometry

    Science.gov (United States)

    Hvastkovs, Eli G.; Schenkman, John B.; Rusling, James F.

    2012-01-01

    New chemicals or drugs must be guaranteed safe before they can be marketed. Despite widespread use of bioassay panels for toxicity prediction, products that are toxic to a subset of the population often are not identified until clinical trials. This article reviews new array methodologies based on enzyme/DNA films that form and identify DNA-reactive metabolites that are indicators of potentially genotoxic species. This molecularly based methodology is designed in a rapid screening array that utilizes electrochemiluminescence (ECL) to detect metabolite-DNA reactions, as well as biocolloid reactors that provide the DNA adducts and metabolites for liquid chromatography–mass spectrometry (LC-MS) analysis. ECL arrays provide rapid toxicity screening, and the biocolloid reactor LC-MS approach provides a valuable follow-up on structure, identification, and formation rates of DNA adducts for toxicity hits from the ECL array screening. Specific examples using this strategy are discussed. Integration of high-throughput versions of these toxicity-screening methods with existing drug toxicity bioassays should allow for better human toxicity prediction as well as more informed decision making regarding new chemical and drug candidates. PMID:22482786

  11. Universal screening as the great equalizer: Eliminating disproportionality in special education referrals

    Science.gov (United States)

    Raines, Tara C.

    The overrepresentation of minority students identified for special education services continues to plague schools and serves as a challenge for researchers and practitioners (Ferri & Conner, 2005). Teacher nomination, office discipline referrals (ODR), and functional behavior assessments (FBA) continue to guide referral processes (Bradshaw, Mitchell, O'Brennen, & Leaf, 2010; Eklund, et al., 2009; Mustian, 2010). These methods have been found to be riddled with inconsistencies. Practices used to identify students for behavioral and emotional interventions over-identify students from culturally and linguistically diverse backgrounds. The use of a behavioral and emotional screener to make data-based decisions regarding placement and services could provide an objective assessment of student risk. The first chapter of this dissertation reviews methods used in the identification of students for behavioral and emotional support services. Additionally, the use of universal screening in conjunction with student self-report are proposed as tools for alleviating the overrepresentation of minority students in special education programs for behavioral and emotional disorders. The second chapter of this dissertation explores the measurement equivalence of Behavior Assessment System for Children, Second Edition (BASC-2) Behavioral and Emotional Screening System Student form (BESS Student) across the Black, Hispanic, and White participants in the norming sample. The BESS Student as a universal screening tool is poised to alleviate the disproportionate number of children of color identified by schools as having behavior and emotional disorders. This instrument also provides an avenue to identify students with internalizing disorders who are often overlooked in present referral practices (Bradshaw, Buckley, & Ialongo, 2008; Kataoka, Zhang, & Wells, 2002). The findings of the measurement equivalence study suggests that the BESS Student is, as designed, identifying behavioral and

  12. Clinically targeted screening for congenital CMV - potential for integration into the National Hearing Screening Programme.

    Science.gov (United States)

    Kadambari, S; Luck, S; Davis, A; Williams, Ej; Berrington, J; Griffiths, Pd; Sharland, M

    2013-10-01

    Screening for a condition should only be undertaken if certain strict criteria are met. Congenital CMV (cCMV) is a leading cause of sensorineuronal hearing loss (SNHL) and meets many of these criteria, but is not currently screened for in the UK. Ganciclovir reduces CMV-induced progressive SNHL if treatment is begun in the first month of life. The Newborn Hearing Screening Programme (NHSP) has been shown to identify SNHL at the earliest possible age. The potential of integrating screening for cCMV into the NHSP is discussed to consolidate the link between screening, early diagnosis and management. The early diagnosis and treatment of cCMV may prevent a small proportion of late SNHL. In the absence of any screening programme, we provide evidence that clinically targeted screening through the NHSP is a potential option in the UK, enhancing the diagnostic pathway and enabling appropriate early treatment to reduce long-term morbidity. ©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  13. Multimedia messages in genetics: design, development, and evaluation of a computer-based instructional resource for secondary school students in a Tay Sachs disease carrier screening program.

