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Sample records for models screen tscreen

  1. Use of external metabolizing systems when testing for endocrine disruption in the T-screen assay

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Olesen, Pelle Thonning; Nellemann, Christine Lydia

    2011-01-01

    different in vitro systems for biotransformation of ten known endocrine disrupting chemicals (EDs): five azole fungicides, three parabens and 2 phthalates, b) to determine possible changes in the ability of the EDs to bind and activate the thyroid receptor (TR) in the in vitro T-screen assay after...... tested the human liver S9 mix and the PCB-induced rat microsomes gave an almost complete metabolic transformation of the tested parabens and phthalates. No marked difference the effects in the T-screen assay was observed between the parent compounds and the effects of the tested metabolic extracts...

  2. T-Screen as a tool to identify thyroid hormone receptor active compounds

    NARCIS (Netherlands)

    Gutleb, A.C.; Meerts, I.A.T.M.; Bergsma, J.H.; Schriks, M.; Murk, A.J.

    2005-01-01

    The T-Screen represents an in vitro bioassay based on thyroid hormone dependent cell proliferation of a rat pituitary tumour cell line (GH3) in serum-free medium. It can be used to study interference of compounds with thyroid hormone at the cellular level, thus bridging the gap between limitations o

  3. Use of external metabolizing systems when testing for endocrine disruption in the T-screen assay.

    Science.gov (United States)

    Taxvig, Camilla; Olesen, Pelle Thonning; Nellemann, Christine

    2011-02-01

    Although, it is well-established that information on the metabolism of a substance is important in the evaluation of its toxic potential, there is limited experience with incorporating metabolic aspects into in vitro tests for endocrine disrupters. The aim of the current study was a) to study different in vitro systems for biotransformation of ten known endocrine disrupting chemicals (EDs): five azole fungicides, three parabens and 2 phthalates, b) to determine possible changes in the ability of the EDs to bind and activate the thyroid receptor (TR) in the in vitro T-screen assay after biotransformation and c) to investigate the endogenous metabolic capacity of the GH3 cells, the cell line used in the T-screen assay, which is a proliferation assay used for the in vitro detection of agonistic and antagonistic properties of compounds at the level of the TR. The two in vitro metabolizing systems tested the human liver S9 mix and the PCB-induced rat microsomes gave an almost complete metabolic transformation of the tested parabens and phthalates. No marked difference the effects in the T-screen assay was observed between the parent compounds and the effects of the tested metabolic extracts. The GH3 cells themselves significantly metabolized the two tested phthalates dimethyl phthalate (DMP) and diethyl phthalate (DEP). Overall the results and qualitative data from the current study show that an in vitro metabolizing system using liver S9 or microsomes could be a convenient method for the incorporation of metabolic and toxicokinetic aspects into in vitro testing for endocrine disrupting effects.

  4. LABORATORY MODELS FOR SCREENING ANALGESICS

    Directory of Open Access Journals (Sweden)

    Parle Milind

    2013-01-01

    Full Text Available Pain is a complex unpleasant phenomenon composed of sensory experiences that include time, space, intensity, emotion, cognition and motivation. Analgesics are the agents, which selectively relieve pain by acting in the CNS or by peripheral pain mechanisms without significantly altering consciousness. Analgesics may be narcotic or non-narcotic. The study of pain in animals raises ethical, philosophical and technical problems. Philosophically, there is a problem that pain cannot be monitored directly in animals but can only be measured by examining their responses to nociceptive stimuli. The observed reactions are almost always motor responses ranging from spinal reflexes to complex behavior. The animal models employed for screening of analgesic agents, include Pain-state models based on the use of thermal stimuli, mechanical stimuli, electrical stimuli and chemical stimuli. The neuronal basis of most of the above laboratory models is poorly understood, however their application is profitable in predicting analgesic activity of newly discovered substances.

  5. Screening for Prediabetes Using Machine Learning Models

    Directory of Open Access Journals (Sweden)

    Soo Beom Choi

    2014-01-01

    Full Text Available The global prevalence of diabetes is rapidly increasing. Studies support the necessity of screening and interventions for prediabetes, which could result in serious complications and diabetes. This study aimed at developing an intelligence-based screening model for prediabetes. Data from the Korean National Health and Nutrition Examination Survey (KNHANES were used, excluding subjects with diabetes. The KNHANES 2010 data (n=4685 were used for training and internal validation, while data from KNHANES 2011 (n=4566 were used for external validation. We developed two models to screen for prediabetes using an artificial neural network (ANN and support vector machine (SVM and performed a systematic evaluation of the models using internal and external validation. We compared the performance of our models with that of a screening score model based on logistic regression analysis for prediabetes that had been developed previously. The SVM model showed the areas under the curve of 0.731 in the external datasets, which is higher than those of the ANN model (0.729 and the screening score model (0.712, respectively. The prescreening methods developed in this study performed better than the screening score model that had been developed previously and may be more effective method for prediabetes screening.

  6. How does early detection by screening affect disease progression?: Modeling estimated benefits in prostate cancer screening

    NARCIS (Netherlands)

    E.M. Wever (Elisabeth); G. Draisma (Gerrit); E.A.M. Heijnsdijk (Eveline); H.J. de Koning (Harry)

    2011-01-01

    textabstractBackground. Simulation models are essential tools for estimating benefits of cancer screening programs. Such models include a screening-effect model that represents how early detection by screening followed by treatment affects disease-specific survival. Two commonly used screening-effec

  7. Transport properties of fully screened Kondo models

    NARCIS (Netherlands)

    Hörig, Christoph B M; Mora, Christophe; Schuricht, Dirk

    2014-01-01

    We study the nonequilibrium transport properties of fully (exactly) screened Kondo quantum dots subject to a finite bias voltage or a finite temperature. First, we calculate the Fermi-liquid coefficients of the conductance for models with arbitrary spin, i.e., its leading behavior for small bias vol

  8. Magnetic field screening effect in electroweak model

    CERN Document Server

    Bakry, A; Zhang, P M; Zou, L P

    2014-01-01

    It is shown that in the Weinberg-Salam model a magnetic field screening effect for static magnetic solutions takes place. The origin of that phenomenon is conditioned by features of the electro-weak interaction, namely, there is mutual cancellation of Abelian magnetic fields created by the SU(2) gauge fields and Higgs boson. The effect implies monopole charge screening in finite energy system of monopoles and antimonopoles. We consider another manifestation of the screening effect which leads to an essential energy decrease of magnetic solutions. Applying variational method we have found a magnetic field configuration with a topological azimuthal magnetic flux which minimizes the energy functional and possesses a total energy of order 1 TeV. We suppose that corresponding magnetic bound state exists in the electroweak theory and can be detected in experiment.

  9. Evaluation of Endocrine Disrupting Effects of Nitrate after In Utero Exposure in Rats and of Nitrate and Nitrite in the H295R and T-Screen Assay

    DEFF Research Database (Denmark)

    Hansen, Pernille Reimer; Taxvig, Camilla; Christiansen, Sofie;

    2009-01-01

    Animal studies have shown that nitrate acts as an endocrine disrupter affecting the androgen production in adult males. This raises a concern for more severe endocrine disrupting effects after exposure during the sensitive period of prenatal male sexual development. As there are no existing studi...

  10. Quantitative assessment model for gastric cancer screening

    Institute of Scientific and Technical Information of China (English)

    Kun Chen; Wei-Ping Yu; Liang Song; Yi-Min Zhu

    2005-01-01

    AIM: To set up a mathematic model for gastric cancer screening and to evaluate its function in mass screening for gastric cancer.METHODS: A case control study was carried on in 66patients and 198 normal people, then the risk and protective factors of gastric cancer were determined, including heavy manual work, foods such as small yellow-fin tuna, dried small shrimps, squills, crabs, mothers suffering from gastric diseases, spouse alive, use of refrigerators and hot food,etc. According to some principles and methods of probability and fuzzy mathematics, a quantitative assessment model was established as follows: first, we selected some factors significant in statistics, and calculated weight coefficient for each one by two different methods; second, population space was divided into gastric cancer fuzzy subset and non gastric cancer fuzzy subset, then a mathematic model for each subset was established, we got a mathematic expression of attribute degree (AD).RESULTS: Based on the data of 63 patients and 693 normal people, AD of each subject was calculated. Considering the sensitivity and specificity, the thresholds of AD values calculated were configured with 0.20 and 0.17, respectively.According to these thresholds, the sensitivity and specificity of the quantitative model were about 69% and 63%.Moreover, statistical test showed that the identification outcomes of these two different calculation methods were identical (P>0.05).CONCLUSION: The validity of this method is satisfactory.It is convenient, feasible, economic and can be used to determine individual and population risks of gastric cancer.

  11. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

    NARCIS (Netherlands)

    Alvarenga Fernandes Sin, Olga; Michels, Helen; Nollen, Ellen A. A.

    2014-01-01

    Caenorhabditis elegans comprises unique features that make it an attractive model organism in diverse fields of biology. Genetic screens are powerful to identify genes and C. elegans can be customized to forward or reverse genetic screens and to establish gene function. These genetic screens can be

  12. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases

    NARCIS (Netherlands)

    Alvarenga Fernandes Sin, Olga; Michels, Helen; Nollen, Ellen A. A.

    2014-01-01

    Caenorhabditis elegans comprises unique features that make it an attractive model organism in diverse fields of biology. Genetic screens are powerful to identify genes and C. elegans can be customized to forward or reverse genetic screens and to establish gene function. These genetic screens can be

  13. Mathematical Models of the Sinusoidal Screen Family

    Directory of Open Access Journals (Sweden)

    Tajana Koren

    2011-06-01

    Full Text Available In this paper we will define a family of sinusoidal screening elements and explore the possibilities of their application in graphic arts, securities printing and design solutions in photography and typography editing. For this purpose mathematical expressions of sinusoidal families were converted into a Postscript language. The introduction of a random variable results in a countless number of various mutations which cannot be repeated without knowing the programming code itself. The use of the family of screens in protection of securities is thus of great importance. Other possible application of modulated sinusoidal screens is related to the large format color printing. This paper will test the application of sinusoidal screens in vector graphics, pixel graphics and typography. The development of parameters in the sinusoidal screen element algorithms gives new forms defined within screening cells with strict requirements of coverage implementation. Individual solutions include stochastic algorithms, as well as the autonomy of screening forms in regard to multicolor printing channels.

  14. A Drosophila Model for Screening Antiobesity Agents

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    Tran Thanh Men

    2016-01-01

    Full Text Available Although triacylglycerol, the major component for lipid storage, is essential for normal physiology, its excessive accumulation causes obesity in adipose tissue and is associated with organ dysfunction in nonadipose tissue. Here, we focused on the Drosophila model to develop therapeutics for preventing obesity. The brummer (bmm gene in Drosophila melanogaster is known to be homologous with human adipocyte triglyceride lipase, which is related to the regulation of lipid storage. We established a Drosophila model for monitoring bmm expression by introducing the green fluorescent protein (GFP gene as a downstream reporter of the bmm promoter. The third-instar larvae of Drosophila showed the GFP signal in all tissues observed and specifically in the salivary gland nucleus. To confirm the relationship between bmm expression and obesity, the effect of oral administration of glucose diets on bmm promoter activity was analyzed. The Drosophila flies given high-glucose diets showed higher lipid contents, indicating the obesity phenotype; this was suggested by a weaker intensity of the GFP signal as well as reduced bmm mRNA expression. These results demonstrated that the transgenic Drosophila model established in this study is useful for screening antiobesity agents. We also report the effects of oral administration of histone deacetylase inhibitors and some vegetables on the bmm promoter activity.

  15. Application of an Aesthetic Evaluation Model to Data Entry Screens.

    Science.gov (United States)

    Ngo, D. C. L.; Byrne, J. G.

    2001-01-01

    Describes a new model for quantitatively assessing screen formats. Results of applying the model to data entry screens support the use of the model. Also described is a critiquing mechanism embedded in a user interface design environment as a demonstration of this approach. (Author/AEF)

  16. Effects of mammography screening under different screening schedules: Model estimates of potential benefits and harms

    NARCIS (Netherlands)

    J.S. Mandelblatt (Jeanne); K.A. Cronin (Kathleen); S. Bailey (Stephanie); D.A. Berry (Donald); H.J. de Koning (Harry); G. Draisma (Gerrit); H. Huang (Hailiang); S.J. Lee (Stephanie Joi); M.F. Munsell (Mark); S.K. Plevritis (Sylvia); P.M. Ravdin (P.); C.B. Schechter (Clyde); B. Sigal (Bronislava); M.A. Stoto (Michael); N.K. Stout (Natasha); N.T. van Ravesteyn (Nicolien); J. Venier (John); M. Zelen (Marvin); E. Feuer (Eric)

    2009-01-01

    textabstractBackground: Despite trials of mammography and widespread use, optimal screening policy is controversial. Objective: To evaluate U.S. breast cancer screening strategies. Design: 6 models using common data elements. Data Sources: National data on age-specific incidence, competing mortality

  17. [Models of the organization of neonatal screening].

    Science.gov (United States)

    Cassio, A; Piazzi, S; Colli, C; Balsamo, A; Bozza, D; Salardi, S; Sprovieri, G; Cacciari, E

    1994-01-01

    The authors evaluate the different organizational strategies of a congenital hypothyroidism screening program. Positive and negative aspects of laboratory screening tests (TSH only, T4-supplemental TSH, TSH and T4), organization strategies (centralization or decentralization), recall and first follow-up criteria are examined. The authors consider that the necessity for an early diagnostic confirmation can be associated with a precise etiologic diagnosis and an evaluation of the prenatal severity of congenital hypothyroidism factors. Some European and North-American experiences are compared with the activity of a regional Italian screening center.

  18. A Multiscale Model Evaluates Screening for Neoplasia in Barrett's Esophagus.

    Directory of Open Access Journals (Sweden)

    Kit Curtius

    2015-05-01

    Full Text Available Barrett's esophagus (BE patients are routinely screened for high grade dysplasia (HGD and esophageal adenocarcinoma (EAC through endoscopic screening, during which multiple esophageal tissue samples are removed for histological analysis. We propose a computational method called the multistage clonal expansion for EAC (MSCE-EAC screening model that is used for screening BE patients in silico to evaluate the effects of biopsy sampling, diagnostic sensitivity, and treatment on disease burden. Our framework seamlessly integrates relevant cell-level processes during EAC development with a spatial screening process to provide a clinically relevant model for detecting dysplastic and malignant clones within the crypt-structured BE tissue. With this computational approach, we retain spatio-temporal information about small, unobserved tissue lesions in BE that may remain undetected during biopsy-based screening but could be detected with high-resolution imaging. This allows evaluation of the efficacy and sensitivity of current screening protocols to detect neoplasia (dysplasia and early preclinical EAC in the esophageal lining. We demonstrate the clinical utility of this model by predicting three important clinical outcomes: (1 the probability that small cancers are missed during biopsy-based screening, (2 the potential gains in neoplasia detection probabilities if screening occurred via high-resolution tomographic imaging, and (3 the efficacy of ablative treatments that result in the curative depletion of metaplastic and neoplastic cell populations in BE in terms of the long-term impact on reducing EAC incidence.

  19. Economic evaluation of newborn hearing screening: modelling costs and outcomes

    Directory of Open Access Journals (Sweden)

    von Voß, Hubertus

    2003-12-01

    Full Text Available Objectives: The prevalence of newborn hearing disorders is 1-3 per 1,000. Crucial for later outcome are correct diagnosis and effective treatment as soon as possible. With BERA and TEOAE low-risk techniques for early detection are available. Universal screening is recommended but not realised in most European health care systems.Aim of the study was to examine the scientific evidence of newborn hearing screening and a comparison of medical outcome and costs of different programmes, differentiated by type of strategy (risk screening, universal screening, no systematical screening. Methods: In an interdisciplinary health technology assessment project all studies on newborn hearing screening detected in a standardized comprehensive literature search were identified and data on medical outcome, costs, and cost-effectiveness extracted. A Markov model was designed to calculate cost-effectiveness ratios. Results: Economic data were extracted from 20 relevant publications out of 39 publications found. In the model total costs for screening of 100,000 newborns with a time horizon of ten years were calculated: 2.0 Mio.€ for universal screening (U, 1.0 Mio.€ for risk screening (R, and 0.6 Mio.€ for no screening (N. The costs per child detected: 13,395€ (U respectively 6,715€ (R, and 4,125€ (N. At 6 months of life the following percentages of cases are detected: U 72%, R 43%, N 13%. Conclusions: A remarkable small number of economic publications mainly of low methodological quality was found. In our own model we found reasonable cost-effectiveness ratios also for universal screening. Considering the outcome advantages of higher numbers of detected cases a universal newborn hearing screening is recommended.

  20. Chemical genetics and drug screening in Drosophila cancer models

    Institute of Scientific and Technical Information of China (English)

    Mara Gladstone; Tin Tin Su

    2011-01-01

    Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.

  1. Costs and effects of chlamydial screening : Dynamic versus static modeling

    NARCIS (Netherlands)

    Welte, R; Postma, M; Leidl, R; Kretzschmar, M

    2005-01-01

    Objective: The objective of this study was to assess the impact of modeling type on the economic evaluation of screening programs for asymptomatic Chlamydia trachomatis infections. Study: We compared a stochastic network simulation model (dynamic model) with a decision analysis model (static model)

  2. Costs and effects of chlamydial screening : Dynamic versus static modeling

    NARCIS (Netherlands)

    Welte, R; Postma, M; Leidl, R; Kretzschmar, M

    2005-01-01

    Objective: The objective of this study was to assess the impact of modeling type on the economic evaluation of screening programs for asymptomatic Chlamydia trachomatis infections. Study: We compared a stochastic network simulation model (dynamic model) with a decision analysis model (static model)

  3. Modeling of autoresonant control of a parametrically excited screen machine

    Science.gov (United States)

    Abolfazl Zahedi, S.; Babitsky, Vladimir

    2016-10-01

    Modelling of nonlinear dynamic response of a screen machine described by the nonlinear coupled differential equations and excited by the system of autoresonant control is presented. The displacement signal of the screen is fed to the screen excitation directly by means of positive feedback. Negative feedback is used to fix the level of screen amplitude response within the expected range. The screen is anticipated to vibrate with a parametric resonance and the excitation, stabilization and control response of the system are studied in the stable mode. Autoresonant control is thoroughly investigated and output tracking is reported. The control developed provides the possibility of self-tuning and self-adaptation mechanisms that allow the screen machine to maintain a parametric resonant mode of oscillation under a wide range of uncertainty of mass and viscosity.

  4. Screening for prostatic cancer. Investigational models

    DEFF Research Database (Denmark)

    Iversen, P; Torp-Pedersen, S T

    1991-01-01

    Prostatic cancer has a long natural history and a significant preclinical period, during which the disease is detectable. Thus, this common malignancy in males fulfills some of the most important criteria for initiating screening programs. However, the still enigmatic epidemiology also includes...

  5. [Cancer screening in Hungary: World Bank supported model programs].

    Science.gov (United States)

    Bodó, M; Döbrössy, L; Liszka, G; Ottó, S; Péter, Z

    1997-07-13

    Since 1995, a model cancer screening program has been in operation in Hungary, the overall purpose of which is to promote the establishment of effective and efficient screening programs by means of adapting the internationally agreed principles of organized screening to the needs and opportunities in Hungary. The establishment and operation of a national population-based cancer registration system is an other aim of the Program. The model program--financed partly from a loan from the World Bank, partly from local funds provided by the Government of Hungary--is to develop standard procedure for cervical, breast and colorectal screening and to end up with tested recommendations for introduction of organized screening of proved effectiveness, integrated into the health care system, on country-wide service bases in Hungary.

  6. An economic model of adult hearing screening

    Directory of Open Access Journals (Sweden)

    A. Morris

    2011-03-01

    Full Text Available Populations are ageing and older adults make an increasing contribution to society, yet uncorrected hearing loss is common over the age of 50 years, increasing in prevalence and severity with age. The consequences of uncorrected hearing loss can be profound for hearing-impaired individuals and their communication partners but there is evidence that adults commonly delay 10-15 years before seeking help for hearing difficulty (Stephens et al., 1990; Davis et al., 2007 and the most common reason is the belief that their hearing is not bad enough (Ipsos-Mori/RNID survey, 2005. Hearing aids are currently the mainstay of intervention for hearing loss; evidence shows benefit to social functioning and quality of life even for mild hearing loss (Mulrow et al., 1990; Chisolm et al., 2007 and long term outcomes are better when they are obtained early (Davis et al., 2007. Screening adults for hearing loss would expedite intervention and reduce unmet need, leading to improved quality of life for many older adults. Previous work suggests adult hearing screening (AHS should target adults aged 50-65 years, old enough for prevalence to justify screening but young enough to gain from early intervention...

  7. Non-Communicable Disease Preventive Screening by HIV Care Model.

    Science.gov (United States)

    Rhodes, Corinne M; Chang, Yuchiao; Regan, Susan; Triant, Virginia A

    2017-01-01

    The Human Immunodeficiency Virus (HIV) epidemic has evolved, with an increasing non-communicable disease (NCD) burden emerging and need for long-term management, yet there are limited data to help delineate the optimal care model to screen for NCDs for this patient population. The primary aim was to compare rates of NCD preventive screening in persons living with HIV/AIDS (PLWHA) by type of HIV care model, focusing on metabolic/cardiovascular disease (CVD) and cancer screening. We hypothesized that primary care models that included generalists would have higher preventive screening rates. Prospective observational cohort study. Partners HealthCare System (PHS) encompassing Brigham & Women's Hospital, Massachusetts General Hospital, and affiliated community health centers. PLWHA age >18 engaged in active primary care at PHS. HIV care model categorized as infectious disease (ID) providers only, generalist providers only, or ID plus generalist providers. Odds of screening for metabolic/CVD outcomes including hypertension (HTN), obesity, hyperlipidemia (HL), and diabetes (DM) and cancer including colorectal cancer (CRC), cervical cancer, and breast cancer. In a cohort of 1565 PLWHA, distribution by HIV care model was 875 ID (56%), 90 generalists (6%), and 600 ID plus generalists (38%). Patients in the generalist group had lower odds of viral suppression but similar CD4 counts and ART exposure as compared with ID and ID plus generalist groups. In analyses adjusting for sociodemographic and clinical covariates and clustering within provider, there were no significant differences in metabolic/CVD or cancer screening rates among the three HIV care models. There were no notable differences in metabolic/CVD or cancer screening rates by HIV care model after adjusting for sociodemographic and clinical factors. These findings suggest that HIV patients receive similar preventive health care for NCDs independent of HIV care model.

  8. Item Screening in Graphical Loglinear Rasch Models

    DEFF Research Database (Denmark)

    Kreiner, Svend; Christensen, Karl Bang

    2011-01-01

    the initial item analysis may disclose a great deal of spurious and misleading evidence of DIF and local dependence that has to disposed of during the modelling procedure. Like graphical models, graphical loglinear Rasch models possess Markov properties that are useful during the statistical analysis......In behavioural sciences, local dependence and DIF are common, and purification procedures that eliminate items with these weaknesses often result in short scales with poor reliability. Graphical loglinear Rasch models (Kreiner & Christensen, in Statistical Methods for Quality of Life Studies, ed....... by M. Mesbah, F.C. Cole & M.T. Lee, Kluwer Academic, pp. 187–203, 2002) where uniform DIF and uniform local dependence are permitted solve this dilemma by modelling the local dependence and DIF. Identifying loglinear Rasch models by a stepwise model search is often very time consuming, since...

  9. In Vivo RNAi-Based Screens: Studies in Model Organisms

    Directory of Open Access Journals (Sweden)

    Miki Yamamoto-Hino

    2013-11-01

    Full Text Available RNA interference (RNAi is a technique widely used for gene silencing in organisms and cultured cells, and depends on sequence homology between double-stranded RNA (dsRNA and target mRNA molecules. Numerous cell-based genome-wide screens have successfully identified novel genes involved in various biological processes, including signal transduction, cell viability/death, and cell morphology. However, cell-based screens cannot address cellular processes such as development, behavior, and immunity. Drosophila and Caenorhabditis elegans are two model organisms whose whole bodies and individual body parts have been subjected to RNAi-based genome-wide screening. Moreover, Drosophila RNAi allows the manipulation of gene function in a spatiotemporal manner when it is implemented using the Gal4/UAS system. Using this inducible RNAi technique, various large-scale screens have been performed in Drosophila, demonstrating that the method is straightforward and valuable. However, accumulated results reveal that the results of RNAi-based screens have relatively high levels of error, such as false positives and negatives. Here, we review in vivo RNAi screens in Drosophila and the methods that could be used to remove ambiguity from screening results.

  10. Coupled mode parametric resonance in a vibrating screen model

    CERN Document Server

    Slepyan, Leonid I

    2013-01-01

    We consider a simple dynamic model of the vibrating screen operating in the parametric resonance (PR) mode. This model was used in the course of designing and setting of such a screen in LPMC. The PR-based screen compares favorably with conventional types of such machines, where the transverse oscillations are excited directly. It is characterized by larger values of the amplitude and by insensitivity to damping in a rather wide range. The model represents an initially strained system of two equal masses connected by a linearly elastic string. Self-equilibrated, longitudinal, harmonic forces act on the masses. Under certain conditions this results in transverse, finite-amplitude oscillations of the string. The problem is reduced to a system of two ordinary differential equations coupled by the geometric nonlinearity. Damping in both the transverse and longitudinal oscillations is taken into account. Free and forced oscillations of this mass-string system are examined analytically and numerically. The energy e...

  11. A Toy Model of Colour Screening in the Proton

    CERN Document Server

    Dischler, J; Dischler, Johann; Sjöstrand, Torbjörn

    2001-01-01

    In hadronic collisions, the mini-jet cross section is formally divergent in the limit pT -> 0. We argue that this divergence is tamed by some effective colour correlation length scale of the hadron. A toy model of the hadronic structure is introduced, that allows an estimate of the screening effects, and especially their energy dependence.

  12. Optimization Model for Environmental Stress Screening of Electronic Components

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Environmental stress screening (ESS) is a technological process to reduce the costly early field failure ofelectronic components. This paper builds an optimization model for ESS of electronic components to obtain the optimalESS duration. The failure phenomena of ESS are modeled by mix ed distribution, and optimal ESS duration is definedby maximizing life-cycle cost savings under the condition of meeting reliability requirement.

  13. Schwinger boson approach to the fully screened Kondo model.

    Science.gov (United States)

    Rech, J; Coleman, P; Zarand, G; Parcollet, O

    2006-01-13

    We apply the Schwinger boson scheme to the fully screened Kondo model and generalize the method to include antiferromagnetic interactions between ions. Our approach captures the Kondo crossover from local moment behavior to a Fermi liquid with a nontrivial Wilson ratio. When applied to the two-impurity model, the mean-field theory describes the "Varma-Jones" quantum phase transition between a valence bond state and a heavy Fermi liquid.

  14. An Effective Parameter Screening Strategy for High Dimensional Watershed Models

    Science.gov (United States)

    Khare, Y. P.; Martinez, C. J.; Munoz-Carpena, R.

    2014-12-01

    Watershed simulation models can assess the impacts of natural and anthropogenic disturbances on natural systems. These models have become important tools for tackling a range of water resources problems through their implementation in the formulation and evaluation of Best Management Practices, Total Maximum Daily Loads, and Basin Management Action Plans. For accurate applications of watershed models they need to be thoroughly evaluated through global uncertainty and sensitivity analyses (UA/SA). However, due to the high dimensionality of these models such evaluation becomes extremely time- and resource-consuming. Parameter screening, the qualitative separation of important parameters, has been suggested as an essential step before applying rigorous evaluation techniques such as the Sobol' and Fourier Amplitude Sensitivity Test (FAST) methods in the UA/SA framework. The method of elementary effects (EE) (Morris, 1991) is one of the most widely used screening methodologies. Some of the common parameter sampling strategies for EE, e.g. Optimized Trajectories [OT] (Campolongo et al., 2007) and Modified Optimized Trajectories [MOT] (Ruano et al., 2012), suffer from inconsistencies in the generated parameter distributions, infeasible sample generation time, etc. In this work, we have formulated a new parameter sampling strategy - Sampling for Uniformity (SU) - for parameter screening which is based on the principles of the uniformity of the generated parameter distributions and the spread of the parameter sample. A rigorous multi-criteria evaluation (time, distribution, spread and screening efficiency) of OT, MOT, and SU indicated that SU is superior to other sampling strategies. Comparison of the EE-based parameter importance rankings with those of Sobol' helped to quantify the qualitativeness of the EE parameter screening approach, reinforcing the fact that one should use EE only to reduce the resource burden required by FAST/Sobol' analyses but not to replace it.

  15. Unifying Screening Processes Within the PROSPR Consortium: A Conceptual Model for Breast, Cervical, and Colorectal Cancer Screening

    Science.gov (United States)

    Kim, Jane J.; Schapira, Marilyn M.; Tosteson, Anna N. A.; Zauber, Ann G.; Geiger, Ann M.; Kamineni, Aruna; Weaver, Donald L.; Tiro, Jasmin A.

    2015-01-01

    General frameworks of the cancer screening process are available, but none directly compare the process in detail across different organ sites. This limits the ability of medical and public health professionals to develop and evaluate coordinated screening programs that apply resources and population management strategies available for one cancer site to other sites. We present a trans-organ conceptual model that incorporates a single screening episode for breast, cervical, and colorectal cancers into a unified framework based on clinical guidelines and protocols; the model concepts could be expanded to other organ sites. The model covers four types of care in the screening process: risk assessment, detection, diagnosis, and treatment. Interfaces between different provider teams (eg, primary care and specialty care), including communication and transfer of responsibility, may occur when transitioning between types of care. Our model highlights across each organ site similarities and differences in steps, interfaces, and transitions in the screening process and documents the conclusion of a screening episode. This model was developed within the National Cancer Institute–funded consortium Population-based Research Optimizing Screening through Personalized Regimens (PROSPR). PROSPR aims to optimize the screening process for breast, cervical, and colorectal cancer and includes seven research centers and a statistical coordinating center. Given current health care reform initiatives in the United States, this conceptual model can facilitate the development of comprehensive quality metrics for cancer screening and promote trans-organ comparative cancer screening research. PROSPR findings will support the design of interventions that improve screening outcomes across multiple cancer sites. PMID:25957378

  16. An oral multispecies biofilm model for high content screening applications

    Science.gov (United States)

    Kommerein, Nadine; Stumpp, Sascha N.; Müsken, Mathias; Ehlert, Nina; Winkel, Andreas; Häussler, Susanne; Behrens, Peter; Buettner, Falk F. R.; Stiesch, Meike

    2017-01-01

    Peri-implantitis caused by multispecies biofilms is a major complication in dental implant treatment. The bacterial infection surrounding dental implants can lead to bone loss and, in turn, to implant failure. A promising strategy to prevent these common complications is the development of implant surfaces that inhibit biofilm development. A reproducible and easy-to-use biofilm model as a test system for large scale screening of new implant surfaces with putative antibacterial potency is therefore of major importance. In the present study, we developed a highly reproducible in vitro four-species biofilm model consisting of the highly relevant oral bacterial species Streptococcus oralis, Actinomyces naeslundii, Veillonella dispar and Porphyromonas gingivalis. The application of live/dead staining, quantitative real time PCR (qRT-PCR), scanning electron microscopy (SEM) and urea-NaCl fluorescence in situ hybridization (urea-NaCl-FISH) revealed that the four-species biofilm community is robust in terms of biovolume, live/dead distribution and individual species distribution over time. The biofilm community is dominated by S. oralis, followed by V. dispar, A. naeslundii and P. gingivalis. The percentage distribution in this model closely reflects the situation in early native plaques and is therefore well suited as an in vitro model test system. Furthermore, despite its nearly native composition, the multispecies model does not depend on nutrient additives, such as native human saliva or serum, and is an inexpensive, easy to handle and highly reproducible alternative to the available model systems. The 96-well plate format enables high content screening for optimized implant surfaces impeding biofilm formation or the testing of multiple antimicrobial treatment strategies to fight multispecies biofilm infections, both exemplary proven in the manuscript. PMID:28296966

  17. Nonparametric Independence Screening in Sparse Ultra-High Dimensional Additive Models

    CERN Document Server

    Fan, Jianqing; Song, Rui

    2011-01-01

    A variable screening procedure via correlation learning was proposed Fan and Lv (2008) to reduce dimensionality in sparse ultra-high dimensional models. Even when the true model is linear, the marginal regression can be highly nonlinear. To address this issue, we further extend the correlation learning to marginal nonparametric learning. Our nonparametric independence screening is called NIS, a specific member of the sure independence screening. Several closely related variable screening procedures are proposed. Under the nonparametric additive models, it is shown that under some mild technical conditions, the proposed independence screening methods enjoy a sure screening property. The extent to which the dimensionality can be reduced by independence screening is also explicitly quantified. As a methodological extension, an iterative nonparametric independence screening (INIS) is also proposed to enhance the finite sample performance for fitting sparse additive models. The simulation results and a real data a...

  18. Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

    Directory of Open Access Journals (Sweden)

    Siemers Eric R

    2010-04-01

    Full Text Available Abstract Background Alzheimer's Disease (AD affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development. Methods A time-to-event (TTE simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death. Results The base case results indicated increased AD free years (AD-FYs through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90. Conclusions This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.

  19. Towards a Semiotic of Screen Media: Problems in the Use of Linguistic Models.

    Science.gov (United States)

    Corcoran, Farrel

    1981-01-01

    Considers whether linguistic models can be used to examine how information is structured in the screen media. Highlights differences between language and screen media that make the transference difficult. Raises interesting questions about media literacy and whether screen media may have important perceptual and cognitive effects. (JMF)

  20. Screening out irrelevant cell-based models of disease.

    Science.gov (United States)

    Horvath, Peter; Aulner, Nathalie; Bickle, Marc; Davies, Anthony M; Nery, Elaine Del; Ebner, Daniel; Montoya, Maria C; Östling, Päivi; Pietiäinen, Vilja; Price, Leo S; Shorte, Spencer L; Turcatti, Gerardo; von Schantz, Carina; Carragher, Neil O

    2016-11-01

    The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell- and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates.

  1. A Computational model for compressed sensing RNAi cellular screening

    Science.gov (United States)

    2012-01-01

    Background RNA interference (RNAi) becomes an increasingly important and effective genetic tool to study the function of target genes by suppressing specific genes of interest. This system approach helps identify signaling pathways and cellular phase types by tracking intensity and/or morphological changes of cells. The traditional RNAi screening scheme, in which one siRNA is designed to knockdown one specific mRNA target, needs a large library of siRNAs and turns out to be time-consuming and expensive. Results In this paper, we propose a conceptual model, called compressed sensing RNAi (csRNAi), which employs a unique combination of group of small interfering RNAs (siRNAs) to knockdown a much larger size of genes. This strategy is based on the fact that one gene can be partially bound with several small interfering RNAs (siRNAs) and conversely, one siRNA can bind to a few genes with distinct binding affinity. This model constructs a multi-to-multi correspondence between siRNAs and their targets, with siRNAs much fewer than mRNA targets, compared with the conventional scheme. Mathematically this problem involves an underdetermined system of equations (linear or nonlinear), which is ill-posed in general. However, the recently developed compressed sensing (CS) theory can solve this problem. We present a mathematical model to describe the csRNAi system based on both CS theory and biological concerns. To build this model, we first search nucleotide motifs in a target gene set. Then we propose a machine learning based method to find the effective siRNAs with novel features, such as image features and speech features to describe an siRNA sequence. Numerical simulations show that we can reduce the siRNA library to one third of that in the conventional scheme. In addition, the features to describe siRNAs outperform the existing ones substantially. Conclusions This csRNAi system is very promising in saving both time and cost for large-scale RNAi screening experiments which

  2. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    Science.gov (United States)

    Davis, A; Smith, P; Ferguson, M; Stephens, D; Gianopoulos, I

    2007-10-01

    greater benefit through additional years of use/better adaptation to use than those of the same age and hearing impairment who were fitted with hearing aids later. Different screening programmes were modelled. The 35 dB HL better ear average hearing impairment level was found to be a good, robust and justifiable target group for screening and here the most efficient and practicable method was to use two questions in primary care concerning hearing problems and a hearing screen using a pure tone at 3 kHz 35 dB HL. The average cost of the screening programme was 13 pounds per person screened or about 100 pounds if treatment costs were included. Making the conservative assumption that identification gives an extra 9 years using hearing aids, the costs of screening and intervention were in the range of 800-1000 pounds per quality-adjusted life-year when using the Health Utilities Index and about 2500 pounds using the Short Form 6 Dimensions metric. A simple systematic screen, using an audiometric screening instrument, has been shown to be acceptable to people in the age range 55-74 years, is likely to provide substantial benefit and may be cost-effective to those in that target group. Hearing screening appears to meet the National Screening Committee's criteria in most respects, provided screening is targeted at those with at least 35 dB HL better ear average. Based on the research carried out here there is sufficient evidence to support a larger and more definitive study of hearing screening. Further research into who should be referred for and benefit from audiological assessment and provision of hearing aid in a primary care trust setting is needed as is investigation into screening devices and the various aspects of introducing such a programme.

  3. $ND$ and $NB$ systems in quark delocalization color screening model

    CERN Document Server

    Zhao, Lifang; Ping, Jialun

    2016-01-01

    The $ND$ and $NB$ systems with $I=0$ and $1$, $J^{P}=\\frac{1}{2}^{\\pm}$, $\\frac{3}{2}^{\\pm}$, and $\\frac{5}{2}^{\\pm}$ are investigated within the framework of quark delocalization color screening model. The results show that all the positive parity states are unbound. By coupling to the $ND^{*}$ channel, the state $ND$ with $I=0,~J^{P}=\\frac{1}{2}^{-}$ can form a bound state, which can be invoked to explain the observed $\\Sigma(2800)$ state. The mass of the $ND^{*}$ with $I=0,~J^{P}=\\frac{3}{2}^{-}$ is close to that of the reported $\\Lambda_{c}(2940)^{+}$, which indicates that $\\Lambda_{c}(2940)^{+}$ can be explained as a $ND^{*}$ molecular state in QDCSM. Besides, the $\\Delta D^{*}$ with $I=1,~J^{P}=\\frac{5}{2}^{-}$ is also a possible resonance state. The results of the bottom case of $NB$ system are similar to those of the $ND$ system. Searching for these states will be a challenging subject of experiments.

  4. ND and NB systems in quark delocalization color screening model

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Lifang [Nanjing College of Information Technology, Department of Quality-Oriented Education, Nanjing (China); Huang, Hongxia; Ping, Jialun [Nanjing Normal University, Department of Physics, Nanjing (China)

    2017-02-15

    The ND and NB systems with I = 0 and 1, J{sup P} = (1)/(2){sup ±}, (3)/(2){sup ±}, and (5)/(2){sup ±} are investigated within the framework of the quark delocalization color screening model. The results show that all the positive-parity states are unbound. By coupling to the ND* channel, the state ND with I = 0, J{sup P} = (1)/(2){sup -} can form a bound state, which can be invoked to explain the observed Σ(2800) state. The mass of the ND* with I = 0, J{sup P} = (3)/(2){sup -} is close to that of the reported Λ{sub c}(2940){sup +}, which indicates that Λ{sub c}(2940){sup +} can be explained as a ND* molecular state in QDCSM. Besides, the ΔD* with I = 1, J{sup P} = (5)/(2){sup -} is also a possible resonance state. The results of the bottom case of the NB system are similar to those of the ND system. Searching for these states will be a challenging subject of experiments. (orig.)

  5. COSMO-RS-based extractant screening for phenol extraction as model system

    NARCIS (Netherlands)

    Burghoff, B.; Goetheer, E.L.V.; Haan, A.B. de

    2008-01-01

    The focus of this investigation is the development of a fast and reliable extractant screening approach. Phenol extraction is selected as the model process. A quantum chemical conductor-like screening model for real solvents (COSMO-RS) is combined with molecular design considerations. For this purpo

  6. Validation of a model to estimate personalised screening frequency to monitor diabetic retinopathy

    NARCIS (Netherlands)

    Heijden, A.A. van der; Walraven, I.; Riet, E. van 't; Aspelund, T.; Lund, S.H.; Elders, P.; Polak, B.C.P.; Moll, A.C.; Keunen, J.E.E.; Dekker, J.M.; Nijpels, G.

    2014-01-01

    AIMS/HYPOTHESIS: Our study aimed to validate a model to determine a personalised screening frequency for diabetic retinopathy. METHODS: A model calculating a personalised screening interval for monitoring retinopathy based on patients' risk profile was validated using the data of 3,319 type 2 diabet

  7. Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study

    DEFF Research Database (Denmark)

    Jensen, Dorte; Mølsted-Pedersen, Lars; Beck-Nielsen, Henning;

    2003-01-01

    This study was performed to prospectively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators.......This study was performed to prospectively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators....

  8. Comparing benefits from many possible computed tomography lung cancer screening programs: extrapolating from the National Lung Screening Trial using comparative modeling.

    Directory of Open Access Journals (Sweden)

    Pamela M McMahon

    Full Text Available The National Lung Screening Trial (NLST demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking.We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. 'Efficient' (within model programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 'consensus efficient' (identified as efficient across models programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient.Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics.

  9. Echo-based screening of rheumatic heart disease in children: a cost-effectiveness Markov model.

    Science.gov (United States)

    Zachariah, Justin P; Samnaliev, Mihail

    2015-06-01

    To project the cost-effectiveness of population-based echo screening to prevent rheumatic heart disease (RHD) consequences. RHD is a leading cause of cardiovascular mortality and morbidity during adolescence and young adulthood in low- and middle-per capita income settings. Echocardiography-based screening approaches can dramatically expand the number of children identified at risk of progressive RHD. Cost-effectiveness analysis can inform public health agencies and payers about the net economic benefit of such large-scale population-based screening. A Markov model was constructed comparing a no-screen to echo screen approach. The echo screen program was modeled as a 2-staged screen of a cohort of 11-year-old children with initial short screening performed by dedicated technicians and follow-up complete echo by cardiologists. Penicillin RHD prophylaxis was modeled to only reduce rheumatic fever recurrence-related exacerbation. Quality-adjusted life years (QALYs) and societal costs (in 2010 Australian dollars) associated with each approach were estimated. One-way, two-way and probabilistic sensitivity analyses were performed on RHD prevalence and transition probabilities; echocardiography test characteristics; and societal level costs including supplies, transportation, and labor. The incremental costs and QALYs of the screen compared to no screen strategy were -$432 (95% CI = -$1357 to $575) and 0.007 (95% CI = -0.0101 to 0.0237), respectively. The joint probability that the screen was both less costly and more effective exceeded 80%. Sensitivity analyses suggested screen strategy dominance depends mostly on the probability of transitioning out of sub-clinical RHD. Two-stage echo RHD screening and secondary prophylaxis may achieve modestly improved outcomes at lower cost compared to clinical detection and deserves closer attention from health policy stakeholders.

  10. Screening for gestational diabetes mellitus by a model based on risk indicators

    DEFF Research Database (Denmark)

    Jensen, Dorte Møller; Mølsted-Pedersen, Lars; Beck-Nielsen, Henning

    2003-01-01

    OBJECTIVE: This study was performed to prospectively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators. STUDY DESIGN: In a prospective multicenter study with 5235 consecutive pregnant women, diagnostic testing with a 2-hour 75-g oral glucose...... was comparable with universal screening by fasting glucose or a 1-hour 50-g glucose challenge test. Both screening and diagnostic testing could be avoided in two thirds of all pregnant women....

  11. Screening model for nanowire surface-charge sensors in liquid

    DEFF Research Database (Denmark)

    Sørensen, Martin Hedegård; Mortensen, Asger; Brandbyge, Mads

    2007-01-01

    The conductance change of nanowire field-effect transistors is considered a highly sensitive probe for surface charge. However, Debye screening of relevant physiological liquid environments challenge device performance due to competing screening from the ionic liquid and nanowire charge carriers......., and the length of the functionalization molecules. The analytical results are compared to finite-element calculations on a realistic geometry. ©2007 American Institute of Physics........ The authors discuss this effect within Thomas-Fermi and Debye-Hückel theory and derive analytical results for cylindrical wires which can be used to estimate the sensitivity of nanowire surface-charge sensors. They study the interplay between the nanowire radius, the Thomas-Fermi and Debye screening lengths...

  12. Study on conglutination model for fine moist material during screening

    Institute of Scientific and Technical Information of China (English)

    陈惜明; 邓凡政; 赵跃民; 朱红; 高庆宇

    2002-01-01

    All coal preparation in which fine coal is handled depends to some extent on the wettability of coal surface by water. The content of external water in fine moist material plays significant role on screening. This article probed into the causations why fine moist materials adhere to the screen deck on common vibrator in the process of screening. Although the wetting that results from interactions between the coal surface and water molecules that are determined by the composition of coal matrix (interrelated with coal rank) and heterogeneous constituents such as oxygen function groups, mineral impurities and pores have something to do with adhering, we found that the effect of wettability is not the key causation to agglomeration, in other words, water bridges among particles are the key causation to the fine moist materials adhesion. This paper also shows how the capillary adhesive forces forms and how to calculate and measure these forces.

  13. Perspective: On the active site model in computational catalyst screening

    Science.gov (United States)

    Reuter, Karsten; Plaisance, Craig P.; Oberhofer, Harald; Andersen, Mie

    2017-01-01

    First-principles screening approaches exploiting energy trends in surface adsorption represent an unparalleled success story in recent computational catalysis research. Here we argue that our still limited understanding of the structure of active sites is one of the major bottlenecks towards an ever extended and reliable use of such computational screening for catalyst discovery. For low-index transition metal surfaces, the prevalently chosen high-symmetry (terrace and step) sites offered by the nominal bulk-truncated crystal lattice might be justified. For more complex surfaces and composite catalyst materials, computational screening studies will need to actively embrace a considerable uncertainty with respect to what truly are the active sites. By systematically exploring the space of possible active site motifs, such studies might eventually contribute towards a targeted design of optimized sites in future catalysts.

  14. Nonparametric Independence Screening in Sparse Ultra-High Dimensional Additive Models.

    Science.gov (United States)

    Fan, Jianqing; Feng, Yang; Song, Rui

    2011-06-01

    A variable screening procedure via correlation learning was proposed in Fan and Lv (2008) to reduce dimensionality in sparse ultra-high dimensional models. Even when the true model is linear, the marginal regression can be highly nonlinear. To address this issue, we further extend the correlation learning to marginal nonparametric learning. Our nonparametric independence screening is called NIS, a specific member of the sure independence screening. Several closely related variable screening procedures are proposed. Under general nonparametric models, it is shown that under some mild technical conditions, the proposed independence screening methods enjoy a sure screening property. The extent to which the dimensionality can be reduced by independence screening is also explicitly quantified. As a methodological extension, a data-driven thresholding and an iterative nonparametric independence screening (INIS) are also proposed to enhance the finite sample performance for fitting sparse additive models. The simulation results and a real data analysis demonstrate that the proposed procedure works well with moderate sample size and large dimension and performs better than competing methods.

  15. Down Syndrome Health Screening--The Fife Model

    Science.gov (United States)

    Jones, Jill; Hathaway, Dorothy; Gilhooley, Mary; Leech, Amanda; MacLeod, Susan

    2010-01-01

    People with Down syndrome have a greater risk of developing a range of health problems, including cardiac problems, thyroid disorders, sensory impairments, reduced muscle tone (hypotonia) and Alzheimer's disease. Despite this increased risk, regular screening is not typically offered to individuals with Down syndrome. A multidisciplinary health…

  16. Down Syndrome Health Screening--The Fife Model

    Science.gov (United States)

    Jones, Jill; Hathaway, Dorothy; Gilhooley, Mary; Leech, Amanda; MacLeod, Susan

    2010-01-01

    People with Down syndrome have a greater risk of developing a range of health problems, including cardiac problems, thyroid disorders, sensory impairments, reduced muscle tone (hypotonia) and Alzheimer's disease. Despite this increased risk, regular screening is not typically offered to individuals with Down syndrome. A multidisciplinary health…

  17. SCREENING CHEMICALS FOR ESTROGEN RECEPTOR BIOACTIVITY USING A COMPUTATIONAL MODEL

    Science.gov (United States)

    The U.S. Environmental Protection Agency (EPA) is considering the use high-throughput and computational methods for regulatory applications in the Endocrine Disruptor Screening Program (EDSP). To use these new tools for regulatory decision making, computational methods must be a...

  18. Steroidogenesis in vitro : towards relevant models for endocrine disruptor screening

    NARCIS (Netherlands)

    Roelofs, M.J.E.

    2016-01-01

    Starting our search for in vitro alternative methods to screen for steroidogenesis toxicity, we focused on the effects of (suggested) endocrine disrupting compounds (EDCs) on cytochrome P450 17 (CYP17) enzyme activity. CYP17 is responsible for conversion of progestagens to dehydroepiandrosterone (DH

  19. Is prostate cancer screening cost-effective? A microsimulation model of prostate-specific antigen-based screening for British Columbia, Canada.

    Science.gov (United States)

    Pataky, Reka; Gulati, Roman; Etzioni, Ruth; Black, Peter; Chi, Kim N; Coldman, Andrew J; Pickles, Tom; Tyldesley, Scott; Peacock, Stuart

    2014-08-15

    Prostate-specific antigen (PSA) screening for prostate cancer may reduce mortality, but it incurs considerable risk of over diagnosis and potential harm to quality of life. Our objective was to evaluate the cost-effectiveness of PSA screening, with and without adjustment for quality of life, for the British Columbia (BC) population. We adapted an existing natural history model using BC incidence, treatment, cost and mortality patterns. The modeled mortality benefit of screening derives from a stage-shift mechanism, assuming mortality reduction consistent with the European Study of Randomized Screening for Prostate Cancer. The model projected outcomes for 40-year-old men under 14 combinations of screening ages and frequencies. Cost and utility estimates were explored with deterministic sensitivity analysis. The incremental cost-effectiveness of regular screening ranged from $36,300/LYG, for screening every four years from ages 55 to 69 years, to $588,300/LYG, for screening every two years from ages 40 to 74 years. The marginal benefits of increasing screening frequency to 2 years or starting screening at age 40 years were small and came at significant cost. After utility adjustment, all screening strategies resulted in a loss of quality-adjusted life years (QALYs); however, this result was very sensitive to utility estimates. Plausible outcomes under a range of screening strategies inform discussion of prostate cancer screening policy in BC and similar jurisdictions. Screening may be cost-effective, but the sensitivity of results to utility values suggests individual preferences for quality versus quantity of life should be a key consideration.

  20. A Markov Model to Analyze Cost-Effectiveness of Screening for Severe Combined Immunodeficiency (SCID)

    Science.gov (United States)

    Chan, Kee; APRN, Joie Davis; Pai, Sung-Yun; Bonilla, Francisco A.; Puck, Jennifer M; Apkon, Michael

    2011-01-01

    Objective To evaluate the cost-effectiveness of universal neonatal screening for T cell lymphocytopenia in enhancing quality of life and life expectancy for children with severe combined immunodeficiency (SCID). Methods Decision trees were created and analyzed to estimate the cost, life years, and quality adjusted life years (QALYs) across a population when universal screening for lack of T cells is used to detect SCID, as implemented in five states, compared to detection based on recognizing symptoms and signs of disease. Terminal values of each tree limb were derived through Markov models simulating the natural history of three cohorts: unaffected subjects; those-diagnosed with SCID as neonates (early diagnosis); and those diagnosed after becoming symptomatic and arousing clinical suspicion (late diagnosis). Models considered the costs of screening and of care including hematopoietic cell transplantation for affected individuals. Key decision variables were derived from the literature and from a survey of families with children affected by SCID, which was used to describe the clinical history and healthcare utilization for affected subjects. Sensitivity analyses were conducted to explore the influence of these decision variables. Results Over a 70 year time horizon, the average cost per infant was $8.89 without screening and $14.33 with universal screening. The model predicted that universal screening in the U.S. would cost approximately $22.4 million/year with a gain of 880 life years and 802 QALYs. Sensitivity analyses showed that screening test specificity and disease incidence were critical driving forces affecting the incremental cost-effectiveness ratio (ICER). Assuming a SCID incidence of 1/75,000 births and test specificity and sensitivity each at 0.99, screening remained cost-effective up to a maximum cost of $15 per infant screened. Conclusion At our current estimated screening cost of $4.22/infant, universal screening for SCID would be a cost effective

  1. Exploring High Strangeness Dibaryons with the Extended Quark Delocalization and Color Screening Model

    Institute of Scientific and Technical Information of China (English)

    PANG Hou-Rong; PING Jia-Lun; WANG Fan; ZHAO En-Guang

    2004-01-01

    Promising high strangeness dibaryons are studied by the extended quark delocalization and color screening model. It is shown that besides H particle and di-Ω, there might be other dibaryon candidates worth to be searched experimentally such as NΩ.

  2. A screening model for assessing water quality in small, dynamic estuaries

    CSIR Research Space (South Africa)

    Taljaard, Susan

    2017-09-01

    Full Text Available , a design science approach is adopted to develop a screening (box) model for the water quality assessment of South African estuaries. The key design principles are first distilled from literature on the nutrient dynamics and hydro...

  3. Scale model investigations into the insertion loss of screens under the influence of wind

    DEFF Research Database (Denmark)

    Rasmussen, Karsten bo; Arranz, Marta galindo

    1996-01-01

    in the frequency domain. The meteorological data representing the wind conditions have been determined by means of hot-wire anemometry in positions on both sides of the screen as well as directly over the screen. The measured data are compared with calculated results from PE calculations and from an alternative......A hard screen on an absorbing ground is investigated experimentally under the influence of wind. The experimental data are the result of model experiments in a 1:25 scale model within a wind tunnel. The sound propagation is measured using a triggered spark source and averaging on a power basis...

  4. A globally applicable screening model for detecting individuals with undiagnosed diabetes

    DEFF Research Database (Denmark)

    Vistisen, Dorte; Lee, Crystal M Y; Colagiuri, Stephen

    2012-01-01

    Current risk scores for undiagnosed diabetes are additive in structure. We sought to derive a globally applicable screening model based on established non-invasive risk factors for diabetes but with a more flexible structure.......Current risk scores for undiagnosed diabetes are additive in structure. We sought to derive a globally applicable screening model based on established non-invasive risk factors for diabetes but with a more flexible structure....

  5. Evaluating lung cancer screening in China: Implications for eligibility criteria design from a microsimulation modeling approach.

    Science.gov (United States)

    Sheehan, Deirdre F; Criss, Steven D; Gazelle, G Scott; Pandharipande, Pari V; Kong, Chung Yin

    2017-01-01

    More than half of males in China are current smokers and evidence from western countries tells us that an unprecedented number of smoking-attributable deaths will occur as the Chinese population ages. We used the China Lung Cancer Policy Model (LCPM) to simulate effects of computed tomography (CT)-based lung cancer screening in China, comparing the impact of a screening guideline published in 2015 by a Chinese expert group to a version developed for the United States by the U.S. Centers for Medicare & Medicaid Services (CMS). The China LCPM, built using an existing lung cancer microsimulation model, can project population outcomes associated with interventions for smoking-related diseases. After calibrating the model to published Chinese smoking prevalence and lung cancer mortality rates, we simulated screening from 2016 to 2050 based on eligibility criteria from the CMS and Chinese guidelines, which differ by age to begin and end screening, pack-years smoked, and years since quitting. Outcomes included number of screens, mortality reduction, and life-years saved for each strategy. We projected that in the absence of screening, 14.98 million lung cancer deaths would occur between 2016 and 2050. Screening with the CMS guideline would prevent 0.72 million deaths and 5.8 million life-years lost, resulting in 6.58% and 1.97% mortality reduction in males and females, respectively. Screening with the Chinese guideline would prevent 0.74 million deaths and 6.6 million life-years lost, resulting in 6.30% and 2.79% mortality reduction in males and females, respectively. Through 2050, 1.43 billion screens would be required using the Chinese screening strategy, compared to 988 million screens using the CMS guideline. In conclusion, CT-based lung cancer screening implemented in 2016 and based on the Chinese screening guideline would prevent about 20,000 (2.9%) more lung cancer deaths through 2050, but would require about 445 million (44.7%) more screens than the CMS guideline.

  6. Evaluating lung cancer screening in China: Implications for eligibility criteria design from a microsimulation modeling approach

    Science.gov (United States)

    Sheehan, Deirdre F.; Criss, Steven D.; Gazelle, G. Scott; Pandharipande, Pari V.

    2017-01-01

    More than half of males in China are current smokers and evidence from western countries tells us that an unprecedented number of smoking-attributable deaths will occur as the Chinese population ages. We used the China Lung Cancer Policy Model (LCPM) to simulate effects of computed tomography (CT)-based lung cancer screening in China, comparing the impact of a screening guideline published in 2015 by a Chinese expert group to a version developed for the United States by the U.S. Centers for Medicare & Medicaid Services (CMS). The China LCPM, built using an existing lung cancer microsimulation model, can project population outcomes associated with interventions for smoking-related diseases. After calibrating the model to published Chinese smoking prevalence and lung cancer mortality rates, we simulated screening from 2016 to 2050 based on eligibility criteria from the CMS and Chinese guidelines, which differ by age to begin and end screening, pack-years smoked, and years since quitting. Outcomes included number of screens, mortality reduction, and life-years saved for each strategy. We projected that in the absence of screening, 14.98 million lung cancer deaths would occur between 2016 and 2050. Screening with the CMS guideline would prevent 0.72 million deaths and 5.8 million life-years lost, resulting in 6.58% and 1.97% mortality reduction in males and females, respectively. Screening with the Chinese guideline would prevent 0.74 million deaths and 6.6 million life-years lost, resulting in 6.30% and 2.79% mortality reduction in males and females, respectively. Through 2050, 1.43 billion screens would be required using the Chinese screening strategy, compared to 988 million screens using the CMS guideline. In conclusion, CT-based lung cancer screening implemented in 2016 and based on the Chinese screening guideline would prevent about 20,000 (2.9%) more lung cancer deaths through 2050, but would require about 445 million (44.7%) more screens than the CMS guideline

  7. Cost-Effectiveness of a Community Pharmacist-Led Sleep Apnea Screening Program - A Markov Model.

    Directory of Open Access Journals (Sweden)

    Clémence Perraudin

    Full Text Available Despite the high prevalence and major public health ramifications, obstructive sleep apnea syndrome (OSAS remains underdiagnosed. In many developed countries, because community pharmacists (CP are easily accessible, they have been developing additional clinical services that integrate the services of and collaborate with other healthcare providers (general practitioners (GPs, nurses, etc.. Alternative strategies for primary care screening programs for OSAS involving the CP are discussed.To estimate the quality of life, costs, and cost-effectiveness of three screening strategies among patients who are at risk of having moderate to severe OSAS in primary care.Markov decision model.Published data.Hypothetical cohort of 50-year-old male patients with symptoms highly evocative of OSAS.The 5 years after initial evaluation for OSAS.Societal.Screening strategy with CP (CP-GP collaboration, screening strategy without CP (GP alone and no screening.Quality of life, survival and costs for each screening strategy.Under almost all modeled conditions, the involvement of CPs in OSAS screening was cost effective. The maximal incremental cost for "screening strategy with CP" was about 455€ per QALY gained.Our results were robust but primarily sensitive to the treatment costs by continuous positive airway pressure, and the costs of untreated OSAS. The probabilistic sensitivity analysis showed that the "screening strategy with CP" was dominant in 80% of cases. It was more effective and less costly in 47% of cases, and within the cost-effective range (maximum incremental cost effectiveness ratio at €6186.67/QALY in 33% of cases.CP involvement in OSAS screening is a cost-effective strategy. This proposal is consistent with the trend in Europe and the United States to extend the practices and responsibilities of the pharmacist in primary care.

  8. Collaborative modeling of the benefits and harms associated with different U.S. Breast cancer screening strategies

    NARCIS (Netherlands)

    J.S. Mandelblatt (Jeanne); N.K. Stout (Natasha); C.B. Schechter (Clyde); J.J. Van Den Broek (Jeroen J.); D.L. Miglioretti (Diana); M. Krapcho (Martin); A. Trentham-Dietz (Amy); D. Munoz (Diego); S.J. Lee (Sandra J.); D.A. Berry (Donald); N.T. van Ravesteyn (Nicolien); O. Alagoz (Oguzhan); K. Kerlikowske (Karla); A.N.A. Tosteson (Anna N.A.); A.M. Near (Aimee); A. Hoeffken (Amanda); Y. Chang (Yaojen); E.A.M. Heijnsdijk (Eveline); G. Chisholm (Gary); X. Huang (Xuelin); H. Huang (Hailiang); M.A. Ergun (Mehmet Ali); R. Gangnon (Ronald); B.L. Sprague (Brian L.); S. Plevritis (Sylvia); E. Feuer (Eric); H.J. de Koning (Harry); K.A. Cronin (Kathleen)

    2016-01-01

    textabstractBackground: Controversy persists about optimal mammography screening strategies. Objective: To evaluate screening outcomes, taking into account advances in mammography and treatment of breast cancer. Design: Collaboration of 6 simulation models using national data on incidence, digital

  9. Circuit models for Salisbury screens made from unidirectional carbon fiber composite sandwich structures

    Science.gov (United States)

    Riley, Elliot J.; Lenzing, Erik H.; Narayanan, Ram M.

    2016-05-01

    Carbon fiber composite materials have many useful structural material properties. The electromagnetic perfor- mance of these materials is of great interest for future applications. The work presented in this paper deals with the construction of Salisbury screen microwave absorbers made from unidirectional carbon fiber composite sand- wich structures. Specifically, absorbers centered at 7.25 GHz and 12.56 GHz are investigated. Circuit models are created to match the measured performance of the carbon fiber Salisbury screens using a genetic algorithm to extract lumped element circuit values. The screens presented in this paper utilize unidirectional carbon fiber sheets in place of the resistive sheet utilized in the classic Salisbury screen. The theory, models, prototypes, and measurements of these absorbers are discussed.

  10. Validity of "sputtering and re-condensation" model in active screen cage plasma nitriding process

    Science.gov (United States)

    Saeed, A.; Khan, A. W.; Jan, F.; Abrar, M.; Khalid, M.; Zakaullah, M.

    2013-05-01

    The validity of "sputtering and re-condensation" model in active screen plasma nitriding for nitrogen mass transfer mechanism is investigated. The dominant species including NH, Fe-I, N2+, N-I and N2 along with Hα and Hβ lines are observed in the optical emission spectroscopy (OES) analysis. Active screen cage and dc plasma nitriding of AISI 316 stainless steel as function of treatment time is also investigated. The structure and phases composition of the nitrided layer is studied by X-ray diffraction (XRD). Surface morphology is studied by scanning electron microscopy (SEM) and hardness profile is obtained by Vicker's microhardness tester. Increasing trend in microhardness is observed in both cases but the increase in active screen plasma nitriding is about 3 times greater than that achieved by dc plasma nitriding. On the basis of metallurgical and OES observations the use of "sputtering and re-condensation" model in active screen plasma nitriding is tested.

  11. An Efficient Variable Screening Method for Effective Surrogate Models for Reliability-Based Design Optimization

    Science.gov (United States)

    2014-04-01

    reliability-based design optimization ( RBDO ) process, surrogate models are frequently used to reduce the number of simulations because analysis of a...the RBDO problem and thus mitigate the curse of dimensionality. Therefore, it is desirable to develop an efficient and effective variable...screening method for reduction of the dimension of the RBDO problem. In this paper, requirements of the variable screening method for deterministic design

  12. Forecasting Human African Trypanosomiasis Prevalences from Population Screening Data Using Continuous Time Models

    Science.gov (United States)

    Hasker, Epco; Lumbala, Crispin; Lutumba, Pascal; de Vlas, Sake J.; van de Klundert, Joris

    2016-01-01

    To eliminate and eradicate gambiense human African trypanosomiasis (HAT), maximizing the effectiveness of active case finding is of key importance. The progression of the epidemic is largely influenced by the planning of these operations. This paper introduces and analyzes five models for predicting HAT prevalence in a given village based on past observed prevalence levels and past screening activities in that village. Based on the quality of prevalence level predictions in 143 villages in Kwamouth (DRC), and based on the theoretical foundation underlying the models, we consider variants of the Logistic Model—a model inspired by the SIS epidemic model—to be most suitable for predicting HAT prevalence levels. Furthermore, we demonstrate the applicability of this model to predict the effects of planning policies for screening operations. Our analysis yields an analytical expression for the screening frequency required to reach eradication (zero prevalence) and a simple approach for determining the frequency required to reach elimination within a given time frame (one case per 10000). Furthermore, the model predictions suggest that annual screening is only expected to lead to eradication if at least half of the cases are detected during the screening rounds. This paper extends knowledge on control strategies for HAT and serves as a basis for further modeling and optimization studies. PMID:27657937

  13. Spectroscopic diagnostics of active screen plasma nitriding processes: on the interplay of active screen and model probe plasmas

    Science.gov (United States)

    Hamann, S.; Börner, K.; Burlacov, I.; Spies, H.-J.; Röpcke, J.

    2015-09-01

    In a reactor used for active screen plasma nitriding (ASPN) the interplay of two plasma types, (i) the plasma of the cylindrical active screen driven in a pulsed dc mode (f = 1 kHz, 60% duty cycle) and (ii) the plasma at an internal model probe driven in a cw dc mode, ignited in a low pressure H2-N2 gas mixture (p = 3 mbar) containing small amounts of CH4 and CO2 have been studied by tunable diode laser infrared absorption (TDLAS) and optical emission spectroscopy (OES) techniques. Applying in situ TDLAS the evolution of the carbon containing precursors, CH4 and CO2, and of the reaction products, NH3, HCN, CO and H2O, has been monitored. The degree of dissociation of the carbon containing precursor molecules varied between 70% and 92%. The concentrations of the reaction products were found to be in the range 1012…1015 molecules cm-3. By analyzing the development of the molecular concentrations at changes of gas mixtures and plasma power values, it was found that (i) HCN and NH3 are the main products of plasma conversion in the case of methane admixture and (ii) CO, HCN and NH3 in the carbon dioxide case. The fragmentation efficiencies of methane and carbon dioxide (RF(CH4)  ≈  1…2   ×   1015 molecules J-1, RF(CO2)  ≈  0.5…1.0   ×   1016 molecules J-1) and the respective conversion efficiencies to the product molecules (R C(product) ≈ 1013-1015 molecules J-1) have been determined for different gas mixtures and plasma power values, while the influence of probe and screen plasmas, i.e. the phenomena caused by the interplay of both plasma sources, was analyzed. The additional usage of the plasma at the model probe has a sensitive influence on the generation of the reaction products, in particular that of NH3 and HCN. With the help of OES the rotational temperature of the screen plasma could be determined, which increases with power from 770 K to 950 K. Also with power the ionic component of nitrogen molecules, i

  14. Development and verification of a model for estimating the screening utility in the detection of PCBs in transformer oil.

    Science.gov (United States)

    Terakado, Shingo; Glass, Thomas R; Sasaki, Kazuhiro; Ohmura, Naoya

    2014-01-01

    A simple new model for estimating the screening performance (false positive and false negative rates) of a given test for a specific sample population is presented. The model is shown to give good results on a test population, and is used to estimate the performance on a sampled population. Using the model developed in conjunction with regulatory requirements and the relative costs of the confirmatory and screening tests allows evaluation of the screening test's utility in terms of cost savings. Testers can use the methods developed to estimate the utility of a screening program using available screening tests with their own sample populations.

  15. Foam Assisted WAG, Snorre Revisit with New Foam Screening Model

    DEFF Research Database (Denmark)

    Spirov, Pavel; Rudyk, Svetlana Nikolayevna; Khan, Arif

    2012-01-01

    on a complex geological model for quick feasibility studies, either for onward practical pilot or as justification for more detailed technical study. The simulation showed that Foam model is applicable. The mismatch between history and actual GOR in some periods of injection is due to the complexity...... as quick reference for future general foam pilot simulations at field scale....

  16. Including ethical considerations in models for first-trimester screening for pre-eclampsia

    DEFF Research Database (Denmark)

    Jørgensen, Jennifer Maureen; Hedley, Paula L.; Gjerris, Mickey;

    2014-01-01

    Recent efforts to develop reliable and efficient early pregnancy screening programmes for pre-eclampsia have focused on com-bining clinical, biochemical and biophysical markers. The same model has been used for first-trimester screening for fetal aneuploidies i.e. prenatal diagnosis (PD), which...... is routinely offered to all pregnant women in many developed countries. Some studies suggest combining PD and pre-eclampsia screening, so women can be offered testing for a number of conditions at the same clinical visit. A combination of these tests may be practical in terms of saving time and resources......; however, the combination raises ethical issues. First-trimester PD and pre-eclampsia screening entail qualitative differences which alter the requirements for disclosure, non-directedness and consent with regard to the informed consent process. This article explores the differences related to the ethical...

  17. Screening of the meson fields in the Nambu - Jona-Lasinio model

    Energy Technology Data Exchange (ETDEWEB)

    Florkowski, W. [Institute of Nuclear Physics, Cracow (Poland)]|[Gesellschaft fuer Schwerionenforschung mbH, Darmstadt (Germany); Friman, B.L. [Gesellschaft fuer Schwerionenforschung mbH, Darmstadt (Germany)]|[Technische Hochschule Darmstadt (Germany). Inst. fuer Kernphysik

    1993-03-01

    The spatial dependence of the finite-temperature meson correlation function in the (pseudo)scalar channel is studied in the Nambu-Jona-Lasinio model. The screening masses, obtained from the asymptotic behaviour of the static correlation function, are found to differ substantially from the dynamic masses, defined by a pole of the meson propagator. In particular, at high temperatures, the meson screening masses are large, although there are no well defined meson modes. In the high-temperature limit, the screening masses approach 2{pi}T, which corresponds to a gas of non-interacting, massless quarks. However interaction effects remain well beyond the chiral transition temperatures. The overall temperature dependence of the screening masses is in agreement with lattice results. (author). 26 refs, 5 figs.

  18. Maternal serologic screening to prevent congenital toxoplasmosis: a decision-analytic economic model.

    Directory of Open Access Journals (Sweden)

    Eileen Stillwaggon

    2011-09-01

    Full Text Available OBJECTIVE: To determine a cost-minimizing option for congenital toxoplasmosis in the United States. METHODOLOGY/PRINCIPAL FINDINGS: A decision-analytic and cost-minimization model was constructed to compare monthly maternal serological screening, prenatal treatment, and post-natal follow-up and treatment according to the current French (Paris protocol, versus no systematic screening or perinatal treatment. Costs are based on published estimates of lifetime societal costs of developmental disabilities and current diagnostic and treatment costs. Probabilities are based on published results and clinical practice in the United States and France. One- and two-way sensitivity analyses are used to evaluate robustness of results. Universal monthly maternal screening for congenital toxoplasmosis with follow-up and treatment, following the French protocol, is found to be cost-saving, with savings of $620 per child screened. Results are robust to changes in test costs, value of statistical life, seroprevalence in women of childbearing age, fetal loss due to amniocentesis, and to bivariate analysis of test costs and incidence of primary T. gondii infection in pregnancy. Given the parameters in this model and a maternal screening test cost of $12, screening is cost-saving for rates of congenital infection above 1 per 10,000 live births. If universal testing generates economies of scale in diagnostic tools-lowering test costs to about $2 per test-universal screening is cost-saving at rates of congenital infection well below the lowest reported rates in the United States of 1 per 10,000 live births. CONCLUSION/SIGNIFICANCE: Universal screening according to the French protocol is cost saving for the US population within broad parameters for costs and probabilities.

  19. Dynamic ligand-based pharmacophore modeling and virtual screening to identify mycobacterial cyclopropane synthase inhibitors

    Indian Academy of Sciences (India)

    CHINMAYEE CHOUDHURY; U DEVA PRIYAKUMAR; G NARAHARI SASTRY

    2016-05-01

    Multidrug resistance in Mycobacterium tuberculosis (M. Tb) and its coexistence with HIV arethe biggest therapeutic challenges in anti-M. Tb drug discovery. The current study reports a Virtual Screening(VS) strategy to identify potential inhibitors of Mycobacterial cyclopropane synthase (CmaA1), an importantM. Tb target considering the above challenges. Five ligand-based pharmacophore models were generatedfrom 40 different conformations of the cofactors of CmaA1 taken from molecular dynamics (MD) simulationstrajectories of CmaA1. The screening abilities of these models were validated by screening 23 inhibitors and1398 non-inhibitors of CmaA1. A VS protocol was designed with four levels of screening i.e., ligand-basedpharmacophore screening, structure-based pharmacophore screening, docking and absorption, distribution,metabolism, excretion and the toxicity (ADMET) filters. In an attempt towards repurposing the existing drugsto inhibit CmaA1, 6,429 drugs reported in DrugBank were considered for screening. To find compounds thatinhibit multiple targets of M. Tb as well as HIV, we also chose 701 and 11,109 compounds showing activitybelow 1 μM range on M. Tb and HIV cell lines, respectively, collected from ChEMBL database. Thus, a totalof 18,239 compounds were screened against CmaA1, and 12 compounds were identified as potential hits forCmaA1 at the end of the fourth step. Detailed analysis of the structures revealed these compounds to interactwith key active site residues of CmaA1.

  20. A nutritional risk screening model for patients with liver cirrhosis established using discriminant analysis

    Directory of Open Access Journals (Sweden)

    ZHU Binghua

    2017-06-01

    Full Text Available ObjectiveTo establish a nutritional risk screening model for patients with liver cirrhosis using discriminant analysis. MethodsThe clinical data of 273 patients with liver cirrhosis who were admitted to Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from August 2015 to March 2016 were collected. Body height, body weight, upper arm circumference, triceps skinfold thickness, subscapular skinfold thickness, and hand grip strength were measured and recorded, and then body mass index (BMI and upper arm muscle circumference were calculated. Laboratory markers including liver function parameters, renal function parameters, and vitamins were measured. The patients were asked to complete Nutritional Risk Screening 2002 and Malnutrition Universal Screening Tool (MUST, and a self-developed nutritional risk screening pathway was used for nutritional risk classification. Observation scales of the four diagnostic methods in traditional Chinese medicine were used to collect patients′ symptoms and signs. Continuous data were expressed as mean±SD (x±s; an analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Discriminant analysis was used for model establishment, and cross validation was used for model verification. ResultsThe nutritional risk screening pathway for patients with liver cirrhosis was used for the screening of respondents, and there were 49 patients (17.95% in non-risk group, 49 (17.95% in possible-risk group, and 175 (64.10% in risk group. The distance criterion function was used to establish the nutritional risk screening model for patients with liver cirrhosis: D1=-11.885+0.310×BMI+0150×MAC+0.005×P-Alb-0.001×Vit B12+0.103×Vit D-0.89×ascites-0.404×weakness-0.560×hypochondriac pain+0035×dysphoria with feverish sensation (note: if a patient has ascites, weakness, hypochondriac pain

  1. Tailoring Breast Cancer Screening Intervals by Breast Density and Risk for Women Aged 50 Years or Older: Collaborative Modeling of Screening Outcomes.

    Science.gov (United States)

    Trentham-Dietz, Amy; Kerlikowske, Karla; Stout, Natasha K; Miglioretti, Diana L; Schechter, Clyde B; Ergun, Mehmet Ali; van den Broek, Jeroen J; Alagoz, Oguzhan; Sprague, Brian L; van Ravesteyn, Nicolien T; Near, Aimee M; Gangnon, Ronald E; Hampton, John M; Chandler, Young; de Koning, Harry J; Mandelblatt, Jeanne S; Tosteson, Anna N A

    2016-11-15

    Biennial screening is generally recommended for average-risk women aged 50 to 74 years, but tailored screening may provide greater benefits. To estimate outcomes for various screening intervals after age 50 years based on breast density and risk for breast cancer. Collaborative simulation modeling using national incidence, breast density, and screening performance data. United States. Women aged 50 years or older with various combinations of breast density and relative risk (RR) of 1.0, 1.3, 2.0, or 4.0. Annual, biennial, or triennial digital mammography screening from ages 50 to 74 years (vs. no screening) and ages 65 to 74 years (vs. biennial digital mammography from ages 50 to 64 years). Lifetime breast cancer deaths, life expectancy and quality-adjusted life-years (QALYs), false-positive mammograms, benign biopsy results, overdiagnosis, cost-effectiveness, and ratio of false-positive results to breast cancer deaths averted. Screening benefits and overdiagnosis increase with breast density and RR. False-positive mammograms and benign results on biopsy decrease with increasing risk. Among women with fatty breasts or scattered fibroglandular density and an RR of 1.0 or 1.3, breast cancer deaths averted were similar for triennial versus biennial screening for both age groups (50 to 74 years, median of 3.4 to 5.1 vs. 4.1 to 6.5 deaths averted; 65 to 74 years, median of 1.5 to 2.1 vs. 1.8 to 2.6 deaths averted). Breast cancer deaths averted increased with annual versus biennial screening for women aged 50 to 74 years at all levels of breast density and an RR of 4.0, and those aged 65 to 74 years with heterogeneously or extremely dense breasts and an RR of 4.0. However, harms were almost 2-fold higher. Triennial screening for the average-risk subgroup and annual screening for the highest-risk subgroup cost less than $100 000 per QALY gained. Models did not consider women younger than 50 years, those with an RR less than 1, or other imaging methods. Average-risk women

  2. Subtraction of Spurious Centre-of-Mass Motion in Quark Delocalization and Colour Screening Model

    Institute of Scientific and Technical Information of China (English)

    CHEN Ling-Zhi; PANG Hou-Rong; HUANG Hong-Xia; PING Jia-Lun; WANG Fan

    2007-01-01

    The quark delocalization colour screening model provides an alternative approach for the NN intermediate range attraction, which is attributed to the σ meson exchange in the meson exchange and chiral quark model.However the quark delocalization induces the spurious centre-of-mass motion (CMM). A method for subtracting the spurious CMM proposed before is applied to the new scattering calculation. The subtraction of the spurious CMM results in an additional NN attraction. The NN scattering data are refitted by a fine tune of the colour screening constant.

  3. Modelling the cumulative risk of a false-positive screening test.

    Science.gov (United States)

    Hubbard, Rebecca A; Miglioretti, Diana L; Smith, Robert A

    2010-10-01

    The goal of a screening test is to reduce morbidity and mortality through the early detection of disease; but the benefits of screening must be weighed against potential harms, such as false-positive (FP) results, which may lead to increased healthcare costs, patient anxiety, and other adverse outcomes associated with diagnostic follow-up procedures. Accurate estimation of the cumulative risk of an FP test after multiple screening rounds is important for program evaluation and goal setting, as well as informing individuals undergoing screening what they should expect from testing over time. Estimation of the cumulative FP risk is complicated by the existence of censoring and possible dependence of the censoring time on the event history. Current statistical methods for estimating the cumulative FP risk from censored data follow two distinct approaches, either conditioning on the number of screening tests observed or marginalizing over this random variable. We review these current methods, identify their limitations and possibly unrealistic assumptions, and propose simple extensions to address some of these limitations. We discuss areas where additional extensions may be useful. We illustrate methods for estimating the cumulative FP recall risk of screening mammography and investigate the appropriateness of modelling assumptions using 13 years of data collected by the Breast Cancer Surveillance Consortium (BCSC). In the BCSC data we found evidence of violations of modelling assumptions of both classes of statistical methods. The estimated risk of an FP recall after 10 screening mammograms varied between 58% and 77% depending on the approach used, with an estimate of 63% based on what we feel are the most reasonable modelling assumptions.

  4. Foam Assisted WAG, Snorre Revisit with New Foam Screening Model

    DEFF Research Database (Denmark)

    Spirov, Pavel; Rudyk, Svetlana Nikolayevna; Khan, Arif

    2012-01-01

    This study deals with simulation model of Foam Assisted Water Alternating Gas (FAWAG) method that had been implemented to two Norwegian Reservoirs. Being studied on number of pilot projects, the method proved successful, but Field Scale simulation was never understood properly. New phenomenologic...

  5. Detecting acromegaly: screening for disease with a morphable model.

    Science.gov (United States)

    Learned-Miller, Erik; Lu, Qifeng; Paisley, Angela; Trainer, Peter; Blanz, Volker; Dedden, Katrin; Miller, Ralph

    2006-01-01

    Acromegaly is a rare disorder which affects about 50 of every million people. The disease typically causes swelling of the hands, feet, and face, and eventually permanent changes to areas such as the jaw, brow ridge, and cheek bones. The disease is often missed by physicians and progresses beyond where it might if it were identified and treated earlier. We consider a semi-automated approach to detecting acromegaly, using a novel combination of support vector machines (SVMs) and a morphable model. Our training set consists of 24 frontal photographs of acromegalic patients and 25 of disease-free subjects. We modelled each subject's face in an analysis-by-synthesis loop using the three-dimensional morphable face model of Blanz and Vetter. The model parameters capture many features of the 3D shape of the subject's head from just a single photograph, and are used directly for classification. We report encouraging results of a classifier built from the training set of real human subjects.

  6. The impact of syphilis screening among female sex workers in China: a modelling study.

    Directory of Open Access Journals (Sweden)

    Kate M Mitchell

    Full Text Available BACKGROUND: In China, female sex workers (FSWs are at high risk of syphilis infection, but are hard to reach for interventions. Point-of-care testing introduces opportunities for expanding syphilis control measures. Modelling is used to estimate the impact of using rapid tests to screen FSWs for syphilis. In other settings, modelling has predicted large rebounds in infectious syphilis following screening, which may undermine any impact achieved. METHODS: A deterministic syphilis transmission model among FSWs and clients was fitted to data from Yunnan Province (FSW syphilis prevalence = 7.5%, and used to estimate the impact of rapid syphilis testing and treatment for FSWs. Impact projections were compared for different model structures that included risk heterogeneity amongst FSWs, incoming syphilis infections amongst new FSWs and clients and re-infection from FSWs' regular non-commercial partners. The rebound in syphilis prevalence after screening ceased was explored. RESULTS: All model structures suggest yearly syphilis screening could substantially reduce (by 72-88% syphilis prevalence amongst FSWs in this setting over five years. However, incoming syphilis infections amongst new FSWs and clients or re-infections from regular non-commercial partners of FSWs can considerably reduce (>30% the proportion of infections averted. Including heterogeneity in risk amongst FSWs had little effect upon the proportion of infections averted. In this setting, the rebound in syphilis prevalence after screening ceased is predicted to be slight, but it could be large in high prevalence settings. CONCLUSIONS: Rapid test screening could dramatically reduce syphilis prevalence amongst hard-to-reach groups, but strategies to reduce re-infection from regular non-commercial partners are needed to maximise impact.

  7. The Impact of Syphilis Screening among Female Sex Workers in China: A Modelling Study

    Science.gov (United States)

    Mitchell, Kate M.; Cox, Andrew P.; Mabey, David; Tucker, Joseph D.; Peeling, Rosanna W.; Vickerman, Peter

    2013-01-01

    Background In China, female sex workers (FSWs) are at high risk of syphilis infection, but are hard to reach for interventions. Point-of-care testing introduces opportunities for expanding syphilis control measures. Modelling is used to estimate the impact of using rapid tests to screen FSWs for syphilis. In other settings, modelling has predicted large rebounds in infectious syphilis following screening, which may undermine any impact achieved. Methods A deterministic syphilis transmission model among FSWs and clients was fitted to data from Yunnan Province (FSW syphilis prevalence = 7.5%), and used to estimate the impact of rapid syphilis testing and treatment for FSWs. Impact projections were compared for different model structures that included risk heterogeneity amongst FSWs, incoming syphilis infections amongst new FSWs and clients and re-infection from FSWs' regular non-commercial partners. The rebound in syphilis prevalence after screening ceased was explored. Results All model structures suggest yearly syphilis screening could substantially reduce (by 72–88%) syphilis prevalence amongst FSWs in this setting over five years. However, incoming syphilis infections amongst new FSWs and clients or re-infections from regular non-commercial partners of FSWs can considerably reduce (>30%) the proportion of infections averted. Including heterogeneity in risk amongst FSWs had little effect upon the proportion of infections averted. In this setting, the rebound in syphilis prevalence after screening ceased is predicted to be slight, but it could be large in high prevalence settings. Conclusions Rapid test screening could dramatically reduce syphilis prevalence amongst hard-to-reach groups, but strategies to reduce re-infection from regular non-commercial partners are needed to maximise impact. PMID:23383249

  8. Cost Effectiveness of Screening Colonoscopy Depends on Adequate Bowel Preparation Rates – A Modeling Study

    Science.gov (United States)

    Kingsley, James; Karanth, Siddharth; Revere, Frances Lee

    2016-01-01

    Background Inadequate bowel preparation during screening colonoscopy necessitates repeating colonoscopy. Studies suggest inadequate bowel preparation rates of 20–60%. This increases the cost of colonoscopy for our society. Aim The aim of this study is to determine the impact of inadequate bowel preparation rate on the cost effectiveness of colonoscopy compared to other screening strategies for colorectal cancer (CRC). Methods A microsimulation model of CRC screening strategies for the general population at average risk for CRC. The strategies include fecal immunochemistry test (FIT) every year, colonoscopy every ten years, sigmoidoscopy every five years, or stool DNA test every 3 years. The screening could be performed at private practice offices, outpatient hospitals, and ambulatory surgical centers. Results At the current assumed inadequate bowel preparation rate of 25%, the cost of colonoscopy as a screening strategy is above society’s willingness to pay (<$50,000/QALY). Threshold analysis demonstrated that an inadequate bowel preparation rate of 13% or less is necessary before colonoscopy is considered more cost effective than FIT. At inadequate bowel preparation rates of 25%, colonoscopy is still more cost effective compared to sigmoidoscopy and stool DNA test. Sensitivity analysis of all inputs adjusted by ±10% showed incremental cost effectiveness ratio values were influenced most by the specificity, adherence, and sensitivity of FIT and colonoscopy. Conclusions Screening colonoscopy is not a cost effective strategy when compared with fecal immunochemical test, as long as the inadequate bowel preparation rate is greater than 13%. PMID:27936028

  9. Utilizing high throughput screening data for predictive toxicology models: protocols and application to MLSCN assays

    Science.gov (United States)

    Guha, Rajarshi; Schürer, Stephan C.

    2008-06-01

    Computational toxicology is emerging as an encouraging alternative to experimental testing. The Molecular Libraries Screening Center Network (MLSCN) as part of the NIH Molecular Libraries Roadmap has recently started generating large and diverse screening datasets, which are publicly available in PubChem. In this report, we investigate various aspects of developing computational models to predict cell toxicity based on cell proliferation screening data generated in the MLSCN. By capturing feature-based information in those datasets, such predictive models would be useful in evaluating cell-based screening results in general (for example from reporter assays) and could be used as an aid to identify and eliminate potentially undesired compounds. Specifically we present the results of random forest ensemble models developed using different cell proliferation datasets and highlight protocols to take into account their extremely imbalanced nature. Depending on the nature of the datasets and the descriptors employed we were able to achieve percentage correct classification rates between 70% and 85% on the prediction set, though the accuracy rate dropped significantly when the models were applied to in vivo data. In this context we also compare the MLSCN cell proliferation results with animal acute toxicity data to investigate to what extent animal toxicity can be correlated and potentially predicted by proliferation results. Finally, we present a visualization technique that allows one to compare a new dataset to the training set of the models to decide whether the new dataset may be reliably predicted.

  10. Modelling Goldmann applanation tonometry to improve accuracy of glaucoma screening

    CSIR Research Space (South Africa)

    Botha, N

    2012-10-01

    Full Text Available of visual field ? CSIR 2012 Slide 4 How is glaucoma diagnosed? Glaucoma management? ?Most common treatment is to lower the IOP ?Three methods: ?Medical therapy ?Laser therapy ?Surgery INTRAOCULAR PRESSURE IS IMPORTANT Williams, S.E.I., 2007... Slide 11 Minimise the root mean square error: Fixed: ?C1 = 0.004 MPa ?D1 = 0.4 Bryant, M.R. & McDonnell, P.J., 1996. Constitutive Law s for Biomechanical Modeling of Refractive Surgery. Journal of Biomechanical Engineering, 118(4), pp.473...

  11. Application of multimedia models for screening assessment of long-range transport potential and overall persistence.

    NARCIS (Netherlands)

    Klasmeier, Jörg; Matthies, Michael; Macleod, Matthew; Fenner, Kathrin; Scheringer, Martin; Stroebe, Maximilian; Gall, Anne Christine le; McKone, Thomas; Meent, Dik van de; Wania, Frank

    2006-01-01

    We propose a multimedia model-based methodology to evaluate whether a chemical substance qualifies as POP-like based on overall persistence (Pov) and potential for long-range transport (LRTP). It relies upon screening chemicals against the Pov and LRTP characteristics of selected reference chemicals

  12. Using the Cascade Model to Improve Antenatal Screening for the Hemoglobin Disorders

    Science.gov (United States)

    Gould, Dinah; Papadopoulos, Irena; Kelly, Daniel

    2012-01-01

    Introduction: The inherited hemoglobin disorders constitute a major public health problem. Facilitators (experienced hemoglobin counselors) were trained to deliver knowledge and skills to "frontline" practitioners to enable them to support parents during antenatal screening via a cascade (train-the-trainer) model. Objectives of…

  13. Using the Cascade Model to Improve Antenatal Screening for the Hemoglobin Disorders

    Science.gov (United States)

    Gould, Dinah; Papadopoulos, Irena; Kelly, Daniel

    2012-01-01

    Introduction: The inherited hemoglobin disorders constitute a major public health problem. Facilitators (experienced hemoglobin counselors) were trained to deliver knowledge and skills to "frontline" practitioners to enable them to support parents during antenatal screening via a cascade (train-the-trainer) model. Objectives of evaluation were to…

  14. Nucleon-Nucleon Phase Shifts in the Extended Quark-Delocalization Colour-Screening Model

    Institute of Scientific and Technical Information of China (English)

    LU Xi-Feng; PING Jia-Lun; WANG Fan

    2003-01-01

    An alternative method is applied to the study of nucleon-nucleon scattering phase shifts within the framework of the extended quark demoralization colour-screening model, in which the one-pion exchange with short-range cutoff is included.

  15. PLASMA PROTEIN PROFILING AS A HIGH THROUGHPUT TOOL FOR CHEMICAL SCREENING USING A SMALL FISH MODEL

    Science.gov (United States)

    Hudson, R. Tod, Michael J. Hemmer, Kimberly A. Salinas, Sherry S. Wilkinson, James Watts, James T. Winstead, Peggy S. Harris, Amy Kirkpatrick and Calvin C. Walker. In press. Plasma Protein Profiling as a High Throughput Tool for Chemical Screening Using a Small Fish Model (Abstra...

  16. Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies: Modeling Study for the US Preventive Services Task Force.

    Science.gov (United States)

    Knudsen, Amy B; Zauber, Ann G; Rutter, Carolyn M; Naber, Steffie K; Doria-Rose, V Paul; Pabiniak, Chester; Johanson, Colden; Fischer, Sara E; Lansdorp-Vogelaar, Iris; Kuntz, Karen M

    2016-06-21

    The US Preventive Services Task Force (USPSTF) is updating its 2008 colorectal cancer (CRC) screening recommendations. To inform the USPSTF by modeling the benefits, burden, and harms of CRC screening strategies; estimating the optimal ages to begin and end screening; and identifying a set of model-recommendable strategies that provide similar life-years gained (LYG) and a comparable balance between LYG and screening burden. Comparative modeling with 3 microsimulation models of a hypothetical cohort of previously unscreened US 40-year-olds with no prior CRC diagnosis. Screening with sensitive guaiac-based fecal occult blood testing, fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy with or without stool testing, computed tomographic colonography (CTC), or colonoscopy starting at age 45, 50, or 55 years and ending at age 75, 80, or 85 years. Screening intervals varied by modality. Full adherence for all strategies was assumed. Life-years gained compared with no screening (benefit), lifetime number of colonoscopies required (burden), lifetime number of colonoscopy complications (harms), and ratios of incremental burden and benefit (efficiency ratios) per 1000 40-year-olds. The screening strategies provided LYG in the range of 152 to 313 per 1000 40-year-olds. Lifetime colonoscopy burden per 1000 persons ranged from fewer than 900 (FIT every 3 years from ages 55-75 years) to more than 7500 (colonoscopy screening every 5 years from ages 45-85 years). Harm from screening was at most 23 complications per 1000 persons screened. Strategies with screening beginning at age 50 years generally provided more LYG as well as more additional LYG per additional colonoscopy than strategies with screening beginning at age 55 years. There were limited empirical data to support a start age of 45 years. For persons adequately screened up to age 75 years, additional screening yielded small increases in LYG relative to the increase in colonoscopy

  17. Screening for a Chronic Disease: A Multiple Stage Duration Model with Partial Observability.

    Science.gov (United States)

    Mroz, Thomas A; Picone, Gabriel; Sloan, Frank; Yashkin, Arseniy P

    2016-08-01

    We estimate a dynamic multi-stage duration model to investigate how early detection of diabetes can delay the onset of lower extremity complications and death. We allow for partial observability of the disease stage, unmeasured heterogeneity, and endogenous timing of diabetes screening. Timely diagnosis appears important. We evaluate the effectiveness of two potential policies to reduce the monetary costs of frequent screening in terms of lost longevity. Compared to the status quo, the more restrictive policy yields an implicit value for an additional year of life of about $50,000, while the less restrictive policy implies a value of about $120,000.

  18. Screening Masses of Hot SU(2) Gauge Theory from the 3D Adjoint Higgs Model

    CERN Document Server

    Karsch, Frithjof; Petreczky, P

    1999-01-01

    We study the Landau gauge propagators of the lattice SU(2) 3d adjoint Higgs model, considered as an effective theory of high temperature 4d SU(2) gauge theory. From the long distance behaviour of the propagators we extract the screening masses. It is shown that the pole masses extracted from the propagators agree well with the screening masses obtained recently in finite temperature SU(2) theory. The relation of the propagator masses to the masses extracted from gauge invariant correlators is also discussed. In so-called lambda gauges non-perturbative evidence is given for the gauge independence of pole masses within this class of gauges.

  19. Dynamics based pharmacophore models for screening potential inhibitors of mycobacterial cyclopropane synthase.

    Science.gov (United States)

    Choudhury, Chinmayee; Priyakumar, U Deva; Sastry, G Narahari

    2015-04-27

    The therapeutic challenges in the treatment of tuberculosis demand multidisciplinary approaches for the identification of potential drug targets as well as fast and accurate techniques to screen huge chemical libraries. Mycobacterial cyclopropane synthase (CmaA1) has been shown to be essential for the survival of the bacteria due to its critical role in the synthesis of mycolic acids. The present study proposes pharmacophore models based on the structure of CmaA1 taking into account its various states in the cyclopropanation process, and their dynamic nature as assessed using molecular dynamics (MD) simulations. The qualities of these pharmacophore models were validated by mapping 23 molecules that have been previously reported to exhibit inhibitory activities on CmaA1. Additionally, 1398 compounds that have been shown to be inactive for tuberculosis were collected from the ChEMBL database and were screened against the models for validation. The models were further validated by comparing the results from pharmacophore mapping with the results obtained from docking these molecules with the respective protein structures. The best models are suggested by validating all the models based on their screening abilities and by comparing with docking results. The models generated from the MD trajectories were found to perform better than the one generated based on the crystal structure demonstrating the importance of incorporating receptor flexibility in drug design.

  20. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    CERN Document Server

    Nato, A Q J

    2003-01-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for approx 45% of families with multiple breast carcinomas and for approx 80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms whi...

  1. Breast cancer screening behaviors among Korean American immigrant women: findings from the Health Belief Model.

    Science.gov (United States)

    Lee, Hee Yun; Stange, Mia Ju; Ahluwalia, Jasjit S

    2015-11-01

    This study examined the utilization of clinical breast examinations (CBEs) and mammograms among Korean American immigrant women and investigated how the six constructs of Health Belief Model (HBM) are associated with the receipt of breast cancer screening. Using a quota sampling strategy, 202 Korean American immigrant women were recruited in metropolitan areas in the northeastern United States. Approximately 64% of the participants reported having had at least one CBE in their lifetime, and about 81% of the sample had undergone at least one mammogram in their lifetime. Women who perceived themselves to be susceptible to breast cancer were more likely to have undergone a CBE, and women who had lower barriers to screening or demonstrated a higher level of confidence were more likely than their counterparts to undergo a mammogram. Findings suggest that HBM constructs such as susceptibility, barriers, and confidence should be considered when designing interventions aimed at promoting breast cancer screening.

  2. Nonparametric Independence Screening in Sparse Ultra-High Dimensional Varying Coefficient Models.

    Science.gov (United States)

    Fan, Jianqing; Ma, Yunbei; Dai, Wei

    2014-01-01

    The varying-coefficient model is an important class of nonparametric statistical model that allows us to examine how the effects of covariates vary with exposure variables. When the number of covariates is large, the issue of variable selection arises. In this paper, we propose and investigate marginal nonparametric screening methods to screen variables in sparse ultra-high dimensional varying-coefficient models. The proposed nonparametric independence screening (NIS) selects variables by ranking a measure of the nonparametric marginal contributions of each covariate given the exposure variable. The sure independent screening property is established under some mild technical conditions when the dimensionality is of nonpolynomial order, and the dimensionality reduction of NIS is quantified. To enhance the practical utility and finite sample performance, two data-driven iterative NIS methods are proposed for selecting thresholding parameters and variables: conditional permutation and greedy methods, resulting in Conditional-INIS and Greedy-INIS. The effectiveness and flexibility of the proposed methods are further illustrated by simulation studies and real data applications.

  3. A prediction model for advanced colorectal neoplasia in an asymptomatic screening population.

    Science.gov (United States)

    Hong, Sung Noh; Son, Hee Jung; Choi, Sun Kyu; Chang, Dong Kyung; Kim, Young-Ho; Jung, Sin-Ho; Rhee, Poong-Lyul

    2017-01-01

    An electronic medical record (EMR) database of a large unselected population who received screening colonoscopies may minimize sampling error and represent real-world estimates of risk for screening target lesions of advanced colorectal neoplasia (CRN). Our aim was to develop and validate a prediction model for assessing the probability of advanced CRN using a clinical data warehouse. A total of 49,450 screenees underwent their first colonoscopy as part of a health check-up from 2002 to 2012 at Samsung Medical Center, and the dataset was constructed by means of natural language processing from the computerized EMR system. The screenees were randomized into training and validation sets. The prediction model was developed using logistic regression. The model performance was validated and compared with existing models using area under receiver operating curve (AUC) analysis. In the training set, age, gender, smoking duration, drinking frequency, and aspirin use were identified as independent predictors for advanced CRN (adjusted P < .01). The developed model had good discrimination (AUC = 0.726) and was internally validated (AUC = 0.713). The high-risk group had a 3.7-fold increased risk of advanced CRN compared to the low-risk group (1.1% vs. 4.0%, P < .001). The discrimination performance of the present model for high-risk patients with advanced CRN was better than that of the Asia-Pacific Colorectal Screening score (AUC = 0.678, P < .001) and Schroy's CAN index (AUC = 0.672, P < .001). The present 5-item risk model can be calculated readily using a simple questionnaire and can identify the low- and high-risk groups of advanced CRN at the first screening colonoscopy. This model may increase colorectal cancer risk awareness and assist healthcare providers in encouraging the high-risk group to undergo a colonoscopy.

  4. A fitness screening model for increasing fitness assessment and research experiences in undergraduate exercise science students.

    Science.gov (United States)

    Brown, Gregory A; Lynott, Frank; Heelan, Kate A

    2008-09-01

    When students analyze and present original data they have collected, and hence have a cultivated sense of curiosity about the data, student learning is enhanced. It is often difficult to provide students an opportunity to practice their skills, use their knowledge, and gain research experiences during a typical course laboratory. This article describes a model of an out-of-classroom experience during which undergraduate exercise science students provide a free health and fitness screening to the campus community. Although some evidence of the effectiveness of this experience is presented, this is not a detailed evaluation of either the service or learning benefits of the fitness screening. Working in small learning groups in the classroom, students develop hypotheses about the health and fitness of the population to be screened. Then, as part of the health and fitness screening, participants are evaluated for muscular strength, aerobic fitness, body composition, blood pressure, physical activity, and blood cholesterol levels. Students then analyze the data collected during the screening, accept or reject their hypotheses based on statistical analyses of the data, and make in-class presentations of their findings. This learning experience has been used successfully to illustrate the levels of obesity, hypercholesterolemia, and lack of physical fitness in the campus community as well as provide an opportunity for students to use statistical procedures to analyze data. It has also provided students with an opportunity to practice fitness assessment and interpersonal skills that will enhance their future careers.

  5. Stem cells: a model for screening, discovery and development of drugs

    Directory of Open Access Journals (Sweden)

    Kitambi SS

    2011-09-01

    Full Text Available Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.Keywords: therapeutics, stem cells, cancer stem cells, screening models, drug development, high throughput screening

  6. The cost-effectiveness of neonatal screening for Cystic Fibrosis: an analysis of alternative scenarios using a decision model

    Directory of Open Access Journals (Sweden)

    Tu Karen

    2005-08-01

    Full Text Available Abstract Background The use of neonatal screening for cystic fibrosis is widely debated in the United Kingdom and elsewhere, but the evidence available to inform policy is limited. This paper explores the cost-effectiveness of adding screening for cystic fibrosis to an existing routine neonatal screening programme for congenital hypothyroidism and phenylketonuria, under alternative scenarios and assumptions. Methods The study is based on a decision model comparing screening to no screening in terms of a number of outcome measures, including diagnosis of cystic fibrosis, life-time treatment costs, life years and QALYs gained. The setting is a hypothetical UK health region without an existing neonatal screening programme for cystic fibrosis. Results Under initial assumptions, neonatal screening (using an immunoreactive trypsin/DNA two stage screening protocol costs £5,387 per infant diagnosed, or £1.83 per infant screened (1998 costs. Neonatal screening for cystic fibrosis produces an incremental cost-effectiveness of £6,864 per QALY gained, in our base case scenario (an assumed benefit of a 6 month delay in the emergence of symptoms. A difference of 11 months or more in the emergence of symptoms (and mean survival means neonatal screening is both less costly and produces better outcomes than no screening. Conclusion Neonatal screening is expensive as a method of diagnosis. Neonatal screening may be a cost-effective intervention if the hypothesised delays in the onset of symptoms are confirmed. Implementing both antenatal and neonatal screening would undermine potential economic benefits, since a reduction in the birth incidence of cystic fibrosis would reduce the cost-effectiveness of neonatal screening.

  7. Assessments of cognitive abilities in a mouse model of Parkinson's disease with a touch screen test.

    Science.gov (United States)

    Kwak, Chuljung; Lim, Chae-Seok; Kaang, Bong-Kiun

    2016-03-15

    Patients with Parkinson's disease (PD) experience both motor output deficits and cognitive disabilities. Various PD rodent models have been developed to investigate the genetic and brain circuit-related causes of PD and have contributed to the basic and clinical research and to therapeutic strategies for this disease. Most studies using PD rodent models have focused on the motor output deficits, rather than cognitive disabilities due to the lack of appropriate testing tools that do not require significant motor abilities. In this study, we assessed the cognitive disabilities of PD model mice using a touch screen test that required only little motor ability. We found that the PD model mice, which had motor deficits caused by unilateral striatal dopaminergic degeneration, successfully underwent operant conditioning with a touch screen test. Additionally, we found that the PD model mice demonstrated impaired location discrimination, but intact attention and reversal learning in the cognitive tests. Therefore, the touch screen test is useful for assessing hidden cognitive disabilities in disease model animals with decreased motor function.

  8. Formalize clinical processes into electronic health information systems: Modelling a screening service for diabetic retinopathy.

    Science.gov (United States)

    Eguzkiza, Aitor; Trigo, Jesús Daniel; Martínez-Espronceda, Miguel; Serrano, Luis; Andonegui, José

    2015-08-01

    Most healthcare services use information and communication technologies to reduce and redistribute the workload associated with follow-up of chronic conditions. However, the lack of normalization of the information handled in and exchanged between such services hinders the scalability and extendibility. The use of medical standards for modelling and exchanging information, especially dual-model based approaches, can enhance the features of screening services. Hence, the approach of this paper is twofold. First, this article presents a generic methodology to model patient-centered clinical processes. Second, a proof of concept of the proposed methodology was conducted within the diabetic retinopathy (DR) screening service of the Health Service of Navarre (Spain) in compliance with a specific dual-model norm (openEHR). As a result, a set of elements required for deploying a model-driven DR screening service has been established, namely: clinical concepts, archetypes, termsets, templates, guideline definition rules, and user interface definitions. This model fosters reusability, because those elements are available to be downloaded and integrated in any healthcare service, and interoperability, since from then on such services can share information seamlessly.

  9. Which strategies reduce breast cancer mortality most? Collaborative modeling of optimal screening, treatment, and obesity prevention.

    Science.gov (United States)

    Mandelblatt, Jeanne; van Ravesteyn, Nicolien; Schechter, Clyde; Chang, Yaojen; Huang, An-Tsun; Near, Aimee M; de Koning, Harry; Jemal, Ahmedin

    2013-07-15

    US breast cancer mortality is declining, but thousands of women still die each year. Two established simulation models examine 6 strategies that include increased screening and/or treatment or elimination of obesity versus continuation of current patterns. The models use common national data on incidence and obesity prevalence, competing causes of death, mammography characteristics, treatment effects, and survival/cure. Parameters are modified based on obesity (defined as BMI  ≥  30 kg/m(2) ). Outcomes are presented for the year 2025 among women aged 25+ and include numbers of cases, deaths, mammograms and false-positives; age-adjusted incidence and mortality; breast cancer mortality reduction and deaths averted; and probability of dying of breast cancer. If current patterns continue, the models project that there would be about 50,100-57,400 (range across models) annual breast cancer deaths in 2025. If 90% of women were screened annually from ages 40 to 54 and biennially from ages 55 to 99 (or death), then 5100-6100 fewer deaths would occur versus current patterns, but incidence, mammograms, and false-positives would increase. If all women received the indicated systemic treatment (with no screening change), then 11,400-14,500 more deaths would be averted versus current patterns, but increased toxicity could occur. If 100% received screening plus indicated therapy, there would be 18,100-20,400 fewer deaths. Eliminating obesity yields 3300-5700 fewer breast cancer deaths versus continuation of current obesity levels. Maximal reductions in breast cancer deaths could be achieved through optimizing treatment use, followed by increasing screening use and obesity prevention. © 2013 American Cancer Society.