    Science.gov (United States)

    Gason, Alexandra A; Aitken, MaryAnne; Delatycki, Martin B; Sheffield, Edith; Metcalfe, Sylvia A

    2004-01-01

    Tay Sachs disease is a recessively inherited neurodegenerative disorder, for which carrier screening programs exist worldwide. Education for those offered a screening test is essential in facilitating informed decision-making. In Melbourne, Australia, we have designed, developed, and evaluated a computer-based instructional resource for use in the Tay Sachs disease carrier screening program for secondary school students attending Jewish schools. The resource entitled "Genetics in the Community: Tay Sachs disease" was designed on a platform of educational learning theory. The development of the resource included formative evaluation using qualitative data analysis supported by descriptive quantitative data. The final resource was evaluated within the screening program and compared with the standard oral presentation using a questionnaire. Knowledge outcomes were measured both before and after either of the educational formats. Data from the formative evaluation were used to refine the content and functionality of the final resource. The questionnaire evaluation of 302 students over two years showed the multimedia resource to be equally effective as an oral educational presentation in facilitating participants' knowledge construction. The resource offers a large number of potential benefits, which are not limited to the Tay Sachs disease carrier screening program setting, such as delivery of a consistent educational message, short delivery time, and minimum financial and resource commitment. This article outlines the value of considering educational theory and describes the process of multimedia development providing a framework that may be of value when designing genetics multimedia resources in general.

  14. Providing floating capabilities in latest-generation sand screens

    Energy Technology Data Exchange (ETDEWEB)

    Bowen, E.G.; Coronado, M.P. [Society of Petroleum Engineers, Richardson, TX (United States)]|[Baker Hughes, Houston, TX (United States)

    2008-10-15

    Alternative production methods are needed for the massive reserves located in the bitumen region of Canada's tar sands. The area has over 100 installations of sand screens/slotted liners in both injection and production legs using steam-assisted gravity drainage (SAGD) technology. Multiple wells must be drilled from a single pad because of the sensitive nature of the environment. With significant depths of these wells, a floating sand screen provides assurance that the sand screen will reach the desired depth. Paraffin is generally used to plug the flow access of the screen during installation. This paper discussed a new technology that has been developed to allow for sand screen installations without relying on paraffin wax to withstand differential pressure. The new technology uses a hydro-mechanical valving system incorporated into the screen design to temporarily close off the screen while being run in the hole. The paper described how the technology could provide a reliable, time-saving solution for SAGD installations when floating sand control screens are needed. The paper discussed current technology and its limitations, sand screen installation, screen design for floating applications, and additional applications. It was concluded that this technology solution provides a unique alternative to the methods currently used to install sand screens with SAGD technology in the fast growing Canadian market for bitumen recovery. 2 refs., 5 figs.

  15. Spent-fuel-stabilizer screening studies

    International Nuclear Information System (INIS)

    Wynhoff, N.; Girault, S.E.; Fish, R.L.

    1980-11-01

    A broad range of potential stabilizer materials was identified and screened for packaging spent fuel assemblies for underground storage. The screening took into consideration the thermal gradient, stress, differential thermal expansion, nuclear criticality, radiation shielding, cost, and availability. Recommended stabilizer materials for further testing include silica, quartz, mullite, zircon, bentonite, graphite, gases, lead, Zn alloys, Cu alloys, etc

  16. Comparison of screening questionnaires to identify psoriatic arthritis in a primary-care population: a cross-sectional study.

    Science.gov (United States)

    Coates, L C; Savage, L; Waxman, R; Moverley, A R; Worthington, S; Helliwell, P S

    2016-09-01

    Many questionnaires are available for assessment of psoriatic arthritis (PsA), but there is little evidence comparing them. To test the proposed CONTEST questionnaire, which was developed to identify patients with psoriasis who have undiagnosed PsA, and compare it with the validated Psoriasis Epidemiology Screening Tool (PEST) questionnaire in a primary-care setting. A random sample of adult patients with psoriasis and no diagnosis of arthritis was identified from five general practice surgeries in Yorkshire, U.K. Consenting patients completed both questionnaires and were assessed by a dermatologist and rheumatologist. Diagnosis of PsA was made by the assessing rheumatologist. Receiver operator characteristic (ROC) curve analysis examined the sensitivity and specificity of potential cut points. In total 932 packs were sent to recruit 191 (20·5%) participants. Of these, 169 (88·5%) were confirmed to have current or previous psoriasis. Using physician diagnosis 17 (10·1%) were found to have previously undiagnosed PsA, while 90 (53·3%) had another musculoskeletal complaint and 62 (36·7%) had no musculoskeletal problems. Using ROC curve analysis, all of the questionnaires showed a significant ability to identify PsA. The area under the curve (AUC) for the CONTEST questionnaires was slightly higher than that of PEST (0·69 and 0·70 vs. 0·65), but there was no significant difference identified. Examining the sensitivities and specificities for the different cut points suggested that a PEST score ≥ 2 would perform better in this dataset, and the optimal scores for CONTEST and CONTEST plus joint manikin were 3 and 4, respectively. The accuracy of the questionnaires to identify PsA appeared similar, with a slightly higher AUC for the CONTEST questionnaires. The optimal cut points in this study appeared lower than in previous studies. © 2016 British Association of Dermatologists.