  10. Cost savings from a teledentistry model for school dental screening: an Australian health system perspective.

    Science.gov (United States)

    Estai, Mohamed; Bunt, Stuart; Kanagasingam, Yogesan; Tennant, Marc

    2017-06-05

    Objective The aim of the present study was to compare the costs of teledentistry and traditional dental screening approaches in Australian school children.Methods A cost-minimisation analysis was performed from the perspective of the oral health system, comparing the cost of dental screening in school children using a traditional visual examination approach with the cost of mid-level dental practitioners (MLDPs), such as dental therapists, screening the same cohort of children remotely using teledentistry. A model was developed to simulate the costs (over a 12-month period) of the two models of dental screening for all school children (2.7million children) aged 5-14 years across all Australian states and territories. The fixed costs and the variable costs, including staff salary, travel and accommodation costs, and cost of supply were calculated. All costs are given in Australian dollars.Results The total estimated cost of the teledentistry model was $50million. The fixed cost of teledentistry was $1million and that of staff salaries (tele-assistants, charters and their supervisors, as well as information technology support was estimated to be $49million. The estimated staff salary saved with the teledentistry model was $56million, and the estimated travel allowance and supply expenses avoided were $16million and $14million respectively; an annual reduction of $85million in total.Conclusions The present study shows that the teledentistry model of dental screening can minimise costs. The estimated savings were due primarily to the low salaries of dental therapists and the avoidance of travel and accommodation costs. Such savings could be redistributed to improve infrastructure and oral health services in rural or other underserved areas.What is known about the topic? Caries is a preventable disease, which, if it remains untreated, can cause significant morbidity requiring costly treatment. Regular dental screening and oral health education have the great potential

  11. Double screening

    Energy Technology Data Exchange (ETDEWEB)

    Gratia, Pierre [Department of Physics, University of Chicago,South Ellis Avenue, Chicago, IL 60637 (United States); Hu, Wayne [Department of Astronomy and Astrophysics, University of Chicago,South Ellis Avenue, Chicago, IL 60637 (United States); Enrico Fermi Institute and Kavli Institute for Cosmological Physics, University of Chicago,South Ellis Avenue, Chicago, IL 60637 (United States); Joyce, Austin [Enrico Fermi Institute and Kavli Institute for Cosmological Physics, University of Chicago,South Ellis Avenue, Chicago, IL 60637 (United States); Ribeiro, Raquel H. [School of Physics and Astronomy, Queen Mary University of London,Mile End Road, London, E1 4NS (United Kingdom)

    2016-06-15

    Attempts to modify gravity in the infrared typically require a screening mechanism to ensure consistency with local tests of gravity. These screening mechanisms fit into three broad classes; we investigate theories which are capable of exhibiting more than one type of screening. Specifically, we focus on a simple model which exhibits both Vainshtein and kinetic screening. We point out that due to the two characteristic length scales in the problem, the type of screening that dominates depends on the mass of the sourcing object, allowing for different phenomenology at different scales. We consider embedding this double screening phenomenology in a broader cosmological scenario and show that the simplest examples that exhibit double screening are radiatively stable.

  12. A simple model for screening the local impacts of atmospheric ammonia.

    Science.gov (United States)

    Theobald, M R; Bealey, W J; Tang, Y S; Vallejo, A; Sutton, M A

    2009-11-15

    The dry deposition of ammonia from the atmosphere to the surface can lead to eutrophication of sensitive ecosystems and acidification of the soil. A large proportion of the ammonia emitted from agricultural sources can be deposited within a few kilometres and, therefore, impacts of ammonia dry deposition often occur near to the source. To assess these impacts, short-range atmospheric dispersion models are often applied to simulate the emission, dispersion and deposition of ammonia. However, these models can be time-consuming to run and often require detailed input data and, therefore, for multiple assessments it is useful to have a method of screening to discard scenarios where impacts are expected to be negligible. The SCAIL model (Simple Calculation of Ammonia Impact Limits) has been developed for this purpose. SCAIL estimates the atmospheric concentration and dry deposition at the nearest edge of a sensitive ecosystem (receptor) downwind of an ammonia source. These estimates are calculated based on simple meteorological data, the emission rate of the source, land cover type and distance to the receptor. Analysis of the model predictions showed that uncertainty in the model input data leads to an uncertainty in concentration and dry deposition estimates of 25-30% and 40-45% respectively. Detailed atmospheric dispersion models will also have similar uncertainties since they use similar types of input data. Comparison of the concentration predictions with previous measurements made around eight farms showed that the model significantly underestimated concentrations although the model performance was similar to existing screening techniques. The measurement dataset was used to calibrate the SCAIL model which subsequently performed better, using independent verification data, than existing models calibrated in a similar way. The benefits of the SCAIL model are already being seen in the UK, where it is used to screen farms for potential impacts on statutory nature

  13. A screening tool for delineating subregions of steady recharge within groundwater models

    Science.gov (United States)

    Dickinson, Jesse E.; Ferré, T. P. A.; Bakker, Mark; Crompton, Becky

    2014-01-01

    We have developed a screening method for simplifying groundwater models by delineating areas within the domain that can be represented using steady-state groundwater recharge. The screening method is based on an analytical solution for the damping of sinusoidal infiltration variations in homogeneous soils in the vadose zone. The damping depth is defined as the depth at which the flux variation damps to 5% of the variation at the land surface. Groundwater recharge may be considered steady where the damping depth is above the depth of the water table. The analytical solution approximates the vadose zone diffusivity as constant, and we evaluated when this approximation is reasonable. We evaluated the analytical solution through comparison of the damping depth computed by the analytic solution with the damping depth simulated by a numerical model that allows variable diffusivity. This comparison showed that the screening method conservatively identifies areas of steady recharge and is more accurate when water content and diffusivity are nearly constant. Nomograms of the damping factor (the ratio of the flux amplitude at any depth to the amplitude at the land surface) and the damping depth were constructed for clay and sand for periodic variations between 1 and 365 d and flux means and amplitudes from nearly 0 to 1 × 10−3 m d−1. We applied the screening tool to Central Valley, California, to identify areas of steady recharge. A MATLAB script was developed to compute the damping factor for any soil and any sinusoidal flux variation.

  14. Methodological considerations for economic modelling of latent tuberculous infection screening in migrants.

    Science.gov (United States)

    Shedrawy, J; Siroka, A; Oxlade, O; Matteelli, A; Lönnroth, K

    2017-09-01

    Tuberculosis (TB) in migrants from endemic to low-incidence countries results mainly from the reactivation of latent tuberculous infection (LTBI). LTBI screening policies for migrants vary greatly between countries, and the evidence on the cost-effectiveness of the different approaches is weak and heterogeneous. The aim of this review was to assess the methodology used in published economic evaluations of LTBI screening among migrants to identify critical methodological options that must be considered when using modelling to determine value for money from different economic perspectives. Three electronic databases were searched and 10 articles were included. There was considerable variation across this small number of studies with regard to economic perspective, main outcomes, modelling technique, screening options and target populations considered, as well as in parameterisation of the epidemiological situation, test accuracy, efficacy, safety and programme performance. Only one study adopted a societal perspective; others adopted a health care or wider government perspective. Parameters representing the cascade of screening and treating LTBI varied widely, with some studies using highly aspirational scenarios. This review emphasises the need for a more harmonised approach for economic analysis, and better transparency in how policy options and economic perspectives influence methodological choices. Variability is justifiable for some parameters. However, sufficient data are available to standardise others. A societal perspective is ideal, but can be challenging due to limited data. Assumptions about programme performance should be based on empirical data or at least realistic assumptions. Results should be interpreted within specific contexts and policy options, with cautious generalisations.

  15. Applying a stage model of behavior change to colon cancer screening.

    Science.gov (United States)

    Costanza, Mary E; Luckmann, Roger; Stoddard, Anne M; Avrunin, Jill S; White, Mary Jo; Stark, Jennifer R; Clemow, Lynn; Rosal, Milagros C

    2005-01-01

    There has been limited use of stages of change models in characterizing colorectal cancer (CRC) screening. We assess the applicability of the Precaution Adoption Model (PAPM) by determining the distribution of stages of adoption and by elucidating differences among stages. The study is based on 1394 responses (69%) to a survey mailed in 2002 to patients in a primary care population. Survey measures included: self-reported CRC screening, sociodemographic characteristics, health system characteristics, attitudes and beliefs about CRC screening, perceived vulnerability to CRC, and worry about CRC. The main outcome was PAPM stage of adoption of CRC screening based on the ACS preferred guidelines: colonoscopy every 10 years alone or the combination annual FOBT plus sigmoidoscopy every 5 years. 57% were up-to-date with at least one test; 36% were up-to-date with the ACS preferred guidelines; provider recommendation, positive family history of CRC, and positive decisional balance score were significantly associated with higher compared to lower PAPM stages. The combination of PAPM stage assignment and other factors provides useful information for designing tailored interventions. There are special challenges in developing and interpreting PAPM stage assignments when a guideline offers multiple pathways to adherence and recommends a combination of two tests as a preferred option.

  16. A larval zebrafish model of bipolar disorder as a screening platform for neuro-therapeutics.

    Science.gov (United States)

    Ellis, Lee David; Soanes, Kelly Howard

    2012-08-01

    Modelling neurological diseases has proven extraordinarily difficult due to the phenotypic complexity of each disorder. The zebrafish has become a useful model system with which to study abnormal neurological and behavioural activity and holds promise as a model of human disease. While most of the disease modelling using zebrafish has made use of adults, larvae hold tremendous promise for the high-throughput screening of potential therapeutics. The further development of larval disease models will strengthen their ability to contribute to the drug screening process. Here we have used zebrafish larvae to model the symptoms of bipolar disorder by treating larvae with sub-convulsive concentrations of the GABA antagonist pentylenetetrazol (PTZ). A number of therapeutics that act on different targets, in addition to those that have been used to treat bipolar disorder, were tested against this model to assess its predictive value. Carbamazepine, valproic acid, baclofen and honokiol, were found to oppose various aspects of the PTZ-induced changes in activity. Lidocaine and haloperidol exacerbated the PTZ-induced activity changes and sulpiride had no effect. By comparing the degree of phenotypic rescue with the mechanism of action of each therapeutic we have shown that the low-concentration PTZ model can produce a number of intermediate phenotypes that model symptoms of bipolar disorder, may be useful in modelling other disease states, and will help predict the efficacy of novel therapeutics.

  17. Adaptive Gaussian mixture models for pre-screening in GPR data

    Science.gov (United States)

    Torrione, Peter; Morton, Kenneth, Jr.; Besaw, Lance E.

    2011-06-01

    Due to the large amount of data generated by vehicle-mounted ground penetrating radar (GPR) antennae arrays, advanced feature extraction and classification can only be performed on a small subset of data during real-time operation. As a result, most GPR based landmine detection systems implement "pre-screening" algorithms to processes all of the data generated by the antennae array and identify locations with anomalous signatures for more advanced processing. These pre-screening algorithms must be computationally efficient and obtain high probability of detection, but can permit a false alarm rate which might be higher than the total system requirements. Many approaches to prescreening have previously been proposed, including linear prediction coefficients, the LMS algorithm, and CFAR-based approaches. Similar pre-screening techniques have also been developed in the field of video processing to identify anomalous behavior or anomalous objects. One such algorithm, an online k-means approximation to an adaptive Gaussian mixture model (GMM), is particularly well-suited to application for pre-screening in GPR data due to its computational efficiency, non-linear nature, and relevance of the logic underlying the algorithm to GPR processing. In this work we explore the application of an adaptive GMM-based approach for anomaly detection from the video processing literature to pre-screening in GPR data. Results with the ARA Nemesis landmine detection system demonstrate significant pre-screening performance improvements compared to alternative approaches, and indicate that the proposed algorithm is a complimentary technique to existing methods.

  18. Tribolium castaneum as a model for high-throughput RNAi screening.

    Science.gov (United States)

    Knorr, Eileen; Bingsohn, Linda; Kanost, Michael R; Vilcinskas, Andreas

    2013-01-01

    Coleopteran insects are a highly diverse and successful order, and many beetle species are significant agricultural pests. New biorational strategies for managing populations of beetles and other insect species are needed as pests develop resistance to chemical insecticides and Bt toxins. There is now an opportunity to use genome sequence data to identify genes that are essential for insect growth, development, or survival as new targets for designing control technology. This goal requires a method for high-throughput in vivo screening of thousands of genes to identify candidate genes that, when their expression is disrupted, have a phenotype that may be useful in insect pest control. Tribolium castaneum, the red flour beetle, is a model organism that offers considerable advantages for such screening, including ease of rearing in large numbers, a sequenced genome, and a strong, systemic RNAi response for specific depletion of gene transcripts. The RNAi effect in T. castaneum can be elicited in any tissue and any stage by the injection of dsRNA into the hemocoel, and injection of dsRNA into adult females can even be used to identify phenotypes in offspring. A pilot RNAi screen (iBeetle) is underway. Several T. castaneum genes with promising RNAi phenotypes for further development as mechanisms for plant protection have been identified. These include heat shock protein 90, chitin synthase, the segmentation gene hairy, and a matrix metalloprotease. Candidate genes identified in T. castaneum screens can then be tested in agricultural pest species (in which screening is not feasible), to evaluate their effectiveness for use in potential plant-based RNAi control strategies. Delivery of dsRNA expressed by genetically modified crops to the midgut of phytophagous insects is under investigation as a new tool for very specific protection of plants from insect pest species. The T. castaneum screening platform offers a system for discovery of candidate genes with high potential

  19. Performance Evaluation Test of the Orbit Screen Model 68A and the Komplet Model 48-25 Rock Crusher

    Science.gov (United States)

    2008-08-01

    screen and on a Komplet Italia , s.r.l., Model 48-25 rock crusher. The test was conducted during August 2008 at a U.S. Army test site in central... Italia , s.r.l., Model 48-25 Rock Crusher.......................................................... 2 2.3 ASV SR-80 Rubber-Tracked Skid-Steer Loader... Italia , s.r.l., Rock Crusher Testing ......................................................................... 16 5.1 Crushing Performance Test

  20. Application of screening model for assessing subsurface NAPL contamination and remediation

    Energy Technology Data Exchange (ETDEWEB)

    MacFarlane, S.; Shiu, W.Y. [Univ. of Toronto, Ontario (Canada); Mackay, D. [Trent Univ., Peterborough, Ontario (Canada)

    1997-12-31

    To select the most appropriate technique for remediating non-aqueous phase liquids (NAPL)-contaminated sites a full understanding is required of the characteristics of the site, the contaminant, and the effectiveness of the remedial measure. A screening model has been developed (MacFarlane and Mackay, in press) for evaluating the partitioning of components of NAPLs present in the subsurface environment and for providing order of magnitude estimates of the effectiveness, in terms of recovery time, of a variety of remedial technologies including water and solvent flushing, air and steam stripping, and enhanced degradation. The model calculations employ the fugacity concept which is found to simplify and clarify the calculations. Two types of calculations are employed in the screening assessment. Level 1 fugacity calculations are simple multimedia equilibrium calculations that deduce how a chemical partitions between media or phases in a defined environment. Level 2 fugacity calculations account for or quantify losses of chemical being conveyed out of the environment by advective flows in phases such as air or water or by degradation by chemical or biochemical reactions. The screening model was originally applied to an existing fractured bedrock site in Smithville, Ontario which is contaminated with a NAPL containing polychlorinated biphenyls, trichlorobenzene, and trichloroethylene. In this paper, the model approach is illustrated for vinyl chloride which may be present at the site due to biochemical reactions occurring in the subsurface. It is their aim to show that this approach can provide screening level insights into the behavior and remediation of NAPLs and can serve as a first step and justification towards more detailed modeling.

  1. Evaluation of a risk factor scoring model in screening for undiagnosed diabetes in China population

    Institute of Scientific and Technical Information of China (English)

    Jian-jun DONG; Neng-jun LOU; Jia-jun ZHAO; Zhong-wen ZHANG; Lu-lu QIU; Ying ZHOU; Lin LIAO

    2011-01-01

    Objective:To develop a risk scoring model for screening for undiagnosed type 2 diabetes in Chinese population.Methods:A total of 5348 subjects from two districts of Jinan City,Shandong Province,China were enrolled.Group A (2985) included individuals from east of the city and Group B (2363) from west of the city.Screening questionnaires and a standard oral glucose tolerance test (OGTr) were completed by all subjects.Based on the stepwise logistic regression analysis of Group A,variables were selected to establish the risk scoring model.The validity and effectiveness of this model were evaluated in Group B.Results:Based on stepwise logistic regression analysis performed with data of Group A,variables including age,body mass index (BMI),waist-to-hip ratio (WHR),systolic pressure,diastolic pressure,heart rate,family history of diabetes,and history of high glucose were accepted into the risk scoring model.The risk for having diabetes increased along with aggregate scores.When Youden index was closest to 1,the optimal cutoff value was set up at 51.At this point,the diabetes risk scoring model could identify diabetes patients with a sensitivity of 83.3% and a specificity of 66.5%,making the positive predictive value 12.83%and negative predictive value 98.53%.We compared our model with the Finnish and Danish model and concluded that our model has superior validity in Chinese population.Conclusions:Our diabetes risk scoring model has satisfactory sensitivity and specificity for identifying undiagnosed diabetes in our population,which might be a simple and practical tool suitable for massive diabetes screening.

  2. PBT assessment and prioritization by PBT Index and consensus modeling: comparison of screening results from structural models.

    Science.gov (United States)

    Gramatica, Paola; Cassani, Stefano; Sangion, Alessandro

    2015-04-01

    The limited availability of comprehensive data for Persistence, Bioaccumulation and Toxicity (PBT) of chemicals is a serious hindrance to the assignment of compounds to the categories of PBT and vPvB; REACH regulation requires authorization for the use of such chemicals, and additionally plans for safer alternatives. In the context of screening and priority-setting tools for PBT-assessment, the cumulative PBT Index model, implemented in QSARINS (QSAR-INSUBRIA), new software tool for the development and validation of multiple linear regression QSAR models, offers a new holistic approach for the identification of chemicals with cumulative PBT properties directly from their molecular structure. In this study the Insubria PBT Index in QSARINS is applied to the screening and prioritization of various data sets, containing a large variety of chemicals of heterogeneous molecular structure, previously screened by various authors by different methods, for their potential PBT behavior. Particular attention is devoted to the model Applicability Domain, using different approaches such as Descriptor Range, Leverage, and Principal Component Analysis (PCA) of the modeling molecular descriptors, in order to discriminate between interpolated and extrapolated predictions. The results of this screening, which is based only on the molecular structure features and is not dependent on single threshold values for P, B and T, are compared with those obtained by the on-line US-EPA PBT Profiler. Good agreement between the various approaches is found, supporting the utility of a consensus approach in priority-setting studies. The main discrepancies are highlighted and commented on. Moreover, a priority list containing the most hazardous compounds identified in agreement between the two tools is drafted. The PBT Index, implemented in QSARINS, which was demonstrated to be a practical, precautionary and reliable screening tool for PBT-behavior directly from the molecular structure, can be

  3. Ion-biomolecule collisions studied within the independent atom model including geometric screening corrections

    Science.gov (United States)

    Lüdde, H. J.; Achenbach, A.; Kalkbrenner, T.; Jankowiak, H. C.; Kirchner, T.

    2016-05-01

    A recently introduced model to account for geometric screening corrections in an independent-atom-model description of ion-molecule collisions is applied to proton collisions from amino acids and DNA and RNA nucleobases. The correction coefficients are obtained from using a pixel counting method (PCM) for the exact calculation of the effective cross sectional area that emerges when the molecular cross section is pictured as a structure of (overlapping) atomic cross sections. This structure varies with the relative orientation of the molecule with respect to the projectile beam direction and, accordingly, orientation-independent total cross sections are obtained from averaging the pixel count over many orientations. We present net capture and net ionization cross sections over wide ranges of impact energy and analyze the strength of the screening effect by comparing the PCM results with Bragg additivity rule cross sections and with experimental data where available. Work supported by NSERC, Canada.

  4. Generic Screening Models for Assessing Exposures to the Public and ICRP Reference Animals and Plants

    Energy Technology Data Exchange (ETDEWEB)

    Yankovich, Tamara L.; Proehl, Gerhard; Telleria, Diego [International Atomic Energy Agency, P.O. Box 100, 1400 Vienna (Austria); Berkovskyy, Volodymyr [Ukrainian Radiation Protection Institute (RPI), 53, Melnikova Street, 04050, Kiev (Ukraine)

    2014-07-01

    With the update of the IAEA Fundamental Safety Principles (SF-1) stating the objective to protect people and the environment from harmful effects of ionizing radiation, it has been necessary to update International Basic Safety Standards (BSS) on Radiation Protection and Safety of Radiation Sources and the underlying safety guides and technical documents to provide guidance on how this could be achieved in practice. The current paper provides an update on the status and plans to revise the IAEA Safety Report 'Generic Models for Use in Assessing the Impact of Discharges of Radioactive Substances to the Environment' (SRS 19) that was published in 2001. The models of SRS 19 (2001), which was focused on assessment of exposures to the public, is being expanded into three volumes that provide methodologies for screening assessments for the public, as well as for flora and fauna. The revised SRS 19 guide will ultimately facilitate the application of screening models for different levels of assessment using updated parameter values from database that have been developed as part of the IAEA's EMRAS (Environmental Modelling for Radiation Safety) and EMRAS II international model validation programmes. The scope of the revised SRS 19 covers prospective screening assessment of doses to the representative person and Reference Animals and Plants (RAPs), and will provide simple and robust assessment methods for radiological assessment related to planning and design, applying a graded approach. Tabulated screening coefficients and environmental dilution factors will be included for 825 radionuclides. The screening coefficients are developed assuming equilibrium conditions; they can be used to assess radiological impacts arising from routine discharges of radionuclides to terrestrial and aquatic receptors for planned exposure situations. Volumes 1 and 2 of the revised SRS 19 are at an advanced stage of completion and are focused on 'Screening Assessment of Public

  5. Measurement and Monte Carlo modeling of the spatial response of scintillation screens

    Energy Technology Data Exchange (ETDEWEB)

    Pistrui-Maximean, S.A. [CNDRI (NDT using Ionizing Radiation) Laboratory, INSA-Lyon, 69621 Villeurbanne (France)], E-mail: spistrui@gmail.com; Letang, J.M. [CNDRI (NDT using Ionizing Radiation) Laboratory, INSA-Lyon, 69621 Villeurbanne (France)], E-mail: jean-michel.letang@insa-lyon.fr; Freud, N. [CNDRI (NDT using Ionizing Radiation) Laboratory, INSA-Lyon, 69621 Villeurbanne (France); Koch, A. [Thales Electron Devices, 38430 Moirans (France); Walenta, A.H. [Detectors and Electronics Department, FB Physik, Siegen University, 57068 Siegen (Germany); Montarou, G. [Corpuscular Physics Laboratory, Blaise Pascal University, 63177 Aubiere (France); Babot, D. [CNDRI (NDT using Ionizing Radiation) Laboratory, INSA-Lyon, 69621 Villeurbanne (France)

    2007-11-01

    In this article, we propose a detailed protocol to carry out measurements of the spatial response of scintillation screens and to assess the agreement with simulated results. The experimental measurements have been carried out using a practical implementation of the slit method. A Monte Carlo simulation model of scintillator screens, implemented with the toolkit Geant4, has been used to study the influence of the acquisition setup parameters and to compare with the experimental results. An algorithm of global stochastic optimization based on a localized random search method has been implemented to adjust the optical parameters (optical scattering and absorption coefficients). The algorithm has been tested for different X-ray tube voltages (40, 70 and 100 kV). A satisfactory convergence between the results simulated with the optimized model and the experimental measurements is obtained.

  6. Impact of template choice on homology model efficiency in virtual screening.

    Science.gov (United States)

    Rataj, Krzysztof; Witek, Jagna; Mordalski, Stefan; Kosciolek, Tomasz; Bojarski, Andrzej J

    2014-06-23

    Homology modeling is a reliable method of predicting the three-dimensional structures of proteins that lack NMR or X-ray crystallographic data. It employs the assumption that a structural resemblance exists between closely related proteins. Despite the availability of many crystal structures of possible templates, only the closest ones are chosen for homology modeling purposes. To validate the aforementioned approach, we performed homology modeling of four serotonin receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R) for virtual screening purposes, using 10 available G-Protein Coupled Receptors (GPCR) templates with diverse evolutionary distances to the targets, with various approaches to alignment construction and model building. The resulting models were further validated in two steps by means of ligand docking and enrichment calculation, using Glide software. The final quality of the models was determined in virtual screening-like experiments by the AUROC score of the resulting ROC curves. The outcome of this research showed that no correlation between sequence identity and model quality was found, leading to the conclusion that the closest phylogenetic relative is not always the best template for homology modeling.

  7. Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non-invasive prenatal testing.

    Science.gov (United States)

    Maxwell, Susannah; O'Leary, Peter; Dickinson, Jan E; Suthers, Graeme K

    2017-08-01

    Contingent screening for trisomy 21 using non-invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21. To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non-invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut-offs from a public health system perspective. Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non-invasive prenatal testing screening models and compared these to conventional screening, offering women with a high-risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut-offs. High-risk women were offered invasive testing. Intermediate-risk women were offered non-invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis. The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309-66 686. The number of diagnoses and cost per diagnosis increased as the intermediate-risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non-invasive prenatal testing. Contingent non-invasive prenatal testing models using more sensitive combined first trimester screening risk cut-offs than conventional screening improved the detection rate of trisomy 21, reduced procedure-related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening. © 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  8. 3D models of epithelial-mesenchymal transition in breast cancer metastasis: high-throughput screening assay development, validation, and pilot screen.

    Science.gov (United States)

    Li, Qun; Chen, Chaoyu; Kapadia, Amit; Zhou, Qiong; Harper, Mary Kay; Schaack, Jerome; LaBarbera, Daniel V

    2011-02-01

    Despite advancements in therapies developed for the treatment of cancer, patient prognosis and mortality rates have improved minimally, and metastasis remains the primary cause of cancer mortality worldwide. An underlying mechanism promoting metastasis in many types of cancer is epithelial-mesenchymal transition (EMT). Here the authors report a novel 3D model of EMT and metastatic breast cancer suitable for high-throughput screening (HTS) drug discovery. The primary assay incorporates the expression of the prognostic biomarker vimentin, as a luciferase reporter of EMT, in basil-like/triple-negative MDA-MB-231 breast carcinoma spheroids. Using this model, the authors developed a number of known antitumor agents as control modulators of EMT. U0126, PKC412, PF2341066, dasatinib, and axitinib downregulated vimentin expression by 70% to 90% as compared to untreated spheroids. Counterassays were developed to measure spheroid viability and the invasive potential of MDA-MB-231 spheroids after small-molecule treatment and used to confirm hits from primary screening. Finally, the authors conducted a pilot screen to validate this model for HTS using a purified library of marine secondary metabolites. From 230 compounds screened, they obtained a Z' score of 0.64, indicative of an excellent assay, and confirmed 4 hits, including isonaamidine B, papuamine, mycalolide E, and jaspamide. This HTS model demonstrates the potential to identify small-molecule modulators of EMT that could be used to discover novel antimetastatic agents for the treatment of cancer.

  9. A semiparametric censoring bias model for estimating the cumulative risk of a false-positive screening test under dependent censoring.

    Science.gov (United States)

    Hubbard, Rebecca A; Miglioretti, Diana L

    2013-03-01

    False-positive test results are among the most common harms of screening tests and may lead to more invasive and expensive diagnostic testing procedures. Estimating the cumulative risk of a false-positive screening test result after repeat screening rounds is, therefore, important for evaluating potential screening regimens. Existing estimators of the cumulative false-positive risk are limited by strong assumptions about censoring mechanisms and parametric assumptions about variation in risk across screening rounds. To address these limitations, we propose a semiparametric censoring bias model for cumulative false-positive risk that allows for dependent censoring without specifying a fixed functional form for variation in risk across screening rounds. Simulation studies demonstrated that the censoring bias model performs similarly to existing models under independent censoring and can largely eliminate bias under dependent censoring. We used the existing and newly proposed models to estimate the cumulative false-positive risk and variation in risk as a function of baseline age and family history of breast cancer after 10 years of annual screening mammography using data from the Breast Cancer Surveillance Consortium. Ignoring potential dependent censoring in this context leads to underestimation of the cumulative risk of false-positive results. Models that provide accurate estimates under dependent censoring are critical for providing appropriate information for evaluating screening tests.

  10. [Screening, Brief Intervention, Referral to Treatment(SBIRT) model for alcohol use disorder in Japan].

    Science.gov (United States)

    Isono, Hiroki; Yoshimoto, Hisashi

    2015-09-01

    The prevalence of alcohol dependence in Japan was 0.9% in 2013, but up to 16% adults drink alcohol at levels of unhealthy use. Primary care physicians play an important role in recognizing alcohol use disorder, helping patients change their behavior, and preventing its medical complications. The Screening, Brief Intervention, Referral to Treatment (SBIRT) model is an evidence-based, cost-effective intervention implemented worldwide to reduce alcohol use disorder.

  11. High Throughput Screen for Novel Antimicrobials using a Whole Animal Infection Model

    OpenAIRE

    Moy, Terence I.; Annie L Conery; Larkins-Ford, Jonah; Wu, Gang; Mazitschek, Ralph; Casadei, Gabriele; Lewis, Kim; Carpenter, Anne E.; Ausubel, Frederick M.

    2009-01-01

    The nematode Caenorhabditis elegans is a unique whole animal model system for identifying small molecules with in vivo anti-infective properties. C. elegans can be infected with a broad range of human pathogens, including Enterococcus faecalis, an important human nosocomial pathogen with a mortality rate of up to 37% that is increasingly acquiring resistance to antibiotics. Here, we describe an automated, high throughput screen of 37,200 compounds and natural product extracts for those that e...

  12. Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study.

    Science.gov (United States)

    Jensen, Dorte M; Mølsted-Pedersen, Lars; Beck-Nielsen, Henning; Westergaard, Jes G; Ovesen, Per; Damm, Peter

    2003-11-01

    This study was performed to prospectively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators. In a prospective multicenter study with 5235 consecutive pregnant women, diagnostic testing with a 2-hour 75-g oral glucose tolerance test was routinely performed in women with risk indicators and offered to women without risk indicators as part of the study. Forty-four percent of the women underwent testing, 43% declined participation, 6% did not speak Danish, and 7% could not be contacted. By extrapolation of the results from tested women to the whole group in question, a 2.4% prevalence of gestational diabetes mellitus was calculated. Sensitivity and specificity of the model was 80.6 (73.7-87.6) and 64.8 (63.5-66.1), respectively (95% CIs). Under ideal conditions, sensitivity of the model was comparable with universal screening by fasting glucose or a 1-hour 50-g glucose challenge test. Both screening and diagnostic testing could be avoided in two thirds of all pregnant women.

  13. Lung cancer risk prediction to select smokers for screening CT--a model based on the Italian COSMOS trial.

    Science.gov (United States)

    Maisonneuve, Patrick; Bagnardi, Vincenzo; Bellomi, Massimo; Spaggiari, Lorenzo; Pelosi, Giuseppe; Rampinelli, Cristiano; Bertolotti, Raffaella; Rotmensz, Nicole; Field, John K; Decensi, Andrea; Veronesi, Giulia

    2011-11-01

    Screening with low-dose helical computed tomography (CT) has been shown to significantly reduce lung cancer mortality but the optimal target population and time interval to subsequent screening are yet to be defined. We developed two models to stratify individual smokers according to risk of developing lung cancer. We first used the number of lung cancers detected at baseline screening CT in the 5,203 asymptomatic participants of the COSMOS trial to recalibrate the Bach model, which we propose using to select smokers for screening. Next, we incorporated lung nodule characteristics and presence of emphysema identified at baseline CT into the Bach model and proposed the resulting multivariable model to predict lung cancer risk in screened smokers after baseline CT. Age and smoking exposure were the main determinants of lung cancer risk. The recalibrated Bach model accurately predicted lung cancers detected during the first year of screening. Presence of nonsolid nodules (RR = 10.1, 95% CI = 5.57-18.5), nodule size more than 8 mm (RR = 9.89, 95% CI = 5.84-16.8), and emphysema (RR = 2.36, 95% CI = 1.59-3.49) at baseline CT were all significant predictors of subsequent lung cancers. Incorporation of these variables into the Bach model increased the predictive value of the multivariable model (c-index = 0.759, internal validation). The recalibrated Bach model seems suitable for selecting the higher risk population for recruitment for large-scale CT screening. The Bach model incorporating CT findings at baseline screening could help defining the time interval to subsequent screening in individual participants. Further studies are necessary to validate these models.

  14. Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

    Science.gov (United States)

    Klein, Brian D; Jacobson, Catherine A; Metcalf, Cameron S; Smith, Misty D; Wilcox, Karen S; Hampson, Aidan J; Kehne, John H

    2017-07-01

    Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

  15. In vivo models of cardiac diseases: application to drug development and screening.

    Science.gov (United States)

    Rokutan, Hirofumi; Anker, Stefan D; Springer, Jochen

    2010-01-01

    Cardiac disease is the top cause of human mortality in the Western world. Current drug therapy for cardiac disease has been established via experimental studies using a variety of in vivo animal models. The purpose of this review is to discuss the features (advantages and limitations) of the mainly used in vivo models of cardiac disease and provide the reader with an overview of how they can be utilized in the development and screening of cardiac drugs. A search for articles focusing on and including in vivo models for the main areas of cardiac diseases was performed on PubMed. We also searched the reference lists of identified articles for further original articles. Large and small animal models including genetically modified ones have made accomplishments in the process of cardiac drug development with different clinical relevance. However, there is still a clear need for lessening the gap between human and experimental models by improving in vivo models.

  16. Debye screening and a Thomas - Fermi model of a dyonic atom in a two potential theory of electromagnetism

    Energy Technology Data Exchange (ETDEWEB)

    Wolf, C. [North Adams State College, MA (United States)

    1993-02-01

    We study the screening of a central Abelian dyon by a surrounding dyon cloud in a two potential theory of electromagnetism. A generalized formula for the Debye screening length is obtained and a Thomas - Fermi Model for a charged cloud surrounding a central Dyonic Core is studied. 20 refs.

  17. Modeling human papillomavirus and cervical cancer in the United States for analyses of screening and vaccination

    Directory of Open Access Journals (Sweden)

    Ortendahl Jesse

    2007-10-01

    Full Text Available Abstract Background To provide quantitative insight into current U.S. policy choices for cervical cancer prevention, we developed a model of human papillomavirus (HPV and cervical cancer, explicitly incorporating uncertainty about the natural history of disease. Methods We developed a stochastic microsimulation of cervical cancer that distinguishes different HPV types by their incidence, clearance, persistence, and progression. Input parameter sets were sampled randomly from uniform distributions, and simulations undertaken with each set. Through systematic reviews and formal data synthesis, we established multiple epidemiologic targets for model calibration, including age-specific prevalence of HPV by type, age-specific prevalence of cervical intraepithelial neoplasia (CIN, HPV type distribution within CIN and cancer, and age-specific cancer incidence. For each set of sampled input parameters, likelihood-based goodness-of-fit (GOF scores were computed based on comparisons between model-predicted outcomes and calibration targets. Using 50 randomly resampled, good-fitting parameter sets, we assessed the external consistency and face validity of the model, comparing predicted screening outcomes to independent data. To illustrate the advantage of this approach in reflecting parameter uncertainty, we used the 50 sets to project the distribution of health outcomes in U.S. women under different cervical cancer prevention strategies. Results Approximately 200 good-fitting parameter sets were identified from 1,000,000 simulated sets. Modeled screening outcomes were externally consistent with results from multiple independent data sources. Based on 50 good-fitting parameter sets, the expected reductions in lifetime risk of cancer with annual or biennial screening were 76% (range across 50 sets: 69–82% and 69% (60–77%, respectively. The reduction from vaccination alone was 75%, although it ranged from 60% to 88%, reflecting considerable parameter

  18. Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Discovery of Novel Akt2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Jia Fei, Lu Zhou, Tao Liu, Xiang-Yang Tang

    2013-01-01

    Full Text Available Akt2 is considered as a potential target for cancer therapy. In order to find novel Akt2 inhibitors which have different scaffolds, structure-based pharmacophore model and 3D-QSAR pharmacophore model were built and validated by different methods. Then, they were used for chemical databases virtual screening. The selected compounds were further analyzed and refined using drug-like filters and ADMET analysis. Finally, seven hits with different scaffolds were picked out for docking studies. These seven hits were predicted to have high inhibitory activity and good ADMET properties, they may act as novel leads for Akt2 inhibitors designing.

  19. Curating and Preparing High-Throughput Screening Data for Quantitative Structure-Activity Relationship Modeling.

    Science.gov (United States)

    Kim, Marlene T; Wang, Wenyi; Sedykh, Alexander; Zhu, Hao

    2016-01-01

    Publicly available bioassay data often contains errors. Curating massive bioassay data, especially high-throughput screening (HTS) data, for Quantitative Structure-Activity Relationship (QSAR) modeling requires the assistance of automated data curation tools. Using automated data curation tools are beneficial to users, especially ones without prior computer skills, because many platforms have been developed and optimized based on standardized requirements. As a result, the users do not need to extensively configure the curation tool prior to the application procedure. In this chapter, a freely available automatic tool to curate and prepare HTS data for QSAR modeling purposes will be described.

  20. Virtual Screening Models for Prediction of HIV-1 RT Associated RNase H Inhibition

    DEFF Research Database (Denmark)

    Poongavanam, Vasanthanathan; Kongsted, Jacob

    2013-01-01

    The increasing resistance to current therapeutic agents for HIV drug regiment remains a major problem for effective acquired immune deficiency syndrome (AIDS) therapy. Many potential inhibitors have today been developed which inhibits key cellular pathways in the HIV cycle. Inhibition of HIV-1...... of choice in terms of best retrieval of active from inactive compounds and efficiency and efficacy schemes. Moreover, shape similarity, machine learning and FLAP models could also be used for further validation or filtration in virtual screening processes. The best models could potentially be use...

  1. A post-developmental genetic screen for zebrafish models of inherited liver disease.

    Directory of Open Access Journals (Sweden)

    Seok-Hyung Kim

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is one of the most common causes of chronic liver disease such as simple steatosis, nonalcoholic steatohepatitis (NASH, cirrhosis and fibrosis. However, the molecular pathogenesis and genetic variations causing NAFLD are poorly understood. The high prevalence and incidence of NAFLD suggests that genetic variations on a large number of genes might be involved in NAFLD. To identify genetic variants causing inherited liver disease, we used zebrafish as a model system for a large-scale mutant screen, and adopted a whole genome sequencing approach for rapid identification of mutated genes found in our screen. Here, we report on a forward genetic screen of ENU mutagenized zebrafish. From 250 F2 lines of ENU mutagenized zebrafish during post-developmental stages (5 to 8 days post fertilization, we identified 19 unique mutant zebrafish lines displaying visual evidence of hepatomegaly and/or steatosis with no developmental defects. Histological analysis of mutants revealed several specific phenotypes, including common steatosis, micro/macrovesicular steatosis, hepatomegaly, ballooning, and acute hepatocellular necrosis. This work has identified multiple post-developmental mutants and establishes zebrafish as a novel animal model for post-developmental inherited liver disease.

  2. A Markov Decision Process Model for Cervical Cancer Screening Policies in Colombia.

    Science.gov (United States)

    Akhavan-Tabatabaei, Raha; Sánchez, Diana Marcela; Yeung, Thomas G

    2017-02-01

    Cervical cancer is the second most common cancer in women around the world, and the human papillomavirus (HPV) is universally known as the necessary agent for developing this disease. Through early detection of abnormal cells and HPV virus types, cervical cancer incidents can be reduced and disease progression prevented. We propose a finite-horizon Markov decision process model to determine the optimal screening policies for cervical cancer prevention. The optimal decision is given in terms of when and what type of screening test to be performed on a patient based on her current diagnosis, age, HPV contraction risk, and screening test results. The cost function considers the tradeoff between the cost of prevention and treatment procedures and the risk of taking no action while taking into account a cost assigned to loss of life quality in each state. We apply the model to data collected from a representative sample of 1141 affiliates at a health care provider located in Bogotá, Colombia. To track the disease incidence more effectively and avoid higher cancer rates and future costs, the optimal policies recommend more frequent colposcopies and Pap tests for women with riskier profiles.

  3. A post-developmental genetic screen for zebrafish models of inherited liver disease.

    Science.gov (United States)

    Kim, Seok-Hyung; Wu, Shu-Yu; Baek, Jeong-In; Choi, Soo Young; Su, Yanhui; Flynn, Charles R; Gamse, Joshua T; Ess, Kevin C; Hardiman, Gary; Lipschutz, Joshua H; Abumrad, Naji N; Rockey, Don C

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease such as simple steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis and fibrosis. However, the molecular pathogenesis and genetic variations causing NAFLD are poorly understood. The high prevalence and incidence of NAFLD suggests that genetic variations on a large number of genes might be involved in NAFLD. To identify genetic variants causing inherited liver disease, we used zebrafish as a model system for a large-scale mutant screen, and adopted a whole genome sequencing approach for rapid identification of mutated genes found in our screen. Here, we report on a forward genetic screen of ENU mutagenized zebrafish. From 250 F2 lines of ENU mutagenized zebrafish during post-developmental stages (5 to 8 days post fertilization), we identified 19 unique mutant zebrafish lines displaying visual evidence of hepatomegaly and/or steatosis with no developmental defects. Histological analysis of mutants revealed several specific phenotypes, including common steatosis, micro/macrovesicular steatosis, hepatomegaly, ballooning, and acute hepatocellular necrosis. This work has identified multiple post-developmental mutants and establishes zebrafish as a novel animal model for post-developmental inherited liver disease.

  4. Modelling and comparison studies of packed screen regenerators for active magnetocaloric refrigeration

    DEFF Research Database (Denmark)

    Lei, Tian; Engelbrecht, Kurt; Nielsen, K. K.

    2011-01-01

    such as relatively large pressure drop and almost fixed porosity make loss reductions and further optimization challenging. This paper proposes and focuses on packed screen regenerators, which may exhibit lower pressure drop and equivalent heat transfer performance to packed sphere regenerators. A 1D AMR model......In active magnetic regeneration (AMR) systems, not only the magnetocaloric properties of materials, but also the regenerator geometry plays an important role in the system performance. Packed sphere regenerators are often employed in existing prototypes, however, the characteristics...... is improved and applied to simulate the regenerators. The performance of the new regenerators is studied and compared with that of the packed sphere regenerators. Possible fabrication methods of the packed screen regenerators are also discussed....

  5. Modeling of a stacked-screen regenerator in an oscillatory flow

    Science.gov (United States)

    Hsu, Shu Han; Biwa, Tetsushi

    2017-01-01

    In this paper, we model tortuous flow channels of a stacked-screen regenerator as a bundle of cylindrical tubes to analyze and design thermoacoustic Stirling engines. The oscillatory flow resistance of stacked-screen regenerators is measured and compared with those obtained using empirical equations to verify the applicability of those empirical equations to oscillating flows of pressurized Ar and He gases. It is then converted to an effective radius parameterized by Re h and r 0/δν, where Re h represents the Reynolds number based on velocity oscillation amplitude, r 0 is Ueda’s effective radius ( = \\sqrt{d\\text{h}D} /2, where d h is the hydraulic diameter and D is the mesh wire diameter), and δν denotes the viscous penetration depth. The applicability of the proposed effective radius is demonstrated experimentally when the axial temperature gradient is imposed on the regenerator.

  6. Competing risks model in screening for preeclampsia by maternal characteristics and medical history.

    Science.gov (United States)

    Wright, David; Syngelaki, Argyro; Akolekar, Ranjit; Poon, Leona C; Nicolaides, Kypros H

    2015-07-01

    The purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history. This was a screening study of 120,492 singleton pregnancies at 11-13 weeks' gestation, including 2704 pregnancies (2.2%) that experienced preeclampsia. A survival-time model for the gestational age at delivery with preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of preeclampsia. A 5-fold cross validation study was conducted to compare the performance of the new model with the National Institute for Health and Clinical Excellence (NICE) guidelines. In the new model, increased risk for preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racial origin, medical history of chronic hypertension, diabetes mellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of preeclampsia, and conception by in vitro fertilization. The risk for preeclampsia decreases with increasing maternal height and in parous women with no previous preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen-positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total preeclampsia and preeclampsia requiring delivery at preeclampsia. Such estimation of the a priori risk for preeclampsia is an essential first step in the use of Bayes theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of

  7. Development of a receptor model for efficient in silico screening of HIV-1 integrase inhibitors.

    Science.gov (United States)

    Quevedo, Mario A; Ribone, Sergio R; Briñón, Margarita C; Dehaen, Wim

    2014-07-01

    Integrase (IN) is a key viral enzyme for the replication of the type-1 human immunodeficiency virus (HIV-1), and as such constitutes a relevant therapeutic target for the development of anti-HIV agents. However, the lack of crystallographic data of HIV IN complexed with the corresponding viral DNA has historically hindered the application of modern structure-based drug design techniques to the discovery of new potent IN inhibitors (INIs). Consequently, the development and validation of reliable HIV IN structural models that may be useful for the screening of large databases of chemical compounds is of particular interest. In this study, four HIV-1 IN homology models were evaluated respect to their capability to predict the inhibition potency of a training set comprising 36 previously reported INIs with IC50 values in the low nanomolar to the high micromolar range. Also, 9 inactive structurally related compounds were included in this training set. In addition, a crystallographic structure of the IN-DNA complex corresponding to the prototype foamy virus (PFV) was also evaluated as structural model for the screening of inhibitors. The applicability of high throughput screening techniques, such as blind and ligand-guided exhaustive rigid docking was assessed. The receptor models were also refined by molecular dynamics and clustering techniques to assess protein sidechain flexibility and solvent effect on inhibitor binding. Among the studied models, we conclude that the one derived from the X-ray structure of the PFV integrase exhibited the best performance to rank the potencies of the compounds in the training set, with the predictive power being further improved by explicitly modeling five water molecules within the catalytic side of IN. Also, accounting for protein sidechain flexibility enhanced the prediction of inhibition potencies among the studied compounds. Finally, an interaction fingerprint pattern was established for the fast identification of potent IN

  8. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    Science.gov (United States)

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-05-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40 %) when compared to docking with a single structure model (PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development.

  9. BioSig3D: High Content Screening of Three-Dimensional Cell Culture Models: e0148379

    National Research Council Canada - National Science Library

    Cemal Cagatay Bilgin; Gerald Fontenay; Qingsu Cheng; Hang Chang; Ju Han; Bahram Parvin

    2016-01-01

    ...) cell culture models that are imaged in full 3D volume. It provides an end-to-end solution for designing high content screening assays, based on colony organization that is derived from segmentation of nuclei in each colony...

  10. Data Sources for the Model-based Small Area Estimates of Cancer Risk Factors and Screening Behaviors - Small Area Estimates

    Science.gov (United States)

    The model-based estimates of important cancer risk factors and screening behaviors are obtained by combining the responses to the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS).

  11. Simple Screened Hydrogen Model of Excitons in Two-Dimensional Materials

    DEFF Research Database (Denmark)

    Olsen, Thomas; Latini, Simone; Rasmussen, Filip Anselm;

    2016-01-01

    We present a generalized hydrogen model for the binding energies (EB) and radii of excitons in two-dimensional (2D) materials that sheds light on the fundamental differences between excitons in two and three dimensions. In contrast to the well-known hydrogen model of three-dimensional (3D) excitons...... the recently observed linear scaling of exciton binding energies with band gap. It is also shown that the model accurately reproduces the nonhydrogenic Rydberg series in WS2 and can account for screening from the environment....... that only depends on the excitonic mass and the 2D polarizability α. The model is shown to produce accurate results for 51 transition metal dichalcogenides. Remarkably, over a wide range of polarizabilities the binding energy becomes independent of the mass and we obtain E2DB≈3/(4πα), which explains...

  12. Using model-based screening to help discover unknown environmental contaminants.

    Science.gov (United States)

    McLachlan, Michael S; Kierkegaard, Amelie; Radke, Michael; Sobek, Anna; Malmvärn, Anna; Alsberg, Tomas; Arnot, Jon A; Brown, Trevor N; Wania, Frank; Breivik, Knut; Xu, Shihe

    2014-07-01

    Of the tens of thousands of chemicals in use, only a small fraction have been analyzed in environmental samples. To effectively identify environmental contaminants, methods to prioritize chemicals for analytical method development are required. We used a high-throughput model of chemical emissions, fate, and bioaccumulation to identify chemicals likely to have high concentrations in specific environmental media, and we prioritized these for target analysis. This model-based screening was applied to 215 organosilicon chemicals culled from industrial chemical production statistics. The model-based screening prioritized several recognized organosilicon contaminants and generated hypotheses leading to the selection of three chemicals that have not previously been identified as potential environmental contaminants for target analysis. Trace analytical methods were developed, and the chemicals were analyzed in air, sewage sludge, and sediment. All three substances were found to be environmental contaminants. Phenyl-tris(trimethylsiloxy)silane was present in all samples analyzed, with concentrations of ∼50 pg m(-3) in Stockholm air and ∼0.5 ng g(-1) dw in sediment from the Stockholm archipelago. Tris(trifluoropropyl)trimethyl-cyclotrisiloxane and tetrakis(trifluoropropyl)tetramethyl-cyclotetrasiloxane were found in sediments from Lake Mjøsa at ∼1 ng g(-1) dw. The discovery of three novel environmental contaminants shows that models can be useful for prioritizing chemicals for exploratory assessment.

  13. High-Throughput Screen of Natural Product Extracts in A Yeast Model of Polyglutamine Proteotoxicity

    Science.gov (United States)

    Walter, Gladis M.; Raveh, Avi; Mok, Sue-Ann; McQuade, Thomas J.; Arevang, Carl J.; Schultz, Pamela J.; Smith, Matthew C.; Asare, Samuel; Cruz, Patricia G.; Wisen, Susanne; Matainaho, Teatulohi; Sherman, David H.; Gestwicki, Jason E.

    2014-01-01

    Proteins with expanded polyglutamine (polyQ) segments cause a number of fatal neurodegenerative disorders, including Huntington’s disease (HD). Previous high-throughput screens in cellular and biochemical models of HD have revealed compounds that mitigate polyQ aggregation and proteotoxicity, providing insight into the mechanisms of disease and leads for potential therapeutics. However, the structural diversity of natural products has not yet been fully mobilized toward these goals. Here, we have screened a collection of ~11 000 natural product extracts for the ability to recover the slow growth of ΔProQ103-expressing yeast cells in 384-well plates (Z’ ~ 0.7, CV ~ 8%). This screen identified actinomycin D as a strong inhibitor of polyQ aggregation and proteotoxicity at nanomolar concentrations (~50–500 ng/mL). We found that a low dose of actinomycin D increased the levels of the heat-shock proteins Hsp104, Hsp70 and Hsp26 and enhanced binding of Hsp70 to the polyQ in yeast. Actinomycin also suppressed aggregation of polyQ in mammalian cells, suggesting a conserved mechanism. These results establish natural products as a rich source of compounds with interesting mechanisms of action against polyQ disorders. PMID:24636344

  14. Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

    Directory of Open Access Journals (Sweden)

    Shikhar Gupta

    2014-01-01

    Full Text Available In this study, we have employed in silico methodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.

  15. A model for patient-direct screening and referral for familial cancer risk.

    Science.gov (United States)

    Niendorf, Kristin B; Geller, Melissa A; Vogel, Rachel Isaksson; Church, Timothy R; Leininger, Anna; Bakke, Angela; Madoff, Robert D

    2016-10-01

    Patients at increased familial risk of cancer are sub-optimally identified and referred for genetic counseling. We describe a systematic model for information collection, screening and referral for hereditary cancer risk. Individuals from three different clinical and research populations were screened for hereditary cancer risk using a two-tier process: a 7-item screener followed by review of family history by a genetic counselor and application of published criteria. A total of 869 subjects participated in the study; 769 in this high risk population had increased familial cancer risk based on the screening questionnaire. Of these eligible participants, 500 (65.0 %) provided family histories and 332 (66.4 %) of these were found to be at high risk of a hereditary cancer syndrome, 102 (20.4 %) at moderate familial cancer risk, and 66 (13.2 %) at average risk. Three months following receipt of the risk result letter, nearly all respondents found the process at least somewhat helpful (98.4 %). All participants identified as high-risk were mailed a letter recommending genetic counseling and were provided appointment tools. After 1 year, only 13 (7.3 %) of 179 high risk respondents reported pursuit of recommended genetic counseling. Participants were willing to provide family history information for the purposes of risk assessment; however, few patients pursued recommended genetic services. This suggests that cancer family history registries are feasible and viable but that further research is needed to increase the uptake of genetic counseling.

  16. Applying the Health Belief Model in Predicting Breast Cancer Screening Behavior of Women

    Directory of Open Access Journals (Sweden)

    Masoudiyekta

    2015-10-01

    Full Text Available Background Breast cancer is the most common cancer among Iranian women. However, early detection of this cancer leads to a timely treatment and better prognosis, which significantly improves the survival rate in patients. Objectives The purpose of this study was to predict the breast cancer screening behavior of women who referred to health centers in Dezful, Iran, using the health belief model (HBM. Patients and Methods This descriptive-analytical study was conducted on 226 women who were selected with cluster sampling method from those referred to Dezful health centers. Data collection tool was a researcher made questionnaire based on the constructs of the HBM. Data analysis was performed using SPSS software and through methods of descriptive statistics, Pearson correlation, and regression. Results According to the findings of the study, the knowledge and performance of women were poor, and there was a significant relationship between women’s performance and variables of knowledge, perceived sensitivity, perceived benefits, perceived barriers, self-efficacy, and cues to action. In addition, variables of knowledge (P = 0.001, perceived sensitivity (P = 0.022, and self-efficacy (P = 0.001 were predictors of performance in women participating in this study. Conclusions Poor knowledge and performance of women indicates a crucial need for formal educational programs to sensitize women regarding the importance of breast cancer screening. These educational programs should consider factors affecting breast cancer screening behaviors.

  17. Examining Screening-Level Multimedia Models Through a Comparison Framework for Landfill Management.

    Science.gov (United States)

    Asif, Zunaira; Chen, Zhi

    2016-01-01

    Two models for evaluating transport and fate of benzene were studied and compared in this paper. A fugacity model and an analytical environmental multimedia model (AEMM) were used to reconcile fate and mass transfer of benzene observed in a landfill site. The comparison of two models were based on average concentrations and partition behavior of benzene among three different phases i.e., air, soil, and groundwater. In the study of fugacity method about 99.6 % of the total benzene flux was distributed into air from landfill source. According to AEMM the diffusion gas flux was also predominant mechanism for benzene released from landfill and advection of gas and liquid was second dominant transport mechanism at steady-state conditions. Overall study of fugacity modeling (Level I and II) confirms the fate and transport mechanism of benzene released from landfill by comparing it with AEMM. However, the values of predicted concentrations, advection, and diffusion flux of benzene using fugacity model were different from AEMM results due to variation in input parameters. In comparison with experimental observations, fugacity model showed more error difference as compared to AEMM as fugacity model is treated as a single unit box model. This study confirms that fugacity model is a screening level tool to be used in conjunction with detailed remediation followed by AEMM that can be evolved as strategic decision-making stage.

  18. A review on the advance of experimental assay methods and models in drug screening   %药物筛选模型研究进展

    Institute of Scientific and Technical Information of China (English)

    胡娟娟; 杜冠华

    2001-01-01

    The experimental models for drug screening are very important points in drug discovery. Although the drug screening techniques have been developed, such as high throughput screening (HTS), the screening assay methods (models) still limited drug discovery. In present paper, advanced animal models, cell assays and molecular methodology used for drug discovery were reviewed. The characteristics and requires of the assay methods used for drug discovery in HTS were also discussed.

  19. Cervical cancer screening in Australia: modelled evaluation of the impact of changing the recommended interval from two to three years

    Directory of Open Access Journals (Sweden)

    Howard Kirsten

    2010-11-01

    Full Text Available Abstract Background The National Cervical Screening Program in Australia currently recommends that sexually active women between the ages of 18-70 years attend routine screening every 2 years. The publically funded National HPV Vaccination Program commenced in 2007, with catch-up in females aged 12-26 years conducted until 2009; and this may prompt consideration of whether the screening interval and other aspects of the organized screening program could be reviewed. The aim of the current evaluation was to assess the epidemiologic outcomes and cost implications of changing the recommended screening interval in Australia to 3 years. Methods We used a modelling approach to evaluate the effects of moving to a 3-yearly recommended screening interval. We used data from the Victorian Cervical Cytology Registry over the period 1997-2007 to model compliance with routine screening under current practice, and registry data from other countries with 3-yearly recommendations to inform assumptions about future screening behaviour under two alternative systems for screening organisation - retention of a reminder-based system (as in New Zealand, or a move to a call-and-recall system (as in England. Results A 3-yearly recommendation is predicted to be of similar effectiveness to the current 2-yearly recommendation, resulting in no substantial change to the total number of incident cervical cancer cases or cancer deaths, or to the estimated 0.68% average cumulative lifetime risk of cervical cancer in unvaccinated Australian women. However, a 3-yearly screening policy would be associated with decreases in the annual number of colposcopy and biopsy procedures performed (by 4-10% and decreases in the number of treatments for pre-invasive lesions (by 2-4%. The magnitude of the decrease in the number of diagnostic procedures and treatments would depend on the method of screening organization, with call-and-recall screening associated with the highest reductions. The

  20. Ionic screening of charged impurities in electrolytically gated graphene: A partially linearized Poisson-Boltzmann model.

    Science.gov (United States)

    Sharma, P; Mišković, Z L

    2015-10-07

    We present a model describing the electrostatic interactions across a structure that consists of a single layer of graphene with large area, lying above an oxide substrate of finite thickness, with its surface exposed to a thick layer of liquid electrolyte containing salt ions. Our goal is to analyze the co-operative screening of the potential fluctuation in a doped graphene due to randomness in the positions of fixed charged impurities in the oxide by the charge carriers in graphene and by the mobile ions in the diffuse layer of the electrolyte. In order to account for a possibly large potential drop in the diffuse later that may arise in an electrolytically gated graphene, we use a partially linearized Poisson-Boltzmann (PB) model of the electrolyte, in which we solve a fully nonlinear PB equation for the surface average of the potential in one dimension, whereas the lateral fluctuations of the potential in graphene are tackled by linearizing the PB equation about the average potential. In this way, we are able to describe the regime of equilibrium doping of graphene to large densities for arbitrary values of the ion concentration without restrictions to the potential drop in the electrolyte. We evaluate the electrostatic Green's function for the partially linearized PB model, which is used to express the screening contributions of the graphene layer and the nearby electrolyte by means of an effective dielectric function. We find that, while the screened potential of a single charged impurity at large in-graphene distances exhibits a strong dependence on the ion concentration in the electrolyte and on the doping density in graphene, in the case of a spatially correlated two-dimensional ensemble of impurities, this dependence is largely suppressed in the autocovariance of the fluctuating potential.

  1. Evaluation of mass screening for cancer : a model-based approach

    NARCIS (Netherlands)

    G.J. van Oortmarssen (Gerrit)

    1995-01-01

    textabstractThe main goal in evaluation of screening for cancer is to assist in decision making about a screening program: Should it be initiated at all? What screening policies can be recommended: what age groups, what frequency of screening. Should special attention be paid to high risk groups? If

  2. Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis.

    Science.gov (United States)

    Baggaley, Rebecca F; Irvine, Michael A; Leber, Werner; Cambiano, Valentina; Figueroa, Jose; McMullen, Heather; Anderson, Jane; Santos, Andreia C; Terris-Prestholt, Fern; Miners, Alec; Hollingsworth, T Déirdre; Griffiths, Chris J

    2017-07-28

    Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment. Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years. Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high

  3. The transtheoretical model, health belief model, and breast cancer screening among Iranian women with a family history of breast cancer

    Directory of Open Access Journals (Sweden)

    Ziba Farajzadegan

    2016-01-01

    Full Text Available Background: Participation of Iranian women with a family history of breast cancer in breast cancer screening programs is low. This study evaluates the compliance of women having a family history of breast cancer with clinical breast exam (CBE according to the stage of transtheoretical model (TTM and health belief model (HBM. Materials and Methods: In this cross-sectional study, we used Persian version of champion's HBM scale to collect factors associated with TTM stages applied to screening from women over 20 years and older. The obtained data were analyzed by SPSS, using descriptive statistics, Chi-square test, independent t-test, and analysis of covariance. Results: Final sample size was 162 women. Thirty-three percent were in action/maintenance stage. Older women, family history of breast cancer in first-degree relatives, personal history of breast disease, insurance coverage, and a history of breast self-examination were associated with action/maintenance stage. Furthermore, women in action/maintenance stages had significantly fewer perceived barriers in terms of CBE in comparison to women in other stages (P < 0.05. There was no significant difference in other HBM subscales scores between various stages of CBE screening behavior (P < 0.05. Conclusion: The finding indicates that the rate of women in action/maintenance stage of CBE is low. Moreover, results show a strong association between perceived barriers and having a regular CBE. These clarify the necessity of promoting national target programs for breast cancer screening, which should be considered as the first preference for reducing CBE barriers.

  4. A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth.

    Science.gov (United States)

    Lal-Nag, Madhu; McGee, Lauren; Guha, Rajarshi; Lengyel, Ernst; Kenny, Hilary A; Ferrer, Marc

    2017-06-01

    The tumor microenvironment plays an important role in the processes of tumor growth, metastasis, and drug resistance. We have used a multilayered 3D primary cell culture model that reproduces the human ovarian cancer metastatic microenvironment to study the effect of the microenvironment on the pharmacological responses of different classes of drugs on cancer cell proliferation. A collection of oncology drugs was screened to identify compounds that inhibited the proliferation of ovarian cancer cells growing as monolayers or forming spheroids, on plastic and on a 3D microenvironment culture model of the omentum metastatic site, and also cells already in preformed spheroids. Target-based analysis of the pharmacological responses revealed that several classes of targets were more efficacious in cancer cells growing in the absence of the metastatic microenvironment, and other target classes were less efficacious in cancer cells in preformed spheres compared to forming spheroid cultures. These findings show that both the cellular context of the tumor microenvironment and cell adhesion mode have an essential role in cancer cell drug resistance. Therefore, it is important to perform screens for new drugs using model systems that more faithfully recapitulate the tissue composition at the site of tumor growth and metastasis.

  5. An EOQ model for imperfect quality items with partial backordering under screening errors

    Directory of Open Access Journals (Sweden)

    Ehsan Sharifi

    2015-12-01

    Full Text Available In practice, when a lot size received, an inspection process is necessary to identify the defective items. In addition, the inspection process itself is not error-free and it may contain misclassification errors. In this paper, an economic order quantity model for imperfect quality items with partial backordering under screening errors is studied. The objective is to maximize the expected annual profit by optimizing the order size and the maximum number of backorder units. Also, the aim of this paper is to develop a general and practical model that is more realistic in the competitive commercial situations. For authenticity of the developed model, a case study and a numerical example are illustrated, and the sensitivity analysis is also carried out.

  6. Conformational Solvation Studies of LIGNOLs with Molecular Dynamics and Conductor-Like Screening Model

    Directory of Open Access Journals (Sweden)

    Thomas Sandberg

    2012-08-01

    Full Text Available Molecular dynamics (MD simulations were performed on sterically hindered -conidendrin-based chiral 1,4-diols (LIGNOLs from the naturally occurring lignan hydroxymatairesinol (HMR using the GROMACS software. The aim of this study was to explore the conformational behaviour of the LIGNOLs in aqueous solution adopting the TIP4P model. The topologies of the LIGNOLs were constructed manually and they were modeled with the OPLS-AA force field implemented in GROMACS. The four most relevant torsional angles in the LIGNOLs were properly analyzed during the simulations. The determining property for the conformation preferred in aqueous solution was found to be the lowest energy in gas phase. The solvation effects on the LIGNOLs were also studied by quantum chemical calculations applying the COnductor-like Screening MOdel (COSMO. The hydration studies of the MD simulations showed that several of these LIGNOLs, produced from a renewable source, have a great potential of acting as chiral catalysts.

  7. An in vitro model for screening estrogen activity of environmental samples after metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Chahbane, N.; Schramm, K.W. [GSF - Forschungszentrum fuer Umwelt und Gesundheit Neuherberg GmbH, Oberschleissheim (Germany). Inst. fuer Oekologische Chemie; Kettrup, A. [Technische Univ. Muenchen, Freising (Germany). Lehrstuhl fuer Oekologische Chemie

    2004-09-15

    For a few years, yeast estrogen assay (YES) was accepted as a reliable and economic model for screening of environmental estrogens. Though the chemicals directly act with estrogen receptor (ER) can be filtered out by this model, there are still chemicals act with ER only after metabolism and some chemicals eliminate their estrogen activities after metabolism. That is to say, their metabolites exert or have stronger estrogen activities than themselves, which can be called bio-activation. In this case, for the lack of the metabolism enzyme system as human and other animals, only the assay with recombinant yeast cells is insufficient. So, it is necessary to combine the YES with metabolism procedure to evaluate the estrogen activities of these chemicals. The most common method used currently for in vitro metabolic activation in mutagenicity testing and also be applied to the estrogen screening field is S-9 mixture. Also, there is an attempt to develop a chemical model for cytochrome P450 as a bio-mimetic metabolic activation system. All these methods can be used as in vitro models for metabolism. Compare with these models, using whole H4II E cells for metabolism is an alternative and with superiorities. It has the excellence of short experiment period as all other in vitro models, but is much more close to the real surroundings as in vivo. Furthermore, the activity of 7-ethoxyresorufin-O-deethylase (EROD) can be easily measured during the whole incubation period for us to discuss the metabolic activities in a quantitative foundation, not only in qualitative. Methoxychlor is one of the chemicals with bio-activation ability. When directly used in the YES, it shows weak estrogen activity. But a main metabolite of methoxychlor, 2,2-bis (p-hydroxyphenyl) - 1,1,1-trichloroethane (HPTE) is a known estrogen mimic. For the long time using methoxychlor as a pesticide and its clear background, it is an ideal chemical to establish this in vitro system.

  8. Development and verification of a screening model for surface spreading of petroleum

    Science.gov (United States)

    Hussein, Maged; Jin, Minghui; Weaver, James W.

    2002-08-01

    Overflows and leakage from aboveground storage tanks and pipelines carrying crude oil and petroleum products occur frequently. The spilled hydrocarbons pose environmental threats by contaminating the surrounding soil and the underlying ground water. Predicting the fate and transport of these chemicals is required for environmental risk assessment and for remedial measure design. The present paper discusses the formulation and application of the Oil Surface Flow Screening Model (OILSFSM) for predicting the surface flow of oil by taking into account infiltration and evaporation. Surface flow is simulated using a semi-analytical model based on the lubrication theory approximation of viscous flow. Infiltration is simulated using a version of the Green and Ampt infiltration model, which is modified to account for oil properties. Evaporation of volatile compounds is simulated using a compositional model that accounts for the changes in the fraction of each compound in the spilled oil. The coupling between surface flow, infiltration and evaporation is achieved by incorporating the infiltration and evaporation fluxes into the global continuity equation of the spilled oil. The model was verified against numerical models for infiltration and analytical models for surface flow. The verification study demonstrates the applicability of the model.

  9. COLLABORATIVE MODELING OF THE BENEFITS AND HARMS ASSOCIATED WITH DIFFERENT U.S. BREAST CANCER SCREENING STRATEGIES

    Science.gov (United States)

    Mandelblatt, Jeanne S.; Stout, Natasha K.; Schechter, Clyde B.; van den Broek, Jeroen J.; Miglioretti, Diana; Krapcho, Martin; Trentham-Dietz, Amy; Munoz, Diego; Lee, Sandra J.; Berry, Donald A.; van Ravesteyn, Nicolien T.; Alagoz, Oguzhan; Kerlikowske, Karla; Tosteson, Anna N.A.; Near, Aimee M.; Hoeffken, Amanda; Chang, Yaojen; Heijnsdijk, Eveline A.; Chisholm, Gary; Huang, Xuelin; Huang, Hui; Ergun, Mehmet Ali; Gangnon, Ronald; Sprague, Brian L.; Plevritis, Sylvia; Feuer, Eric; de Koning, Harry J.; Cronin, Kathleen A.

    2016-01-01

    Background Controversy persists about optimal mammography screening strategies. Objective To evaluate mammography strategies considering screening and treatment advances. Design Collaboration of six simulation models. Data Sources National data on incidence, risk, breast density, digital mammography performance, treatment effects, and other-cause mortality. Target Population An average-risk cohort. Time Horizon Lifetime. Perspective Societal. Interventions Mammograms from age 40, 45 or 50 to 74 at annual or biennial intervals, or annually from 40 or 45 to 49 then biennially to 74, assuming 100% screening and treatment adherence. Outcome Measures Screening benefits (vs. no screening) include percent breast cancer mortality reduction, deaths averted, and life-years gained. Harms include number of mammograms, false-positives, benign biopsies, and overdiagnosis. Results for Average-Risk Women Biennial strategies maintain 79.8%-81.3% (range across strategies and models: 68.3–98.9%) of annual screening benefits with almost half the false-positives and fewer overdiagnoses. Screening biennially from ages 50–74 achieves a median 25.8% (range: 24.1%-31.8%) breast cancer mortality reduction; annual screening from ages 40–74 years reduces mortality an additional 12.0% (range: 5.7%-17.2%) vs. no screening, but yields 1988 more false-positives and 7 more overdiagnoses per 1000 women screened. Annual screening from ages 50–74 had similar benefits as other strategies but more harms, so would not be recommended. Sub-population Results Annual screening starting at age 40 for women who have a two- to four-fold increase in risk has a similar balance of harms and benefits as biennial screening of average-risk women from 50–74. Limitations We do not consider other imaging technologies, polygenic risk, or non-adherence. Conclusion These results suggest that biennial screening is efficient for average-risk groups, but decisions on strategies depend on the weight given to the

  10. Effect of public knowledge, attitudes, and behavior on willingness to undergo colorectal cancer screening using the health belief model

    Directory of Open Access Journals (Sweden)

    Majid A Almadi

    2015-01-01

    Full Text Available Background/Aims: Success of colorectal cancer (CRC screening is dependent in part on the proportion of uptake by the targeted population. We aimed in this study to identify factors that were associated with willingness to undergo CRC screening based on the health belief model (HBM. Patients and Methods: This was a cross-sectional study among citizens of Riyadh, Saudi Arabia. Demographic data collected included gender, age, education, marital status, employment status, a history of CRC in the family or knowing a friend with CRC, as well as income. A questionnaire was developed in Arabic based on the HBM and included enquiries on knowledge about CRC symptoms and risk factors, types of CRC screening tests, perceived risk of CRC, previously undergoing CRC screening, intent to undergo CRC screening, perceived barriers to CRC screening, perceived severity of CRC, as well as attitudes toward CRC and its screening. Results: Five hundred participants were included. The mean age was 41.0 years (SD 10.7. Males were 50% and only 6.7% of those between 50 and 55 years of age had undergone CRC screening. Of those surveyed, 70.7% were willing to undergo CRC screening. Also, 70.5% thought that CRC is curable, 73.3% believed it was preventable, whereas 56.7% thought it was a fatal disease. Neither gender, level of education, occupation, income, marital status, nor general knowledge about CRC was found to be associated with the willingness to undergo CRC screening. Recognizing that colonoscopy was a screening test (OR 1.55, 95% CI; 1.04-2.29 was associated with a strong desire to undergo CRC screening while choosing a stool-based test was associated with not willing to undergo CRC screening (OR 0.59, 95%CI; 0.38-0.91. Conclusion: We found that the majority of those interviewed were willing to undergo CRC screening and identified a number of barriers as well as potential areas that could be targeted in the promotion of CRC screening uptake if such a national

  11. Development of polarizable models for molecular mechanical calculations. 3. Polarizable water models conforming to Thole polarization screening schemes.

    Science.gov (United States)

    Wang, Jun; Cieplak, Piotr; Cai, Qin; Hsieh, Meng-Juei; Wang, Junmei; Duan, Yong; Luo, Ray

    2012-07-19

    As an integrated step toward a coherent polarizable force field for biomolecular modeling, we analyzed four polarizable water models to evaluate their consistencies with the Thole polarization screening schemes utilized in our latest Amber polarizable force field. Specifically, we studied the performance of both the Thole linear and exponential schemes in these water models to assess their abilities to reproduce experimental water properties. The analysis shows that the tested water models reproduce most of the room-temperature properties of liquid water reasonably well but fall short of reproducing the dynamic properties and temperature-dependent properties. This study demonstrates the necessity to further fine-tune water polarizable potentials for more robust polarizable force fields for biomolecular simulations.

  12. Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells

    Institute of Scientific and Technical Information of China (English)

    Xiao-hong XU; Zhong ZHONG

    2013-01-01

    With the general decline of pharmaceutical research productivity,there are concerns that many components of the drug discovery process need to be redesigned and optimized.For example,the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases,leading to biases in assays,targets,or compounds that do not effectively address disease mechanisms.Recent advances in stem cell research,especially in the development of induced pluripotent stem cell (iPSC) technology,provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells.In this article,we will review the progress made to date on cellular disease models using human stem cells,with a focus on patient-specific iPSCs for neurological diseases.We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases,diseases with various known genetic components,and complex diseases caused by a combination of genetic,environmental and other factors.

  13. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

    Science.gov (United States)

    Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

    2016-08-18

    Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

  14. Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells.

    Science.gov (United States)

    Xu, Xiao-hong; Zhong, Zhong

    2013-06-01

    With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors.

  15. Establishment of a cell model for screening antibody drugs against rheumatoid arthritis with ADCC and CDC.

    Science.gov (United States)

    Yan, Li; Hu, Rui; Tu, Song; Cheng, Wen-Jun; Zheng, Qiong; Wang, Jun-Wen; Kan, Wu-Sheng; Ren, Yi-Jun

    2015-01-01

    TNFα played a dominant role in the development and progression of rheumatoid arthritis (RA). Clinical trials proved the efficacies of anti-TNFα agents for curing RA. However, most researchers were concentrating on their abilities of neutralizing TNFα, the potencies of different anti-TNFα agents varied a lot due to the antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). For better understanding and differentiating the potentiality of various candidate anti-TNF reagents at the stage of new drug research and development, present study established a cell model expressing the transmembrane TNFα for usage in in vitro ADCC or CDC assay, meanwhile, the assay protocol described here could provide guidelines for screening macromolecular antibody drugs. A stable cell subline bearing transmembrane TNFα was first established by conventional transfection method, the expression of transmembrane TNFα was approved by flow cytometer, and the performance of the stable subline in ADCC and CDC assay was evaluated, using human peripheral blood mononuclear cells as effector cells, and Adalimumab as the anti-TNFα reagent. The stable cell subline demonstrated high level of surface expression of transmembrane TNFα, and Adalimumab exerted both ADCC and CDC effects on this cell model. In conclusion, the stable cell line we established in present research could be used in ADCC or CDC assay for screening antibody drugs, which would provide in-depth understanding of the potencies of candidate antibody drugs in addition to the traditional TNFα neutralizing assay.

  16. Discovery of Entamoeba histolytica hexokinase 1 inhibitors through homology modeling and virtual screening.

    Science.gov (United States)

    Saucedo-Mendiola, María Leticia; Salas-Pacheco, José Manuel; Nájera, Hugo; Rojo-Domínguez, Arturo; Yépez-Mulia, Lilián; Avitia-Domínguez, Claudia; Téllez-Valencia, Alfredo

    2014-06-01

    Entamoeba histolytica, the parasite which causes amebiasis is responsible for 110,000 deaths a year. Entamoeba histolytica depends on glycolysis to obtain ATP for cellular work. According to metabolic flux studies, hexokinase exerts the highest flux control of this metabolic pathway; therefore, it is an excellent target in the search of new antiamebic drugs. To this end, a tridimensional model of E. histolytica hexokinase 1 (EhHK1) was constructed and validated by homology modeling. After virtual screening of 14,400 small molecules, the 100 with the best docking scores were selected, purchased and assessed in their inhibitory capacity. The results showed that three molecules (compounds 2921, 11275 and 2755) inhibited EhHK1 with an I50 of 48, 91 and 96 µM, respectively. Thus, we found the first inhibitors of EhHK1 that can be used in the search of new chemotherapeutic agents against amebiasis.

  17. A Screening-Level Hydroeconomic Model of South Florida Water Resources System

    Science.gov (United States)

    Mirchi, A.; Watkins, D. W., Jr.; Flaxman, M.; Wiesmann, D.

    2014-12-01

    South Florida's water resources management is characterized by system-wide tradeoffs associated with maintaining the ecological integrity of natural environments such as the Everglades while meeting the water demands of the agricultural sector and growing urban areas. As these tradeoffs become more pronounced due to pressures from climate change, sea level rise, and population growth, it will be increasingly challenging for policy makers and stakeholders to reach consensus on water resources management objectives and planning horizons. A hydroeconomic optimization model of south Florida's water resources system is developed to incorporate the value of water for preserving ecosystem services alongside water supplies to the Everglades Agricultural Area and urban areas. Results of this screening-level network flow model facilitate quantitative analysis and provide insights for long-term adaptive management strategies for the region's water resources.

  18. Prospective Assessment of an innovative test for prostate cancer screening using the VITA process model framework.

    Science.gov (United States)

    Gantner-Bär, Marion; Meier, Florian; Kolominsky-Rabas, Peter; Djanatliev, Anatoli; Metzger, Armin; Voigt, Wieland; Prokosch, Hans-Ulrich; Sedlmayr, Martin

    2014-01-01

    Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare system. However, bringing new technologies, methods and procedures into the healthcare market is challenging. Enormous amounts of financial, personnel and organizational resources are required with no upfront certainty for the medical and economic benefit. A new and innovative approach uses interdisciplinary medical, technical and economic expertise to forecast effects of healthcare innovations already at the early research and concept phase of an idea and before major investments are made. A process model framework was developed to operationalize this structured assessment of healthcare innovations. The Visionary Iterative Tailored Approach (VITA) is based on conceptual modeling, simulation and health economics evaluation. Its application for the prospective assessment of an innovative prostate cancer screening is presented.

  19. Cost-effectiveness of enhanced syphilis screening among HIV-positive men who have sex with men: a microsimulation model.

    Directory of Open Access Journals (Sweden)

    Ashleigh R Tuite

    Full Text Available Syphilis co-infection risk has increased substantially among HIV-infected men who have sex with men (MSM. Frequent screening for syphilis and treatment of men who test positive might be a practical means of controlling the risk of infection and disease sequelae in this population.We evaluated the cost-effectiveness of strategies that increased the frequency and population coverage of syphilis screening in HIV-infected MSM receiving HIV care, relative to current standard of care.We developed a state-transition microsimulation model of syphilis natural history and medical care in HIV-infected MSM receiving care for HIV. We performed Monte Carlo simulations using input data derived from a large observational cohort in Ontario, Canada, and from published biomedical literature. Simulations compared usual care (57% of the population screened annually to different combinations of more frequent (3- or 6-monthly screening and higher coverage (100% screened. We estimated expected disease-specific outcomes, quality-adjusted survival, costs, and cost-effectiveness associated with each strategy from the perspective of a public health care payer.Usual care was more costly and less effective than strategies with more frequent or higher coverage screening. Higher coverage strategies (with screening frequency of 3 or 6 months were expected to be cost-effective based on usually cited willingness-to-pay thresholds. These findings were robust in the face of probabilistic sensitivity analyses, alternate cost-effectiveness thresholds, and alternate assumptions about duration of risk, program characteristics, and management of underlying HIV.We project that higher coverage and more frequent syphilis screening of HIV-infected MSM would be a highly cost-effective health intervention, with many potentially viable screening strategies projected to both save costs and improve health when compared to usual care. The baseline requirement for regular blood testing in this

  20. Heat Transfer Modeling of Staggered Bundle with Round Tubes Screened by Mesh

    Directory of Open Access Journals (Sweden)

    Dymo B.V.

    2016-04-01

    Full Text Available The article presents the results of CFD modeling of heat transfer and aerodynamic drag for the first three rows of cross-flowed staggered bundle consisting of round tubes screened by wire mesh. Geometric model of this bundle was developed. Selection of optimal parameters of the bundle finite element model realizes on the base of transition shear stress transport model. Two separate geometric models for even and odd rows of bundle have been elaborated for the scope of computational resources optimization. The results of numerical modeling of heat transfer for the first three rows of the bundle were approximated with the criteria dependences. It has been established that heat transfer stabilization occurs from the second row of the bundle. Stabilized heat transfer is 15 % higher than that for the first row of the bundle and 1.2 … 1.7 times as large in comparison with equivalent bare-tube bundle in a range of Reynolds number from 5000 to 35000. Aerodynamic drag data for the first three rows of the bundle have been obtained.

  1. A screening model to predict microalgae biomass growth in photobioreactors and raceway ponds.

    Science.gov (United States)

    Huesemann, M H; Van Wagenen, J; Miller, T; Chavis, A; Hobbs, S; Crowe, B

    2013-06-01

    A microalgae biomass growth model was developed for screening novel strains for their potential to exhibit high biomass productivities under nutrient-replete conditions in photobioreactors or outdoor ponds. Growth is modeled by first estimating the light attenuation by biomass according to Beer-Lambert's Law, and then calculating the specific growth rate in discretized culture volume slices that receive declining light intensities due to attenuation. The model uses only two physical and two species-specific biological input parameters, all of which are relatively easy to determine: incident light intensity, culture depth, as well as the biomass light absorption coefficient and the specific growth rate as a function of light intensity. Roux bottle culture experiments were performed with Nannochloropsis salina at constant temperature (23°C) at six different incident light intensities (10, 25, 50, 100, 250, and 850 µmol/m(2)  s) to determine both the specific growth rate under non-shading conditions and the biomass light absorption coefficient as a function of light intensity. The model was successful in predicting the biomass growth rate in these Roux bottle batch cultures during the light-limited linear phase at different incident light intensities. Model predictions were moderately sensitive to minor variations in the values of input parameters. The model was also successful in predicting the growth performance of Chlorella sp. cultured in LED-lighted 800 L raceway ponds operated in batch mode at constant temperature (30°C) and constant light intensity (1,650 µmol/m(2)  s). Measurements of oxygen concentrations as a function of time demonstrated that following exposure to darkness, it takes at least 5 s for cells to initiate dark respiration. As a result, biomass loss due to dark respiration in the aphotic zone of a culture is unlikely to occur in highly mixed small-scale photobioreactors where cells move rapidly in and out of the light. By contrast

  2. A Screening Model to Predict Microalgae Biomass Growth in Photobioreactors and Raceway Ponds

    Energy Technology Data Exchange (ETDEWEB)

    Huesemann, Michael H.; Van Wagenen, Jonathan M.; Miller, Tyler W.; Chavis, Aaron R.; Hobbs, Watts B.; Crowe, Braden J.

    2013-06-01

    A microalgae biomass growth model was developed for screening novel strains for their potential to exhibit high biomass productivities under nutrient-replete conditions in photobioreactors or outdoor ponds. Growth is modeled by first estimating the light attenuation by biomass according to Beer-Lambert’s law, and then calculating the specific growth rate in discretized culture volume slices that receive declining light intensities due to attenuation. The model requires only two physical and two species-specific biological input parameters, all of which are relatively easy to determine: incident light intensity, culture depth, as well as the biomass light absorption coefficient and the specific growth rate as a function of light intensity. Roux bottle culture experiments were performed with Nannochloropsis salina at constant temperature (23 °C) at six different incident light intensities (5, 10, 25, 50, 100, 250, and 850 μmol/m2∙ sec) to determine both the specific growth rate under non-shading conditions and the biomass light absorption coefficient as a function of light intensity. The model was successful in predicting the biomass growth rate in these Roux bottle cultures during the light-limited linear phase at different incident light intensities. Model predictions were moderately sensitive to minor variations in the values of input parameters. The model was also successful in predicting the growth performance of Chlorella sp. cultured in LED-lighted 800 L raceway ponds operated at constant temperature (30 °C) and constant light intensity (1650 μmol/m2∙ sec). Measurements of oxygen concentrations as a function of time demonstrated that following exposure to darkness, it takes at least 5 seconds for cells to initiate dark respiration. As a result, biomass loss due to dark respiration in the aphotic zone of a culture is unlikely to occur in highly mixed small-scale photobioreactors where cells move rapidly in and out of the light. By contrast, as

  3. Clinical and genetic aspects of bicuspid aortic valve: a proposed model for family screening based on a review of literature

    Directory of Open Access Journals (Sweden)

    Hubert Baars

    2015-04-01

    Full Text Available Bicuspid aortic valve (BAV is the most common congenital cardiac defect causing serious morbidity including valvular dysfunction and thoracic aortic aneurysms (TAA in around 30% of BAV patients. Cardiological screening of first-degree relatives is advised in recent guidelines given the observed familial clustering of BAV. However, guidelines regarding screening of family members and DNA testing are not unequivocal. The aim of this review is to provide an overview of the literature on echocardiographic screening in first-degree relatives of BAV patients and to propose a model for family screening. In addition, we provide a flowchart for DNA testing. We performed a PubMed search and included studies providing data on echocardiographic screening in asymptomatic relatives of BAV patients. Nine studies were included. In 5.8-47.4% of the families BAV was shown to be familial. Of the screened first-degree relatives 1.8-11% was found to be affected with BAV. Results regarding a potential risk of TAA in first-degree relatives with a tricuspid aortic valve (TAV were conflicting. The reported familial clustering of BAV underlines the importance of cardiological screening in relatives. After reviewing the available family history, patient characteristics and the results of cardiological screening in relatives, follow-up in relatives with a TAV and/or DNA testing may be advised in a subset of families. In this study we propose a model for the clinical and genetic work-up in BAV families, based on the most extensive literature review on family screening performed until now.

  4. Rapid Screening for Exposure to "Non-Target" Pharmaceuticals from Wastewater Effluents by Combining HRMS-Based Suspect Screening and Exposure Modeling.

    Science.gov (United States)

    Singer, Heinz P; Wössner, Annika E; McArdell, Christa S; Fenner, Kathrin

    2016-07-01

    Active pharmaceutical ingredients (APIs) have raised considerable concern over the past decade due to their widespread detection in water resources and their potential to affect ecosystem health. This triggered many attempts to prioritize the large number of known APIs to target monitoring efforts and testing of fate and effects. However, so far, a comprehensive approach to screen for their presence in surface waters has been missing. Here, we explore a combination of an automated suspect screening approach based on liquid chromatography coupled to high-resolution mass spectrometry and a model-based prioritization using consumption data, readily predictable fate properties and a generic mass balance model for activated sludge treatment to comprehensively detect APIs with relevant exposure in wastewater treatment plant effluents. The procedure afforded the detection of 27 APIs that had not been covered in our previous target method, which included 119 parent APIs. The newly detected APIs included seven compounds with a high potential for bioaccumulation and persistence, and also three compounds that were suspected to stem from point sources rather than from consumption as medicines. Analytical suspect screening proved to be more selective than model-based prioritization, making it the method of choice for focusing analytical method development or fate and effect testing on those APIs most relevant to the aquatic environment. However, we found that state-of-the-practice exposure modeling used to predict potential high-exposure substances can be a useful complement to point toward oversights and known or suspected detection gaps in the analytical method, most of which were related to insufficient ionization.

  5. BioSig3D: High Content Screening of Three-Dimensional Cell Culture Models.

    Directory of Open Access Journals (Sweden)

    Cemal Cagatay Bilgin

    Full Text Available BioSig3D is a computational platform for high-content screening of three-dimensional (3D cell culture models that are imaged in full 3D volume. It provides an end-to-end solution for designing high content screening assays, based on colony organization that is derived from segmentation of nuclei in each colony. BioSig3D also enables visualization of raw and processed 3D volumetric data for quality control, and integrates advanced bioinformatics analysis. The system consists of multiple computational and annotation modules that are coupled together with a strong use of controlled vocabularies to reduce ambiguities between different users. It is a web-based system that allows users to: design an experiment by defining experimental variables, upload a large set of volumetric images into the system, analyze and visualize the dataset, and either display computed indices as a heatmap, or phenotypic subtypes for heterogeneity analysis, or download computed indices for statistical analysis or integrative biology. BioSig3D has been used to profile baseline colony formations with two experiments: (i morphogenesis of a panel of human mammary epithelial cell lines (HMEC, and (ii heterogeneity in colony formation using an immortalized non-transformed cell line. These experiments reveal intrinsic growth properties of well-characterized cell lines that are routinely used for biological studies. BioSig3D is being released with seed datasets and video-based documentation.

  6. Computer-assisted lesion detection system for stomach screening using stomach shape and appearance models

    Science.gov (United States)

    Midoh, Y.; Nakamura, M.; Takashima, M.; Nakamae, K.; Fujioka, H.

    2007-03-01

    In Japan, stomach cancer is one of the three most common causes of death from cancer. Since periodic health checks of stomach X-rays have become more widely carried out, the physicians' burdens have been increasing in the mass screening to detect initial symptoms of a disease. For the purpose of automatic diagnosis, we try to develop a computer-assisted lesion detection system for stomach screening. The proposed system has two databases. One is the stomach shape database that consists of the computer graphics stomach 3D models based on biomechanics simulation and their projected 2D images. The other is the normal appearance database that is constructed by learning patterns in a normal patient training set. The stomach contour is extracted from an X-ray image including a barium filled region by the following steps. Firstly, the approximated stomach region is obtained by nonrigid registration based on mutual information. We define nonrigid transformation as one that includes translations, rotations, scaling, air-barium interface and weights of eigenvectors determined by principal components analysis in the stomach shape database. Secondly, the accurate stomach contour is extracted from the gradient of an image by using the Dynamic Programming. After then, stomach lesions are detected by inspecting whether the Mahalanobis distance from the mean in the normal appearance database is longer than a suitable value on the extracted stomach contour. We applied our system to 75 X-ray images of barium-filled stomach to show its validity.

  7. High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.

    Science.gov (United States)

    Bancos, Irina; Bida, John Paul; Tian, Defeng; Bundrick, Mary; John, Kristen; Holte, Molly Nelson; Her, Yeng F; Evans, Debra; Saenz, Dyana T; Poeschla, Eric M; Hook, Derek; Georg, Gunda; Maher, L James

    2013-01-01

    Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD(+) in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor.

  8. Hierarchical dose-response modeling for high-throughput toxicity screening of environmental chemicals.

    Science.gov (United States)

    Wilson, Ander; Reif, David M; Reich, Brian J

    2014-03-01

    High-throughput screening (HTS) of environmental chemicals is used to identify chemicals with high potential for adverse human health and environmental effects from among the thousands of untested chemicals. Predicting physiologically relevant activity with HTS data requires estimating the response of a large number of chemicals across a battery of screening assays based on sparse dose-response data for each chemical-assay combination. Many standard dose-response methods are inadequate because they treat each curve separately and under-perform when there are as few as 6-10 observations per curve. We propose a semiparametric Bayesian model that borrows strength across chemicals and assays. Our method directly parametrizes the efficacy and potency of the chemicals as well as the probability of response. We use the ToxCast data from the U.S. Environmental Protection Agency (EPA) as motivation. We demonstrate that our hierarchical method provides more accurate estimates of the probability of response, efficacy, and potency than separate curve estimation in a simulation study. We use our semiparametric method to compare the efficacy of chemicals in the ToxCast data to well-characterized reference chemicals on estrogen receptor α (ERα) and peroxisome proliferator-activated receptor γ (PPARγ) assays, then estimate the probability that other chemicals are active at lower concentrations than the reference chemicals.

  9. BioSig3D: High Content Screening of Three-Dimensional Cell Culture Models.

    Science.gov (United States)

    Bilgin, Cemal Cagatay; Fontenay, Gerald; Cheng, Qingsu; Chang, Hang; Han, Ju; Parvin, Bahram

    2016-01-01

    BioSig3D is a computational platform for high-content screening of three-dimensional (3D) cell culture models that are imaged in full 3D volume. It provides an end-to-end solution for designing high content screening assays, based on colony organization that is derived from segmentation of nuclei in each colony. BioSig3D also enables visualization of raw and processed 3D volumetric data for quality control, and integrates advanced bioinformatics analysis. The system consists of multiple computational and annotation modules that are coupled together with a strong use of controlled vocabularies to reduce ambiguities between different users. It is a web-based system that allows users to: design an experiment by defining experimental variables, upload a large set of volumetric images into the system, analyze and visualize the dataset, and either display computed indices as a heatmap, or phenotypic subtypes for heterogeneity analysis, or download computed indices for statistical analysis or integrative biology. BioSig3D has been used to profile baseline colony formations with two experiments: (i) morphogenesis of a panel of human mammary epithelial cell lines (HMEC), and (ii) heterogeneity in colony formation using an immortalized non-transformed cell line. These experiments reveal intrinsic growth properties of well-characterized cell lines that are routinely used for biological studies. BioSig3D is being released with seed datasets and video-based documentation.

  10. The use of screening effects in modelling route-based daytime road surface temperature

    Science.gov (United States)

    Hu, Yumei; Almkvist, Esben; Lindberg, Fredrik; Bogren, Jörgen; Gustavsson, Torbjörn

    2016-07-01

    Winter road maintenance is essential for road safety. Accurate predictions of the road surface temperature (RST) and conditions can enhance the efficiency of winter road maintenance. Screening effects, which encompass shading effects and the influence of the sky-view factor ( ψ s ), influence RST distributions because they affect road surface radiation fluxes. In this work, light detection and ranging (Lidar) data are used to derive shadow patterns and ψ s values, and the resulting shadow patterns are used to model route-based RST distributions along two stretches of road in Sweden. The shading patterns and road surface radiation fluxes calculated from the Lidar data generally agreed well with measured RST values. Variation in land use types and the angle between the road direction and solar azimuth may introduce uncertainties, and accounting for these factors may improve the results obtained in certain cases. A simple shading model that only accounts for the direct radiation at the instant of measurement is often sufficient to provide reasonably accurate RST estimates. However, in certain cases, such as those involving measurements close to sunset, it is important to consider the radiation accumulated over several hours. The inclusion of ψ s improves the model performance even more in such cases. Overall, RST models based on the accumulated direct shortwave radiation offered an optimal balance of simplicity and accuracy. General radiation models were built for country road and highway environments, explaining up to 70 and 65 %, respectively, of the observed variation in RST along the corresponding stretches of road.

  11. A globally applicable location-specific screening model for assessing the relative risk of pesticide leaching

    Energy Technology Data Exchange (ETDEWEB)

    Whelan, M.J. [Unilever Safety and Environmental Assurance Centre, Colworth House, Sharnbrook, Bedfordshire, MK44 1LQ (United Kingdom)]. E-mail: mick.whelan@unilever.com; Davenport, E.J. [Unilever Safety and Environmental Assurance Centre, Colworth House, Sharnbrook, Bedfordshire, MK44 1LQ (United Kingdom); Smith, B.G. [Unilever Sustainable Agriculture Team, Colworth House, Sharnbrook, Bedfordshire, MK44 1LQ (United Kingdom)

    2007-05-15

    A screening model of pesticide leaching loss is described which forms part of a multi-criteria risk-based indicator system called PRoMPT (Pesticide Risk Management and Profiling Tool). The leaching model evaluates pesticide fate in soil for any application rate and time of application (including multiple applications), for any land-based location in the world. It considers a generic evaluative environment with fixed dimensions and soil properties. The soil profile is conceptualised as a number of discrete layers. Equilibrium partitioning between adsorbed and dissolved chemical (based on the organic carbon-water partition coefficient [K {sub OC}]) is assumed in each time step, in each layer. Non-leaching losses are described using first order kinetics. Drainage is assumed to be uniform throughout the soil profile but varies temporally. The drainage rate, which can be augmented by evapotranspiration-adjusted irrigation, is derived from long-term mean monthly water balance model calculations performed for 30 arc-minute grid cells across the entire ice-free land surface of the earth. Although, such predictions are approximate, they do capture the seasonality and relative magnitude of drainage and allow the model to be applied anywhere, without the need for extensive data compilation. PRoMPT predictions are shown to be consistent with those made by more sophisticated models (PRZM, PELMO and PEARL) for the FOCUS groundwater scenarios.

  12. In silico screening of estrogen-like chemicals based on different nonlinear classification models.

    Science.gov (United States)

    Liu, Huanxiang; Papa, Ester; Walker, John D; Gramatica, Paola

    2007-07-01

    Increasing concern is being shown by the scientific community, government regulators, and the public about endocrine-disrupting chemicals that are adversely affecting human and wildlife health through a variety of mechanisms. There is a great need for an effective means of rapidly assessing endocrine-disrupting activity, especially estrogen-simulating activity, because of the large number of such chemicals in the environment. In this study, quantitative structure activity relationship (QSAR) models were developed to quickly and effectively identify possible estrogen-like chemicals based on 232 structurally-diverse chemicals (training set) by using several nonlinear classification methodologies (least-square support vector machine (LS-SVM), counter-propagation artificial neural network (CP-ANN), and k nearest neighbour (kNN)) based on molecular structural descriptors. The models were externally validated by 87 chemicals (prediction set) not included in the training set. All three methods can give satisfactory prediction results both for training and prediction sets, and the most accurate model was obtained by the LS-SVM approach through the comparison of performance. In addition, our model was also applied to about 58,000 discrete organic chemicals; about 76% were predicted not to bind to Estrogen Receptor. The obtained results indicate that the proposed QSAR models are robust, widely applicable and could provide a feasible and practical tool for the rapid screening of potential estrogens.

  13. Adolescent idiopathic scoliosis screening for school, community, and clinical health promotion practice utilizing the PRECEDE-PROCEED model

    Directory of Open Access Journals (Sweden)

    Wyatt Lawrence A

    2005-11-01

    Full Text Available Abstract Background Screening for adolescent idiopathic scoliosis (AIS is a commonly performed procedure for school children during the high risk years. The PRECEDE-PROCEDE (PP model is a health promotion planning model that has not been utilized for the clinical diagnosis of AIS. The purpose of this research is to study AIS in the school age population using the PP model and its relevance for community, school, and clinical health promotion. Methods MEDLINE was utilized to locate AIS data. Studies were screened for relevance and applicability under the auspices of the PP model. Where data was unavailable, expert opinion was utilized based on consensus. Results The social assessment of quality of life is limited with few studies approaching the long-term effects of AIS. Epidemiologically, AIS is the most common form of scoliosis and leading orthopedic problem in children. Behavioral/environmental studies focus on discovering etiologic relationships yet this data is confounded because AIS is not a behavioral. Illness and parenting health behaviors can be appreciated. The educational diagnosis is confounded because AIS is an orthopedic disorder and not behavioral. The administration/policy diagnosis is hindered in that scoliosis screening programs are not considered cost-effective. Policies are determined in some schools because 26 states mandate school scoliosis screening. There exists potential error with the Adam's test. The most widely used measure in the PP model, the Health Belief Model, has not been utilized in any AIS research. Conclusion The PP model is a useful tool for a comprehensive study of a particular health concern. This research showed where gaps in AIS research exist suggesting that there may be problems to the implementation of school screening. Until research disparities are filled, implementation of AIS screening by school, community, and clinical health promotion will be compromised. Lack of data and perceived importance by

  14. Establishment of a P-glycoprotein substrate screening model and its preliminary application

    Institute of Scientific and Technical Information of China (English)

    Yi Wang; Jiang Cao; Su Zeng

    2004-01-01

    AIM: To establish a high P-glycoprotein (P-gp) expressing cell line as a model for studying drug absorption and distribution, and to explore the preliminary application of this screening model.METHODS: A full-length MDR1 cDNA fragment in plasmid pMDRA1 was first subcloned into plasmid pET28a(+), then MDR1 cDNA was cut from the recombinant plasmid with double-digestion and ligated into the mammalian expression vector pcDNA3.1(+). The recombinant plasmid pcDNA3.1(+)/MDR1 was transfected into breast cancer cell line Bcap37using the Superfect transfection reagent. Several stably transfected clones were obtained after selection with G418.Real-time fluorescent quantitative RT- PCR and Western blot methods were used to detect the expression of P-gp, and the cellular location of the expressed protein was determined by immunohistochemical staining. Drug sensitivity assay was used to evaluate the biological function of expressed P-gp.Concentration of quercetin in cells was determined by highperformance liquid chromatography (HPLC).RESULTS: The recombinant plasmid was confirmed to be inserted in the correct orientation by restrictive enzyme digestion and DNA sequencing. Real-time fluorescent quantitative RT-PCR showed a higher level of P-cp mRNA in transfected cells compared to that in the control cells, and the Western blot result also indicated that P-gp expression in transfected cells was higher than that in control cells. The immunohistochemical staining showed that the expressed P-gp was localized on cell membranes. Drug sensitivity assay showed that the IC50 for adriamycin and colchicine of the transfected cells was higher than that of the control cells.The concentration of quercetin in model cells was lower than that in control cells by HPLC. After P-gp inhibitor verapamil was administered, the concentration of quercetin in model cells was increased.CONCLUSION: A high P-gp expressing ceil line can be established, which could provide a suitable in vitro model system for

  15. New radio model in the fourth screen: radiovision, the radio that you can watch

    Directory of Open Access Journals (Sweden)

    Sandra CAVIA FRAILE

    2016-12-01

    Full Text Available The traditional radio is not strange to the social revolution that Internet and new technologies are raising. In recent years, the fourth screen has led the emergence of new models of radio, including Radiovision. The «radio that you can watch» intends to change and innovate the radio broadcasting media to offer a product that meets the multimedia requirements of users. However, currently, the Radiovisión is still at an early stage and it has many aspects that it should improve and care, as the contents and the staging. It is a big chance for the radio that poses challenges and opportunities both for journalism and journalists.

  16. Bilateral Image Subtraction and Multivariate Models for the Automated Triaging of Screening Mammograms

    Directory of Open Access Journals (Sweden)

    José Celaya-Padilla

    2015-01-01

    Full Text Available Mammography is the most common and effective breast cancer screening test. However, the rate of positive findings is very low, making the radiologic interpretation monotonous and biased toward errors. This work presents a computer-aided diagnosis (CADx method aimed to automatically triage mammogram sets. The method coregisters the left and right mammograms, extracts image features, and classifies the subjects into risk of having malignant calcifications (CS, malignant masses (MS, and healthy subject (HS. In this study, 449 subjects (197 CS, 207 MS, and 45 HS from a public database were used to train and evaluate the CADx. Percentile-rank (p-rank and z-normalizations were used. For the p-rank, the CS versus HS model achieved a cross-validation accuracy of 0.797 with an area under the receiver operating characteristic curve (AUC of 0.882; the MS versus HS model obtained an accuracy of 0.772 and an AUC of 0.842. For the z-normalization, the CS versus HS model achieved an accuracy of 0.825 with an AUC of 0.882 and the MS versus HS model obtained an accuracy of 0.698 and an AUC of 0.807. The proposed method has the potential to rank cases with high probability of malignant findings aiding in the prioritization of radiologists work list.

  17. QSAR classification models for the screening of the endocrine-disrupting activity of perfluorinated compounds.

    Science.gov (United States)

    Kovarich, S; Papa, E; Li, J; Gramatica, P

    2012-01-01

    Perfluorinated compounds (PFCs) are a class of emerging pollutants still widely used in different materials as non-adhesives, waterproof fabrics, fire-fighting foams, etc. Their toxic effects include potential for endocrine-disrupting activity, but the amount of experimental data available for these pollutants is limited. The use of predictive strategies such as quantitative structure-activity relationships (QSARs) is recommended under the REACH regulation, to fill data gaps and to screen and prioritize chemicals for further experimentation, with a consequent reduction of costs and number of tested animals. In this study, local classification models for PFCs were developed to predict their T4-TTR (thyroxin-transthyretin) competing potency. The best models were selected by maximizing the sensitivity and external predictive ability. These models, characterized by robustness, good predictive power and a defined applicability domain, were applied to predict the activity of 33 other PFCs of environmental concern. Finally, classification models recently published by our research group for T4-TTR binding of brominated flame retardants and for estrogenic and anti-androgenic activity were applied to the studied perfluorinated chemicals to compare results and to further evaluate the potential for these PFCs to cause endocrine disruption.

  18. Screening of persistent organic pollutants by QSPR classification models: a comparative study.

    Science.gov (United States)

    Papa, Ester; Gramatica, Paola

    2008-08-01

    A Quantitative Structure-Property Relationships (QSPRs) study for the prediction of the environmental persistence of a set of 250 heterogeneous organic compounds is here presented. Three a priori defined classes of environmental persistence were generated, by Hierarchical Cluster Analysis, from the combination of half-life data in air, water, soil and sediment available for all the studied compounds. QSPR classification models were successfully developed using different techniques (k-NN, CART and CP-ANN) and three interpretable theoretical molecular descriptors. Robust external validation was provided by statistical splitting and also on completely new data. The good performances of all these models were compared and their structural domains were analyzed. The analysis of the errors highlights a slight tendency of persistence overestimation, misclassifying chemicals from a lower to a higher class of persistence, in line with the precautionary principle. Finally, the reliability of the proposed QSPR models was verified further with new data from the literature. The structure-based classification models, applicable for the prediction of potential persistence of heterogeneous organic compounds, could be useful as preliminary support tools for the identification and prioritization of new potential POPs among already existing chemicals as well as "screening prior to synthesis" procedures to avoid the production, and consequent release into the environment, of new POPs.

  19. Mass screening on abdominal aortic aneurysm in men aged 60 to 65 years in The Netherlands. Impact on life expectancy and cost-effectiveness using a Markov model.