  17. Genetic Screens in Yeast to Identify BRCA1 Modifiers

    National Research Council Canada - National Science Library

    Plon, Sharon E

    2004-01-01

    .... The yeast RAD9 protein has similar functions and sequence motifs as BRCA1 and we proposed to identify candidate modifier loci by identifying haploinsufficient mutations at a second locus that alters...

  18. DESIGN OF EXPERIMENTS IN TRUCK COMPANY

    Directory of Open Access Journals (Sweden)

    Bibiana Kaselyova

    2015-07-01

    Full Text Available Purpose: Design of experiment (DOE represent very powerful tool for process improvement vastly supported by six sigma methodology. This approach is mostly used by large and manufacturing orientated companies. Presented research is focused on use of DOE in truck company, which is medium size and service orientated. Such study has several purposes. Firstly, detailed description of improvement effort based on DOE can be used as a methodological framework for companies similar to researched one. Secondly, it provides example of successfully implemented low cost design of experiment practise. Moreover, performed experiment identifies key factors, which influence the lifetime of truck tyres.Design/methodology: The research in this paper is based on experiment conducted in Slovakian Truck Company. It provides detailed case study of whole improvement effort, together with problem formulation, design creation and analysis, as well as the results interpretation. The company wants to improve lifetime of the truck tyres. Next to fuel consumption, consumption of tyres and their replacement represent according to them, one of most costly processes in company. Improvement effort was made through the use of PDCA cycle. It start with analysis of current state of tyres consumption. The variability of tyres consumption based on years and types was investigated. Then the causes of tyres replacement were identified and screening DOE was conducted. After a screening design, the full factorial design of experiment was used to identify main drivers of tyres deterioration and breakdowns. Based on result of DOE, the corrective action were propose and implement.Findings: Based on performed experiment our research describes process of tyres use and replacement. It defines main reasons for tyre breakdown and identify main drivers which influence truck tyres lifetime. Moreover it formulates corrective action to prolong tyres lifetime.Originality: The study represents full

  19. Functional electronic screen printing – electroluminescent smart fabric watch

    OpenAIRE

    de Vos, Marc; Torah, Russel; Beeby, Steve; Tudor, John

    2013-01-01

    Motivation for screen printed smart fabrics.Introduce functional electronic screen printing on fabrics.Printed smart fabric watch design.Printing process for electroluminescent watch.Demonstration video.Conclusions and further work.Examples of other screen printed smart fabrics.

  20. Organizational Factors Affecting the Likelihood of Cancer Screening Among VA Patients.

    Science.gov (United States)

    Chou, Ann F; Rose, Danielle E; Farmer, Melissa; Canelo, Ismelda; Yano, Elizabeth M

    2015-12-01

    Preventive service delivery, including cancer screenings, continues to pose a challenge to quality improvement efforts. Although many studies have focused on person-level characteristics associated with screening, less is known about organizational influences on cancer screening. This study aims to understand the association between organizational factors and adherence to cancer screenings. This study employed a cross-sectional design using organizational-level, patient-level, and area-level data. Dependent variables included breast, cervical, and colorectal cancer screening. Organizational factors describing resource sufficiency were constructed using factor analyses from a survey of 250 Veterans Affairs primary care directors. We conducted random-effects logistic regression analyses, modeling cancer screening as a function of organizational factors, controlling for patient-level and area-level factors. Overall, 87% of the patients received mammograms, 92% received cervical and 78% had colorectal screening. Quality improvement orientation increased the odds of cervical [odds ratio (OR): 1.27; 95% confidence interval (CI), 1.03-1.57] and colorectal cancer screening (OR: 1.10; 95% CI, 1.00-1.20). Authority in determining primary care components increased the odds of mammography screening (OR: 1.23; 95% CI, 1.03-1.51). Sufficiency in clinical staffing increased the odds of mammography and cervical cancer screenings. Several patient-level factors, serving as control variables, were associated with achievement of screenings. Resource sufficiency led to increased odds of screening possibly because they promote excellence in patient care by conveying organizational goals and facilitate goal achievement with resources. Complementary to patient-level factors, our findings identified organizational processes associated with better performance, which offer concrete strategies in which facilities can evaluate their capabilities to implement best practices to foster and