    NARCIS (Netherlands)

    Boll, A.P.M.; Severens, J.L.; Verbeek, A.L.M.; Vliet, J.A. van der

    2003-01-01

    OBJECTIVES: To predict the costs and effects on life expectancy of an AAA screening programme. METHODS: A Markov model was designed to compare the effects of a single screening for a cohort of men 60-65 years with the current no screening strategy. The following health states were distinguished: no

  20. Modeling indoor TV/screen viewing and adult physical and mental health: Health Survey for England, 2012.

    Science.gov (United States)

    Shiue, Ivy

    2016-06-01

    The aim of the present study was to model indoor TV/screen viewing and a series of adult health conditions and cognitive performance in a country-wide, population-based setting in recent years. Data was retrieved from Health Survey for England, 2012. Information on demographics, lifestyle factors, self-reported health conditions, and TV and/or screen watching hours in adults was collected by household interviews. Chi-square test and survey-weighted logistic and multi-nominal modeling were performed. Of 8114 English adults aged 18-98, 4138 people (51.1 %) watched TV and/or screen daily for 2 h or more on average. Two thousand five-hundred people (30.9 %) watched for 3 h or more. TV and/or screening watching for 2+ hours was associated with endocrine or metabolic disorders, diabetes, mental disorders (including poor scores in General Health Questionnaire and Warwick-Edinburgh Mental Well-being Scale), nervous system disorders, eye complaints, circulatory system disorders, respiratory system disorders, musculoskeletal system disorders, and self-rated health. TV and/or screen watching for 3+ hours was associated with digestive disorders and clotting disorder. TV and/or screen watching for 5+ hours was associated with cancer. TV and/or screen watching for 6+, 8+, or 11+ hours was associated with bladder disease, genito-urinary system disorders or bowel disease, respectively. There were no risk associations (within 20 h) found with ear complaints, infectious disease, and blood system disorders. Future educational and public health programs minimizing TV and/or screen viewing in order to protect from physical inactivity and X-radiation might be needed while research on the combined effect of physical inactivity and X-radiation should be explored.

  1. A high-throughput cheese manufacturing model for effective cheese starter culture screening.

    Science.gov (United States)

    Bachmann, H; Kruijswijk, Z; Molenaar, D; Kleerebezem, M; van Hylckama Vlieg, J E T

    2009-12-01

    Cheese making is a process in which enzymatic coagulation of milk is followed by protein separation, carbohydrate removal, and an extended bacterial fermentation. The number of variables in this complex process that influence cheese quality is so large that the developments of new manufacturing protocols are cumbersome. To reduce screening costs, several models have been developed to miniaturize the cheese manufacturing process. However, these models are not able to accommodate the throughputs required for systematic screening programs. Here, we describe a protocol that allows the parallel manufacturing of approximately 600 cheeses in individual cheese vats each with individual process specifications. Protocols for the production of miniaturized Gouda- and Cheddar-type cheeses have been developed. Starting with as little as 1.7 mL of milk, miniature cheeses of about 170 mg can be produced and they closely resemble conventionally produced cheese in terms of acidification profiles, moisture and salt contents, proteolysis, flavor profiles, and microstructure. Flavor profiling of miniature cheeses manufactured with and without mixed-strain adjunct starter cultures allowed the distinguishing of the different cheeses. Moreover, single-strain adjunct starter cultures engineered to overexpress important flavor-related enzymes revealed effects similar to those described in industrial cheese. Benchmarking against industrial cheese produced from the same raw materials established a good correlation between their proteolytic degradation products and their flavor profiles. These miniature cheeses, referred to as microcheeses, open new possibilities to study many aspects of cheese production, which will not only accelerate product development but also allow a more systematic approach to investigate the complex biochemistry and microbiology of cheese making.

  2. 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 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.

  3. VR-SCOSMO: A smooth conductor-like screening model with charge-dependent radii for modeling chemical reactions.

    Science.gov (United States)

    Kuechler, Erich R; Giese, Timothy J; York, Darrin M

    2016-04-28

    To better represent the solvation effects observed along reaction pathways, and of ionic species in general, a charge-dependent variable-radii smooth conductor-like screening model (VR-SCOSMO) is developed. This model is implemented and parameterized with a third order density-functional tight binding quantum model, DFTB3/3OB-OPhyd, a quantum method which was developed for organic and biological compounds, utilizing a specific parameterization for phosphate hydrolysis reactions. Unlike most other applications with the DFTB3/3OB model, an auxiliary set of atomic multipoles is constructed from the underlying DFTB3 density matrix which is used to interact the solute with the solvent response surface. The resulting method is variational, produces smooth energies, and has analytic gradients. As a baseline, a conventional SCOSMO model with fixed radii is also parameterized. The SCOSMO and VR-SCOSMO models shown have comparable accuracy in reproducing neutral-molecule absolute solvation free energies; however, the VR-SCOSMO model is shown to reduce the mean unsigned errors (MUEs) of ionic compounds by half (about 2-3 kcal/mol). The VR-SCOSMO model presents similar accuracy as a charge-dependent Poisson-Boltzmann model introduced by Hou et al. [J. Chem. Theory Comput. 6, 2303 (2010)]. VR-SCOSMO is then used to examine the hydrolysis of trimethylphosphate and seven other phosphoryl transesterification reactions with different leaving groups. Two-dimensional energy landscapes are constructed for these reactions and calculated barriers are compared to those obtained from ab initio polarizable continuum calculations and experiment. Results of the VR-SCOSMO model are in good agreement in both cases, capturing the rate-limiting reaction barrier and the nature of the transition state.

  4. VR-SCOSMO: A smooth conductor-like screening model with charge-dependent radii for modeling chemical reactions

    Science.gov (United States)

    Kuechler, Erich R.; Giese, Timothy J.; York, Darrin M.

    2016-04-01

    To better represent the solvation effects observed along reaction pathways, and of ionic species in general, a charge-dependent variable-radii smooth conductor-like screening model (VR-SCOSMO) is developed. This model is implemented and parameterized with a third order density-functional tight binding quantum model, DFTB3/3OB-OPhyd, a quantum method which was developed for organic and biological compounds, utilizing a specific parameterization for phosphate hydrolysis reactions. Unlike most other applications with the DFTB3/3OB model, an auxiliary set of atomic multipoles is constructed from the underlying DFTB3 density matrix which is used to interact the solute with the solvent response surface. The resulting method is variational, produces smooth energies, and has analytic gradients. As a baseline, a conventional SCOSMO model with fixed radii is also parameterized. The SCOSMO and VR-SCOSMO models shown have comparable accuracy in reproducing neutral-molecule absolute solvation free energies; however, the VR-SCOSMO model is shown to reduce the mean unsigned errors (MUEs) of ionic compounds by half (about 2-3 kcal/mol). The VR-SCOSMO model presents similar accuracy as a charge-dependent Poisson-Boltzmann model introduced by Hou et al. [J. Chem. Theory Comput. 6, 2303 (2010)]. VR-SCOSMO is then used to examine the hydrolysis of trimethylphosphate and seven other phosphoryl transesterification reactions with different leaving groups. Two-dimensional energy landscapes are constructed for these reactions and calculated barriers are compared to those obtained from ab initio polarizable continuum calculations and experiment. Results of the VR-SCOSMO model are in good agreement in both cases, capturing the rate-limiting reaction barrier and the nature of the transition state.

  5. Multiple conformational states in retrospective virtual screening - homology models vs. crystal structures: beta-2 adrenergic receptor case study.

    Science.gov (United States)

    Mordalski, Stefan; Witek, Jagna; Smusz, Sabina; Rataj, Krzysztof; Bojarski, Andrzej J

    2015-01-01

    Distinguishing active from inactive compounds is one of the crucial problems of molecular docking, especially in the context of virtual screening experiments. The randomization of poses and the natural flexibility of the protein make this discrimination even harder. Some of the recent approaches to post-docking analysis use an ensemble of receptor models to mimic this naturally occurring conformational diversity. However, the optimal number of receptor conformations is yet to be determined. In this study, we compare the results of a retrospective screening of beta-2 adrenergic receptor ligands performed on both the ensemble of receptor conformations extracted from ten available crystal structures and an equal number of homology models. Additional analysis was also performed for homology models with up to 20 receptor conformations considered. The docking results were encoded into the Structural Interaction Fingerprints and were automatically analyzed by support vector machine. The use of homology models in such virtual screening application was proved to be superior in comparison to crystal structures. Additionally, increasing the number of receptor conformational states led to enhanced effectiveness of active vs. inactive compounds discrimination. For virtual screening purposes, the use of homology models was found to be most beneficial, even in the presence of crystallographic data regarding the conformational space of the receptor. The results also showed that increasing the number of receptors considered improves the effectiveness of identifying active compounds by machine learning methods. Graphical abstractComparison of machine learning results obtained for various number of beta-2 AR homology models and crystal structures.

  6. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Faye M. Drawnel

    2014-11-01

    Full Text Available Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.

  7. Brain slices as models for neurodegenerative disease and screening platforms to identify novel therapeutics.

    Science.gov (United States)

    Cho, Seongeun; Wood, Andrew; Bowlby, Mark R

    2007-03-01

    Recent improvements in brain slice technology have made this biological preparation increasingly useful for examining pathophysiology of brain diseases in a tissue context. Brain slices maintain many aspects of in vivo biology, including functional local synaptic circuitry with preserved brain architecture, while allowing good experimental access and precise control of the extracellular environment, making them ideal platforms for dissection of molecular pathways underlying neuronal dysfunction. Importantly, these ex vivo systems permit direct treatment with pharmacological agents modulating these responses and thus provide surrogate therapeutic screening systems without recourse to whole animal studies. Virus or particle mediated transgenic expression can also be accomplished relatively easily to study the function of novel genes in a normal or injured brain tissue context.In this review we will discuss acute brain injury models in organotypic hippocampal and co-culture systems and the effects of pharmacological modulation on neurodegeneration. The review will also cover the evidence of developmental plasticity in these ex vivo models, demonstrating emergence of injury-stimulated neuronal progenitor cells, and neurite sprouting and axonal regeneration following pathway lesioning. Neuro-and axo-genesis are emerging as significant factors contributing to brain repair following many acute and chronic neurodegenerative disorders. Therefore brain slice models may provide a critical contextual experimental system to explore regenerative mechanisms in vitro.

  8. Echinococcus metacestodes as laboratory models for the screening of drugs against cestodes and trematodes.

    Science.gov (United States)

    Hemphill, A; Stadelmann, B; Scholl, S; Müller, J; Spiliotis, M; Müller, N; Gottstein, B; Siles-Lucas, M

    2010-03-01

    Among the cestodes, Echinococcus granulosus, Echinococcus multilocularis and Taenia solium represent the most dangerous parasites. Their larval stages cause the diseases cystic echinococcosis (CE), alveolar echinococcosis (AE) and cysticercosis, respectively, which exhibit considerable medical and veterinary health concerns with a profound economic impact. Others caused by other cestodes, such as species of the genera Mesocestoides and Hymenolepis, are relatively rare in humans. In this review, we will focus on E. granulosus and E. multilocularis metacestode laboratory models and will review the use of these models in the search for novel drugs that could be employed for chemotherapeutic treatment of echinococcosis. Clearly, improved therapeutic drugs are needed for the treatment of AE and CE, and this can only be achieved through the development of medium-to-high throughput screening approaches. The most recent achievements in the in vitro culture and genetic manipulation of E. multilocularis cells and metacestodes, and the accessability of the E. multilocularis genome and EST sequence information, have rendered the E. multilocularis model uniquely suited for studies on drug-efficacy and drug target identification. This could lead to the development of novel compounds for the use in chemotherapy against echinococcosis, and possibly against diseases caused by other cestodes, and potentially also trematodes.

  9. Advances in small animal mesentery models for in vivo flow cytometry, dynamic microscopy, and drug screening

    Institute of Scientific and Technical Information of China (English)

    Ekaterina I Galanzha; Vladimir P Zharov; Philips Classic

    2007-01-01

    Using animal mesentery with intravital optical microscopy is a well-established experimental model for studying blood and lymph microcirculation in vivo.Recent advances in cell biology and optical techniques provide the basis for extending this model for new applications, which should generate significantly improved experimental data. This review summarizes the achievements in this specific area, including in vivo label-free blood and lymph photothermal flow cytometry,super-sensitive fluorescence image cytometry, light scattering and speckle flow cytometry, microvessel dynamic microscopy, infrared (IR) angiography, and high-speed imaging of individual cells in fast flow. The capabilities of these techniques, using the rat mesentery model, were demonstrated in various studies; e.g., realtime quantitative detection of circulating and migrating individual blood and cancer cells, studies on vascular dynamics with a focus on lymphatics under normal conditions and under different interventions (e.g. lasers,drugs, nicotine), assessment of lymphatic disturbances from experimental lymphedema, monitoring cell traffic between blood and lymph systems, and highspeed imaging of cell transient deformability in flow.In particular, the obtained results demonstrated that individual cell transportation in living organisms depends on cell type (e.g., normal blood or leukemic cells), the cell's functional state (e.g., live, apoptotic, or necrotic),and the functional status of the organism. Possible future applications, including in vivo early diagnosis and prevention of disease, monitoring immune response and apoptosis, chemo- and radio-sensitivity tests, and drug screening, are also discussed.

  10. Factor Analytic Replication and Model Comparison of the BASC-2 Behavioral and Emotional Screening System.

    Science.gov (United States)

    Splett, Joni Williams; Raborn, Anthony; Lane, Kathleen Lynne; Binney, Alexandra J; Chafouleas, Sandra M

    2017-03-06

    We conducted this study to add to literature of previous conflicting factorial examinations of the BASC-2 Behavioral and Emotional Screening System (BESS), Teacher Form-Child/Adolescent. Data were collected by an urban school district in the southeastern United States including 2,228 students rated by 120 teachers in Fall 2014 and 1,955 students rated by 104 teachers in Spring 2015. In both samples, we replicated and then conceptually and statistically compared factor models to examine the (a) 4-factor structure from which the BESS Teacher Form was developed, and (b) existence of a general factor currently being used. Previous studies examined the 4-factor and bifactor structure of the BESS Teacher Form on separate samples. Our model comparison results support a multidimensional interpretation. We recovered similar fit statistics and standardized factor loadings as previous factor analyses. However, measures of variance accounted for by the general factor were below recommended thresholds of a unidimensional construct. We recommend advancing a factorial model that represents a weighted combination of general and specific factors, but do not support continued use of a unidimensional total T score. Limitations and implications of the study are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  11. An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs.

    Directory of Open Access Journals (Sweden)

    Young-Ki Bae

    Full Text Available The epidermal growth factor receptor (EGFR is a well-established target for cancer treatment. EGFR tyrosine kinase (TK inhibitors, such as gefinitib and erlotinib, have been developed as anti-cancer drugs. Although non-small cell lung carcinoma with an activating EGFR mutation, L858R, responds well to gefinitib and erlotinib, tumors with a doubly mutated EGFR, T790M-L858R, acquire resistance to these drugs. The C. elegans EGFR homolog LET-23 and its downstream signaling pathway have been studied extensively to provide insight into regulatory mechanisms conserved from C. elegans to humans. To develop an in vivo screening system for potential cancer drugs targeting specific EGFR mutants, we expressed three LET-23 chimeras in which the TK domain was replaced with either the human wild-type TK domain (LET-23::hEGFR-TK, a TK domain with the L858R mutation (LET-23::hEGFR-TK[L858R], or a TK domain with the T790M-L858R mutations (LET-23::hEGFR-TK[T790M-L858R] in C. elegans vulval cells using the let-23 promoter. The wild-type hEGFR-TK chimeric protein rescued the let-23 mutant phenotype, and the activating mutant hEGFR-TK chimeras induced a multivulva (Muv phenotype in a wild-type C. elegans background. The anti-cancer drugs gefitinib and erlotinib suppressed the Muv phenotype in LET-23::hEGFR-TK[L858R]-expressing transgenic animals, but not in LET-23::hEGFR-TK[T790M-L858R] transgenic animals. As a pilot screen, 8,960 small chemicals were tested for Muv suppression, and AG1478 (an EGFR-TK inhibitor and U0126 (a MEK inhibitor were identified as potential inhibitors of EGFR-mediated biological function. In conclusion, transgenic C. elegans expressing chimeric LET-23::hEGFR-TK proteins are a model system that can be used in mutation-specific screens for new anti-cancer drugs.

  12. Deciphering the intracellular metabolism of Listeria monocytogenes by mutant screening and modelling

    Directory of Open Access Journals (Sweden)

    Dandekar Thomas

    2010-10-01

    Full Text Available Abstract Background The human pathogen Listeria monocytogenes resides and proliferates within the cytoplasm of epithelial cells. While the virulence factors essentially contributing to this step of the infection cycle are well characterized, the set of listerial genes contributing to intracellular replication remains to be defined on a genome-wide level. Results A comprehensive library of L. monocytogenes strain EGD knockout mutants was constructed upon insertion-duplication mutagenesis, and 1491 mutants were tested for their phenotypes in rich medium and in a Caco-2 cell culture assay. Following sequencing of the plasmid insertion site, 141 different genes required for invasion of and replication in Caco-2 cells were identified. Ten in-frame deletion mutants were constructed that confirmed the data. The genes with known functions are mainly involved in cellular processes including transport, in the intermediary metabolism of sugars, nucleotides and lipids, and in information pathways such as regulatory functions. No function could be ascribed to 18 genes, and a counterpart of eight genes is missing in the apathogenic species L. innocua. Mice infection studies revealed the in vivo requirement of IspE (Lmo0190 involved in mevalonate synthesis, and of the novel ABC transporter Lmo0135-0137 associated with cysteine transport. Based on the data of this genome-scale screening, an extreme pathway and elementary mode analysis was applied that demonstrates the critical role of glycerol and purine metabolism, of fucose utilization, and of the synthesis of glutathione, aspartate semialdehyde, serine and branched chain amino acids during intracellular replication of L. monocytogenes. Conclusion The combination of a genetic screening and a modelling approach revealed that a series of transporters help L. monocytogenes to overcome a putative lack of nutrients within cells, and that a high metabolic flexibility contributes to the intracellular replication of

  13. DockoMatic 2.0: high throughput inverse virtual screening and homology modeling.

    Science.gov (United States)

    Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T; McDougal, Owen M; Andersen, Timothy L

    2013-08-26

    DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to (1) conduct high throughput inverse virtual screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELER programs and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education.

  14. DockoMatic 2.0: High Throughput Inverse Virtual Screening and Homology Modeling

    Science.gov (United States)

    Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T.; McDougal, Owen M.; Andersen, Timothy L.

    2013-01-01

    DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly Graphical User Interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to: (1) conduct high throughput Inverse Virtual Screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying a receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories, and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELLER programs, and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education. PMID:23808933

  15. High throughput ADME screening: practical considerations, impact on the portfolio and enabler of in silico ADME models.

    Science.gov (United States)

    Hop, Cornelis E C A; Cole, Mark J; Davidson, Ralph E; Duignan, David B; Federico, James; Janiszewski, John S; Jenkins, Kelly; Krueger, Suzanne; Lebowitz, Rebecca; Liston, Theodore E; Mitchell, Walter; Snyder, Mark; Steyn, Stefan J; Soglia, John R; Taylor, Christine; Troutman, Matt D; Umland, John; West, Michael; Whalen, Kevin M; Zelesky, Veronica; Zhao, Sabrina X

    2008-11-01

    Evaluation and optimization of drug metabolism and pharmacokinetic data plays an important role in drug discovery and development and several reliable in vitro ADME models are available. Recently higher throughput in vitro ADME screening facilities have been established in order to be able to evaluate an appreciable fraction of synthesized compounds. The ADME screening process can be dissected in five distinct steps: (1) plate management of compounds in need of in vitro ADME data, (2) optimization of the MS/MS method for the compounds, (3) in vitro ADME experiments and sample clean up, (4) collection and reduction of the raw LC-MS/MS data and (5) archival of the processed ADME data. All steps will be described in detail and the value of the data on drug discovery projects will be discussed as well. Finally, in vitro ADME screening can generate large quantities of data obtained under identical conditions to allow building of reliable in silico models.

  16. The dynamic modeling and design improvement of a piezoelectric exciter of a touch screen device for efficient tactile feedback

    Science.gov (United States)

    Park, Young-Min; Kim, Kwang-Joon

    2011-05-01

    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.

  17. Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors.

    Science.gov (United States)

    Fazi, Roberta; Tintori, Cristina; Brai, Annalaura; Botta, Lorenzo; Selvaraj, Manikandan; Garbelli, Anna; Maga, Giovanni; Botta, Maurizio

    2015-11-23

    Targeting cellular cofactors instead of viral enzymes represents a new strategy to combat infectious diseases, which should help to overcome the problem of viral resistance. Recently, it has been revealed that the cellular ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3) is an essential host factor for the replication of several viruses such as HIV, HCV, JEV, Dengue, and West Nile. Accordingly, a drug targeting DDX3 could theoretically inhibit all viruses that are dependent on this host factor. Herein, for the first time, a model of hDDX3 in its closed conformation, which binds the viral RNA was developed by using the homology module of Prime through the Maestro interface of Schrodinger. Next, a structure-based virtual screening protocol was applied to identify DDX3 small molecule inhibitors targeting the RNA binding pocket. As a result, an impressive hit rate of 40% was obtained with the identification of 10 active compounds out of the 25 tested small molecules. The best poses of the active ligands highlighted the crucial residues to be targeted for the inhibition of the helicase activity of DDX3. The obtained results confirm the reliability of the constructed DDX3/RNA model and the proposed computational strategy for investigating novel DDX3 inhibitors.

  18. Screen for child anxiety related emotional disorders: are subscale scores reliable? A bifactor model analysis.

    Science.gov (United States)

    DeSousa, Diogo Araújo; Zibetti, Murilo Ricardo; Trentini, Clarissa Marceli; Koller, Silvia Helena; Manfro, Gisele Gus; Salum, Giovanni Abrahão

    2014-12-01

    The aim of this study was to investigate the utility of creating and scoring subscales for the self-report version of the Screen for Child Anxiety Related Emotional Disorders (SCARED) by examining whether subscale scores provide reliable information after accounting for a general anxiety factor in a bifactor model analysis. A total of 2420 children aged 9-18 answered the SCARED in their schools. Results suggested adequate fit of the bifactor model. The SCARED score variance was hardly influenced by the specific domains after controlling for the common variance in the general factor. The explained common variance (ECV) for the general factor was large (63.96%). After accounting for the general total score (ωh=.83), subscale scores provided very little reliable information (ωh ranged from .005 to .04). Practitioners that use the SCARED should be careful when scoring and interpreting the instrument subscales since there is more common variance to them than specific variance. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

    Science.gov (United States)

    Hansen, Suzanne L; Sterjev, Zoran; Werngreen, Marie; Simonsen, Bodil J; Knudsen, Katrine E; Nielsen, Ane H; Pedersen, Mikael E; Badolo, Lassiana; Kristiansen, Uffe; Vestergaard, Henrik T

    2012-05-05

    The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from naïve, saline-injected and PTZ-kindled mice. Our data suggest that the use of slices from PTZ-kindled mice in the cortical wedge does not increase the predictive validity of the model as an in vitro screening model for AEDs. Traditionally, the incidence of certain seizure types is widely used as a measure to characterize drug action in animal models of epilepsy. In our study, the anticonvulsant effect of the AEDs was investigated in vivo using several observational parameters (i.e., incidence and duration of convulsions, latency to clonic convulsions, and severity of convulsions). We found that including the observational parameter "severity" offered important additional information about the drug profile that would otherwise be lost if only a single parameter as "incidence" was used.

  20. Methodology for the Model-based Small Area Estimates of Cancer Risk Factors and Screening Behaviors - Small Area Estimates

    Science.gov (United States)

    This model-based approach uses data from both the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS) to produce estimates of the prevalence rates of cancer risk factors and screening behaviors at the state, health service area, and county levels.

  1. Development and Application of In Vitro Models for Screening Drugs and Environmental Chemicals that Predict Toxicity in Animals and Humans

    Science.gov (United States)

    Development and Application of In Vitro Models for Screening Drugs and Environmental Chemicals that Predict Toxicity in Animals and Humans (Presented by James McKim, Ph.D., DABT, Founder and Chief Science Officer, CeeTox) (5/25/2012)

  2. Dermal permeation data and models for the prioritization and screening-level exposure assessment of organic chemicals

    Science.gov (United States)

    High throughput screening (HTS) models are being developed and applied to prioritize chemicals for more comprehensive exposure and risk assessment. Dermal pathways are possible exposure routes to humans for thousands of chemicals found in personal care products and the indoor env...

  3. Estimating the coverage of a targeted mobile tuberculosis screening programme among illicit drug users and homeless persons with truncated models

    NARCIS (Netherlands)

    N.A.H. van Hest; G. de Vries (Gerard); F. Smit (Filip); A.D. Grant; J.H. Richardus (Jan Hendrik)

    2008-01-01

    textabstractTruncated models are indirect methods to estimate the size of a hidden population which, in contrast to the capture–recapture method, can be used on a single information source. We estimated the coverage of a tuberculosis screening programme among illicit drug users and homeless persons

  4. Using a Bifactor Model to Assess the Factor Structure of the Phonological Awareness Literacy Screening for Grades 1 through 3

    Science.gov (United States)

    Huang, Francis L.

    2014-01-01

    The factor structure of the Phonological Awareness Literacy Screening for Grades 1 through 3 (PALS 1-3), a widely used early literacy screener in the Commonwealth of Virginia, was investigated using a large sample of public-school second-grade students (n = 14,993). Three alternative factor models (i.e., a one-factor, two-correlated factors, and a…

  5. Tailoring breast cancer screening intervals by breast density and risk for women aged 50 years or older: Collaborative modeling of screening outcomes

    NARCIS (Netherlands)

    A. Trentham-Dietz (Amy); K. Kerlikowske (Karla); N.K. Stout (Natasha); D.L. Miglioretti (Diana); C.B. Schechter (Clyde); M.A. Ergun (Mehmet Ali); J.J. Van Den Broek (Jeroen J.); O. Alagoz (Oguzhan); B.L. Sprague (Brian L.); N.T. van Ravesteyn (Nicolien); A.M. Near (Aimee); R. Gangnon (Ronald); Hampton, J.M. (John M.); Chandler, Y. (Young); H.J. de Koning (Harry); J.S. Mandelblatt (Jeanne); A.N.A. Tosteson (Anna N.A.)

    2016-01-01

    textabstractBackground: Biennial screening is generally recommended for average-risk women aged 50 to 74 years, but tailored screening may provide greater benefits. Objective: To estimate outcomes for various screening intervals after age 50 years based on breast density and risk for breast cancer.

  6. Simulation and fabrication of the atmospheric turbulence phase screen based on a fractal model

    Institute of Scientific and Technical Information of China (English)

    Peng Jia; Sijiong Zhang

    2012-01-01

    An atmospheric turbulence phase screen generated using a fractal method is introduced.It is etched onto fused silica and tested in the laboratory.The etched screen has relatively low cost,high resolution,and can be used in the broad waveband under severe temperature conditions.Our results are shown to agree well with the theory.

  7. Comparative model-based analysis of screening programs for Chlamydia trachomatis infections

    NARCIS (Netherlands)

    Kretzschmar, M; Welte, R; van den Hoek, A; Postma, Maarten

    2001-01-01

    The design of a screening program for asymptomatic genital infections with Chlamydia trachomatis, requires decisions about which sex or age group should be targeted and whether partner referral should be included in the program. To investigate the effects of Various screening programs on the prevale

  8. Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.

    Science.gov (United States)

    Ung, Peter Man-Un; Song, Wenxin; Cheng, Lili; Zhao, Xinbin; Hu, Hailin; Chen, Ligong; Schlessinger, Avner

    2016-07-15

    The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as d-glucose and d-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.g., breast carcinoma) to support the increased anaerobic glycolysis and the Warburg effect. Thus, hGLUT1 is an emerging therapeutic target, which also transports commonly used cancer biomarkers (e.g., (18)F-DG). In this study, we use computational prediction followed by experimental testing, to characterize hGLUT1. We construct homology models of hGLUT1 in a partially occluded outward open ("occluded") conformation based on the X-ray structure of the E. coli xylose transporter, XylE. Comparison of the binding site of the occluded models to experimentally determined hGLUT structures revealed a hydrophobic pocket adjacent to the sugar-binding site, which was tested experimentally via site-directed mutagenesis. Virtual screening of various libraries of purchasable compounds against the occluded models, followed by experimental testing with cellular assays revealed seven previously unknown hGLUT1 ligands with IC50 values ranging from 0.45 μM to 59 μM. These ligands represent three unique chemotypes that are chemically different from any other known hGLUT1 ligands. The newly characterized hydrophobic pocket can potentially be utilized by the new ligands for increased affinity. Furthermore, the previously unknown hGLUT1 ligands can serve as chemical tools to further characterize hGLUT1 function or lead molecules for future drug development.

  9. Model-based screening for critical wet-weather discharges related to micropollutants from urban areas.

    Science.gov (United States)

    Mutzner, Lena; Staufer, Philipp; Ort, Christoph

    2016-11-01

    Wet-weather discharges contribute to anthropogenic micropollutant loads entering the aquatic environment. Thousands of wet-weather discharges exist in Swiss sewer systems, and we do not have the capacity to monitor them all. We consequently propose a model-based approach designed to identify critical discharge points in order to support effective monitoring. We applied a dynamic substance flow model to four substances representing different entry routes: indoor (Triclosan, Mecoprop, Copper) as well as rainfall-mobilized (Glyphosate, Mecoprop, Copper) inputs. The accumulation on different urban land-use surfaces in dry weather and subsequent substance-specific wash-off is taken into account. For evaluation, we use a conservative screening approach to detect critical discharge points. This approach considers only local dilution generated onsite from natural, unpolluted areas, i.e. excluding upstream dilution. Despite our conservative assumptions, we find that the environmental quality standards for Glyphosate and Mecoprop are not exceeded during any 10-min time interval over a representative one-year simulation period for all 2500 Swiss municipalities. In contrast, the environmental quality standard is exceeded during at least 20% of the discharge time at 83% of all modelled discharge points for Copper and at 71% for Triclosan. For Copper, this corresponds to a total median duration of approximately 19 days per year. For Triclosan, discharged only via combined sewer overflows, this means a median duration of approximately 10 days per year. In general, stormwater outlets contribute more to the calculated effect than combined sewer overflows for rainfall-mobilized substances. We further evaluate the Urban Index (Aurban,impervious/Anatural) as a proxy for critical discharge points: catchments where Triclosan and Copper exceed the corresponding environmental quality standard often have an Urban Index >0.03. A dynamic substance flow analysis allows us to identify the most

  10. A DPSIR model for ecological security assessment through indicator screening: a case study at Dianchi Lake in China.

    Science.gov (United States)

    Wang, Zhen; Zhou, Jingqing; Loaiciga, Hugo; Guo, Huaicheng; Hong, Song

    2015-01-01

    Given the important role of lake ecosystems in social and economic development, and the current severe environmental degradation in China, a systematic diagnosis of the ecological security of lakes is essential for sustainable development. A Driving-force, Pressure, Status, Impact, and Risk (DPSIR) model, combined with data screening for lake ecological security assessment was developed to overcome the disadvantages of data selection in existing assessment methods. Correlation and principal component analysis were used to select independent and representative data. The DPSIR model was then applied to evaluate the ecological security of Dianchi Lake in China during 1988-2007 using an ecological security index. The results revealed a V-shaped trend. The application of the DPSIR model with data screening provided useful information regarding the status of the lake's ecosystem, while ensuring information efficiency and eliminating multicollinearity. The modeling approach described here is practical and operationally efficient, and provides an attractive alternative approach to assess the ecological security of lakes.

  11. Cancer screening: a mathematical model relating secreted blood biomarker levels to tumor sizes.

    Directory of Open Access Journals (Sweden)

    Amelie M Lutz

    2008-08-01

    Full Text Available BACKGROUND: Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden. METHODS AND FINDINGS: Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1 the compartment (plasma is well-mixed and kinetically homogenous; (2 the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1 exclusively by the tumor cells or (2 by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]. Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3 and 3,610.14 mm(3 for CA125 and between 0.21 mm(3 and 131.51 mm(3 for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged

  12. Toward making the mean spherical approximation of primitive model electrolytes analytic: an analytic approximation of the MSA screening parameter.

    Science.gov (United States)

    Gillespie, Dirk

    2011-01-28

    The mean spherical approximation (MSA) for the primitive model of electrolytes provides reasonable estimates of thermodynamic quantities such as the excess chemical potential and screening length. It is especially widely used because of its explicit formulas so that numerically solving equations is minimized. As originally formulated, the MSA screening parameter Γ (akin to the reciprocal of the Debye screening length) does not have an explicit analytic formula; an equation for Γ must be solved numerically. Here, an analytic approximation for Γ is presented whose relative error is generally ≲10(-5). If more accuracy is desired, one step of an iterative procedure (which also produces an explicit formula for Γ) is shown to give relative errors within machine precision in many cases. Even when ion diameter ratios are ∼10 and ion valences are ∼10, the relative error for the analytic approximation is still ≲10(-3) and for the single iterative substitution it is ≲10(-9).

  13. A model of tuberculosis screening for pregnant women in resource-limited settings using Xpert MTB/RIF.

    Science.gov (United States)

    Turnbull, Eleanor R; Kancheya, Nzali G; Harris, Jennifer B; Topp, Stephanie M; Henostroza, German; Reid, Stewart E

    2012-01-01

    Timely diagnosis and treatment of maternal tuberculosis (TB) is important to reduce morbidity and mortality for both the mother and child, particularly in women who are coinfected with HIV. The World Health Organization (WHO) recommends the integration of TB/HIV screening into antenatal services but available diagnostic tools are slow and insensitive, resulting in delays in treatment initiation. Recently the WHO endorsed Xpert MTB/RIF, a highly sensitive, real-time PCR assay for Mycobacterium tuberculosis that simultaneously detects rifampicin resistance directly from sputum and provides results within 100 minutes. We propose a model for same-day TB screening and diagnosis of all pregnant women at antenatal care using Xpert MTB/RIF. Pilot studies are urgently required to evaluate strategies for the integration of TB screening into antenatal clinics using new diagnostic technologies.

  14. A Model of Tuberculosis Screening for Pregnant Women in Resource-Limited Settings Using Xpert MTB/RIF

    Directory of Open Access Journals (Sweden)

    Eleanor R. Turnbull

    2012-01-01

    Full Text Available Timely diagnosis and treatment of maternal tuberculosis (TB is important to reduce morbidity and mortality for both the mother and child, particularly in women who are coinfected with HIV. The World Health Organization (WHO recommends the integration of TB/HIV screening into antenatal services but available diagnostic tools are slow and insensitive, resulting in delays in treatment initiation. Recently the WHO endorsed Xpert MTB/RIF, a highly sensitive, real-time PCR assay for Mycobacterium tuberculosis that simultaneously detects rifampicin resistance directly from sputum and provides results within 100 minutes. We propose a model for same-day TB screening and diagnosis of all pregnant women at antenatal care using Xpert MTB/RIF. Pilot studies are urgently required to evaluate strategies for the integration of TB screening into antenatal clinics using new diagnostic technologies.

  15. Plasma-screening effects on the electronic structure of multiply charged Al ions using Debye and ionsphere models

    CERN Document Server

    Das, Madhulita; Pal, S

    2016-01-01

    We analyze atomic structures of plasma embedded aluminum (Al) atom and its ions in the weakly and strongly coupling regimes. The plasma screening effects in these atomic systems are accounted for using the Debye and ion sphere (IS) potentials for the weakly coupling and strongly coupling plasmas, respectively. Within the Debye model, special attention is given to investigate the spherical and non-spherical plasma-screening effects considering in the electron-electron interaction potential. The relativistic coupled-cluster (RCC) method has been employed to describe the relativistic and electronic correlation effects in the above atomic systems. The variation in the ionization potentials (IPs) and excitation energies (EEs) of the plasma embedded Al ions are presented. It is found that the atomic systems exhibit more stability when the exact screening effects are taken into account. It is also showed that in the presence of strongly coupled plasma environment, the highly ionized Al ions show blue and red shifts ...

  16. Screening of central functions of amino acids and their metabolites for sedative and hypnotic effects using chick models.

    Science.gov (United States)

    Furuse, Mitsuhiro

    2015-09-01

    The chick has a practical advantage in the screening process in that chicks require only small quantities of drugs. The chick separation stress paradigm has traditionally been recognized as a valid form of anxiolytic screening. Further, chick behavior involving standing motionless with eyes closed or sitting motionless with head drooped is nearly always associated with electrophysiological sleep. When centrally administered, some DNA-encoded L-α-amino acids, as well as some DNA-non-encoded amino acids, such as metabolites of L-α-amino acids, D-amino acid and β-amino acid, have shown sedative and/or hypnotic effects in chicks. The effects of some of these amino acids have subsequently been confirmed in humans. In conclusion, the chick model is convenient and useful for screening central functions of amino acids and their metabolites for hypnosis and sedation.

  17. Evaluation of Caenorhabditis elegans as an acute lethality and a neurotoxicity screening model

    Energy Technology Data Exchange (ETDEWEB)

    Williams, P.L.

    1988-01-01

    This investigation evaluated C. elegans as a lethality and neurotoxicity screening model. The lethality experiments were performed in both agar and an aquatic medium. The salts of 8 metals (Hg, Be, Al, Cu, Zn, Pb, Cd, and Sr) were used in the agar studies and the salts of 14 metals (Ag, Hg, Cu, Be, Al, Pb, Cr, As, Tl, Zn, Cd, Ni, Sr, and Sb) were used in the aquatic tests. In each of these tests an LC50 value was determined. The data from the agar plates were compared to the published mammalian oral LD50 values for salts of the same metals. Within this set of chemicals C. elegans was found to be a predictor of mammalian acute lethality, generating LC50 values parallel to the rat and mouse LD50 values. The aquatic data were compared to data from EPA Ambient Water Quality Criteria documents. C. elegans was found to be less sensitive than Daphnia but generally more sensitive than the other invertebrate organisms that are presently used. The neurotoxicity testing also was performed in both agar and an aquatic media. The testing in agar was conducted with the salts of 4 metals (Cu, Be, Pb, and Hg) and 2 organophosphate pesticides (malathion and vapona). The studies in an aquatic medium tested the salts of 4 metals (Cu, Be, Pb, and Hg).

  18. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening.

    Science.gov (United States)

    Sharma, Arun; Wu, Joseph C; Wu, Sean M

    2013-12-24

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

  19. Fault identification using piezoelectric impedance measurement and model-based intelligent inference with pre-screening

    Science.gov (United States)

    Shuai, Q.; Zhou, K.; Zhou, Shiyu; Tang, J.

    2017-04-01

    While piezoelectric impedance/admittance measurements have been used for fault detection and identification, the actual identification of fault location and severity remains to be a challenging topic. On one hand, the approach that uses these measurements entertains high detection sensitivity owing to the high-frequency actuation/sensing nature. On the other hand, high-frequency analysis requires high dimensionality in the model and the subsequent inverse analysis contains a very large number of unknowns which often renders the identification problem under-determined. A new fault identification algorithm is developed in this research for piezoelectric impedance/admittance based measurement. Taking advantage of the algebraic relation between the sensitivity matrix and the admittance change measurement, we devise a pre-screening scheme that can rank the likelihoods of fault locations with estimated fault severity levels, which drastically reduces the fault parameter space. A Bayesian inference approach is then incorporated to pinpoint the fault location and severity with high computational efficiency. The proposed approach is examined and validated through case studies.

  20. Designing Capital-Intensive Systems with Architectural and Operational Flexibility Using a Screening Model

    Science.gov (United States)

    Lin, Jijun; de Weck, Olivier; de Neufville, Richard; Robinson, Bob; MacGowan, David

    Development of capital intensive systems, such as offshore oil platforms or other industrial infrastructure, generally requires a significant amount of capital investment under various resource, technical, and market uncertainties. It is a very challenging task for development co-owners or joint ventures because important decisions, such as system architectures, have to be made while uncertainty remains high. This paper develops a screening model and a simulation framework to quickly explore the design space for complex engineering systems under uncertainty allowing promising strategies or architectures to be identified. Flexibility in systems’ design and operation is proposed as a proactive means to enable systems to adapt to future uncertainty. Architectural and operational flexibility can improve systems’ lifecycle value by mitigating downside risks and capturing upside opportunities. In order to effectively explore different flexible strategies addressing a view of uncertainty which changes with time, a computational framework based on Monte Carlo simulation is proposed in this paper. This framework is applied to study flexible development strategies for a representative offshore petroleum project. The complexity of this problem comes from multi-domain uncertainties, large architectural design space, and structure of flexibility decision rules. The results demonstrate that architectural and operational flexibility can significantly improve projects’ Expected Net Present Value (ENPV), reduce downside risks, and improve upside gains, compared to adopting an inflexible strategy appropriate to the view of uncertainty at the start of the project. In this particular case study, the most flexible strategy improves ENPV by 85% over an inflexible base case.

  1. Factors Affecting Cervical Cancer Screening Behaviors Based On the Precaution Adoption Process Model: A Qualitative Study.

    Science.gov (United States)

    Bahmani, Afshin; Baghianimoghadam, Mohammah Hossein; Enjezab, Behnaz; Mazloomy Mahmoodabad, Seyed Saeed; Askarshahi, Mohsen

    2015-11-17

    One of the most preventable cancers in women is cervical cancer. Pap smear test is an effective screening program; however, it is not conducted very frequently. The aim of this study is explaining the determinants affecting women's participation in the Pap smear test based on precaution adoption process model with a qualitative approach. This study was a qualitative approach using a Directed Content Analysis methodology which was conducted in 2014. Participants were 30 rural women who participated in this study voluntarily in sarvabad, Iran. Purposive sampling was initiated and continued until data saturation. Semi-structured interviews were the primary method of data collection. Data were analyzed using qualitative content analysis and continuous comparisons. Women`s information and awareness about cervical cancer and Pap smear is insufficient and most of them believed that they were not at risk; however, they perceived the severity of the disease. Some of them had no adequate understanding of the test benefits. They pointed to the lack of time, financial difficulties, fear of test result and lack of awareness as the main barriers against the Pap smear test; however, they did not say that they were not willing to do the test. Findings could help health policy makers to find the right area and purpose to facilitate the participation of women in the Pap smear test.

  2. Large-scale screening of disease model through ENU mutagenesis in mice

    Institute of Scientific and Technical Information of China (English)

    HE Fang; WANG Zixing; ZHAO Jing; BAO Jie; DING Jun; RUAN Haibin; XIE Qing; ZHANG Zuoming; GAO Xiang

    2003-01-01

    Manipulation of mouse genome has merged as one of the most important approaches for studying gene function and establishing the disease model because of the high homology between human genome and mouse genome. In this study, the chemical mutagen ethylnitrosourea (ENU) was employed for inducing germ cell mutations in male C57BL/6J mice. The first generation (G1) of the backcross of these mutated mice, totally 3172, was screened for abnormal phenotypes on gross morphology, behavior, learning and memory, auditory brainstem response (ABR), electrocardiogram (ECG), electroretinogram (ERG), flash-visual evoked potential (F-VEP), bone mineral density, and blood sugar level. 595 mice have been identified with specific dominant abnormalities. Fur color changes, eye defects and hearing loss occurred at the highest frequency. Abnormalities related to metabolism alteration are least frequent. Interestingly, eye defects displayed significant left-right asymmetry and sex preference. Sex preference is also observed in mice with abnormal bone mineral density. Among 104 G1 generation mutant mice examined for inheritability, 14 of them have been confirmed for passing abnormal phenotypes to their progenies. However, we did not observe behavior abnormalities of G1 mice to be inheritable, suggesting multi-gene control for these complicated functions in mice. In conclusion, the generation of these mutants paves the way for understanding molecular and cellular mechanisms of these abnormal phenotypes, and accelerates the cloning of disease-related genes.

  3. Comprehensive antigen screening identifies Moraxella catarrhalis proteins that induce protection in a mouse pulmonary clearance model.

    Directory of Open Access Journals (Sweden)

    Margarita Smidt

    Full Text Available Moraxella catarrhalis is one of the three most common causative bacterial pathogens of otitis media, however no effective vaccine against M. catarrhalis has been developed so far. To identify M. catarrhalis vaccine candidate antigens, we used carefully selected sera from children with otitis media and healthy individuals to screen small-fragment genomic libraries that are expressed to display frame-selected peptides on a bacterial cell surface. This ANTIGENome technology led to the identification of 214 antigens, 23 of which were selected by in vitro or in vivo studies for additional characterization. Eight of the 23 candidates were tested in a Moraxella mouse pulmonary clearance model, and 3 of these antigens induced significantly faster bacterial clearance compared to adjuvant or to the previously characterized antigen OmpCD. The most significant protection data were obtained with the antigen MCR_1416 (Msp22, which was further investigated for its biological function by in vitro studies suggesting that Msp22 is a heme binding protein. This study comprises one of the most exhaustive studies to identify potential vaccine candidate antigens against the bacterial pathogen M. catarrhalis.

  4. Bioreactor process parameter screening utilizing a Plackett-Burman design for a model monoclonal antibody.

    Science.gov (United States)

    Agarabi, Cyrus D; Schiel, John E; Lute, Scott C; Chavez, Brittany K; Boyne, Michael T; Brorson, Kurt A; Khan, Mansoor A; Read, Erik K

    2015-06-01

    Consistent high-quality antibody yield is a key goal for cell culture bioprocessing. This endpoint is typically achieved in commercial settings through product and process engineering of bioreactor parameters during development. When the process is complex and not optimized, small changes in composition and control may yield a finished product of less desirable quality. Therefore, changes proposed to currently validated processes usually require justification and are reported to the US FDA for approval. Recently, design-of-experiments-based approaches have been explored to rapidly and efficiently achieve this goal of optimized yield with a better understanding of product and process variables that affect a product's critical quality attributes. Here, we present a laboratory-scale model culture where we apply a Plackett-Burman screening design to parallel cultures to study the main effects of 11 process variables. This exercise allowed us to determine the relative importance of these variables and identify the most important factors to be further optimized in order to control both desirable and undesirable glycan profiles. We found engineering changes relating to culture temperature and nonessential amino acid supplementation significantly impacted glycan profiles associated with fucosylation, β-galactosylation, and sialylation. All of these are important for monoclonal antibody product quality.

  5. The value of the 4-day headdown bedrest model for screening countermeasures

    Science.gov (United States)

    Vernikos, J.; Keil, L.; Ertl, A. C.; Wade, C. E.; Greenleaf, J. E.; Ohara, D.; Ludwig, D.

    1992-01-01

    In order to evaluate the benefits of periodic exposure to the +G(z) vector as a countermeasure to the physiological responses to minus 6 degree head down bedrest (HDT), we considered a two-tiered approach: (a) to use 4 days HDT as a quick and inexpensive means of screening countermeasures, (b) to use a 60 day HDT to validate the most promising candidates. The approach and results of a 4 day study are described here. Methods: Nine males were admitted to our Human Research Facility for one ambulatory control day followed by 4 days HDT and were released on the next day after completion of a peak oxygen consumption test (VO(sub 2 peak)). A battery of tests was selected and standardized to evaluate the known early effects of HDT on plasma volume, early bone markers, orthostatic tolerance, physical performance, and fluid and electrolytes and their hormone regulation. Fluid sodium (Na) and potassium (K) intake and output in the urine were monitored throughout. Plasma volume was determined with a modified Evans Blue method and orthostatic tolerance with a 60 degree head-up tilt test for 30 minutes - both of which were determined on the ambulatory control day and on day 4 of HDT. Immediately after completion of the tilt test subjects were returned to the minus 6 degree position until the next morning when a VO(sub 2 peak) (horizontal ergometer) was done. This was compared to a similar control test determined on 2 separate occasions before subject admission. Results: Four hours after going HDT produced significant decreases (p less than 0.05) in the circulating concentration of fluid and electrolyte regulating hormones. Plasma volume, orthostatic tolerance and VO(sub 2 peak) changed significantly after 4 days HDT. There was also the expected natriuresis on day 1 of HDT but no significant diuresis. The consistency of the pre-bedrest VO(sub 2 peak) tilt tests and plasma volumes was remarkable. Conclusions: The 4 day HDT model seems highly promising for screening a variety of

  6. Discovery of peptide ligands through docking and virtual screening at nicotinic acetylcholine receptor homology models.

    Science.gov (United States)

    Leffler, Abba E; Kuryatov, Alexander; Zebroski, Henry A; Powell, Susan R; Filipenko, Petr; Hussein, Adel K; Gorson, Juliette; Heizmann, Anna; Lyskov, Sergey; Tsien, Richard W; Poget, Sébastien F; Nicke, Annette; Lindstrom, Jon; Rudy, Bernardo; Bonneau, Richard; Holford, Mandë

    2017-09-19

    Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the α4β2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin α-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock α-GID and its analogs to an α4β2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive α-GID mutants (α-GID[A10V], α-GID[V13I], and α-GID[V13Y]) and one inactive variant (α-GID[A10Q]). Two mutants, α-GID[A10V] and α-GID[V13Y], had substantially reduced potency at the human α7 nAChR relative to α-GID, a desirable feature for α-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the α-GID:α4β2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock.

  7. An inducible krasV12 transgenic zebrafish model for liver tumorigenesis and chemical drug screening

    Directory of Open Access Journals (Sweden)

    Anh Tuan Nguyen

    2012-01-01

    Because Ras signaling is frequently activated by major hepatocellular carcinoma etiological factors, a transgenic zebrafish constitutively expressing the krasV12 oncogene in the liver was previously generated by our laboratory. Although this model depicted and uncovered the conservation between zebrafish and human liver tumorigenesis, the low tumor incidence and early mortality limit its use for further studies of tumor progression and inhibition. Here, we employed a mifepristone-inducible transgenic system to achieve inducible krasV12 expression in the liver. The system consisted of two transgenic lines: the liver-driver line had a liver-specific fabp10 promoter to produce the LexPR chimeric transactivator, and the Ras-effector line contained a LexA-binding site to control EGFP-krasV12 expression. In double-transgenic zebrafish (driver-effector embryos and adults, we demonstrated mifepristone-inducible EGFP-krasV12 expression in the liver. Robust and homogeneous liver tumors developed in 100% of double-transgenic fish after 1 month of induction and the tumors progressed from hyperplasia by 1 week post-treatment (wpt to carcinoma by 4 wpt. Strikingly, liver tumorigenesis was found to be ‘addicted’ to Ras signaling for tumor maintenance, because mifepristone withdrawal led to tumor regression via cell death in transgenic fish. We further demonstrated the potential use of the transparent EGFP-krasV12 larvae in inhibitor treatments to suppress Ras-driven liver tumorigenesis by targeting its downstream effectors, including the Raf-MEK-ERK and PI3K-AKT-mTOR pathways. Collectively, this mifepristone-inducible and reversible krasV12 transgenic system offers a novel model for understanding hepatocarcinogenesis and a high-throughput screening platform for anti-cancer drugs.

  8. Refined Dummy Atom Model of Mg(2+) by Simple Parameter Screening Strategy with Revised Experimental Solvation Free Energy.

    Science.gov (United States)

    Jiang, Yang; Zhang, Haiyang; Feng, Wei; Tan, Tianwei

    2015-12-28

    Metal ions play an important role in the catalysis of metalloenzymes. To investigate metalloenzymes via molecular modeling, a set of accurate force field parameters for metal ions is highly imperative. To extend its application range and improve the performance, the dummy atom model of metal ions was refined through a simple parameter screening strategy using the Mg(2+) ion as an example. Using the AMBER ff03 force field with the TIP3P model, the refined model accurately reproduced the experimental geometric and thermodynamic properties of Mg(2+). Compared with point charge models and previous dummy atom models, the refined dummy atom model yields an enhanced performance for producing reliable ATP/GTP-Mg(2+)-protein conformations in three metalloenzyme systems with single or double metal centers. Similar to other unbounded models, the refined model failed to reproduce the Mg-Mg distance and favored a monodentate binding of carboxylate groups, and these drawbacks needed to be considered with care. The outperformance of the refined model is mainly attributed to the use of a revised (more accurate) experimental solvation free energy and a suitable free energy correction protocol. This work provides a parameter screening strategy that can be readily applied to refine the dummy atom models for metal ions.

  9. Validity of “sputtering and re-condensation” model in active screen cage plasma nitriding process

    Energy Technology Data Exchange (ETDEWEB)

    Saeed, A., E-mail: phyadi@gmail.com [Department of Physics, Gomal University, 29050 D.I. Khan (Pakistan); National Centre for Physics, Quaid-i-Azam University Campus Islamabad 45320 (Pakistan); Khan, A.W. [Department of Physics, Gomal University, 29050 D.I. Khan (Pakistan); National Centre for Physics, Quaid-i-Azam University Campus Islamabad 45320 (Pakistan); Jan, F. [Department of Physics, Quaid-i-Azam University, 45320 Islamabad (Pakistan); Abrar, M. [Institute of Physics and Electronics, University of Peshawar, 25120 Peshawar (Pakistan); Khalid, M. [Department of Physics, Gomal University, 29050 D.I. Khan (Pakistan); Zakaullah, M. [Department of Physics, Quaid-i-Azam University, 45320 Islamabad (Pakistan)

    2013-05-15

    The validity of “sputtering and re-condensation” model in active screen plasma nitriding for nitrogen mass transfer mechanism is investigated. The dominant species including NH, Fe-I, N{sub 2}{sup +}, N-I and N{sub 2} along with H{sub α} and H{sub β} lines are observed in the optical emission spectroscopy (OES) analysis. Active screen cage and dc plasma nitriding of AISI 316 stainless steel as function of treatment time is also investigated. The structure and phases composition of the nitrided layer is studied by X-ray diffraction (XRD). Surface morphology is studied by scanning electron microscopy (SEM) and hardness profile is obtained by Vicker's microhardness tester. Increasing trend in microhardness is observed in both cases but the increase in active screen plasma nitriding is about 3 times greater than that achieved by dc plasma nitriding. On the basis of metallurgical and OES observations the use of “sputtering and re-condensation” model in active screen plasma nitriding is tested.

  10. Impact of screening and early detection of impaired fasting glucose tolerance and type 2 diabetes in Canada: a Markov model simulation

    Directory of Open Access Journals (Sweden)

    Badawi A

    2012-04-01

    Full Text Available Soroush Mortaz*, Christine Wessman*, Ross Duncan, Rachel Gray, Alaa Badawi Office of Biotechnology Genomics and Population Health, Public Health Agency of Canada, Toronto, Ontario, Canada*Both authors contributed equally to this workBackground: Type 2 diabetes mellitus (T2DM is a major global health problem. An estimated 20%–50% of diabetic subjects in Canada are currently undiagnosed, and around 20%–30% have already developed complications. Screening for high blood glucose levels can identify people with prediabetic conditions and permit introduction of timely and effective prevention. This study examines the benefit of screening for impaired fasting glucose (IFG and T2DM. If intervention is introduced at this prediabetic stage, it can be most effective in delaying the onset and complications of T2DM.Methods: Using a Markov model simulation, we compare the cost-effectiveness of screening for prediabetes (IFG and T2DM with the strategy of no screening. An initial cohort of normoglycemic, prediabetic, or undiagnosed diabetic adults with one or more T2DM risk factors was used to model the strategies mentioned over a 10-year period. Subjects without known prediabetes or diabetes are screened every 3 years and persons with prediabetes were tested for diabetes on an annual basis. The model weighs the increase in quality-adjusted life-years (QALYs associated with early detection of prediabetes and earlier diagnosis of T2DM due to lifestyle intervention and early treatment in asymptomatic subjects.Results: Costs for each QALY gained were $2281 for conventional screening compared with $2890 for no screening. Thus, in this base-case analysis, conventional screening with a frequency of once every 3 years was favored over no screening. Furthermore, conventional screening was more favorable compared with no screening over a wide range of willingness-to-pay thresholds. Changing the frequency of screening did not affect the overall results. Screening

  11. Integrated Model of Chemical Perturbations of a Biological PathwayUsing 18 In Vitro High Throughput Screening Assays for the Estrogen Receptor

    Science.gov (United States)

    We demonstrate a computational network model that integrates 18 in vitro, high-throughput screening assays measuring estrogen receptor (ER) binding, dimerization, chromatin binding, transcriptional activation and ER-dependent cell proliferation. The network model uses activity pa...

  12. Evidence for cervical cancer mortality with screening program in Taiwan, 1981–2010: age-period-cohort model

    Directory of Open Access Journals (Sweden)

    Su Shih-Yung

    2013-01-01

    Full Text Available Abstract Background Cervical cancer is the most common cancer experienced by women worldwide; however, screening techniques are very effective for reducing the risk of death. The national cervical cancer screening program was implemented in Taiwan in 1995. The objective of this study was to examine and provide evidence of the cervical cancer mortality trends for the periods before and after the screening program was implemented. Methods Data from 1981 to 2010 of the causes of death registered were obtained from the Department of Health, Taiwan. Age-standardized mortality rates, age-specific rates, and age-period-cohort models that employed the sequential method were used to assess temporal changes that occurred between 1981 and 2010, with 1995 used as the separating year. Results The results showed that for both time periods of 1981 to 1995 and 1996 to 2010, age and period had significant effects, whereas the birth cohort effects were insignificant. For patients between 80 and 84 years of age, the mortality rate for 1981 to 1995 and 1996 to 2010 was 48.34 and 68.08. The cervical cancer mortality rate for 1996 to 2010 was 1.0 for patients between 75 and 79 years of age and 1.4 for patients between 80 and 84 years of age compared to that for 1981 to 1995. Regarding the period effect, the mortality trend decreased 2-fold from 1996 to 2010. Conclusions The results of this study indicate a decline in cervical cancer mortality trends after the screening program involving Papanicolaou tests was implemented in 1995. However, the positive effects of the screening program were not observed in elderly women because of treatment delays during the initial implementation of the screening program.

  13. Three-dimensional cell culture models for anticancer drug screening: Worth the effort?

    Science.gov (United States)

    Verjans, Eddy-Tim; Doijen, Jordi; Luyten, Walter; Landuyt, Bart; Schoofs, Liliane

    2017-06-15

    High attrition of new oncology drug candidates in clinical trials is partially caused by the poor predictive capacity of artificial monolayer cell culture assays early in drug discovery. Monolayer assays do not take the natural three-dimensional (3D) microenvironment of cells into account. As a result, false positive compounds often enter clinical trials, leading to high dropout rates and a waste of time and money. Over the past 2 decades, tissue engineers and cell biologists have developed a broad range of 3D in vitro culturing tools that better represent in vivo cell biology. These tools preserve the 3D architecture of cells and can be used to predict toxicity of and resistance against antitumor agents. Recent progress in tissue engineering further improves 3D models by taking into account the tumor microenvironment, which is important for metastatic progression and vascularization. However, the widespread implementation of 3D cell cultures into cell-based research programs has been limited by various factors, including their cost and reproducibility. In addition, different 3D cell culture techniques often produce spheroids of different size and shape, which can strongly influence drug efficacy and toxicity. Hence, it is imperative to morphometrically characterize multicellular spheroids to avoid generalizations among different spheroid types. Standardized 3D culturing procedures could further reduce data variability and enhance biological relevance. Here, we critically evaluate the benefits and challenges inherent to growing cells in 3D, along with an overview of the techniques used to form spheroids. This is done with a specific focus on antitumor drug screening. © 2017 Wiley Periodicals, Inc.

  14. Development and application of an aerosol screening model for size-resolved urban aerosols.

    Science.gov (United States)

    Stanier, Charles O; Lee, Sang-Rin

    2014-06-01

    Predictive models of vehicular ultrafine particles less than 0.1 microm in diameter (UFPs*) and other urban pollutants with high spatial and temporal variation are useful and important in applications such as (1) decision support for infrastructure projects, emissions controls, and transportation-mode shifts; (2) the interpretation and enhancement of observations (e.g., source apportionment, extrapolation, interpolation, and gap-filling in space and time); and (3) the generation of spatially and temporally resolved exposure estimates where monitoring is unfeasible. The objective of the current study was to develop, test, and apply the Aerosol Screening Model (ASM), a new physically based vehicular UFP model for use in near-road environments. The ASM simulates hourly average outdoor concentrations of roadway-derived aerosols and gases. Its distinguishing features include user-specified spatial resolution; use of the Weather Research and Forecasting (WRF) meteorologic model for winds estimates; use of a database of more than 100,000 road segments in the Los Angeles, California, region, including freeway ramps and local streets; and extensive testing against more than 9000 hours of observed particle concentrations at 11 sites. After initialization of air parcels at an upwind boundary, the model solves for vehicle emissions, dispersion, coagulation, and deposition using a Lagrangian modeling framework. The Lagrangian parcel of air is subdivided vertically (into 11 levels) and in the crosswind direction (into 3 parcels). It has overall dimensions of 10 m (downwind), 300 m (vertically), and 2.1 km (crosswind). The simulation is typically started 4 km upwind from the receptor, that is, the location at which the exposure is to be estimated. As parcels approach the receptor, depending on the user-specified resolution, step size is decreased, and crosswind resolution is enhanced through subdivision of parcels in the crosswind direction. Hourly concentrations and size

  15. A simple model for predicting lung cancer occurrence in a lung cancer screening program: The Pittsburgh Predictor.

    Science.gov (United States)

    Wilson, David O; Weissfeld, Joel

    2015-07-01

    A user-friendly method for assessing lung cancer risk may help standardize selection of current and former smokers for screening. We evaluated a simple 4-factor model, the Pittsburgh Predictor, against two well-known, but more complicated models for predicting lung cancer risk. Trained against outcomes observed in the National Lung Screening Trial (NLST), the Pittsburgh Predictor used four risk factors, duration of smoking, smoking status, smoking intensity, and age, to predict 6-year lung cancer incidence. After calibrating the Bach and PLCOM2012 models to outcomes observed in the low-dose computed tomography arm of the NLST, we compared model calibration, discrimination, and clinical usefulness (net benefit) in the NLST and Pittsburgh Lung Screening Study (PLuSS) populations. The Pittsburgh Predictor, Bach, and PLCOM2012 represented risk equally well, except for the tendency of PLCOM2012 to overestimate risk in subjects at highest risk. Relative to the Pittsburgh Predictor, Bach and PLCOM2012 increased the area under the receiver operator characteristic curve by 0.007-0.009 and 0.012-0.021 units, respectively, depending on study population. Across a clinically relevant span of 6-year lung cancer risk thresholds (0.01-0.05), Bach and PLCOM2012 increased net benefit by less than 0.1% in NLST and 0.3% in PLuSS. In exchange for a small reduction in prediction accuracy, a simpler lung cancer risk prediction model may facilitate standardized procedures for advising and selecting patients with respect to lung cancer screening. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Is computer aided detection (CAD) cost effective in screening mammography? A model based on the CADET II study

    Science.gov (United States)

    2011-01-01

    provides updated estimates of CAD costs in a full-field digital system and assessment cost for women who are re-called after initial screening. However, the model is highly sensitive to various parameters e.g. reading time, reader qualification, and equipment cost. PMID:21241473

  17. Is computer aided detection (CAD cost effective in screening mammography? A model based on the CADET II study

    Directory of Open Access Journals (Sweden)

    Wallis Matthew G

    2011-01-01

    in UK. This study provides updated estimates of CAD costs in a full-field digital system and assessment cost for women who are re-called after initial screening. However, the model is highly sensitive to various parameters e.g. reading time, reader qualification, and equipment cost.

  18. Predictive models for anti-tubercular molecules using machine learning on high-throughput biological screening datasets

    Directory of Open Access Journals (Sweden)

    Periwal Vinita

    2011-11-01

    Full Text Available Abstract Background Tuberculosis is a contagious disease caused by Mycobacterium tuberculosis (Mtb, affecting more than two billion people around the globe and is one of the major causes of morbidity and mortality in the developing world. Recent reports suggest that Mtb has been developing resistance to the widely used anti-tubercular drugs resulting in the emergence and spread of multi drug-resistant (MDR and extensively drug-resistant (XDR strains throughout the world. In view of this global epidemic, there is an urgent need to facilitate fast and efficient lead identification methodologies. Target based screening of large compound libraries has been widely used as a fast and efficient approach for lead identification, but is restricted by the knowledge about the target structure. Whole organism screens on the other hand are target-agnostic and have been now widely employed as an alternative for lead identification but they are limited by the time and cost involved in running the screens for large compound libraries. This could be possibly be circumvented by using computational approaches to prioritize molecules for screening programmes. Results We utilized physicochemical properties of compounds to train four supervised classifiers (Naïve Bayes, Random Forest, J48 and SMO on three publicly available bioassay screens of Mtb inhibitors and validated the robustness of the predictive models using various statistical measures. Conclusions This study is a comprehensive analysis of high-throughput bioassay data for anti-tubercular activity and the application of machine learning approaches to create target-agnostic predictive models for anti-tubercular agents.

  19. Mutation-Guided Unbiased Modeling of the Fat Sensor GPR119 for High-Yield Agonist Screening

    DEFF Research Database (Denmark)

    Norn, Christoffer; Pedersen, Maria Hauge; Engelstoft, Maja S.

    2015-01-01

    multiple X-ray receptor structures in combination with a fully flexible ligand docking protocol to det. the binding conformation of AR231453, a small-mol. agonist, in the GPR119 receptor. Resulting models converge to one conformation that explains the majority of data from mutation studies...... and is consistent with the structure-activity relationship for a large no. of AR231453 analogs. Another key property of the refined models is their success in sepg. active ligands from decoys in a large-scale virtual screening. These results demonstrate that mutation-guided receptor modeling can provide predictions...

  20. Combined magnetic screen made of Bi-2223 bulk cylinder and YBCO tape rings—Modeling and experiments

    Science.gov (United States)

    Tomków, Ł.; Ciszek, M.; Chorowski, M.

    2015-01-01

    Recent advances in the measurements with sensitive magnetic field sensors made the issue of magnetic shielding important. The application of high temperature superconductors allows to obtain full shielding in zero field cooling conditions for DC and low frequency magnetic fields by the means of the Meissner effect. However, currently used conventional bulk magnetic shields maintain full shielding only in low magnetic fields—up to approximately 10 mT. In this paper, it is proposed to apply an additional screen made of a coated superconducting tape in order to increase the magnetic field interval of full shielding region. Computer model of such set of screens was created in Matlab and validated experimentally. Improvement of shielding quality was observed experimentally and calculated with the model.

  1. Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening.

    Science.gov (United States)

    Manoharan, Prabu; Chennoju, Kiranmai; Ghoshal, Nanda

    2015-07-01

    BACE1 is an attractive target in Alzheimer's disease (AD) treatment. A rational drug design effort for the inhibition of BACE1 is actively pursued by researchers in both academic and pharmaceutical industries. This continued effort led to the steady accumulation of BACE1 crystal structures, co-complexed with different classes of inhibitors. This wealth of information is used in this study to develop target specific proteochemometric models and these models are exploited for predicting the prospective BACE1 inhibitors. The models developed in this study have performed excellently in predicting the computationally generated poses, separately obtained from single and ensemble docking approaches. The simple protein-ligand contact (SPLC) model outperforms other sophisticated high end models, in virtual screening performance, developed during this study. In an attempt to account for BACE1 protein active site flexibility information in predictive models, we included the change in the area of solvent accessible surface and the change in the volume of solvent accessible surface in our models. The ensemble and single receptor docking results obtained from this study indicate that the structural water mediated interactions improve the virtual screening results. Also, these waters are essential for recapitulating bioactive conformation during docking study. The proteochemometric models developed in this study can be used for the prediction of BACE1 inhibitors, during the early stage of AD drug discovery.

  2. Screening of 397 chemicals and development of a quantitative structure-activity relationship model for androgen receptor antagonism

    DEFF Research Database (Denmark)

    Vinggaard, Annemarie; Niemelä, Jay Russell; Wedebye, Eva Bay;

    2008-01-01

    We have screened 397 chemicals for human androgen receptor (AR) antagonism by a sensitive reporter gene assay to generate data for the development of a quantitative structure-activity relationship (QSAR) model. A total of 523 chemicals comprising data on 292 chemicals from our laboratory and data...... by the synthetic androgen R1881. The MultiCASE expert system was used to construct a QSAR model for AR antagonizing potential. A "5 Times, 2-Fold 50% Cross Validation" of the model showed a sensitivity of 64%, a specificity of 84%, and a concordance of 76%. Data for 102 chemicals were generated for an external...... validation of the model resulting in a sensitivity of 57%, a specificity of 98%, and a concordance of 92% of the model. The model was run on a set of 176103 chemicals, and 47% were within the domain of the model. Approximately 8% of chemicals was predicted active for AR antagonism. We conclude...

  3. Determinants of participation in colorectal cancer screening among community-dwelling Chinese older people: Testing a comprehensive model using a descriptive correlational study.

    Science.gov (United States)

    Leung, Doris Y P; Wong, Eliza M L; Chan, Carmen W H

    2016-04-01

    The prevalence of colorectal cancer (CRC) among older people is high. Screening for CRC presents a cost-effective secondary prevention and control strategy which results in a significant reduction in mortality. This study aims to describe the prevalence of CRC screening and examine its risk factors among Chinese community-dwelling older people guided by a comprehensive model combining Health Belief Model and Extended Parallel Processing Model. A descriptive correlational study was conducted. A convenience sample of 240 community-dwelling adults aged ≥60 was recruited in May-July in 2012 in Hong Kong. Participants were asked to complete a questionnaire which collected information on demographic variables, CRC-related psychosocial variables and whether they had a CRC screening in the past 10 years. Among the participants, 25.4% reported having a CRC screening test. Results of logistic regression analyses indicated that participants with a higher level in cue to action, and lower perceived knowledge barriers and severity-fear were significantly associated with participation in CRC screening. But there were no significant associations between fatalism and cancer fear with screening. The prevalence of CRC screening was low in Hong Kong Chinese community-dwelling elders. A number of modifiable factors associated with CRC screening were identified which provides specific targets for interventions. This study also adds to the knowledge regarding the associations between fatalism and fear with CRC screening behaviors among Chinese older people. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. A 3D model of SARS_CoV 3CL proteinase and its inhibitors design by virtual screening

    Institute of Scientific and Technical Information of China (English)

    LUOCheng; CHENJing; LUOHai-Bin; CHENLi-Li; LIGuo-Wei; SUNTao; YUChang-Ying; YUELi-Duo; SHENJian-Hua; JIANGHua-Liang; XIONGBin; GUIChun-Shan; XUXiao-Ying; DUANWen-Hu; SHENJing-Kang; QINLei; SHITi-Liu; LIYi-Xue; CHENKai-Xian; LUOXiao-Min; SHENXu

    2003-01-01

    AIM:To constructed a three-dimensional (3D) model for the 3C like (3CL) proteinase of SARS coronavirus (SARS_CoV), and to design inhibitors of the 3CL proteinase based on the 3D model. METHODS: Bioinformatics analyses were performed to search the homologous proteins of the SARS_CoV 3CL proteinase from the GenBank and PDB database. A 3D model of the proteinase was constructed by using homology modeling technique. Targeting to the 3D model and its X-ray crystal structure of the main proteinase (Mpro) of transmissible gastroenteritis virus(TGEV), virtual screening was performed employing molecular docking method to identify possible 3CL proteinase inhibitors from small molecular databases. RESULTS:Sequence alignment indicated that the SARS_CoV 3CL proteinase was extremely homologous to TGEV Mpro, especially the substrate-binding pocket (active site). Accordingly, a 3D model for the SARS_CoV 3CL proteinase was constructed based on the crystal structure of TGEV Mpro. The 3D model adopts a similar fold of the TGEV mpro, its structure and binding pocket feature are almost as same as that of TGEV Mpro. The tested virtual screening indicated that 73 available proteinase inhibitors in the MDDR database might dock into both the binding pockets of the TGEV Mpro and the SARS_CoV 3CL proteinase. CONCLUSIONS:Either the 3D model of the SARS_CoV 3CL proteinase or the X-ray crystal stucture of the TGEV Mpro may be used as a starting point for design anti-SARS drugs. Screening the known proteinase inhibitors may be an appreciated shortcut to discover anti-SARS drugs.

  5. Fishing for Nature’s Hits: Establishment of the Zebrafish as a Model for Screening Antidiabetic Natural Products

    Directory of Open Access Journals (Sweden)

    Nadia Tabassum

    2015-01-01

    Full Text Available Diabetes mellitus affects millions of people worldwide and significantly impacts their quality of life. Moreover, life threatening diseases, such as myocardial infarction, blindness, and renal disorders, increase the morbidity rate associated with diabetes. Various natural products from medicinal plants have shown potential as antidiabetes agents in cell-based screening systems. However, many of these potential “hits” fail in mammalian tests, due to issues such as poor pharmacokinetics and/or toxic side effects. To address this problem, the zebrafish (Danio rerio model has been developed as a “bridge” to provide an experimentally convenient animal-based screening system to identify drug candidates that are active in vivo. In this review, we discuss the application of zebrafish to drug screening technologies for diabetes research. Specifically, the discovery of natural product-based antidiabetes compounds using zebrafish will be described. For example, it has recently been demonstrated that antidiabetic natural compounds can be identified in zebrafish using activity guided fractionation of crude plant extracts. Moreover, the development of fluorescent-tagged glucose bioprobes has allowed the screening of natural product-based modulators of glucose homeostasis in zebrafish. We hope that the discussion of these advances will illustrate the value and simplicity of establishing zebrafish-based assays for antidiabetic compounds in natural products-based laboratories.

  6. A mixture model of ductus venosus pulsatility index in screening for aneuploidies at 11-13 weeks' gestation.

    Science.gov (United States)

    Maiz, Nerea; Wright, David; Ferreira, Ana Fatima A; Syngelaki, Argyro; Nicolaides, Kypros H

    2012-01-01

    To assess the value of ductus venosus pulsatility index for veins (DV PIV) in screening for aneuploidies at 11-13 weeks' gestation. Fetal DV PIV was measured in singleton pregnancies undergoing first-trimester screening for aneuploidies. In euploid (n = 44,756) and aneuploid (202 cases of trisomy 21, 72 cases of trisomy 18 and 30 cases of trisomy 13) fetuses, DV PIV was best described by a mixture model of distributions. Performance of screening for aneuploidies by DV PIV alone and in combination with fetal nuchal translucency (NT) thickness and serum free β-hCG and PAPP-A was estimated. In euploid pregnancies there was a bimodal distribution of DV PIV with a dominant crown-rump length (CRL)-dependent part, accounting for around 97% of cases in Caucasians and around 93% in Afro-Caribbeans, and a smaller CRL-independent distribution. In aneuploidies the dominant part was the CRL-independent distribution, which accounted for around 85% cases of trisomies 21 and 18 and 70% of cases of trisomy 13. In screening for trisomy 21 by maternal age, NT and biochemistry at a risk cutoff of 1 in 100, the detection rate was 89.7% and false positive rate was 2.74%; with addition of DV PIV, the values were 93.5 and 1.63%, respectively. Measurement of DV PIV improves the performance of first-trimester combined test for aneuploidies. Copyright © 2012 S. Karger AG, Basel.

  7. Factors associated with prostate cancer screening behavior among men over 50 in Fasa, Iran, based on the PRECEDE model

    OpenAIRE

    Jeihooni, Ali Khani; Kashfi, Seyyed Mansour; Kashfi, Seyyed Hannan; Heydarabadi, Akbar Babaei; Imanzad, Masoumeh; Hafez, Asghar Ashrafi

    2015-01-01

    Background: Prostate cancer is one of the most common and lethal cancers in the world. The incidence of prostate cancer has been increasing in recent years. The purpose of this study was to investigate factors associated with prostate cancer screening behaviors among men over 50 in Fasa, Iran, based on the PRECEDE model. Methods: In this cross-sectional study, 400 men over 50 were studied in Fasa, Iran. Data were collected via a questionnaire on demographic characteristics, such as age, numbe...

  8. A novel screening model for the molecular drug for diabetes and obesity based on tyrosine phosphatase Shp2.

    Science.gov (United States)

    Bu, Yanyan; Shi, Tao; Meng, Minghui; Kong, Guiping; Tian, Yingpu; Chen, Quancheng; Yao, Xinsheng; Feng, Gensheng; Chen, Haifeng; Cheng, Haifeng; Lu, Zhongxian

    2011-01-15

    Tyrosine phosphatase Src-homology phosphotyrosyl phosphatase 2 (Shp2) was identified as a potential molecular target for therapeutic treatment of diabetes and obesity. However, there is still no systematic research on the enhancers for the Shp2 enzyme. The present study established a novel powerful model for the high-throughput screening of Shp2 enhancers and successfully identified a new specific Shp2 enhancer, oleanolic acid, from Chinese herbs. Copyright © 2010 Elsevier Ltd. All rights reserved.

  9. Shapelet analysis of pupil dilation for modeling visuo-cognitive behavior in screening mammography

    Science.gov (United States)

    Alamudun, Folami; Yoon, Hong-Jun; Hammond, Tracy; Hudson, Kathy; Morin-Ducote, Garnetta; Tourassi, Georgia

    2016-03-01

    Our objective is to improve understanding of visuo-cognitive behavior in screening mammography under clinically equivalent experimental conditions. To this end, we examined pupillometric data, acquired using a head-mounted eye-tracking device, from 10 image readers (three breast-imaging radiologists and seven Radiology residents), and their corresponding diagnostic decisions for 100 screening mammograms. The corpus of mammograms comprised cases of varied pathology and breast parenchymal density. We investigated the relationship between pupillometric fluctuations, experienced by an image reader during mammographic screening, indicative of changes in mental workload, the pathological characteristics of a mammographic case, and the image readers' diagnostic decision and overall task performance. To answer these questions, we extract features from pupillometric data, and additionally applied time series shapelet analysis to extract discriminative patterns in changes in pupil dilation. Our results show that pupillometric measures are adequate predictors of mammographic case pathology, and image readers' diagnostic decision and performance with an average accuracy of 80%.

  10. Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation.

    Science.gov (United States)

    Williamson, Tracy P; Amirahmadi, Sara; Joshi, Gururaj; Kaludov, Nikola K; Martinov, Martin N; Johnson, Delinda A; Johnson, Jeffrey A

    2012-12-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master transcription factor of the antioxidant response element pathway, coordinating the induction of detoxifying and antioxidant enzymes. Nrf2 is normally sequestered in the cytoplasm by Kelch-like ECH-associating protein 1 (Keap1). To identify novel small molecules that will disturb Nrf2-Keap1 binding and promote activation of the Nrf2- antioxidant response element pathway, we generated a quantum model based on the structures of known Nrf2- antioxidant response element activators. We used the quantum model to perform in silico screening on over 18 million commercially available chemicals to identify the structures predicted to activate the Nrf2- antioxidant response element pathway based on the quantum model. The top hits were tested in vitro, and half of the predicted hits activated the Nrf2-antioxidant response element pathway significantly in primary cell culture. In addition, we identified a new family of Nrf2-antioxidant response element-activating structures that all have comparable activity to tBHQ and protect against oxidative stress and dopaminergic toxins in vitro. The improved ability to identify potent activators of Nrf2 through the combination of in silico and in vitro screening described here improves the speed and cost associated with screening Nrf2-antioxidant response element -activating compounds for drug development.

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

    Science.gov (United States)

    Brownjohn, Philip W; Smith, James; Portelius, Erik; Serneels, Lutgarde; Kvartsberg, Hlin; De Strooper, Bart; Blennow, Kaj; Zetterberg, Henrik; Livesey, Frederick J

    2017-04-11

    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. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Coupling Numerical and Physical Modeling for Analysis of Flow in a Diversion Structure with Coanda-effect Screens

    Directory of Open Access Journals (Sweden)

    Julie Coonrod

    2011-07-01

    Full Text Available There is an increasing need to screen water in surface water collection systems to remove floating debris and small aquatic organisms to protect receiving water bodies. Recently, the Albuquerque Metropolitan Arroyo Flood Control Authority (AMAFCA, New Mexico, USA has actively introduced structural debris removal from storm-water facilities as a best management practice. In the South Diversion Channel Project, AMAFCA’s objective is to divert the flow at the upstream end of the existing concrete structure and remove debris from this flow using Coanda-effect screens before allowing it to re-enter the channel. Design limitations, such as access to the debris removal site, existing components of the concrete structure, topography of the site, and need for flow-regulating structures complicate the design. This paper shows how numerical modeling tools (Delft3D-FLOW model and physical modeling can be used in conjunction to observe flow patterns in a diversion structure and around Coanda-effect screens, estimate design parameters and thereby provide design recommendations.

  13. Multi-objective vs. single-objective calibration of a hydrologic model using single- and multi-objective screening

    Science.gov (United States)

    Mai, Juliane; Cuntz, Matthias; Shafii, Mahyar; Zink, Matthias; Schäfer, David; Thober, Stephan; Samaniego, Luis; Tolson, Bryan

    2016-04-01

    Hydrologic models are traditionally calibrated against observed streamflow. Recent studies have shown however, that only a few global model parameters are constrained using this kind of integral signal. They can be identified using prior screening techniques. Since different objectives might constrain different parameters, it is advisable to use multiple information to calibrate those models. One common approach is to combine these multiple objectives (MO) into one single objective (SO) function and allow the use of a SO optimization algorithm. Another strategy is to consider the different objectives separately and apply a MO Pareto optimization algorithm. In this study, two major research questions will be addressed: 1) How do multi-objective calibrations compare with corresponding single-objective calibrations? 2) How much do calibration results deteriorate when the number of calibrated parameters is reduced by a prior screening technique? The hydrologic model employed in this study is a distributed hydrologic model (mHM) with 52 model parameters, i.e. transfer coefficients. The model uses grid cells as a primary hydrologic unit, and accounts for processes like snow accumulation and melting, soil moisture dynamics, infiltration, surface runoff, evapotranspiration, subsurface storage and discharge generation. The model is applied in three distinct catchments over Europe. The SO calibrations are performed using the Dynamically Dimensioned Search (DDS) algorithm with a fixed budget while the MO calibrations are achieved using the Pareto Dynamically Dimensioned Search (PA-DDS) algorithm allowing for the same budget. The two objectives used here are the Nash Sutcliffe Efficiency (NSE) of the simulated streamflow and the NSE of the logarithmic transformation. It is shown that the SO DDS results are located close to the edges of the Pareto fronts of the PA-DDS. The MO calibrations are hence preferable due to their supply of multiple equivalent solutions from which the

  14. Systematic screening for Chlamydia trachomatis : Estimating cost-effectiveness using dynamic modeling and Dutch data

    NARCIS (Netherlands)

    de Vries, R.; Van Bergen, J.E.A.M.; de Jong-van den Berg, Lolkje; Postma, Maarten

    2006-01-01

    To estimate the cost-effectiveness of a systematic one-off Chlamydia trachomatis (CT) screening program including partner treatment for Dutch young adults. Data on infection prevalence, participation rates, and sexual behavior were obtained from a large pilot study conducted in The Netherlands. Oppo

  15. Screening for Adverse Childhood Experiences (ACEs) in an Integrated Pediatric Care Model

    Science.gov (United States)

    Purewal, Sukhdip K.; Bucci, Monica; Wang, Lisa Gutiérrez; Koita, Kadiatou; Marques, Sara Silvério; Oh, Debora; Harris, Nadine Burke

    2016-01-01

    Adverse childhood experiences (ACEs) are stressful or traumatic events that place children at risk of negative health, mental health, and behavioral outcomes. The Center for Youth Wellness (CYW), working in partnership with the Bayview Child Health Center (BCHC), pioneered ACE screening for children and adolescents. This article describes the…

  16. Screening and vaccination as determined by the Social Ecological Model and the Theory of Triadic Influence

    NARCIS (Netherlands)

    Nyambe, Anayawa; Hal, Van Guido; Kampen, Jarl K.

    2016-01-01


    Background

    Vaccination and screening are forms of primary and secondary prevention methods. These methods are recommended for controlling the spread of a vast number of diseases and conditions. To determine the most effective preventive methods to be used by a society, multi-level mode

  17. Screening and vaccination as determined by the Social Ecological Model and the Theory of Triadic Influence

    NARCIS (Netherlands)

    Nyambe, Anayawa; Hal, Van Guido; Kampen, Jarl K.

    2016-01-01


    Background

    Vaccination and screening are forms of primary and secondary prevention methods. These methods are recommended for controlling the spread of a vast number of diseases and conditions. To determine the most effective preventive methods to be used by a society, multi-level

  18. Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

    Science.gov (United States)

    Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive signature was constructed from U.S. EPA ToxCast high-throughput screening (HTS) assays that map to...

  19. Modeling nanoscale gas sensors under realistic conditions: Computational screening of metal-doped carbon nanotubes

    DEFF Research Database (Denmark)

    García Lastra, Juan Maria; Mowbray, Duncan; Thygesen, Kristian Sommer

    2010-01-01

    We use computational screening to systematically investigate the use of transition-metal-doped carbon nanotubes for chemical-gas sensing. For a set of relevant target molecules (CO, NH3, and H2S) and the main components of air (N2, O2, and H2O), we calculate the binding energy and change...

  20. Protective Factors Based Model for Screening for Posttraumatic Distress in Adolescents

    Science.gov (United States)

    Pat-Horenczyk, Ruth; Kenan, Avraham Max; Achituv, Michal; Bachar, Eytan

    2014-01-01

    Background: There is growing application of school-based screening to identify post-traumatic distress in students following exposure to trauma. The consensus method is based on self-report questionnaires that assess posttraumatic symptoms, functional impairment, depression or anxiety. Objective: The current research explored the possibility of…

  1. Discovery of novel Bruton's tyrosine kinase inhibitors using a hybrid protocol of virtual screening approaches based on SVM model, pharmacophore and molecular docking.

    Science.gov (United States)

    Wan, Hua-Lin; Wang, Ze-Rong; Li, Lin-Li; Cheng, Chuan; Ji, Pan; Liu, Jing-Jing; Zhang, Hui; Zou, Jun; Yang, Sheng-Yong

    2012-09-01

    Bruton's tyrosine kinase has emerged as a potential target for the treatment for B-cell malignancies and autoimmune diseases. Discovery of Bruton's tyrosine kinase inhibitors has thus attracted much attention recently. In this investigation, we introduced a hybrid protocol of virtual screening methods including support vector machine model-based virtual screening, pharmacophore model-based virtual screening and docking-based virtual screening for retrieving new Bruton's tyrosine kinase inhibitors from commercially available chemical databases. Performances of the hybrid virtual screening approach were evaluated against a test set, which results showed that the hybrid virtual screening approach significantly shortened the overall screening time, and considerably increased the hit rate and enrichment factor compared with the individual method (SB-VS, PB-VS and DB-VS) or their combinations by twos. This hybrid virtual screening approach was then applied to screen several chemical databases including Specs (202,408 compounds) and Enamine (980,000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies. © 2012 John Wiley & Sons A/S.

  2. Molecular modeling on pyruvate phosphate dikinase of Entamoeba histolytica and in silico virtual screening for novel inhibitors

    Science.gov (United States)

    Stephen, Preyesh; Vijayan, Ramachandran; Bhat, Audesh; Subbarao, N.; Bamezai, R. N. K.

    2008-09-01

    Pyruvate phosphate dikinase (PPDK) is the key enzyme essential for the glycolytic pathway in most common and perilous parasite Entamoeba histolytica. Inhibiting the function of this enzyme could control the wide spread of intestinal infections caused by Entamoeba histolytica in humans. With this objective, we modeled the three dimensional structure of the PPDK protein. We used templates with 51% identity and 67% similarity to employ homology-modeling approach. Stereo chemical quality of protein structure was validated by protein structure validation program PROCHECK and VERIFY3D. Experimental proof available in literature along with the in silico studies indicated Lys21, Arg91, Asp323, Glu325 and Gln337 to be the probable active sites in the target protein. Virtual screening was carried out using the genetic docking algorithm GOLD and a consensus scoring function X-Score to substantiate the prediction. The small molecule libraries (ChemDivision database, Diversity dataset, Kinase inhibitor database) were used for screening process. Along with the high scoring results, the interaction studies provided promising ligands for future experimental screening to inhibit the function of PPDK in Entamoeba histolytica. Further, the phylogeny study was carried out to assess the possibility of using the proposed ligands as inhibitors in related pathogens.

  3. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model.

    Science.gov (United States)

    Evers, Andreas; Klebe, Gerhard

    2004-10-21

    The neurokinin-1 (NK1) receptor belongs to the family of G-protein-coupled receptors (GPCRs), which represents one of the most relevant target families in small-molecule drug design. In this paper, we describe a homology modeling of the NK1 receptor based on the high-resolution X-ray structure of rhodopsin and the successful virtual screening based on this protein model. The NK1 receptor model has been generated using our new MOBILE (modeling binding sites including ligand information explicitly) approach. Starting with preliminary homology models, it generates improved models of the protein binding pocket together with bound ligands. Ligand information is used as an integral part in the homology modeling process. For the construction of the NK1 receptor, antagonist CP-96345 was used to restrain the modeling. The quality of the obtained model was validated by probing its ability to accommodate additional known NK1 antagonists from structurally diverse classes. On the basis of the generated model and on the analysis of known NK1 antagonists, a pharmacophore model was deduced, which subsequently guided the 2D and 3D database search with UNITY. As a following step, the remaining hits were docked into the modeled binding pocket of the NK1 receptor. Finally, seven compounds were selected for biochemical testing, from which one showed affinity in the submicromolar range. Our results suggest that ligand-supported homology models of GPCRs may be used as effective platforms for structure-based drug design.

  4. A Teach-Discover-Treat Application of ZincPharmer: An Online Interactive Pharmacophore Modeling and Virtual Screening Tool.

    Directory of Open Access Journals (Sweden)

    David Ryan Koes

    Full Text Available The 2012 Teach-Discover-Treat (TDT community-wide experiment provided a unique opportunity to test prospective virtual screening protocols targeting the anti-malarial target dihydroorotate dehydrogenase (DHODH. Facilitated by ZincPharmer, an open access online interactive pharmacophore search of the ZINC database, the experience resulted in the development of a novel classification scheme that successfully predicted the bound structure of a non-triazolopyrimidine inhibitor, as well as an overall hit rate of 27% of tested active compounds from multiple novel chemical scaffolds. The general approach entailed exhaustively building and screening sparse pharmacophore models comprising of a minimum of three features for each bound ligand in all available DHODH co-crystals and iteratively adding features that increased the number of known binders returned by the query. Collectively, the TDT experiment provided a unique opportunity to teach computational methods of drug discovery, develop innovative methodologies and prospectively discover new compounds active against DHODH.

  5. The Kidney Disease Screening and Awareness Program (KDSAP): a novel translatable model for increasing interest in nephrology careers.

    Science.gov (United States)

    Hsiao, Li-Li; Wu, Jingshing; Yeh, Albert C; Shieh, Eric C; Cui, Cheryl; Li, Ang; Polding, Laura C; Ahmed, Rayhnuma; Lim, Kenneth; Lu, Tzong-Shi; Rhee, Connie M; Bonventre, Joseph V

    2014-09-01

    Despite the increasing prevalence of CKD in the United States, there is a declining interest among United States medical graduates in nephrology as a career choice. Effective programs are needed to generate interest at early educational stages when career choices can be influenced. The Kidney Disease Screening and Awareness Program (KDSAP) is a novel program initiated at Harvard College that increases student knowledge of and interest in kidney health and disease, interest in nephrology career paths, and participation in kidney disease research. This model, built on physician mentoring, kidney screening of underserved populations, direct interactions with kidney patients, and opportunities to participate in kidney research, can be reproduced and translated to other workforce-challenged subspecialties.

  6. Hsp90 inhibitors, part 1: definition of 3-D QSAutogrid/R models as a tool for virtual screening.

    Science.gov (United States)

    Ballante, Flavio; Caroli, Antonia; Wickersham, Richard B; Ragno, Rino

    2014-03-24

    The multichaperone heat shock protein (Hsp) 90 complex mediates the maturation and stability of a variety of oncogenic signaling proteins. For this reason, Hsp90 has emerged as a promising target for anticancer drug development. Herein, we describe a complete computational procedure for building several 3-D QSAR models used as a ligand-based (LB) component of a comprehensive ligand-based (LB) and structure-based (SB) virtual screening (VS) protocol to identify novel molecular scaffolds of Hsp90 inhibitors. By the application of the 3-D QSAutogrid/R method, eight SB PLS 3-D QSAR models were generated, leading to a final multiprobe (MP) 3-D QSAR pharmacophoric model capable of recognizing the most significant chemical features for Hsp90 inhibition. Both the monoprobe and multiprobe models were optimized, cross-validated, and tested against an external test set. The obtained statistical results confirmed the models as robust and predictive to be used in a subsequent VS.

  7. The Effect of Health Belief Model-Based Education on Knowledge and Prostate Cancer Screening Behaviors: A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Maryam Zare

    2016-01-01

    Full Text Available Background: Prostate cancer has been reported as the second leading cause of cancer death among men in 2013. Prevention and early detection of cancer are considered as critical factors in controlling the disease and increasing the survival of patients. Therefore, we aimed to investigate the effect of Health Belief Model (HBM-based education onknowledge and prostate cancer screening behaviors in a randomized controlled trial. Methods: This study was a non-blinded randomized controlled trial. We enrolled 210 men aged 50-70. Balanced block randomization method was used to randomize the final participants who had inclusion criteria into intervention (n=93 and control (n=87 groups. The participants of the intervention group attended training workshops based on HBM. Data were collected using three questionnaires, i.e. demographic questionnaire, Prostate Cancer Screening-Health Belief Model Scale (PCS-HBMS, and the Knowledge about Prostate Cancer Screening questionnaire, all given before and immediately one month after the intervention. Results: The mean scores of the perceived susceptibility, severity, barriers and benefits increased significantly after the intervention (P>0.05 in the intervention group. In the control group, such a difference was reported only for perceived susceptibility (P>0.05. The rate of participation in prostate cancer screening in the intervention group increased from 7.5% to 24% and 43.3% one month and three months after the intervention, respectively. Conclusion: Our findings showed that the health education programs designed based on HBM could positively affect prostate cancer preventive behaviors of individuals by improving their knowledge level and leaving positive effects on perceived susceptibility and severity as well as considering the perceived barriers, benefits and health motivations.

  8. Limits of ligand selectivity from docking to models: in silico screening for A(1 adenosine receptor antagonists.

    Directory of Open Access Journals (Sweden)

    Peter Kolb

    Full Text Available G protein-coupled receptors (GPCRs are attractive targets for pharmaceutical research. With the recent determination of several GPCR X-ray structures, the applicability of structure-based computational methods for ligand identification, such as docking, has increased. Yet, as only about 1% of GPCRs have a known structure, receptor homology modeling remains necessary. In order to investigate the usability of homology models and the inherent selectivity of a particular model in relation to close homologs, we constructed multiple homology models for the A(1 adenosine receptor (A(1AR and docked ∼2.2 M lead-like compounds. High-ranking molecules were tested on the A(1AR as well as the close homologs A(2AAR and A(3AR. While the screen yielded numerous potent and novel ligands (hit rate 21% and highest affinity of 400 nM, it delivered few selective compounds. Moreover, most compounds appeared in the top ranks of only one model. These findings have implications for future screens.

  9. Vision Screening

    Science.gov (United States)

    ... of Prematurity Strabismus Stye (defined) Vision Screening Vision Screening Recommendations Loading... Most Common Searches Adult Strabismus Amblyopia Cataract Conjunctivitis Corneal Abrasions Dilating Eye ...

  10. Exploratory structural equation modeling, bifactor models, and standard confirmatory factor analysis models: application to the BASC-2 Behavioral and Emotional Screening System Teacher Form.

    Science.gov (United States)

    Wiesner, Margit; Schanding, G Thomas

    2013-12-01

    Several psychological assessment instruments are based on the assumption of a general construct that is composed of multiple interrelated domains. Standard confirmatory factor analysis is often not well suited for examining the factor structure of such scales. This study used data from 1885 elementary school students (mean age=8.77 years, SD=1.47 years) to examine the factor structure of the Behavioral Assessment System for Children, Second Edition (BASC-2) Behavioral and Emotional Screening System (BESS) Teacher Form that was designed to assess general risk for emotional/behavioral difficulty among children. The modeling sequence included the relatively new exploratory structural equation modeling (ESEM) approach and bifactor models in addition to more standard techniques. Findings revealed that the factor structure of the BASC-2 BESS Teacher Form is multidimensional. Both ESEM and bifactor models showed good fit to the data. Bifactor models were preferred on conceptual grounds. Findings illuminate the hypothesis-generating power of ESEM and suggest that it might not be optimal for instruments designed to assess a predominant general factor underlying the data.

  11. The health system and population health implications of large-scale diabetes screening in India: a microsimulation model of alternative approaches.

    Directory of Open Access Journals (Sweden)

    Sanjay Basu

    2015-05-01

    Full Text Available Like a growing number of rapidly developing countries, India has begun to develop a system for large-scale community-based screening for diabetes. We sought to identify the implications of using alternative screening instruments to detect people with undiagnosed type 2 diabetes among diverse populations across India.We developed and validated a microsimulation model that incorporated data from 58 studies from across the country into a nationally representative sample of Indians aged 25-65 y old. We estimated the diagnostic and health system implications of three major survey-based screening instruments and random glucometer-based screening. Of the 567 million Indians eligible for screening, depending on which of four screening approaches is utilized, between 158 and 306 million would be expected to screen as "high risk" for type 2 diabetes, and be referred for confirmatory testing. Between 26 million and 37 million of these people would be expected to meet international diagnostic criteria for diabetes, but between 126 million and 273 million would be "false positives." The ratio of false positives to true positives varied from 3.9 (when using random glucose screening to 8.2 (when using a survey-based screening instrument in our model. The cost per case found would be expected to be from US$5.28 (when using random glucose screening to US$17.06 (when using a survey-based screening instrument, presenting a total cost of between US$169 and US$567 million. The major limitation of our analysis is its dependence on published cohort studies that are unlikely fully to capture the poorest and most rural areas of the country. Because these areas are thought to have the lowest diabetes prevalence, this may result in overestimation of the efficacy and health benefits of screening.Large-scale community-based screening is anticipated to produce a large number of false-positive results, particularly if using currently available survey-based screening

  12. Comparison of in vitro and in vivo screening models for androgenic and estrogenic activities.

    Science.gov (United States)

    Sonneveld, Edwin; Riteco, Jacoba A C; Jansen, Hendrina J; Pieterse, Bart; Brouwer, Abraham; Schoonen, Willem G; van der Burg, Bart

    2006-01-01

    Identification of nuclear receptor-mediated endocrine activities is important in a variety of fields, ranging from pharmacological and clinical screening, to food and feed safety, toxicological monitoring, and risk assessment. Traditionally animal studies such as the Hershberger and Allen-Doisy tests are used for the assessment of androgenic and estrogenic potencies, respectively. To allow fast analysis of the activities of new chemicals, food additives, and pharmaceutical compounds, high-throughput screening strategies have been developed. Here, a panel of mainly steroidal compounds, screened in different in vitro assays, was compared with two human U2-OS cell line-based CALUX (Chemically Activated LUciferase eXpression) reporter gene assays for androgens (AR CALUX) and estrogens (ERalpha CALUX). Correlations found between the data of these two CALUX reporter gene assays and data obtained with other in vitro screening assays measuring receptor binding or reporter gene activation (CHO cell line-based) were good (correlation coefficients (r2) between 0.54 and 0.76; p vitro and in vivo data (correlation coefficient r2 = 0.46 for the AR CALUX vs. Hershberger assay and r2 = 0.87 for the ERalpha CALUX vs. Allen-Doisy assay). The variations in the results obtained with the reporter gene assays (CALUX vs. CHO cell line based) were relatively small, showing the robustness of these types of assays. Using hierarchical clustering, bioactivity relationships between compounds but also relationships between various bioassays were determined. The in vitro assays were found to be good predictors of in vivo androgenic or estrogenic activity of a range of compounds, allowing prescreen and/or possible reduction of animal studies.

  13. [Improving the cancer screening model: experience applying an integrated operating system].

    Science.gov (United States)

    Wu, Pei-Hua; Lin, Wen-Li

    2009-12-01

    Cancer patient numbers have continued to rise in recent years. In terms of deaths from various cancers, malignancies are involved in 28.9% of cases. Over the course of disease contraction, treatment and aftercare, patients face unease and pressure of various forms and degrees. Patients may abort treatment due to treatment pain and discomfort. The case manager may play a positive role by following up at appropriate moments to understand patient needs and deliver proper resources in order to avoid cancer recrudescence, which may delay treatment progress. The objective of this study was to improve nursing quality and management performance in cancer patient care. Through the integration of the management information system, A "Cancer Case Screening System" was built using a management information system to shorten the amount of time spent on scanning new cases and to reduce the rate of scanning error. Using a decision matrix, the research team proposed the following solution: (1) Define the system infrastructure currently employed in hospitals; (2) Discuss the Cancer Cases Screening System workflow and determine system specifications; (3) Write the Cancer Cases Screening System program to establish an effective management information system. The time spent on scanning case per day dropped from 117.14 to 28.57 minutes. The error rate was also reduced from 34.65% to 8.87%. These results achieved the objective of the project. Promoting the developed screening system in the broader medical community can help reduce medical treatment costs and increase treatment continuity. This project may be considered and referenced by managers of relevant medical organizations.

  14. A partial exponential lumped parameter model to evaluate groundwater age distributions and nitrate trends in long-screened wells

    Science.gov (United States)

    Jurgens, Bryant; Bohlke, John Karl; Kauffman, Leon J.; Belitz, Kenneth; Esser, Bradley K.

    2016-01-01

    A partial exponential lumped parameter model (PEM) was derived to determine age distributions and nitrate trends in long-screened production wells. The PEM can simulate age distributions for wells screened over any finite interval of an aquifer that has an exponential distribution of age with depth. The PEM has 3 parameters – the ratio of saturated thickness to the top and bottom of the screen and mean age, but these can be reduced to 1 parameter (mean age) by using well construction information and estimates of the saturated thickness. The PEM was tested with data from 30 production wells in a heterogeneous alluvial fan aquifer in California, USA. Well construction data were used to guide parameterization of a PEM for each well and mean age was calibrated to measured environmental tracer data (3H, 3He, CFC-113, and 14C). Results were compared to age distributions generated for individual wells using advective particle tracking models (PTMs). Age distributions from PTMs were more complex than PEM distributions, but PEMs provided better fits to tracer data, partly because the PTMs did not simulate 14C accurately in wells that captured varying amounts of old groundwater recharged at lower rates prior to groundwater development and irrigation. Nitrate trends were simulated independently of the calibration process and the PEM provided good fits for at least 11 of 24 wells. This work shows that the PEM, and lumped parameter models (LPMs) in general, can often identify critical features of the age distributions in wells that are needed to explain observed tracer data and nonpoint source contaminant trends, even in systems where aquifer heterogeneity and water-use complicate distributions of age. While accurate PTMs are preferable for understanding and predicting aquifer-scale responses to water use and contaminant transport, LPMs can be sensitive to local conditions near individual wells that may be inaccurately represented or missing in an aquifer-scale flow model.

  15. A partial exponential lumped parameter model to evaluate groundwater age distributions and nitrate trends in long-screened wells

    Science.gov (United States)

    Jurgens, Bryant C.; Böhlke, J. K.; Kauffman, Leon J.; Belitz, Kenneth; Esser, Bradley K.

    2016-12-01

    A partial exponential lumped parameter model (PEM) was derived to determine age distributions and nitrate trends in long-screened production wells. The PEM can simulate age distributions for wells screened over any finite interval of an aquifer that has an exponential distribution of age with depth. The PEM has 3 parameters - the ratio of saturated thickness to the top and bottom of the screen and mean age, but these can be reduced to 1 parameter (mean age) by using well construction information and estimates of the saturated thickness. The PEM was tested with data from 30 production wells in a heterogeneous alluvial fan aquifer in California, USA. Well construction data were used to guide parameterization of a PEM for each well and mean age was calibrated to measured environmental tracer data (3H, 3He, CFC-113, and 14C). Results were compared to age distributions generated for individual wells using advective particle tracking models (PTMs). Age distributions from PTMs were more complex than PEM distributions, but PEMs provided better fits to tracer data, partly because the PTMs did not simulate 14C accurately in wells that captured varying amounts of old groundwater recharged at lower rates prior to groundwater development and irrigation. Nitrate trends were simulated independently of the calibration process and the PEM provided good fits for at least 11 of 24 wells. This work shows that the PEM, and lumped parameter models (LPMs) in general, can often identify critical features of the age distributions in wells that are needed to explain observed tracer data and nonpoint source contaminant trends, even in systems where aquifer heterogeneity and water-use complicate distributions of age. While accurate PTMs are preferable for understanding and predicting aquifer-scale responses to water use and contaminant transport, LPMs can be sensitive to local conditions near individual wells that may be inaccurately represented or missing in an aquifer-scale flow model.

  16. 3D QSAR modeling of 4-nerolidylcatechol derivatives and virtual screening for identification of potent plasmodium inhibitor

    Directory of Open Access Journals (Sweden)

    Dhrubajyoti Gogoi

    2014-08-01

    Full Text Available The present study was aim to develop a three dimensional quantitative structure–activity relationships (3D QSAR model based on the structure of 4-nerolidylcatechol (IC50=0.67 µM, a novel plant derived Plasmodium inhibitor and its derivatives for identification of efficient antimalarial lead. A statisti-cally validated Partial Least-Squares (PLS based Molecular Field Analysis (MFA model was built up using the training set of eight 4-nerolidylcatechol derivatives and their diverse conformers. A statistically reliable model with good predictive power (cross-validated correlation coefficient q2=0.769 was obtained. Hence, the generated model was used to screen a library of 30,000 compounds of chembridge database (http://www.chembridge.com. Results of drug likeness prediction and ADMET study has suggested six compounds as potential antimalarial/plasmodial lead.

  17. Model prediction for temperature dependence of meson pole masses from lattice QCD results on meson screening masses

    CERN Document Server

    Ishii, Masahiro; Yahiro, Masanobu

    2016-01-01

    We propose a practical effective model by introducing temperature ($T$) dependence to the coupling strengths of four-quark and six-quark Kobayashi-Maskawa-'t Hooft interactions in the 2+1 flavor Polyakov-loop extended Nambu-Jona-Lasinio model. The $T$ dependence is determined from LQCD data on the renormalized chiral condensate around the pseudocritical temperature $T_c^{\\chi}$ of chiral crossover and the screening-mass difference between $\\pi$ and $a_0$ mesons in $T > 1.1T_c^\\chi$ where only the $U(1)_{\\rm A}$-symmetry breaking survives. The model well reproduces LQCD data on screening masses $M_{\\xi}^{\\rm scr}(T)$ for both scalar and pseudoscalar mesons, particularly in $T \\ge T_c^{\\chi}$. Using this effective model, we predict meson pole masses $M_{\\xi}^{\\rm pole}(T)$ for scalar and pseudoscalar mesons. For $\\eta'$ meson, the prediction is consistent with the experimental value at finite $T$ measured in heavy-ion collisions. We point out that the relation $M_{\\xi}^{\\rm scr}(T)-M_{\\xi}^{\\rm pole}(T) \\approx...

  18. A DPSIR model for ecological security assessment through indicator screening: a case study at Dianchi Lake in China.

    Directory of Open Access Journals (Sweden)

    Zhen Wang

    Full Text Available Given the important role of lake ecosystems in social and economic development, and the current severe environmental degradation in China, a systematic diagnosis of the ecological security of lakes is essential for sustainable development. A Driving-force, Pressure, Status, Impact, and Risk (DPSIR model, combined with data screening for lake ecological security assessment was developed to overcome the disadvantages of data selection in existing assessment methods. Correlation and principal component analysis were used to select independent and representative data. The DPSIR model was then applied to evaluate the ecological security of Dianchi Lake in China during 1988-2007 using an ecological security index. The results revealed a V-shaped trend. The application of the DPSIR model with data screening provided useful information regarding the status of the lake's ecosystem, while ensuring information efficiency and eliminating multicollinearity. The modeling approach described here is practical and operationally efficient, and provides an attractive alternative approach to assess the ecological security of lakes.

  19. The gap-startle paradigm for tinnitus screening in animal models: limitations and optimization.

    Science.gov (United States)

    Lobarinas, Edward; Hayes, Sarah H; Allman, Brian L

    2013-01-01

    In 2006, Turner and colleagues (Behav. Neurosci., 120:188-195) introduced the gap-startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5-10 kHz) in order to maintain audibility of the startle stimulus after unilateral high-frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rat's neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse

  20. Behavioral health screening and intervention for women in Argentina: a preliminary model for the childbearing years

    Directory of Open Access Journals (Sweden)

    Suarez Ordoñez RM

    2015-06-01

    Full Text Available Rocio M Suarez Ordoñez,1 Jorgelina Cesolari,2 Casas Ofelia,2 Ivonne Villavicencio,1 Hendrée E Jones31Research Department, Institute of Cognitive Neuroscience INECO Oroño, 2Neonatology Department, Martin Maternity, Rosario, Santa Fe, Argentina; 3UNC Horizons and Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAAbstract: Untreated behavioral disorders in pregnant women and in women of childbearing age pose physical and psychological safety concerns and are barriers to the well-being of both mother and neonate. The present paper underlines the importance of screening in Argentina for behavioral problems in women of childbearing age, particularly pregnant women and their newborns. Emphasized is the need to formalize this comprehensive screening in a protocol that includes domains of mental disorders, behavioral disorders, education, social environment, employment, desire for maternity, substance use including non-prescription use of prescription medications, eating disorders, suicide risk, interpersonal violence, stress, and trauma. Implementation of such a model would require agreement and cooperation between the public and private health sectors as well as in the development of research for validation of the various screening and interventions tools that would be adopted for general use. Keywords: pregnancy, substance use, assessment, measures

  1. Quantitative Phenotyping-Based In Vivo Chemical Screening in a Zebrafish Model of Leukemia Stem Cell Xenotransplantation

    Science.gov (United States)

    Zhang, Beibei; Shimada, Yasuhito; Kuroyanagi, Junya; Umemoto, Noriko; Nishimura, Yuhei; Tanaka, Toshio

    2014-01-01

    Zebrafish-based chemical screening has recently emerged as a rapid and efficient method to identify important compounds that modulate specific biological processes and to test the therapeutic efficacy in disease models, including cancer. In leukemia, the ablation of leukemia stem cells (LSCs) is necessary to permanently eradicate the leukemia cell population. However, because of the very small number of LSCs in leukemia cell populations, their use in xenotransplantation studies (in vivo) and the difficulties in functionally and pathophysiologically replicating clinical conditions in cell culture experiments (in vitro), the progress of drug discovery for LSC inhibitors has been painfully slow. In this study, we developed a novel phenotype-based in vivo screening method using LSCs xenotransplanted into zebrafish. Aldehyde dehydrogenase-positive (ALDH+) cells were purified from chronic myelogenous leukemia K562 cells tagged with a fluorescent protein (Kusabira-orange) and then implanted in young zebrafish at 48 hours post-fertilization. Twenty-four hours after transplantation, the animals were treated with one of eight different therapeutic agents (imatinib, dasatinib, parthenolide, TDZD-8, arsenic trioxide, niclosamide, salinomycin, and thioridazine). Cancer cell proliferation, and cell migration were determined by high-content imaging. Of the eight compounds that were tested, all except imatinib and dasatinib selectively inhibited ALDH+ cell proliferation in zebrafish. In addition, these anti-LSC agents suppressed tumor cell migration in LSC-xenotransplants. Our approach offers a simple, rapid, and reliable in vivo screening system that facilitates the phenotype-driven discovery of drugs effective in suppressing LSCs. PMID:24454867

  2. Cost effectiveness analysis of population-based serology screening and 13C-Urea breath test for Helicobacter pylori to prevent gastric cancer: A markov model

    Institute of Scientific and Technical Information of China (English)

    Feng Xie; Nan Luo; Hin-Peng Lee

    2008-01-01

    AIM: To compare the costs and effectiveness of no screening and no eradication therapy, the populationbased Hdlicobacter pylori (H pylori) serology screening with eradication therapy and 13C-Urea breath test (UBT)with eradication therapy.METHODS: A tarkov model simulation was carried out in all 237900 Chinese males with age between 35 and 44 from the perspective of the public healthcare provider in Singapore. The main outcome measures were the costs, number of gastric cancer cases prevented, life years saved, and quality-adjusted life years (QALYs)gained from screening age to death. The uncertainty surrounding the cost-effectiveness ratio was addressed by one-way sensitivity analyses.RESULTS: Compared to no screening, the incremental cost-effectiveness ratio (ICER) was $16166 per life year saved or $13571 per QALY gained for the serology screening, and $38792 per life year saved and $32525 per QALY gained for the UBT. The ICER was $477079 per life year saved or $390337 per QALY gained for the UBT compared to the serology screening. The costeffectiveness of serology screening over the UBT was robust to most parameters in the model.CONCLUSION: The population-based serology screening for H pylori was more cost-effective than the UBT in prevention of gastric cancer in Singapore Chinese males.

  3. Multistate transitional models for measuring adherence to breast cancer screening: A population-based longitudinal cohort study with over two million women.

    Science.gov (United States)

    Sutradhar, R; Gu, S; Paszat, L F

    2017-06-01

    Objective Prior work on the disparities among women in breast cancer screening adherence has been methodologically limited. This longitudinal study determines and examines the factors associated with becoming adherent. Methods In a cohort of Canadian women aged 50-74, a three-state transitional model was used to examine adherence to screening for breast cancer. The proportion of time spent being non-adherent with screening was calculated for each woman during her observation window. Using age as the time scale, a relative rate multivariable regression was implemented under the three-state transitional model, to examine the association between covariates (all time-varying) and the rate of becoming adherent. Results The cohort consisted of 2,537,960 women with a median follow-up of 8.46 years. Nearly 31% of women were continually up-to-date with breast screening. Once a woman was non-adherent, the rate of becoming adherent was higher among longer term residents (relative rate = 1.289, 95% confidence interval 1.275-1.302), those from wealthier neighbourhoods, and those who had an identifiable primary care provider who was female or had graduated in Canada. Conclusion Individual and physician-level characteristics play an important role in a woman's adherence to screening. This work improves the quality of evidence regarding disparities among women in adherence to breast cancer screening and provides a novel methodological foundation to investigate adherence for other types of screening, including cervix and colorectal cancer screening.

  4. Evaluating the appropriateness of a community pharmacy model for a colorectal cancer screening program in Catalonia (Spain).

    Science.gov (United States)

    Santolaya, M; Aldea, M; Grau, J; Estrada, M; Barau, M; Buron, A; Francesc, M; Castell, A; Rodriguez, C; Gascón, P; Rius, P; Guayta-Escolies, R

    2017-01-01

    Background The traditional model of community pharmacy has changed, with patients, caregivers and consumers having access to many cognitive services other than the traditional dispensing and supply of medicines. In December 2009, a population-based colorectal cancer screening program started in Barcelona, introducing the community pharmacist and the professional expertise of the pharmacist into the organisational model. Aim To evaluate the program implementation process in the pharmacies, identify barriers and facilitators, and know the opinion of the professionals involved in the colorectal cancer screening program in Catalonia (Spain). Methods Cross-sectional study of the pharmacies that participated in the first round of the program during the first and second trimester of 2010 in Barcelona. A validated questionnaire was used to analyse several functional aspects in the implementation process. Qualitative aspects about the opinion of the pharmacist were studied. A descriptive and bivariate analysis was performed. Results All the pharmacies involved in the program (n = 74) participated in the study. The majority of the sample population was composed of women (70.3%), mean age 44.9 years, and most of them (74%) had attended a specific training session. Pharmacists considered their participation in the program to be an added value to their professional role and a way to increase consumer's confidence on this kind of services. The average time to provide the service was estimated to be less than 10 minutes per consumer. Only three (4.1%) pharmacists considered that the program involved a lot of extra work in the daily activities of the pharmacy. The level of satisfaction of the pharmacists was very high. Conclusions Community pharmacies can be a successful alternative and great resource to implement a population cancer screening program. This functional model can improve the accessibility and participation rates on target population. The level of motivation of

  5. Development of a New High-throughput Screening Model for Human High Density Lipoprotein Receptor (CLA-1) Agonists

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective To develop a new high-throughput screening model for human high-density lipoprotein (HDL) receptor (CD36 and LIMPII analogous-1, CLA-1) agonists using CLA-1-expressing insect cells. Methods With the total RNA of human hepatoma cells BEL-7402 as template, the complementary DNA (cDNA) of CLA-1 was amplified by reverse transcription-polymerase chain reaction (RT-PCR). Bac-to-Bac baculovirus expression system was used to express CLA-1 in insect cells. CLA-1 cDNA was cloned downstream of polyhedrin promoter of Autographa californica nuclear polyhedrosis virus (AcNPV) into donor vector pFastBac1 and recombinant pFastBac1-CLA-1 was transformed into E. coli DH10Bac to transpose CLA-1 cDNA to bacmid DNA. Recombinant bacmid-CLA-1 was transfected into Spodoptera frugiperda Sf9 insect cells to produce recombinant baculovirus particles. Recombinant CLA-1 was expressed on the membrane of Sf9 cells infected with the recombinant baculoviruses. A series of parameters of DiI-lipoprotein binding assays of CLA-1-expressing Sf9 cells in 96-well plates were optimized. Results Western blot analysis and DiI-lipoprotein binding assays confirmed that CLA-1 expressed in insect cells had similar immunoreactivity and ligand binding activity as its native counterpart. A reliable and sensitive in vitro cell-based assay was established to assess the activity of CLA-1 and used to screen agonists from different sample libraries. Conclusion Human HDL receptor CLA-1 was successfully expressed in Sf9 insect cells and a novel high-throughput screening model for CLA-1 agonists was developed. Utilization of this model allows us to identify potent and selective CLA-1 agonists which might possibly be used as therapeutics for atherosclerosis.

  6. Endotoxin Molecule Lipopolysaccharide-Induced Zebrafish Inflammation Model: A Novel Screening Method for Anti-Inflammatory Drugs

    Directory of Open Access Journals (Sweden)

    Li-Ling Yang

    2014-02-01

    Full Text Available Lipopolysaccharide (LPS, an endotoxin molecule, has been used to induce inflammatory responses. In this study, LPS was used to establish an in vivo inflammation model in zebrafish for drug screening. We present an experimental method that conveniently and rapidly assesses the anti-inflammatory properties of drugs. The yolks of 3-day post-fertilization (dpf larvae were injected with 0.5 mg/mL LPS to induce fatal inflammation. After LPS stimulation, macrophages were tracked by NR and SB staining and neutrophil migration was observed using the MPO:GFP line. Larval mortality was used as the primary end-point. Expression levels of key cytokines involved in the inflammatory response including IL-1β, IL-6, and TNF-α, were measured using quantitative reverse transcription polymerase chain reaction (RT-PCR. Macrophages and neutrophils were both recruited to the LPS-injected site during the inflammatory response. Mortality was increased by LPS in a dose-dependent manner within 48 h. Analyses of IL-1β, IL-6, and TNF-α expression levels revealed the upregulation of the inflammatory response in the LPS-injected larvae. Further, the anti-inflammatory activity of chlorogenic acid (CA was evaluated in this zebrafish model to screen for anti-inflammatory drugs. A preliminary result showed that CA revealed a similar effect as the corticosteroid dexamethasone (DEX, which was used as a positive control, by inhibiting macrophage and neutrophil recruitment to the LPS site and improving survival. Our results suggest that this zebrafish screening model could be applied to study inflammation-mediated diseases. Moreover, the Traditional Chinese Medicine CA displays potential anti-inflammatory activity.

  7. Application of ED-optimality to screening experiments for analgesic compounds in an experimental model of neuropathic pain.

    Science.gov (United States)

    Taneja, A; Nyberg, J; de Lange, E C M; Danhof, M; Della Pasqua, O

    2012-12-01

    In spite of the evidence regarding high variability in the response to evoked pain, little attention has been paid to its impact on the screening of drugs for inflammatory and neuropathic pain. In this study, we explore the feasibility of introducing optimality concepts to experimental protocols, enabling estimation of parameter and model uncertainty. Pharmacokinetic (PK) and pharmacodynamic data from different experiments in rats were pooled and modelled using nonlinear mixed effects modelling. Pain data on gabapentin and placebo-treated animals were generated in the complete Freund's adjuvant model of neuropathic pain. A logistic regression model was applied to optimise sampling times and dose levels to be used in an experimental protocol. Drug potency (EC(50)) and interindividual variability (IIV) were considered the parameters of interest. Different experimental designs were tested and validated by SSE (stochastic simulation and estimation) taking into account relevant exposure ranges. The pharmacokinetics of gabapentin was described by a two-compartment PK model with first order absorption (CL = 0.159 l h(-1), V(2) = 0.118 l, V(3) = 0.253 l, Ka = 0.26 h(-1), Q = 1.22 l h(-1)). Drug potency (EC(50)) for the anti-allodynic effects was estimated to be 1400 ng ml(-1). Protocol optimisation improved bias and precision of the EC50 by 6 and 11.9. %, respectively, whilst IIV estimates showed improvement of 31.89 and 14.91 %, respectively. Our results show that variability in behavioural models of evoked pain response leads to uncertainty in drug potency estimates, with potential impact on the ranking of compounds during screening. As illustrated for gabapentin, ED-optimality concepts enable analysis of discrete data taking into account experimental constraints.

  8. Identification of Alternative Vapor Intrusion Pathways Using Controlled Pressure Testing, Soil Gas Monitoring, and Screening Model Calculations.

    Science.gov (United States)

    Guo, Yuanming; Holton, Chase; Luo, Hong; Dahlen, Paul; Gorder, Kyle; Dettenmaier, Erik; Johnson, Paul C

    2015-11-17

    Vapor intrusion (VI) pathway assessment and data interpretation have been guided by an historical conceptual model in which vapors originating from contaminated soil or groundwater diffuse upward through soil and are swept into a building by soil gas flow induced by building underpressurization. Recent studies reveal that alternative VI pathways involving neighborhood sewers, land drains, and other major underground piping can also be significant VI contributors, even to buildings beyond the delineated footprint of soil and groundwater contamination. This work illustrates how controlled-pressure-method testing (CPM), soil gas sampling, and screening-level emissions calculations can be used to identify significant alternative VI pathways that might go undetected by conventional sampling under natural conditions at some sites. The combined utility of these tools is shown through data collected at a long-term study house, where a significant alternative VI pathway was discovered and altered so that it could be manipulated to be on or off. Data collected during periods of natural and CPM conditions show that the alternative pathway was significant, but its presence was not identifiable under natural conditions; it was identified under CPM conditions when measured emission rates were 2 orders of magnitude greater than screening-model estimates and subfoundation vertical soil gas profiles changed and were no longer consistent with the conventional VI conceptual model.

  9. Family psychosocial risk screening guided by the Pediatric Psychosocial Preventative Health Model (PPPHM) using the Psychosocial Assessment Tool (PAT).

    Science.gov (United States)

    Kazak, Anne E; Schneider, Stephanie; Didonato, Stephen; Pai, Ahna L H

    2015-05-01

    Although families of children with cancer and other serious medical conditions have documented psychosocial needs, the systematic identification of needs and delivery of evidence-based care remain challenges. Screening for multifaceted family psychosocial risk is a means by which psychosocial treatment needs for pediatric patients and their families can be identified in an effective and inclusive manner. The Pediatric Psychosocial Preventative Health Model (PPPHM) is a model that can guide systematic assessment of family psychosocial risk. The Psychosocial Assessment Tool (PAT) is a brief parent report screener of psychosocial risk based on the PPPHM that can be used for families of infants through adolescents. The PPPHM and the PAT are described in this paper, along with a summary of data supporting systematic risk assessment. The PPPHM outlines three tiers of family psychosocial risk - Universal (low), Targeted (medium), and Clinical (high). The PAT is a validated measure of psychosocial risk. Scores on the PAT, derived from multiple sites and disease conditions, map on to the PPPHM with indications that one-half to two-thirds of families score at the Universal level of risk based on the PAT. The PAT is a unique screener of psychosocial risk, both in terms of its breadth and underlying model (PPPHM), and its length and format. As an example of a means by which families can be screened early in the treatment process, PAT scores and corresponding PPPHM levels can provide direction for the delivery of evidence-based psychosocial care.

  10. Including Antenna Models in Microwave Imaging for Breast-Cancer Screening

    DEFF Research Database (Denmark)

    Rubæk, Tonny; Meincke, Peter

    2006-01-01

    Microwave imaging is emerging as a tool for screening for breast cancer, but the lack of methods for including the characteristics of the antennas of the imaging systems in the imaging algorithms limits their performance. In this paper, a method for incorporating the full antenna characteristics......, in terms of the transmission-matrix representation, in a frequency-domain imaging algorithm is presented. The algorithm is tested on a simulation of the Physical-Anomaly Tomography (PAT) scanner imaging system developed at the Technical University of Denmark and is shown to have superior performance when...

  11. Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling.

    Science.gov (United States)

    Skardal, Aleksander; Shupe, Thomas; Atala, Anthony

    2016-09-01

    In recent years, advances in tissue engineering and microfabrication technologies have enabled rapid growth in the areas of in vitro organoid development as well as organoid-on-a-chip platforms. These 3D model systems often are able to mimic human physiology more accurately than traditional 2D cultures and animal models. In this review, we describe the progress that has been made to generate organ-on-a-chip platforms and, more recently, more complex multi-organoid body-on-a-chip platforms and their applications. Importantly, these systems have the potential to dramatically impact biomedical applications in the areas of drug development, drug and toxicology screening, disease modeling, and the emerging area of personalized precision medicine.

  12. 3D Printing of Tissue Engineered Constructs for In Vitro Modeling of Disease Progression and Drug Screening.

    Science.gov (United States)

    Vanderburgh, Joseph; Sterling, Julie A; Guelcher, Scott A

    2017-01-01

    2D cell culture and preclinical animal models have traditionally been implemented for investigating the underlying cellular mechanisms of human disease progression. However, the increasing significance of 3D vs. 2D cell culture has initiated a new era in cell culture research in which 3D in vitro models are emerging as a bridge between traditional 2D cell culture and in vivo animal models. Additive manufacturing (AM, also known as 3D printing), defined as the layer-by-layer fabrication of parts directed by digital information from a 3D computer-aided design file, offers the advantages of simultaneous rapid prototyping and biofunctionalization as well as the precise placement of cells and extracellular matrix with high resolution. In this review, we highlight recent advances in 3D printing of tissue engineered constructs that recapitulate the physical and cellular properties of the tissue microenvironment for investigating mechanisms of disease progression and for screening drugs.

  13. Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses.

    Science.gov (United States)

    Sullivan, Con; Jurcyzszak, Denise; Goody, Michelle F; Gabor, Kristin A; Longfellow, Jacob R; Millard, Paul J; Kim, Carol H

    2017-01-20

    Each year, seasonal influenza outbreaks profoundly affect societies worldwide. In spite of global efforts, influenza remains an intractable healthcare burden. The principle strategy to curtail infections is yearly vaccination. In individuals who have contracted influenza, antiviral drugs can mitigate symptoms. There is a clear and unmet need to develop alternative strategies to combat influenza. Several animal models have been created to model host-influenza interactions. Here, protocols for generating zebrafish models for systemic and localized human influenza A virus (IAV) infection are described. Using a systemic IAV infection model, small molecules with potential antiviral activity can be screened. As a proof-of-principle, a protocol that demonstrates the efficacy of the antiviral drug Zanamivir in IAV-infected zebrafish is described. It shows how disease phenotypes can be quantified to score the relative efficacy of potential antivirals in IAV-infected zebrafish. In recent years, there has been increased appreciation for the critical role neutrophils play in the human host response to influenza infection. The zebrafish has proven to be an indispensable model for the study of neutrophil biology, with direct impacts on human medicine. A protocol to generate a localized IAV infection in the Tg(mpx:mCherry) zebrafish line to study neutrophil biology in the context of a localized viral infection is described. Neutrophil recruitment to localized infection sites provides an additional quantifiable phenotype for assessing experimental manipulations that may have therapeutic applications. Both zebrafish protocols described faithfully recapitulate aspects of human IAV infection. The zebrafish model possesses numerous inherent advantages, including high fecundity, optical clarity, amenability to drug screening, and availability of transgenic lines, including those in which immune cells such as neutrophils are labeled with fluorescent proteins. The protocols detailed here

  14. Plasma nitriding monitoring reactor: A model reactor for studying plasma nitriding processes using an active screen

    Energy Technology Data Exchange (ETDEWEB)

    Hamann, S., E-mail: hamann@inp-greifswald.de; Röpcke, J. [INP-Greifswald, Felix-Hausdorff-Str. 2, 17489 Greifswald (Germany); Börner, K.; Burlacov, I.; Spies, H.-J. [TU Bergakademie Freiberg, Institute of Materials Engineering, Gustav-Zeuner-Str. 5, 09599 Freiberg (Germany); Strämke, M.; Strämke, S. [ELTRO GmbH, Arnold-Sommerfeld-Ring 3, 52499 Baesweiler (Germany)

    2015-12-15

    A laboratory scale plasma nitriding monitoring reactor (PLANIMOR) has been designed to study the basics of active screen plasma nitriding (ASPN) processes. PLANIMOR consists of a tube reactor vessel, made of borosilicate glass, enabling optical emission spectroscopy (OES) and infrared absorption spectroscopy. The linear setup of the electrode system of the reactor has the advantages to apply the diagnostic approaches on each part of the plasma process, separately. Furthermore, possible changes of the electrical field and of the heat generation, as they could appear in down-scaled cylindrical ASPN reactors, are avoided. PLANIMOR has been used for the nitriding of steel samples, achieving similar results as in an industrial scale ASPN reactor. A compact spectrometer using an external cavity quantum cascade laser combined with an optical multi-pass cell has been applied for the detection of molecular reaction products. This allowed the determination of the concentrations of four stable molecular species (CH{sub 4}, C{sub 2}H{sub 2}, HCN, and NH{sub 3}). With the help of OES, the rotational temperature of the screen plasma could be determined.

  15. Study of a Novel Antiosteoporosis Screening Model Targeted on Cathepsin K

    Institute of Scientific and Technical Information of China (English)

    JUN YANG; GUANG-DONG SHANG; YUE-QIN ZHANG

    2004-01-01

    To establish an effective assay to access the effects of natural products on cathepsin K for screening antiosteoporosis drugs. Methods To obtain the purified cathepsin K, we cloned the target fragment from the mRNA of human osteosacoma cell line MG63 and demonstrated its correctness through DNA sequencing. Cathepsin K was expressed in a high amount in E.coli after IPTG induction, and was purified to near homogenetity through resolution and column purification. The specificity of the protein was shown by Western blotting experiment. The biological activity of the components in the fermentation broth was assayed by their inhibitory effects on cathepsin K and its analog papain. Results With the inhibition of papain activity as a screen index, the fermentation samples of one thousand strains of fungi were tested and 9 strains among them showed strong inhibitory effects. The crude products of the fermentation broth were tested for their specific inhibitory effects on the purified human cathepsin K, the product of fungi 2358 shows the highest specificity against cathepsin K. Conclusions The compounds isolated from fungi 2358 show the highest biological activity and are worth further structure elucidation and function characterization.

  16. Plasma nitriding monitoring reactor: A model reactor for studying plasma nitriding processes using an active screen

    Science.gov (United States)

    Hamann, S.; Börner, K.; Burlacov, I.; Spies, H.-J.; Strämke, M.; Strämke, S.; Röpcke, J.

    2015-12-01

    A laboratory scale plasma nitriding monitoring reactor (PLANIMOR) has been designed to study the basics of active screen plasma nitriding (ASPN) processes. PLANIMOR consists of a tube reactor vessel, made of borosilicate glass, enabling optical emission spectroscopy (OES) and infrared absorption spectroscopy. The linear setup of the electrode system of the reactor has the advantages to apply the diagnostic approaches on each part of the plasma process, separately. Furthermore, possible changes of the electrical field and of the heat generation, as they could appear in down-scaled cylindrical ASPN reactors, are avoided. PLANIMOR has been used for the nitriding of steel samples, achieving similar results as in an industrial scale ASPN reactor. A compact spectrometer using an external cavity quantum cascade laser combined with an optical multi-pass cell has been applied for the detection of molecular reaction products. This allowed the determination of the concentrations of four stable molecular species (CH4, C2H2, HCN, and NH3). With the help of OES, the rotational temperature of the screen plasma could be determined.

  17. Screening for new brewing yeasts in the non-Saccharomyces sector with Torulaspora delbrueckii as model.

    Science.gov (United States)

    Michel, Maximilian; Kopecká, Jana; Meier-Dörnberg, Tim; Zarnkow, Martin; Jacob, Fritz; Hutzler, Mathias

    2016-04-01

    This study describes a screening system for future brewing yeasts focusing on non-Saccharomyces yeasts. The aim was to find new yeast strains that can ferment beer wort into a respectable beer. Ten Torulaspora delbrueckii strains were put through the screening system, which included sugar utilization tests, hop resistance tests, ethanol resistance tests, polymerase chain reaction fingerprinting, propagation tests, amino acid catabolism and anabolism, phenolic off-flavour tests and trial fermentations. Trial fermentations were analysed for extract reduction, pH drop, yeast concentration in bulk fluid and fermentation by-products. All investigated strains were able to partly ferment wort sugars and showed high tolerance to hop compounds and ethanol. One of the investigated yeast strains fermented all the wort sugars and produced a respectable fruity flavour and a beer of average ethanol content with a high volatile flavour compound concentration. Two other strains could possibly be used for pre-fermentation as a bio-flavouring agent for beers that have been post-fermented by Saccharomyces strains as a consequence of their low sugar utilization but good flavour-forming properties.

  18. Plasma nitriding monitoring reactor: A model reactor for studying plasma nitriding processes using an active screen.

    Science.gov (United States)

    Hamann, S; Börner, K; Burlacov, I; Spies, H-J; Strämke, M; Strämke, S; Röpcke, J

    2015-12-01

    A laboratory scale plasma nitriding monitoring reactor (PLANIMOR) has been designed to study the basics of active screen plasma nitriding (ASPN) processes. PLANIMOR consists of a tube reactor vessel, made of borosilicate glass, enabling optical emission spectroscopy (OES) and infrared absorption spectroscopy. The linear setup of the electrode system of the reactor has the advantages to apply the diagnostic approaches on each part of the plasma process, separately. Furthermore, possible changes of the electrical field and of the heat generation, as they could appear in down-scaled cylindrical ASPN reactors, are avoided. PLANIMOR has been used for the nitriding of steel samples, achieving similar results as in an industrial scale ASPN reactor. A compact spectrometer using an external cavity quantum cascade laser combined with an optical multi-pass cell has been applied for the detection of molecular reaction products. This allowed the determination of the concentrations of four stable molecular species (CH4, C2H2, HCN, and NH3). With the help of OES, the rotational temperature of the screen plasma could be determined.

  19. An actor-based model of social network influence on adolescent body size, screen time, and playing sports.

    Directory of Open Access Journals (Sweden)

    David A Shoham

    Full Text Available Recent studies suggest that obesity may be "contagious" between individuals in social networks. Social contagion (influence, however, may not be identifiable using traditional statistical approaches because they cannot distinguish contagion from homophily (the propensity for individuals to select friends who are similar to themselves or from shared environmental influences. In this paper, we apply the stochastic actor-based model (SABM framework developed by Snijders and colleagues to data on adolescent body mass index (BMI, screen time, and playing active sports. Our primary hypothesis was that social influences on adolescent body size and related behaviors are independent of friend selection. Employing the SABM, we simultaneously modeled network dynamics (friendship selection based on homophily and structural characteristics of the network and social influence. We focused on the 2 largest schools in the National Longitudinal Study of Adolescent Health (Add Health and held the school environment constant by examining the 2 school networks separately (N = 624 and 1151. Results show support in both schools for homophily on BMI, but also for social influence on BMI. There was no evidence of homophily on screen time in either school, while only one of the schools showed homophily on playing active sports. There was, however, evidence of social influence on screen time in one of the schools, and playing active sports in both schools. These results suggest that both homophily and social influence are important in understanding patterns of adolescent obesity. Intervention efforts should take into consideration peers' influence on one another, rather than treating "high risk" adolescents in isolation.

  20. Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

    DEFF Research Database (Denmark)

    Markt, Patrick; Petersen, Rasmus K; Flindt, Esben N;

    2008-01-01

    Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow base...

  1. ScreenBEAM: a novel meta-analysis algorithm for functional genomics screens via Bayesian hierarchical modeling | Office of Cancer Genomics

    Science.gov (United States)

    Functional genomics (FG) screens, using RNAi or CRISPR technology, have become a standard tool for systematic, genome-wide loss-of-function studies for therapeutic target discovery. As in many large-scale assays, however, off-target effects, variable reagents' potency and experimental noise must be accounted for appropriately control for false positives.

  2. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    Science.gov (United States)

    Honest, H; Forbes, C A; Durée, K H; Norman, G; Duffy, S B; Tsourapas, A; Roberts, T E; Barton, P M; Jowett, S M; Hyde, C J; Khan, K S

    2009-09-01

    To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and

  3. Estimting parameters of a microsimulation model for breast cancer screening using the score function method

    NARCIS (Netherlands)

    S.Y.G.L. Tan; G.J. van Oortmarssen (Gerrit); N. Piersma (Nanda)

    2000-01-01

    textabstractIn developing decision-making models for the evaluation of medical procedures, the model parameters can be estimated by fitting the model to data observed in trial studies. For complex models that are implemented by discrete event simulation (microsimulation) of individual life

  4. Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease

    Science.gov (United States)

    Garrido-Maraver, Juan; Cordero, Mario D; Moñino, Irene Domínguez; Pereira-Arenas, Sheila; Lechuga-Vieco, Ana V; Cotán, David; De la Mata, Mario; Oropesa-Ávila, Manuel; De Miguel, Manuel; Bautista Lorite, Juan; Rivas Infante, Eloy; Álvarez-Dolado, Manuel; Navas, Plácido; Jackson, Sandra; Francisci, Silvia; Sánchez-Alcázar, José A

    2012-01-01

    BACKGROUND AND PURPOSE MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mitochondrial DNA (mtDNA). Approximately 80% of cases of MELAS syndrome are associated with a m.3243A > G mutation in the MT-TL1 gene, which encodes the mitochondrial tRNALeu (UUR). Currently, no effective treatments are available for this chronic progressive disorder. Treatment strategies in MELAS and other mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors. EXPERIMENTAL APPROACH We evaluated the effectiveness of some common pharmacological agents that have been utilized in the treatment of MELAS, in yeast, fibroblast and cybrid models of the disease. The yeast model harbouring the A14G mutation in the mitochondrial tRNALeu(UUR) gene, which is equivalent to the A3243G mutation in humans, was used in the initial screening. Next, the most effective drugs that were able to rescue the respiratory deficiency in MELAS yeast mutants were tested in fibroblasts and cybrid models of MELAS disease. KEY RESULTS According to our results, supplementation with riboflavin or coenzyme Q10 effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models. CONCLUSIONS AND IMPLICATIONS Our results indicate that cell models have great potential for screening and validating the effects of novel drug candidates for MELAS treatment and presumably also for other diseases with mitochondrial impairment. PMID:22747838

  5. GPCRs from fusarium graminearum detection, modeling and virtual screening - the search for new routes to control head blight disease.

    Science.gov (United States)

    Bresso, Emmanuel; Togawa, Roberto; Hammond-Kosack, Kim; Urban, Martin; Maigret, Bernard; Martins, Natalia Florencio

    2016-12-15

    Fusarium graminearum (FG) is one of the major cereal infecting pathogens causing high economic losses worldwide and resulting in adverse effects on human and animal health. Therefore, the development of new fungicides against FG is an important issue to reduce cereal infection and economic impact. In the strategy for developing new fungicides, a critical step is the identification of new targets against which innovative chemicals weapons can be designed. As several G-protein coupled receptors (GPCRs) are implicated in signaling pathways critical for the fungi development and survival, such proteins could be valuable efficient targets to reduce Fusarium growth and therefore to prevent food contamination. In this study, GPCRs were predicted in the FG proteome using a manually curated pipeline dedicated to the identification of GPCRs. Based on several successive filters, the most appropriate GPCR candidate target for developing new fungicides was selected. Searching for new compounds blocking this particular target requires the knowledge of its 3D-structure. As no experimental X-Ray structure of the selected protein was available, a 3D model was built by homology modeling. The model quality and stability was checked by 100 ns of molecular dynamics simulations. Two stable conformations representative of the conformational families of the protein were extracted from the 100 ns simulation and were used for an ensemble docking campaign. The model quality and stability was checked by 100 ns of molecular dynamics simulations previously to the virtual screening step. The virtual screening step comprised the exploration of a chemical library with 11,000 compounds that were docked to the GPCR model. Among these compounds, we selected the ten top-ranked nontoxic molecules proposed to be experimentally tested to validate the in silico simulation. This study provides an integrated process merging genomics, structural bioinformatics and drug design for proposing innovative

  6. Olanzapine-induced hepatopathy in albino rats: A newer model for screening putative hepatoprotective agents, namely silymarin

    Directory of Open Access Journals (Sweden)

    Sengupta Parama

    2010-01-01

    Full Text Available Backgrounds: This study was conducted to establish olanzapine-induced hepatopathy in Wistar albino rats as a newer model to screen putative hepatoprotective agents namely silymarin. Materials and Methods: Albino rats were divided into three groups, namely vehicle control group (CG, olanzapine-treated group (OZ, and olanzapine plus silymarin (OZS treated groups. Both the OZ and OZS groups were treated with the same dose of intraperitoneal olanzapine for 6 weeks and group OZS additionally received oral silymarin. Baseline and terminal hepatic enzymes (SGOT, SGPT, and ALP were measured in all three groups. Results: Histopathological examination of livers of both OZ and OZS groups showed degenerative changes, whereas those of control group showed normal architecture. Liver enzyme levels showed statistically significant rise in comparison to the control group as well as the respective base line values in both the test groups, but the differences in the rise of liver enzymes between the two test groups were not statistically significant. Conclusion: Olanzapine-induced hepatopathy in rats can be used as a model for screening putative hepatoprotective agents and in our setting silymarin has failed to provide any hepatoprotection.

  7. High-Content Assessment of Cardiac Function Using Heart-on-a-Chip Devices as Drug Screening Model.

    Science.gov (United States)

    Conant, Genevieve; Lai, Benjamin Fook Lun; Lu, Rick Xing Ze; Korolj, Anastasia; Wang, Erika Yan; Radisic, Milica

    2017-06-01

    Drug discovery and development continues to be a challenge to the pharmaceutical industry despite great advances in cell and molecular biology that allow for the design of better targeted therapeutics. Many potential drug compounds fail during the clinical trial due to inefficacy and toxicity that were not predicted during preclinical stages. The fundamental problem lies with the use of traditional drug screening models that still largely rely on the use of cell lines or animal cell monolayers, which leads to lack of predictive power of human tissue and organ response to the drug candidates. More physiologically relevant systems are therefore critical in relieving the burden of high failure rates. Emerging knowledge and techniques in tissue engineering and microfabrication have enabled the development of micro-engineered systems - collectively known as organs-on-chips - that may lead to a paradigm shift in preclinical drug screening assays. In this review we explore the technological advances and challenges in the development of heart-on-a-chip models, by addressing current assessment methods for drug-induced cardiotoxicity and providing a perspective on the modifications that should be implemented to realize the full potential of this system.

  8. Study on the factors related with intention of cancer screening among Korean residents: application of information-motivation-behavioral skills model.

    Science.gov (United States)

    Kim, Bong Ki; Jo, Heui Sug; Lee, Hey Jean

    2015-03-01

    This study investigated the relationship between intention of undergoing cancer screening and information, motivation, and behavioral skills using an information-motivation-behavioral skills model. The authors performed a telephone survey of a random sample of 2030 residents aged 30 to 69 years from 6 counties of Gangwon province, South Korea from July 15 to July 25, 2009. Questions about information, motivation, and behavioral skills were examined using a confirmatory factor analysis and relationships among factors were analyzed using a structure equation model. The intention of undergoing cancer screening showed a positive relationship between intention to undergo cancer screening and information(r = .134, P behavioral skills(r = .129, P behavioral skills as well as information is necessary to improve cancer screening rates. © 2012 APJPH.

  9. Human rhinovirus 3C protease: generation of pharmacophore models for peptidic and nonpeptidic inhibitors and their application in virtual screening.

    Science.gov (United States)

    Steindl, Theodora; Laggner, Christian; Langer, Thierry

    2005-01-01

    Three-dimensional pharmacophore models for peptidic and small organic nonpeptidic inhibitors of the human rhinovirus 3C protease were generated in a structure-based as well as in a ligand-based approach, using the software package Catalyst. The inhibitors possess an electrophilic moiety, often a Michael acceptor function, which covalently binds to a cysteine in the active site of the enzyme. Since this process presents the key step for virus inactivation, the creation of a new function in Catalyst was required in order to include this decisive functionality into the pharmacophore models. In the present study we focus on this feature definition process because it presents an innovative strategy to expand the pharmacophore description ability of the Catalyst software to also include covalent bonds between ligand and binding site. The resulting hypotheses were then used for virtual screening of 3D databases in order to verify their quality and to search for structurally diverse, possible new lead substances.

  10. The Clinical Effectiveness and Cost-Effectiveness of Screening for Age-Related Macular Degeneration in Japan: A Markov Modeling Study.

    Directory of Open Access Journals (Sweden)

    Hiroshi Tamura

    Full Text Available To investigate the cost-effectiveness of screening and subsequent intervention for age-related macular degeneration (AMD in Japan.The clinical effectiveness and cost-effectiveness of screening and subsequent intervention for AMD were assessed using a Markov model. The Markov model simulation began at the age of 40 years and concluded at the age of 90 years. The first-eye and second-eye combined model assumed an annual state-transition probability, development of prodromal symptoms, choroidal neovascularization (CNV, and reduction in visual acuity. Anti-vascular-endothelial-growth-factor (anti-VEGF intravitreal injection therapy and photodynamic therapy (PDT were performed to treat CNV. Intake of supplements was recommended to patients who had prodromal symptoms and unilateral AMD. Data on prevalence, morbidity, transition probability, utility value of each AMD patient, and treatment costs were obtained from published clinical reports.In the base-case analysis, screening for AMD every 5 years, beginning at the age of 50 years, showed a decrease of 41% in the total number of blind patients. The screening program reduced the incidence of blindness more than did the additional intake of supplements. However, the incremental cost-effectiveness ratio (ICER of screening versus no screening was 27,486,352 Japanese yen (JPY, or 259,942 US dollars (USD per quality-adjusted life year (QALY. In the sensitivity analysis, prodromal symptom-related factors for AMD had great impacts on the cost-effectiveness of screening. The lowest ICER obtained from the best scenario was 4,913,717 JPY (46,470 USD per QALY, which was approximately equal to the willingness to pay in Japan.Ophthalmologic screening for AMD in adults is highly effective in reducing the number of patients with blindness but not cost-effective as demonstrated by a Markov model based on clinical data from Japan.

  11. Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling.

    Science.gov (United States)

    Thompson, Chad M; Gaylor, David W; Tachovsky, J Andrew; Perry, Camarie; Carakostas, Michael C; Haws, Laurie C

    2013-12-01

    Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04 mg kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg(-1) per day. The lowest, most conservative, RfD of 0.01 mg kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l(-1). It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane.

  12. Establishment of an in vitro screening model for neurodegeneration induced by antimalarial drugs of the artemisinin-type..

    Science.gov (United States)

    Schmuck, G; Haynes, R K

    2000-01-01

    The establishment of an in vitro screening model for neurodegeneration inducing antimalarial drugs was conducted in stepwise fashion. Firstly, the in vivo selective neurotoxic potency of artemisinin was tested in neuronal cells in vitro in relation to the cytotoxic potency in other organ cell cultures such as liver and kidney or versus glial cells. Secondly, a comparison between different parts of the brain (cortex vs. brain stem) was performed and in the last step, a fast and sensitive screening endpoint was identified. In summary, non-neuronal cell lines such as hepatocytes (HEP-G2), liver epithelial cells (IAR), proximal tubular cells (LLC-PK(1)) and glial cells from the rat (C6) and human (GO-G-IJKT) displayed only moderate sensitivity to artemisinin and its derivatives. The same was found in undifferentiated neuronal cell lines from the mouse (N-18) and from human (Kelly), whereas during differentiation, these cells became much more sensitive. Primary astrocytes from the rat also were not specifically involved. In the comparison of primary neuronal cell cultures from the cortex and brain stem of the rat, the brain stem was found to be more sensitive than the cortex. The neurotoxic potential was determined by cytoskeleton elements (neurofilaments), which were degradated in vitro by diverse neurodegenerative compounds. In comparison of dog and rat primary brain stem cultures, the dog cells were found to be more sensitive to artemisinin than the rat cells. In addition to the primary brain stem cell cultures it was shown that the sprouting assay, which determines persistent delayed neurotoxic effects, is also useful for screening antimalarial drugs. To other compounds, artemether and artesunate, showed that use of the sprouting assay followed by primary brain stem cultures of the rat will be a good strategy to select candidate compounds.

  13. Quantitative phenotyping-based in vivo chemical screening in a zebrafish model of leukemia stem cell xenotransplantation.

    Directory of Open Access Journals (Sweden)

    Beibei Zhang

    Full Text Available Zebrafish-based chemical screening has recently emerged as a rapid and efficient method to identify important compounds that modulate specific biological processes and to test the therapeutic efficacy in disease models, including cancer. In leukemia, the ablation of leukemia stem cells (LSCs is necessary to permanently eradicate the leukemia cell population. However, because of the very small number of LSCs in leukemia cell populations, their use in xenotransplantation studies (in vivo and the difficulties in functionally and pathophysiologically replicating clinical conditions in cell culture experiments (in vitro, the progress of drug discovery for LSC inhibitors has been painfully slow. In this study, we developed a novel phenotype-based in vivo screening method using LSCs xenotransplanted into zebrafish. Aldehyde dehydrogenase-positive (ALDH+ cells were purified from chronic myelogenous leukemia K562 cells tagged with a fluorescent protein (Kusabira-orange and then implanted in young zebrafish at 48 hours post-fertilization. Twenty-four hours after transplantation, the animals were treated with one of eight different therapeutic agents (imatinib, dasatinib, parthenolide, TDZD-8, arsenic trioxide, niclosamide, salinomycin, and thioridazine. Cancer cell proliferation, and cell migration were determined by high-content imaging. Of the eight compounds that were tested, all except imatinib and dasatinib selectively inhibited ALDH+ cell proliferation in zebrafish. In addition, these anti-LSC agents suppressed tumor cell migration in LSC-xenotransplants. Our approach offers a simple, rapid, and reliable in vivo screening system that facilitates the phenotype-driven discovery of drugs effective in suppressing LSCs.

  14. How do microorganisms influence trace element uptake by plants? Screening in an agar model rhizosphere.

    Science.gov (United States)

    Marchetti, M.; Robinson, B. H.; Evangelou, M. W. H.; Vachey, A.; Schwitzguebel, J. P.; Bernier-Latmani, R.; Schulin, R.

    2009-04-01

    Trace elements (TE) are essential for humans and plants, but they may be toxic if their concentration is too high. For this reason, the management of TE in soils is very important. In some cases it may be necessary to increase the uptake of nutrients or TE by plants, for example in a biofortification perspective. Conversely, in some other cases TE uptake by plants should be decreased, for instance to avoid heavy metals entering the food chain via edible crops. Microorganisms living in the rhizosphere affect trace element (TE) uptake by plants. However, due to the complexity of this space and the variety of microorganisms that occur there, it is difficult to isolate the effect of any particular strain. To overcome this hurdle, we developed a system in which we grew plants under sterile conditions in agar and inoculated their rhizosphere with a single, well-defined microbial strain. For many years, agar has been used as a growth substrate for microorganisms and plant tissues. It is cheap, easy to use, and can be autoclaved to ensure its sterility. Because of its widespread use, an experiment conducted using this substrate can be reproduced under the same conditions in any laboratory. In contrast to soil, there is little interaction between the trace elements and the agar matrix. There are many studies investigating the influence of microorganisms on TE uptake by plants. However, so far only a small variety of microorganisms has been tested on few plant species. Therefore, the first objective of our research was to develop a method to rapidly screen a large variety of microorganisms on various plant species. Once this goal was achieved, we sought to study the effect of single, well-defined microbial strains on TE uptake by sunflower and wheat. The substrate for plants growth was a 10% agar solution prepared with modified Hoagland's solution and a TE solution containing 1 mg/kg Pb and molar equivalents of Cu, Ni and Zn. The agar solution was autoclaved and poured into

  15. Depression Screening

    Science.gov (United States)

    ... Centers Diseases + Condition Centers Mental Health Medical Library Depression Screening (PHQ-9) - Instructions The following questions are ... this tool, there is also text-only version . Depression Screening - Manual Instructions The following questions are a ...

  16. Cancer Screening

    Directory of Open Access Journals (Sweden)

    Krishna Prasad

    2004-10-01

    Full Text Available Cancer screening is a means to detect cancer early with the goal of decreasing morbidity and mortality. At present, there is a reasonable consensus regarding screening for breast, cervical and colorectal cances and the role of screening is under trial in case of cancers of the lung,  ovaries and prostate. On the other hand, good screening tests are not available for some of the commonest cancers in India like the oral, pharyngeal, esophageal and stomach cancers.

  17. Cancer Screening

    OpenAIRE

    Krishna Prasad

    2004-01-01

    Cancer screening is a means to detect cancer early with the goal of decreasing morbidity and mortality. At present, there is a reasonable consensus regarding screening for breast, cervical and colorectal cances and the role of screening is under trial in case of cancers of the lung,  ovaries and prostate. On the other hand, good screening tests are not available for some of the commonest cancers in India like the oral, pharyngeal, esophageal and stomach cancers.

  18. Novel Method for Calculating a Nonsubjective Informative Prior for a Bayesian Model in Toxicology Screening: A Theoretical Framework.

    Science.gov (United States)

    Woldegebriel, Michael

    2015-11-17

    In toxicology screening (forensic, food-safety), due to several analytical errors (e.g., retention time shift, lack of repeatability in m/z scans, etc.), the ability to confidently identify/confirm a compound remains a challenge. Due to these uncertainties, a probabilistic approach is currently preferred. However, if a probabilistic approach is followed, the only statistical method that is capable of estimating the probability of whether the compound of interest (COI) is present/absent in a given sample is Bayesian statistics. Bayes' theorem can combine prior information (prior probability) with data (likelihood) to give an optimal probability (posterior probability) reflecting the presence/absence of the COI. In this work, a novel method for calculating an informative prior probability for a Bayesian model in targeted toxicology screening is introduced. In contrast to earlier proposals making use of literature citation rates and the prior knowledge of the analyst, this method presents a thorough and nonsubjective approach. The formulation approaches the probability calculation as a clustering and random draw problem that incorporates few analytical method parameters meticulously estimated to reflect sensitivity and specificity of the system. The practicality of the method has been demonstrated and validated using real data and simulated analytical techniques.

  19. Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling

    Directory of Open Access Journals (Sweden)

    Ly Le

    2011-12-01

    Full Text Available The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF and 2009-H1N1 (Genbank accession number GQ385383 viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.

  20. Discovery of potential M2 channel inhibitors based on the amantadine scaffold via virtual screening and pharmacophore modeling.

    Science.gov (United States)

    Tran, Linh; Choi, Sy Bing; Al-Najjar, Belal O; Yusuf, Muhammad; Wahab, Habibah A; Le, Ly

    2011-12-08

    The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2 protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.

  1. Discovery of Novel Inhibitors for Nek6 Protein through Homology Model Assisted Structure Based Virtual Screening and Molecular Docking Approaches

    Directory of Open Access Journals (Sweden)

    P. Srinivasan

    2014-01-01

    Full Text Available Nek6 is a member of the NIMA (never in mitosis, gene A-related serine/threonine kinase family that plays an important role in the initiation of mitotic cell cycle progression. This work is an attempt to emphasize the structural and functional relationship of Nek6 protein based on homology modeling and binding pocket analysis. The three-dimensional structure of Nek6 was constructed by molecular modeling studies and the best model was further assessed by PROCHECK, ProSA, and ERRAT plot in order to analyze the quality and consistency of generated model. The overall quality of computed model showed 87.4% amino acid residues under the favored region. A 3 ns molecular dynamics simulation confirmed that the structure was reliable and stable. Two lead compounds (Binding database ID: 15666, 18602 were retrieved through structure-based virtual screening and induced fit docking approaches as novel Nek6 inhibitors. Hence, we concluded that the potential compounds may act as new leads for Nek6 inhibitors designing.

  2. Screening of Mycobacterium avium subsp. paratuberculosis Mutants for Attenuation in a Bovine Monocyte-Derived Macrophage Model

    Directory of Open Access Journals (Sweden)

    Elise A Lamont

    2014-06-01

    Full Text Available Vaccination remains a major tool for prevention and progression of Johne’s disease, a chronic enteritis of ruminants worldwide. Currently there is only one licensed vaccine within the United States and two vaccines licensed internationally against Johne’s disease. All licensed vaccines reduce fecal shedding of Mycobacterium avium subsp. paratuberculosis (MAP and delay disease progression. However, there are no available vaccines that prevent disease onset. A joint effort by the Johne’s Disease Integrated Program (JDIP, a USDA-funded consortium, and USDA- APHIS/VS sought to identify transposon insertion mutant strains as vaccine candidates in part of a three phase study. The focus of the Phase I study was to evaluate MAP mutant attenuation in a well-defined in vitro bovine monocyte-derived macrophage (MDM model. Attenuation was determined by colony forming unit (CFUs counts and slope estimates. Based on CFU counts alone, the MDM model did not identify any mutant that significantly differed from the wild-type control, MAP K-10. Slope estimates using mixed models approach identified six mutants as being attenuated. These were enrolled in protection studies involving murine and baby goat vaccination-challenge models. MDM based approach identified trends in attenuation but this did not correlate with protection in a natural host model. These results suggest the need for alternative strategies for Johne’s disease vaccine candidate screening and evaluation.

  3. Utilising established SDL-screening methods as a tool for the functional genomic characterisation of model and non-model organisms.

    Science.gov (United States)

    Usher, Jane; Thomas, Graham; Haynes, Ken

    2015-12-01

    The trend for large-scale genetic and phenotypic screens has revealed a wealth of information on biological systems. A major challenge is understanding how genes function and putative roles in networks. The majority of current gene knowledge is garnered from studies utilising the model yeast Saccharomyces cerevisiae. We demonstrate that synthetic dosage lethal genetic array methodologies can be used to study genetic networks in other yeasts, namely the fungal pathogen Candida glabrata, which has limited forward genetic tools, due to the lack of 'natural' mating. We performed two SDL screens in S. cerevisiae, overexpressing the transcriptional regulator UME6 as bait in the first screen and its C. glabrata ortholog CAGL0F05357g in the second. Analysis revealed that SDL maps share 204 common interactors, with 10 genetic interactions unique to C. glabrata indicating a level of genetic rewiring, indicative of linking genotype to phenotype in fungal pathogens. This was further validated by incorporating our results into the global genetic landscape map of the cell from Costanzo et al. to identify common and novel gene attributes. This data demonstrated the utility large data sets and more robust analysis made possible by interrogating exogenous genes in the context of the eukaryotic global genetic landscape.

  4. A conservative vapour intrusion screening model of oxygen-limited hydrocarbon vapour biodegradation accounting for building footprint size

    Science.gov (United States)

    Knight, John H.; Davis, Gregory B.

    2013-12-01

    Petroleum hydrocarbon vapours pose a reduced risk to indoor air due to biodegradation processes where oxygen is available in the subsurface or below built structures. However, no previous assessment has been available to show the effects of a building footprint (slab size) on oxygen-limited hydrocarbon vapour biodegradation and the potential for oxygen to be present beneath the entire sub-slab region of a building. Here we provide a new, conservative and conceptually simple vapour screening model which links oxygen and hydrocarbon vapour transport and biodegradation in the vicinity and beneath an impervious slab. This defines when vapour risk is insignificant, or conversely when there is potential for vapour to contact the sub-slab of a building. The solution involves complex mathematics to determine the position of an unknown boundary interface between oxygen diffusing in from the ground surface and vapours diffusing upwards from a subsurface vapour source, but the mathematics reduces to a simple relationship between the vapour source concentration and the ratio of the half slab width and depth to the vapour source. Data from known field investigations are shown to be consistent with the model predictions. Examples of 'acceptable' slab sizes for vapour source depths and strengths are given. The predictions are conservative as an estimator of when petroleum hydrocarbon vapours might come in contact with a slab-on-ground building since additional sources of oxygen due to advective flow or diffusion through the slab are ignored. As such the model can be used for screening sites for further investigation.

  5. Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

    Science.gov (United States)

    Schlegel, Birgit; Laggner, Christian; Meier, Rene; Langer, Thierry; Schnell, David; Seifert, Roland; Stark, Holger; Höltje, Hans-Dieter; Sippl, Wolfgang

    2007-08-01

    The human histamine H3 receptor (hH3R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH3R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH3R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH3R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH3R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [3H]Nα-methylhistamine binding assay. The compounds tested showed affinities at hH3R with K i values ranging from 0.079 to 6.3 μM.

  6. Identification of common genetic modifiers of neurodegenerative diseases from an integrative analysis of diverse genetic screens in model organisms

    Directory of Open Access Journals (Sweden)

    Chen Xi

    2012-02-01

    Full Text Available Abstract Background An array of experimental models have been developed in the small model organisms C. elegans, S. cerevisiae and D. melanogaster for the study of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and expanded polyglutamine diseases as exemplified by Huntington's disease (HD and related ataxias. Genetic approaches to determine the nature of regulators of the disease phenotypes have ranged from small scale to essentially whole genome screens. The published data covers distinct models in all three organisms and one important question is the extent to which shared genetic factors can be uncovered that affect several or all disease models. Surprisingly it has appeared that there may be relatively little overlap and that many of the regulators may be organism or disease-specific. There is, however, a need for a fully integrated analysis of the available genetic data based on careful comparison of orthologues across the species to determine the real extent of overlap. Results We carried out an integrated analysis using C. elegans as the baseline model organism since this is the most widely studied in this context. Combination of data from 28 published studies using small to large scale screens in all three small model organisms gave a total of 950 identifications of genetic regulators. Of these 624 were separate genes with orthologues in C. elegans. In addition, 34 of these genes, which all had human orthologues, were found to overlap across studies. Of the common genetic regulators some such as chaperones, ubiquitin-related enzymes (including the E3 ligase CHIP which directly links the two pathways and histone deacetylases were involved in expected pathways whereas others such as the peroxisomal acyl CoA-oxidase suggest novel targets for neurodegenerative disease therapy Conclusions We identified a significant number of overlapping regulators of neurodegenerative disease models. Since the diseases

  7. Risk Profiling May Improve Lung Cancer Screening

    Science.gov (United States)

    A new modeling study suggests that individualized, risk-based selection of ever-smokers for lung cancer screening may prevent more lung cancer deaths and improve the effectiveness and efficiency of screening compared with current screening recommendations

  8. A BENCHMARKING ANALYSIS FOR FIVE RADIONUCLIDE VADOSE ZONE MODELS (CHAIN, MULTIMED_DP, FECTUZ, HYDRUS, AND CHAIN 2D) IN SOIL SCREENING LEVEL CALCULATIONS

    Science.gov (United States)

    Five radionuclide vadose zone models with different degrees of complexity (CHAIN, MULTIMED_DP, FECTUZ, HYDRUS, and CHAIN 2D) were selected for use in soil screening level (SSL) calculations. A benchmarking analysis between the models was conducted for a radionuclide (99Tc) rele...

  9. Pre-clinical in vivo models for the screening of bone biomaterials for oral/craniofacial indications: focus on small-animal models.

    Science.gov (United States)

    Stavropoulos, Andreas; Sculean, Anton; Bosshardt, Dieter D; Buser, Daniel; Klinge, Björn

    2015-06-01

    Preclinical in vivo experimental studies are performed for evaluating proof-of-principle concepts, safety and possible unwanted reactions of candidate bone biomaterials before proceeding to clinical testing. Specifically, models involving small animals have been developed for screening bone biomaterials for their potential to enhance bone formation. No single model can completely recreate the anatomic, physiologic, biomechanic and functional environment of the human mouth and jaws. Relevant aspects regarding physiology, anatomy, dimensions and handling are discussed in this paper to elucidate the advantages and disadvantages of small-animal models. Model selection should be based not on the 'expertise' or capacities of the team, but rather on a scientifically solid rationale, and the animal model selected should reflect the question for which an answer is sought. The rationale for using heterotopic or orthotopic testing sites, and intraosseous, periosseous or extraskeletal defect models, is discussed. The paper also discusses the relevance of critical size defect modeling, with focus on calvarial defects in rodents. In addition, the rabbit sinus model and the capsule model in the rat mandible are presented and discussed in detail. All animal experiments should be designed with care and include sample-size and study-power calculations, thus allowing generation of meaningful data. Moreover, animal experiments are subject to ethical approval by the relevant authority. All procedures and the postoperative handling and care, including postoperative analgesics, should follow best practice.

  10. Perspective: Web-based machine learning models for real-time screening of thermoelectric materials properties

    Science.gov (United States)

    Gaultois, Michael W.; Oliynyk, Anton O.; Mar, Arthur; Sparks, Taylor D.; Mulholland, Gregory J.; Meredig, Bryce

    2016-05-01

    The experimental search for new thermoelectric materials remains largely confined to a limited set of successful chemical and structural families, such as chalcogenides, skutterudites, and Zintl phases. In principle, computational tools such as density functional theory (DFT) offer the possibility of rationally guiding experimental synthesis efforts toward very different chemistries. However, in practice, predicting thermoelectric properties from first principles remains a challenging endeavor [J. Carrete et al., Phys. Rev. X 4, 011019 (2014)], and experimental researchers generally do not directly use computation to drive their own synthesis efforts. To bridge this practical gap between experimental needs and computational tools, we report an open machine learning-based recommendation engine (http://thermoelectrics.citrination.com) for materials researchers that suggests promising new thermoelectric compositions based on pre-screening about 25 000 known materials and also evaluates the feasibility of user-designed compounds. We show this engine can identify interesting chemistries very different from known thermoelectrics. Specifically, we describe the experimental characterization of one example set of compounds derived from our engine, RE12Co5Bi (RE = Gd, Er), which exhibits surprising thermoelectric performance given its unprecedentedly high loading with metallic d and f block elements and warrants further investigation as a new thermoelectric material platform. We show that our engine predicts this family of materials to have low thermal and high electrical conductivities, but modest Seebeck coefficient, all of which are confirmed experimentally. We note that the engine also predicts materials that may simultaneously optimize all three properties entering into zT; we selected RE12Co5Bi for this study due to its interesting chemical composition and known facile synthesis.

  11. Perspective: Web-based machine learning models for real-time screening of thermoelectric materials properties

    Directory of Open Access Journals (Sweden)

    Michael W. Gaultois

    2016-05-01

    Full Text Available The experimental search for new thermoelectric materials remains largely confined to a limited set of successful chemical and structural families, such as chalcogenides, skutterudites, and Zintl phases. In principle, computational tools such as density functional theory (DFT offer the possibility of rationally guiding experimental synthesis efforts toward very different chemistries. However, in practice, predicting thermoelectric properties from first principles remains a challenging endeavor [J. Carrete et al., Phys. Rev. X 4, 011019 (2014], and experimental researchers generally do not directly use computation to drive their own synthesis efforts. To bridge this practical gap between experimental needs and computational tools, we report an open machine learning-based recommendation engine (http://thermoelectrics.citrination.com for materials researchers that suggests promising new thermoelectric compositions based on pre-screening about 25 000 known materials and also evaluates the feasibility of user-designed compounds. We show this engine can identify interesting chemistries very different from known thermoelectrics. Specifically, we describe the experimental characterization of one example set of compounds derived from our engine, RE12Co5Bi (RE = Gd, Er, which exhibits surprising thermoelectric performance given its unprecedentedly high loading with metallic d and f block elements and warrants further investigation as a new thermoelectric material platform. We show that our engine predicts this family of materials to have low thermal and high electrical conductivities, but modest Seebeck coefficient, all of which are confirmed experimentally. We note that the engine also predicts materials that may simultaneously optimize all three properties entering into zT; we selected RE12Co5Bi for this study due to its interesting chemical composition and known facile synthesis.

  12. Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling.

    Directory of Open Access Journals (Sweden)

    Lotta Berg

    Full Text Available Acetylcholinesterase (AChE is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia to treat cholinergic deficiencies (e.g. in Alzheimer's disease, but may also act as dangerous toxins (e.g. nerve agents such as sarin. Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS. Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685•mAChE is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical

  13. Organ-on-a-chip technology and microfluidic whole-body models for pharmacokinetic drug toxicity screening.

    Science.gov (United States)

    Lee, Jong Bum; Sung, Jong Hwan

    2013-11-01

    Microscale cell culture platforms better mimic the in vivo cellular microenvironment than conventional, macroscale systems. Microscale cultures therefore elicit a more authentic response from cultured cells, enabling physiologically realistic in vitro tissue models to be constructed. The fabrication of interconnecting microchambers and microchannels allows drug absorption, distribution, metabolism and elimination to be simulated, and enables precise manipulation of fluid flow to replicate blood circulation. Complex, multi-organ interactions can be investigated using "organ-on-a-chip" toxicology screens. By reproducing the dynamics of multi-organ interaction, the dynamics of various diseases and drug activities can be studied in mechanistic detail. In this review, we summarize the current status of technologies related to pharmacokinetic-based drug toxicity testing, and the use of microtechnology for reproducing the interaction between multiple organs. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Metabolomics-based prediction models of yeast strains for screening of metabolites contributing to ethanol stress tolerance

    Science.gov (United States)

    Hashim, Z.; Fukusaki, E.

    2016-06-01

    The increased demand for clean, sustainable and renewable energy resources has driven the development of various microbial systems to produce biofuels. One of such systems is the ethanol-producing yeast. Although yeast produces ethanol naturally using its native pathways, production yield is low and requires improvement for commercial biofuel production. Moreover, ethanol is toxic to yeast and thus ethanol tolerance should be improved to further enhance ethanol production. In this study, we employed metabolomics-based strategy using 30 single-gene deleted yeast strains to construct multivariate models for ethanol tolerance and screen metabolites that relate to ethanol sensitivity/tolerance. The information obtained from this study can be used as an input for strain improvement via metabolic engineering.

  15. Sulphonamide and sulphonyl-hydrazone cyclic imide derivatives: antinociceptive activity, molecular modeling and in silico ADMET screening.

    Science.gov (United States)

    de Oliveira, Kely N; Souza, Márcia M; Sathler, Plínio Cunha; Magalhães, Uiaran O; Rodrigues, Carlos R; Castro, Helena C; Palm, Patrícia R; Sarda, Maicon; Perotto, Pablo E; Cezar, Sabrina; de Brito, Monique A; Ferreira, Ariane S S R; Cabral, Lúcio Mendes; Machado, Clodoaldo; Nunes, Ricardo J

    2012-10-01

    In this paper, we describe the antinociceptive activity, molecular modeling and in silico ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene derivatives. Among these compounds, the sulphonyl-hydrazones 9 and 11 showed the most potent analgesic activity (ID(50) = 5.1 and 6.8 μmol/kg, respectively). Interestingly, all derivatives evaluated in this study have a better analgesic profile than the control drugs, acetyl salicylic acid and acetaminophen. Derivative 9 was the most promising compound; with a level of activity that was 24 times higher than the control drugs. Our SAR study showed a relationship among the distribution of the frontier orbital HOMO coefficients, HOMO-LUMO energy gap of these molecules and their reactivity. The best analgesic compounds (including 6, 9, 10, 11 and 12) fulfilled the Lipinski "rule-of-five", which is theoretically important for good drug absorption and permeation.

  16. Influence of Spin-Orbit Force on Nucleon-Nucleon Scattering in the Quark Delocalization Colour Screening Model

    Institute of Scientific and Technical Information of China (English)

    HUANG Hong-Xia; CHEN Ling-Zhi; PANG Hou-Rong; PING Jia-Lun; WANG Fan

    2008-01-01

    The symmetric spin-orbit/nteractions of one-gluon-exchange and confinement are included in the nucleon-nucleon phase shift calculation in the framework of quark delocalization colour screening model.The spin-orbit interaction has little influence on D wave phase shift.For the triplet P waves,3 pT is in good agreement with the experimental data and 3 pLS is attractive but not strong enough,whereas 3Pc is too strongly repulsive.Our results indicate that the symmetric spin-orbit interaction of one-gluon-exchange and confinement potential cannot give a good description of the triplet P wave phase shifts.More sophisticated considerations,the delocalization depending on the relative orientation between two duster,might be needed to improve the description of P-wave NN interaction.

  17. Establishing a structured animal model for screening anti-psychological drugs of schizophrenia

    Institute of Scientific and Technical Information of China (English)

    Liang Li; Zhemeng Wu

    2014-01-01

    Although some traditional animal models for studying schizophrenia have been wildly used,many problems remain in their credibility and validity.We propose that structured animal models with the integration of multiple symptom-inducing factors are be better in simulating the symptoms of schizophrenia and represent the new direction of the future ani-mal-model development.In this article,we review previous studies in this line of research and emphasize the importance of combining the behavior paradigm of the structured top-down attentional modulation of prepulse inhibition with multiple path-ogenic factors related to schizophrenia to establish a new model generation,which will be of great significance in investigating both the pathogenesis and the treatment of schizophrenia.

  18. Model-based Small Area Estimates of Cancer Risk Factors and Screening Behaviors - Small Area Estimates

    Science.gov (United States)

    These model-based estimates use two surveys, the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS). The two surveys are combined using novel statistical methodology.

  19. Establishment of a functional secretory IgA transcytosis model system in vitro for functional food screening.

    Science.gov (United States)

    Zuo, Tao; Feng, Xianqi; Zhang, Na; Xue, Changhu; Tang, Qing-Juan

    2015-07-01

    A characteristic mucosal immune response involves the production of antigen-specific secretory immunoglobulin A (SIgA) antibodies. In order to study transcytosis by mimicking the SIgA secretion and to screen for SIgA secretion-promoting substances, we developed a model system of a transfected Madin-Darby canine kidney (MDCK) cell line that expresses the human polymeric immunoglobulin receptor (pIgR). We thus isolated the human dIgA (dimeric IgA)/pIgA (polymeric IgA) complex as the binding ligands. In the present study, a recombinant vector encoding the human pIgR gene was constructed and infected into MDCK cells. Following reverse transcription polymerase chain reaction (RT-PCR), immunoblotting, and immunofluorescence staining, we confirmed that pIgR was expressed in the transfectant MDCK-pIgR cells and was located at the basolateral side of the cell surface. We also confirmed the coexistence of the dIgA/pIgA complex in the IgA myeloma serum. The covalent dIgA/pIgA complex was then isolated from the serum of an IgA multiple myeloma patient using an ÄKTA purifier operation system with a HiPrep 16/60 Sephacryl S-300 HR column, in order to utilize the complex as transcytosis ligands for human pIgR. Finally, we confirmed the uptake of the isolated human dIgA/pIgA complex into MDCK-pIgR cells. We demonstrated that the human dIgA/pIgA complex was transcytosed into the apical side of the monolayer cells. Therefore, our MDCK-human pIgR cell transcytosis model is an operational system and can be used for screening functional food components that promote dIgA/pIgR transcytosis as well as SIgA secretion.

  20. Lung fibrosis: drug screening and disease biomarker identification with a lung slice culture model and subtracted cDNA Library.

    Science.gov (United States)

    Guo, Tong; Lok, Ka Yee; Yu, Changhe; Li, Zhuo

    2014-09-01

    Pulmonary fibrosis is a progressive and irreversible disorder with no appropriate cure. A practical and effective experimental model that recapitulates the disease will greatly benefit the research community and, ultimately, patients. In this study, we tested the lung slice culture (LSC) system for its potential use in drug screening and disease biomarker identification. Fibrosis was induced by treating rat lung slices with 1ng/ml TGF-β1 and 2.5μM CdCl2, quantified by measuring the content of hydroxyproline, and confirmed by detecting the expression of collagen type III alpha 1 (Col3α1) and connective tissue growth factor (CTGF) genes. The anti-fibrotic effects of pirfenidone, spironolactone and eplerenone were assessed by their capability to reduce hydroxyproline content. A subtractive hybridisation technique was used to create two cDNA libraries (subtracted and unsubtracted) from lung slices. The housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was employed to assess the subtraction efficiency of the subtracted cDNA library. Clones from the two libraries were sequenced and the genes were identified by performing a BLAST search on the NCBI GenBank database. Furthermore, the relevance of the genes to fibrosis formation was verified. The results presented here show that fibrosis was effectively induced in cultured lung slices, which exhibited significantly elevated levels of hydroxyproline and Col3α1/CTGF gene expression. Several inhibitors have demonstrated their anti-fibrotic effects by significantly reducing hydroxyproline content. The subtracted cDNA library, which was enriched for differentially expressed genes, was used to successfully identify genes associated with fibrosis. Collectively, the results indicate that our LSC system is an effective model for the screening of drug candidates and for disease biomarker identification.

  1. Establishment of liver specific glucokinase gene knockout mice:a new animal model for screening anti-diabetic drugs

    Institute of Scientific and Technical Information of China (English)

    Ya-li ZHANG; Xiao-hong TAN; Mei-fang XIAO; Hui LI; Yi-qing Mao; Xiao YANG; Huan-ran TAN

    2004-01-01

    AIM: To characterize the liver-specific role of glucokinase in maintaining glucose homeostasis and to create an animal model for diabetes. METHODS: We performed hepatocyte-specific gene knockout of glucokinase in mice using Cre-loxP gene targeting strategy. First, two directly repeated loxP sequences were inserted to flank the exon 9 and exon 10 of glucokinase in genomic DNA. To achieve this, linearized targeting vector was electroporated into ES cells. Then G418- and Gancyclovir-double-resistant clones were picked and screened by PCR analysis and the positives identified by PCR were confirmed by Southern blot. A targeted clone was selected for microinjection into C57BL/6J blastocysts and implanted into pseudopregnant FVB recipient. Chimeric mice and their offspring were analyzed by Southern blot. Then by intercrossing the Alb-Cre transgenic mice with mice containing a conditional gk allele, we obtained mice with liver-specific glucokinase gene knockout. RESULTS: Among 161 double resistant clones 4 were positive to PCR and Southern blot and only one was used for further experiments. Eventually we generated the liver specific glucokinase knockout mice. These mice showed increased glucose level with age and at the age of 6 weeks fasting blood glucose level was significantly higher than control and they also displayed impaired glucose tolerance. CONCLUSION: Our studies indicate that hepatic glucokinase plays an important role in glucose homeostasis and its deficiencies contribute to the development of diabetes. The liver glucokinase knockout mouse is an ideal animal model for MODY2, and it also can be applied for screening anti-diabetic drugs.

  2. Identification of a New Peptide Deformylase Gene From Enterococcus faecium and Establishment of a New Screening Model Targeted on PDF for Novel Antibiotics

    Institute of Scientific and Technical Information of China (English)

    XIAN-BING TANG; SHU-YI SI; YUE-QIN ZHANG

    2004-01-01

    To identify a new peptide deformylase (PDF) gene (Genebank Accession AY238515) from Enterococcus faecium and to establish a new screening model targeted on PDF. Methods A new PDF gene was identified by BLAST analysis and PCR and was subsequently over-expressed in the prokaryotic expression host E.coli Bl21(DE3). Over-expressed protein was purified for enzymatic assay by metal affinity chromatography and a new screening model was established for novel antibiotics. Result A new PDF gene of Enterococcus faecium was identified successfully. Ten positive samples were picked up from 8000 compound library and the microbial fermentation broth samples. Conclusion A new PDF of gene Enterococcus faecium was first identified and the model had a high efficacy. Positive samples screened may be antibacterial agents of broad spectrum.

  3. Colon cancer screening

    Science.gov (United States)

    Screening for colon cancer; Colonoscopy - screening; Sigmoidoscopy - screening; Virtual colonoscopy - screening; Fecal immunochemical test; Stool DNA test; sDNA test; Colorectal cancer - screening; Rectal ...

  4. Decision-analytic modeling to evaluate the long-term effectiveness and cost-effectiveness of HPV-DNA testing in primary cervical cancer screening in Germany

    Directory of Open Access Journals (Sweden)

    Krämer, Alexander

    2010-01-01

    Full Text Available Background: Persistent infections with high-risk types of human papillomavirus (HPV are associated with the development of cervical neoplasia. Compared to cytology HPV testing is more sensitive in detecting high-grade cervical cancer precursors, but with lower specificity. HPV based primary screening for cervical cancer is currently discussed in Germany. Decisions should be based on a systematic evaluation of the long-term effectiveness and cost-effectiveness of HPV based primary screening. Research questions: What is the long-term clinical effectiveness (reduction in lifetime risk of cervical cancer and death due to cervical cancer, life years gained of HPV testing and what is the cost-effectiveness in Euro per life year gained (LYG of including HPV testing in primary cervical cancer screening in the German health care context? How can the screening program be improved with respect to test combination, age at start and end of screening and screening interval and which recommendations should be made for the German health care context? Methods: A previously published and validated decision-analytic model for the German health care context was extended and adapted to the natural history of HPV infection and cervical cancer in order to evaluate different screening strategies that differ by screening interval, and tests, including cytology alone, HPV testing alone or in combination with cytology, and HPV testing with cytology triage for HPV-positive women. German clinical, epidemiological and economic data were used. In the absence of individual data, screening adherence was modelled independently from screening history. Test accuracy data were retrieved from international meta-analyses. Predicted outcomes included reduction in lifetime-risk for cervical cancer cases and deaths, life expectancy, lifetime costs, and discounted incremental cost-effectiveness ratios (ICER. The perspective of the third party payer and 3% annual discount rate were

  5. High-Resolution Longitudinal Screening with Magnetic Resonance Imaging in a Murine Brain Cancer Model

    Directory of Open Access Journals (Sweden)

    Nicholas A. Bock

    2003-11-01

    Full Text Available One of the main limitations of intracranial models of diseases is our present inability to monitor and evaluate the intracranial compartment noninvasively over time. Therefore, there is a growing need for imaging modalities that provide thorough neuropathological evaluations of xenograft and transgenic models of intracranial pathology. In this study, we have established protocols for multiple-mouse magnetic resonance imaging (MRI to follow the growth and behavior of intracranial xenografts of gliomas longitudinally. We successfully obtained weekly images on 16 mice for a total of 5 weeks on a 7-T multiple-mouse MRI. T2- and Ti-weighted imaging with gadolinium enhancement of vascularity was used to detect tumor margins, tumor size, and growth. These experiments, using 3D whole brain images obtained in four mice at once, demonstrate the feasibility of obtaining repeat radiological images in intracranial tumor models and suggest that MRI should be incorporated as a research modality for the investigation of intracranial pathobiology.

  6. Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening.

    Science.gov (United States)

    Damon, C; Luck, M; Toullec, L; Etienne, I; Buchler, M; Hurault de Ligny, B; Choukroun, G; Thierry, A; Vigneau, C; Moulin, B; Heng, A-E; Subra, J-F; Legendre, C; Monnot, A; Yartseva, A; Bateson, M; Laurent-Puig, P; Anglicheau, D; Beaune, P; Loriot, M A; Thervet, E; Pallet, N

    2017-04-01

    Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  7. Developing, Applying, and Evaluating Models for Rapid Screening of Chemical Exposures

    DEFF Research Database (Denmark)

    Arnot, J.; Shin, H.; Ernstoff, Alexi;

    2015-01-01

    to limited exposure data there is limited information on chemical use patterns and production and emission quantities. These data gaps require the application of mass balance, statistical and quantitative structure-activity relationship (QSAR) models to predict exposure and exposure potential for humans...

  8. Lead-Time Models Should Not Be Used to Estimate Overdiagnosis in Cancer Screening

    DEFF Research Database (Denmark)

    Zahl, Per-Henrik; Jørgensen, Karsten Juhl; Gøtzsche, Peter C

    2014-01-01

    Lead-time can mean two different things: Clinical lead-time is the lead-time for clinically relevant tumors; that is, those that are not overdiagnosed. Model-based lead-time is a theoretical construct where the time when the tumor would have caused symptoms is not limited by the person's death. I...

  9. Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model

    DEFF Research Database (Denmark)

    Andersson, O.; Badisco, L.; Hansen, A. H.;

    2014-01-01

    In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain b...

  10. Forecasting Human African Trypanosomiasis Prevalences from Population Screening Data Using Continuous Time Models

    NARCIS (Netherlands)

    H. de Vries (Harwin); A.P.M. Wagelmans (Albert); E.C. Hasker (Epco C.); C. Lumbala (Crispin); P. Lutumba (Pascal); S.J. de Vlas (Sake); J. van de Klundert (Joris)

    2016-01-01

    textabstractTo eliminate and eradicate gambiense human African trypanosomiasis (HAT), maximizing the effectiveness of active case finding is of key importance. The progression of the epidemic is largely influenced by the planning of these operations. This paper introduces and analyzes five models fo

  11. Dosage and Dose Schedule Screening of Drug Combinations in Agent-Based Models Reveals Hidden Synergies.

    Science.gov (United States)

    Barros de Andrade E Sousa, Lisa C; Kühn, Clemens; Tyc, Katarzyna M; Klipp, Edda

    2015-01-01

    The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  12. Modelling physico-chemical properties of (benzo)triazoles, and screening for environmental partitioning.

    Science.gov (United States)

    Bhhatarai, B; Gramatica, P

    2011-01-01

    (Benzo)triazoles are distributed throughout the environment, mainly in water compartments, because of their wide use in industry where they are employed in pharmaceutical, agricultural and deicing products. They are hazardous chemicals that adversely affect humans and other non-target species, and are on the list of substances of very high concern (SVHC) in the new European regulation of chemicals - REACH (Registration, Evaluation, Authorization and Restriction of Chemical substances). Thus there is a vital need for further investigations to understand the behavior of these compounds in biota and the environment. In such a scenario, physico-chemical properties like aqueous solubility, hydrophobicity, vapor pressure and melting point can be useful. However, the limited availability and the high cost of lab testing prevents the acquisition of necessary experimental data that industry must submit for the registration of these chemicals. In such cases a preliminary analysis can be made using Quantitative Structure-Property Relationships (QSPR) models. For such an analysis, we propose Multiple Linear Regression (MLR) models based on theoretical molecular descriptors selected by Genetic Algorithm (GA). Training and prediction sets were prepared a priori by splitting the available experimental data, which were then used to derive statistically robust and predictive (both internally and externally) models. These models, after verification of their structural applicability domain (AD), were used to predict the properties of a total of 351 compounds, including those in the REACH preregistration list. Finally, Principal Component Analysis was applied to the predictions to rank the environmental partitioning properties (relevant for leaching and volatility) of new and untested (benzo)triazoles within the AD of each model. Our study using this approach highlighted compounds dangerous for the aquatic compartment. Similar analyses using predictions obtained by the EPI Suite and

  13. Dosage and dose schedule screening of drug combinations in agent-based models reveals hidden synergies

    Directory of Open Access Journals (Sweden)

    Lisa Corina Barros de Andrade e Sousa1

    2016-01-01

    Full Text Available The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  14. Performance and Cost-Effectiveness of Computed Tomography Lung Cancer Screening Scenarios in a Population-Based Setting: A Microsimulation Modeling Analysis in Ontario, Canada.

    Directory of Open Access Journals (Sweden)

    Kevin Ten Haaf

    2017-02-01

    Full Text Available The National Lung Screening Trial (NLST results indicate that computed tomography (CT lung cancer screening for current and former smokers with three annual screens can be cost-effective in a trial setting. However, the cost-effectiveness in a population-based setting with >3 screening rounds is uncertain. Therefore, the objective of this study was to estimate the cost-effectiveness of lung cancer screening in a population-based setting in Ontario, Canada, and evaluate the effects of screening eligibility criteria.This study used microsimulation modeling informed by various data sources, including the Ontario Health Insurance Plan (OHIP, Ontario Cancer Registry, smoking behavior surveys, and the NLST. Persons, born between 1940 and 1969, were examined from a third-party health care payer perspective across a lifetime horizon. Starting in 2015, 576 CT screening scenarios were examined, varying by age to start and end screening, smoking eligibility criteria, and screening interval. Among the examined outcome measures were lung cancer deaths averted, life-years gained, percentage ever screened, costs (in 2015 Canadian dollars, and overdiagnosis. The results of the base-case analysis indicated that annual screening was more cost-effective than biennial screening. Scenarios with eligibility criteria that required as few as 20 pack-years were dominated by scenarios that required higher numbers of accumulated pack-years. In general, scenarios that applied stringent smoking eligibility criteria (i.e., requiring higher levels of accumulated smoking exposure were more cost-effective than scenarios with less stringent smoking eligibility criteria, with modest differences in life-years gained. Annual screening between ages 55-75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago yielded an incremental cost-effectiveness ratio of $41,136 Canadian dollars ($33,825 in May 1, 2015, United States dollars per life-year gained

  15. A novel model of photo-carrier screening effect on the GaN-based p-i-n ultraviolet detector

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The photo-carrier density in the depletion region of the GaN-based p-i-n ultraviolet(UV) detector is calculated by solving the photo-carrier continuity equation,and the photo-carrier screening electric field is calculated according to Poisson’s equation.Using the numerical calculation method,a novel model of photo-carrier screening effect is presented.Then the influence of photo-carrier screening effect on the distribution of photo-carrier density in the depletion region of p-i-n detector is discussed.The influence of incident power,bias voltage and carrier life time on the photo-carrier screening effect is also analyzed.It is concluded that the influence of photo-carrier screening effect on the performance of GaN-based p-i-n UV detector is non-monotone,the maximum of carrier drift velocity and the minimum of response time can be realized by adjusting the applied voltage.Besides,the incident light duration has strong impact on the photo-carrier screening effect.

  16. Parametric Modeling and Moving Simulation of Vibrating Screen and Tubers on Potato Harvester

    Directory of Open Access Journals (Sweden)

    Huali Yu

    2015-02-01

    Full Text Available In order to overcome the behindhand and inefficient design of potato diggers, feature-based parametric modeling software Autodesk Inventor was used for modeling of potato diggers. The swing sieve, movement simulation with ADAMS was carried out. The complex velocity acceleration and displacement curves were analysed. Collision pressure curves were analysed too. Its velocity is less than or equal to 500 mm/s and its acceleration is more than or equal to 2.5 m/s2 and less than or equal to 20 m/s2. Test results indicated that Collision pressures of small and medium tubers are 120 Newton and 250 Newton, respectively, which are all smaller than damaging pressure. Potato can be transferred freely and damage rate is less than or equal to 4% when the frequency is 5.5 Hz and the swing is 30 mm.

  17. Conceptual design of a regional water quality screening model. [RFF; Reach; HANFORD; ARQUAL; SEAS; NASQUAN

    Energy Technology Data Exchange (ETDEWEB)

    Davis, M J

    1981-01-01

    This water quality assessment methodology is intended to predict concentrations at future times and to estimate the impacts on water quality of energy-related activities (including industrial boilers). Estimates of impacts on water quality at future times are based on incremental changes in pollutant inputs to the body water. Important features of the model are: use of measured concentrations to account for existing conditions; consideration of incremental changes in pollutant loads; emphasis on the energy sector and industrial boilers; analysis restricted to streams only; no attempt to fully account for pollutant behavior; and flexible design, so that future improvements can be incorporated. The basic approach is very similar to the one used by Argonne's ARQUAL model but will allow more complex pollutant behavior and more flexibility in use. (PSB)

  18. Ex vivo transfection of trout pronephros leukocytes, a model for cell culture screening of fish DNA vaccine candidates.

    Science.gov (United States)

    Ortega-Villaizan, M; Martinez-Lopez, A; Garcia-Valtanen, P; Chico, V; Perez, L; Coll, J M; Estepa, A

    2012-09-07

    DNA vaccination opened a new era in controlling and preventing viral diseases since DNA vaccines have shown to be very efficacious where some conventional vaccines have failed, as it occurs in the case of the vaccines against fish novirhabdoviruses. However, there is a big lack of in vitro model assays with immune-related cells for preliminary screening of in vivo DNA vaccine candidates. In an attempt to solve this problem, rainbow trout pronephros cells in early primary culture were transfected with two plasmid DNA constructions, one encoding the green fluorescent protein (GFP) and another encoding the viral haemorrhagic septicaemia virus (VHSV) glycoprotein G (G(VHSV)) - the only viral antigen which has conferred in vivo protection. After assessing the presence of GFP- and G(VHSV)-expressing cells, at transcription and protein levels, the immune response in transfected pronephros cells was evaluated. At 24h post-transfection, G(VHSV) up-regulated migm and tcr transcripts expression, suggesting activation of B and T cells, as well, a high up-regulation of tnfα gene was observed. Seventy-two hours post-transfection, we detected the up-regulation of mx and tnfα genes transcripts and Mx protein which correlated with the induction of an anti-VHSV state. All together we have gathered evidence for successful transfection of pronephros cells with pAE6G, which correlates with in vivo protection results, and is less time-consuming and more rapid than in vivo assays. Therefore, this outcome opens the possibility to use pronephros cells in early primary culture for preliminary screening fish DNA vaccines as well as to further investigate the function that these cells perform in fish immune response orchestration after DNA immunisation.

  19. Modelling the potential of focal screening and treatment as elimination strategy for Plasmodium falciparum malaria in the Peruvian Amazon Region.

    Science.gov (United States)

    Rosas-Aguirre, Angel; Erhart, Annette; Llanos-Cuentas, Alejandro; Branch, Oralee; Berkvens, Dirk; Abatih, Emmanuel; Lambert, Philippe; Frasso, Gianluca; Rodriguez, Hugo; Gamboa, Dionicia; Sihuincha, Moisés; Rosanas-Urgell, Anna; D'Alessandro, Umberto; Speybroeck, Niko

    2015-05-07

    Focal screening and treatment (FSAT) of malaria infections has recently been introduced in Peru to overcome the inherent limitations of passive case detection (PCD) and further decrease the malaria burden. Here, we used a relatively straightforward mathematical model to assess the potential of FSAT as elimination strategy for Plasmodium falciparum malaria in the Peruvian Amazon Region. A baseline model was developed to simulate a scenario with seasonal malaria transmission and the effect of PCD and treatment of symptomatic infections on the P. falciparum malaria transmission in a low endemic area of the Peruvian Amazon. The model was then adjusted to simulate intervention scenarios for predicting the long term additional impact of FSAT on P. falciparum malaria prevalence and incidence. Model parameterization was done using data from a cohort study in a rural Amazonian community as well as published transmission parameters from previous studies in similar areas. The effect of FSAT timing and frequency, using either microscopy or a supposed field PCR, was assessed on both predicted incidence and prevalence rates. The intervention model indicated that the addition of FSAT to PCD significantly reduced the predicted P. falciparum incidence and prevalence. The strongest reduction was observed when three consecutive FSAT were implemented at the beginning of the low transmission season, and if malaria diagnosis was done with PCR. Repeated interventions for consecutive years (10 years with microscopy or 5 years with PCR), would allow reaching near to zero incidence and prevalence rates. The addition of FSAT interventions to PCD may enable to reach P. falciparum elimination levels in low endemic areas of the Amazon Region, yet the progression rates to those levels may vary substantially according to the operational criteria used for the intervention.

  20. Speeding up N-body simulations of modified gravity: chameleon screening models

    Science.gov (United States)

    Bose, Sownak; Li, Baojiu; Barreira, Alexandre; He, Jian-hua; Hellwing, Wojciech A.; Koyama, Kazuya; Llinares, Claudio; Zhao, Gong-Bo

    2017-02-01

    We describe and demonstrate the potential of a new and very efficient method for simulating certain classes of modified gravity theories, such as the widely studied f(R) gravity models. High resolution simulations for such models are currently very slow due to the highly nonlinear partial differential equation that needs to be solved exactly to predict the modified gravitational force. This nonlinearity is partly inherent, but is also exacerbated by the specific numerical algorithm used, which employs a variable redefinition to prevent numerical instabilities. The standard Newton-Gauss-Seidel iterative method used to tackle this problem has a poor convergence rate. Our new method not only avoids this, but also allows the discretised equation to be written in a form that is analytically solvable. We show that this new method greatly improves the performance and efficiency of f(R) simulations. For example, a test simulation with 5123 particles in a box of size 512 Mpc/h is now 5 times faster than before, while a Millennium-resolution simulation for f(R) gravity is estimated to be more than 20 times faster than with the old method. Our new implementation will be particularly useful for running very high resolution, large-sized simulations which, to date, are only possible for the standard model, and also makes it feasible to run large numbers of lower resolution simulations for covariance analyses. We hope that the method will bring us to a new era for precision cosmological tests of gravity.

  1. Screening California Current fishery management scenarios using the Atlantis end-to-end ecosystem model

    Science.gov (United States)

    Kaplan, Isaac C.; Horne, Peter J.; Levin, Phillip S.

    2012-09-01

    End-to-end marine ecosystem models link climate and oceanography to the food web and human activities. These models can be used as forecasting tools, to strategically evaluate management options and to support ecosystem-based management. Here we report the results of such forecasts in the California Current, using an Atlantis end-to-end model. We worked collaboratively with fishery managers at NOAA’s regional offices and staff at the National Marine Sanctuaries (NMS) to explore the impact of fishery policies on management objectives at different spatial scales, from single Marine Sanctuaries to the entire Northern California Current. In addition to examining Status Quo management, we explored the consequences of several gear switching and spatial management scenarios. Of the scenarios that involved large scale management changes, no single scenario maximized all performance metrics. Any policy choice would involve trade-offs between stakeholder groups and policy goals. For example, a coast-wide 25% gear shift from trawl to pot or longline appeared to be one possible compromise between an increase in spatial management (which sacrificed revenue) and scenarios such as the one consolidating bottom impacts to deeper areas (which did not perform substantially differently from Status Quo). Judged on a coast-wide scale, most of the scenarios that involved minor or local management changes (e.g. within Monterey Bay NMS only) yielded results similar to Status Quo. When impacts did occur in these cases, they often involved local interactions that were difficult to predict a priori based solely on fishing patterns. However, judged on the local scale, deviation from Status Quo did emerge, particularly for metrics related to stationary species or variables (i.e. habitat and local metrics of landed value or bycatch). We also found that isolated management actions within Monterey Bay NMS would cause local fishers to pay a cost for conservation, in terms of reductions in landed

  2. Evaluation of primary HPV-DNA testing in relation to visual inspection methods for cervical cancer screening in rural China: an epidemiologic and cost-effectiveness modelling study

    Directory of Open Access Journals (Sweden)

    Kang Yoon-Jung

    2011-06-01

    Full Text Available Abstract Background A new lower-cost rapid-throughput human papillomavirus (HPV test (careHPV, Qiagen, Gaithersburg, USA has been shown to have high sensitivity for the detection of high grade cervical intraepithelial neoplasia. Methods We assessed the outcomes and cost-effectiveness of careHPV screening in rural China, compared to visual inspection with acetic acid, when used alone (VIA or in combination with Lugol's iodine (VIA/VILI. Using data on sexual behaviour, test accuracy, diagnostic practices and costs from studies performed in rural China, we estimated the cost-effectiveness ratio (CER and associated lifetime outcomes for once-lifetime and twice-lifetime screening strategies, and for routine screening at 5-yearly, 10-yearly and IARC-recommended intervals. The optimal age range for once-lifetime screening was also assessed. Results For all strategies, the relative ordering of test technologies in reducing cervical cancer incidence and mortality was VIA (least effective; VIA/VILI; careHPV@1.0 pg/ml and careHPV@0.5 pg/ml (most effective. For once-lifetime strategies, maximum effectiveness was achieved if screening occurred between 35-50 years. Assuming a participation rate of ~70%, once-lifetime screening at age 35 years would reduce cancer mortality by 8% (for VIA to 12% (for careHPV@0.5 over the long term, with a CER of US$557 (for VIA to $959 (for careHPV@1.0 per life year saved (LYS compared to no intervention; referenced to a 2008 GDP per capita in Shanxi Province of $2,975. Correspondingly, regular screening with an age-standardised participation rate of 62% (which has been shown to be achievable in this setting would reduce cervical cancer mortality by 19-28% (for 10-yearly screening to 43-54% (using IARC-recommended intervals, with corresponding CERs ranging from $665 (for 10-yearly VIA to $2,269 (for IARC-recommended intervals using careHPV@1.0 per LYS. Conclusions This modelled analysis suggests that primary careHPV screening

  3. Tethered spheroids as an in vitro hepatocyte model for drug safety screening.

    Science.gov (United States)

    Xia, Lei; Sakban, Rashidah Binte; Qu, Yinghua; Hong, Xin; Zhang, Wenxia; Nugraha, Bramasta; Tong, Wen Hao; Ananthanarayanan, Abhishek; Zheng, Baixue; Chau, Ian Yin-Yan; Jia, Ruirui; McMillian, Michael; Silva, Jose; Dallas, Shannon; Yu, Hanry

    2012-03-01

    Hepatocyte spheroids mimic many in vivo liver-tissue phenotypes but increase in size during extended culture which limits their application in drug testing applications. We have developed an improved hepatocyte 3D spheroid model, namely tethered spheroids, on RGD and galactose-conjugated membranes using an optimized hybrid ratio of the two bioactive ligands. Cells in the spheroid configuration maintained 3D morphology and uncompromised differentiated hepatocyte functions (urea and albumin production), while the spheroid bottom was firmly tethered to the substratum maintaining the spheroid size in multi-well plates. The oblate shape of the tethered spheroids, with an average height of 32 μm, ensured efficient nutrient, oxygen and drug access to all the cells within the spheroid structure. Cytochrome P450 induction by prototypical inducers was demonstrated in the tethered spheroids and was comparable or better than that observed with hepatocyte sandwich cultures. These data suggested that tethered 3D hepatocyte spheroids may be an excellent alternative to 2D hepatocyte culture models for drug safety applications.

  4. Evaluating skin-protective materials against contact irritants and allergens. An in vivo screening human model.

    Science.gov (United States)

    Zhai, H; Willard, P; Maibach, H I

    1998-03-01

    2 acute irritants and 1 allergen were selected: sodium lauryl sulfate (SLS) representative of irritant household and occupational contact dermatitis, the combination of ammonium hydroxide (NH4OH) and urea to simulate diaper dermatitis, and Rhus to evaluate the effect of model protective materials. The putative protective materials and vehicle were applied to both ventral forearms of 10 subjects in each group, according to a randomized code. Test materials were spread over a marked 2.0 cm2 area, massaged in, allowed to dry for 30 min, and reapplied with another 30 min drying period. The model irritants and allergen were then applied (0.025 ml) to an Al-test occlusive patch, which in turn was placed for 24 h over each of the 8 designated sites. Inflammation was scored according to a clinical scale 72 h post-application. Paraffin wax plus Acetulan in cetyl alcohol, and beeswax plus Acetulan in cetyl alcohol, markedly (p clinical significance requires comparison with an open rather than an occluded challenge.

  5. Speeding up $N$-body simulations of modified gravity: Chameleon screening models

    CERN Document Server

    Bose, Sownak; Barreira, Alexandre; He, Jian-hua; Hellwing, Wojciech A; Koyama, Kazuya; Llinares, Claudio; Zhao, Gong-Bo

    2016-01-01

    We describe and demonstrate the potential of a new and very efficient method for simulating certain classes of modified gravity theories, such as the widely studied $f(R)$ gravity models. High resolution simulations for such models are currently very slow due to the highly nonlinear partial differential equation that needs to be solved exactly to predict the modified gravitational force. This nonlinearity is partly inherent, but is also exacerbated by the specific numerical algorithm used, which employs a variable redefinition to prevent numerical instabilities. The standard Newton-Gauss-Seidel iterative method used to tackle this problem has a poor convergence rate. Our new method not only avoids this, but also allows the discretised equation to be written in a form that is analytically solvable. We show that this new method greatly improves the performance and efficiency of $f(R)$ simulations. For example, a test simulation with $512^3$ particles in a box of size $512 \\, \\mathrm{Mpc}/h$ is now 5 times faste...

  6. Discovery of a Dipeptide Epimerase Enzymatic Function Guided by Homology Modeling and Virtual Screening

    Energy Technology Data Exchange (ETDEWEB)

    Kalyanaraman, C.; Imker, H; Fedorov, A; Fedorov, E; Glasner, M; Babbitt, P; Almo, S; Gerlt, J; Jacobson, M

    2008-01-01

    We have developed a computational approach to aid the assignment of enzymatic function for uncharacterized proteins that uses homology modeling to predict the structure of the binding site and in silico docking to identify potential substrates. We apply this method to proteins in the functionally diverse enolase superfamily that are homologous to the characterized L-Ala-D/L-Glu epimerase from Bacillus subtilis. In particular, a protein from Thermotoga martima was predicted to have different substrate specificity, which suggests that it has a different, but as yet unknown, biological function. This prediction was experimentally confirmed, resulting in the assignment of epimerase activity for L-Ala-D/L-Phe, L-Ala-D/L-Tyr, and L-Ala-D/L-His, whereas the enzyme is annotated incorrectly in GenBank as muconate cycloisomerase. Subsequently, crystal structures of the enzyme were determined in complex with three substrates, showing close agreement with the computational models and revealing the structural basis for the observed substrate selectivity.

  7. An Emerging Translational Model to Screen Potential Medicinal Plants for Nephrolithiasis, an Independent Risk Factor for Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    San-Yuan Wu

    2014-01-01

    Full Text Available Pharmacological therapy for urolithiasis using medicinal plants has been increasingly adopted for the prevention of its recurrence. A Drosophila melanogaster model developed for translational research of urolithiasis was applied to evaluate agents with potential antilithic effects and calcium oxalate (CaOx formation. Potential antilithic herbs were prepared in a mixture of food in a diluted concentration of 5,000 from the original extract with 0.5% ethylene glycol (EG as the lithogenic agent. The control group was fed with food only. After 3 weeks, flies (n≥150 for each group were killed using CO2 narcotization, and the Malpighian tubules were dissected, removed, and processed for polarized light microscopy examination of the crystals. The crystal formation rate in the EG group was 100.0%. In the study, 16 tested herbal drugs reached the crystal formation rate of 0.0%, including Salviae miltiorrhizae, Paeonia lactiflora, and Carthami flos. Scutellaria baicalensis enhanced CaOx crystal formation. Two herbal drugs Commiphora molmol and Natrii sulfas caused the death of all flies. Our rapid screening methods provided evidence that some medicinal plants have potential antilithic effects. These useful medicinal plants can be further studied using other animal or human models to verify their effects.

  8. Accurate Modeling of the Cubic and Antiferrodistortive Phases of SrTiO3 with Screened Hybrid Density Functional Theory

    CERN Document Server

    El-Mellouhi, Fadwa; Lucero, Melissa J; Scuseria, Gustavo E

    2011-01-01

    We have calculated the properties of SrTiO3 (STO) using a wide array of density functionals ranging from standard semi-local functionals to modern range-separated hybrids, combined with several basis sets of varying size/quality. We show how these combination's predictive ability varies signi?cantly, both for STO's cubic and antiferrodistortive (AFD) phases, with the greatest variation in functional/basis set e?cacy seen in modeling the AFD phase. The screened hybrid functionals we utilized predict the structural properties of both phases in very good agreement with experiment, especially if used with large (but still computationally tractable) basis sets. The most accurate results presented in this study, namely those from HSE06/modi?ed-def2-TZVP, stand as the most accurate modeling of STO to date when compared to the literature; these results agree well with experimental structural and electronic properties as well as providing insight into the band structure alteration during the phase transition.

  9. Dissecting electrostatic screening, specific ion binding, and ligand binding in an energetic model for glycine riboswitch folding

    Energy Technology Data Exchange (ETDEWEB)

    Lipfert, Jan; Sim, Adelene Y.L.; Herschlag, Daniel; Doniach, Sebastian (Stanford)

    2010-09-17

    Riboswitches are gene-regulating RNAs that are usually found in the 5{prime}-untranslated regions of messenger RNA. As the sugar-phosphate backbone of RNA is highly negatively charged, the folding and ligand-binding interactions of riboswitches are strongly dependent on the presence of cations. Using small angle X-ray scattering (SAXS) and hydroxyl radical footprinting, we examined the cation dependence of the different folding stages of the glycine-binding riboswitch from Vibrio cholerae. We found that the partial folding of the tandem aptamer of this riboswitch in the absence of glycine is supported by all tested mono- and divalent ions, suggesting that this transition is mediated by nonspecific electrostatic screening. Poisson-Boltzmann calculations using SAXS-derived low-resolution structural models allowed us to perform an energetic dissection of this process. The results showed that a model with a constant favorable contribution to folding that is opposed by an unfavorable electrostatic term that varies with ion concentration and valency provides a reasonable quantitative description of the observed folding behavior. Glycine binding, on the other hand, requires specific divalent ions binding based on the observation that Mg{sup 2+}, Ca{sup 2+}, and Mn{sup 2+} facilitated glycine binding, whereas other divalent cations did not. The results provide a case study of how ion-dependent electrostatic relaxation, specific ion binding, and ligand binding can be coupled to shape the energetic landscape of a riboswitch and can begin to be quantitatively dissected.

  10. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids

    Science.gov (United States)

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B.; Crawford, Howard C.; Arrowsmith, Cheryl; Kalloger, Steve E.; Renouf, Daniel J.; Connor, Ashton A; Cleary, Sean; Schaeffer, David F.; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.

    2016-01-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID:26501191

  11. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.

    Science.gov (United States)

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B; Crawford, Howard C; Arrowsmith, Cheryl; Kalloger, Steve E; Renouf, Daniel J; Connor, Ashton A; Cleary, Sean; Schaeffer, David F; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K

    2015-11-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

  12. Xenobiotic effects in cancer related pathways-high throughput screening and proof of concept in animal models

    Institute of Scientific and Technical Information of China (English)

    Ursula E. Schumacher

    2013-01-01

    Xenobiotic drugs and chemicals directly interact with DNA, proteins, or other biomolecules in cells. These direct interactions with molecular targets may trigger a series of downstream effects on metabolic-biochemical and regulatory-signaling networks that can invoke cellular consequences leading to adaptive homeostatic or adverse pathological responses. Regulators for drug and chemicals safety have therefore since long required the testing of toxicity in animal models before drugs and pesticides can enter the market. The US National Research Council of the National Academy of Sciences, in its report, Toxicity Testing in the 21st Century: a Vision and a Strategy[1], proposed that toxicity testing should become less reliant on apical endpoints from whole animal tests and eventually rely instead on quantitative, dose-response models based on information from in vitro assays and in vivo biomarkers, which can be used to screen large numbers of chemicals.The present paper reports about a combination of HTS in vitro assays that can be used to study the potential tumorigenic effect of xenobiotics (drug targets, environmental chemicals) via a set of "sentinel" genes[2] that are functionally interrelated based on evidence weighted functional linkage network (FLN) log-likelihood scores (Linghu et al[3]).

  13. Primary Screening for Proteins Differentially Expressed in the Myocardium of a Rat Model of Acute Methamphetamine Intoxication

    Directory of Open Access Journals (Sweden)

    Guoqiang Qu

    2016-01-01

    Full Text Available The mechanism of myocardial injury induced by the cardiovascular toxicity of methamphetamine (MA has been shown to depend on alterations in myocardial proteins caused by MA. Primary screening of the expression of myocardial proteins in a rat model of MA intoxication was achieved by combining two-dimensional electrophoresis and mass spectrometry analyses, which revealed a total of 100 differentially expressed proteins. Of these, 13 displayed significantly altered expression. Moreover, Western blotting and real-time reverse transcription quantitative polymerase chain reaction analyses of several relative proteins demonstrated that acute MA intoxication lowers protein expression and mRNA transcription of aldehyde dehydrogenase-2 and NADH dehydrogenase (ubiquinone 1 alpha subcomplex subunit 10. In contrast, MA intoxication elevated the protein expression and mRNA transcription of heat shock protein family B (small member 1. By combining behavioral assessments of experimental rat models with the histological and pathological changes evident in cardiomyocytes, a mechanism accounting for MA myocardial toxicity was suggested. MA alters the regulation of gene transcription and the subsequent expression of certain proteins that participate in myocardial respiration and in responding to oxidative stress, resulting in myocardial dysfunction and structural changes that affect the functioning of the cardiovascular system.

  14. Screen-level non-GTS data assimilation in a limited-area mesoscale model

    Directory of Open Access Journals (Sweden)

    M. Milelli

    2010-06-01

    Full Text Available The forecast in areas of very complex topography, as for instance the Alpine region, is still a challenge even for the new generation of numerical weather prediction models which aim at reaching the km-scale. The problem is enhanced by a general lack of standard observations, which is even more evident over the southern side of the Alps. For this reason, it would be useful to increase the performance of the mathematical models by locally assimilating non-conventional data. Since in ARPA Piemonte there is the availability of a great number of non-GTS stations, it has been decided to assimilate the 2 m temperature, coming from this dataset, in the very-high resolution version of the COSMO model, which has a horizontal resolution of about 3 km, more similar to the average resolution of the thermometers. Four different weather situations have been considered, ranging from spring to winter, from cloudy to clear sky. The aim of the work is to investigate the effects of the assimilation of non-GTS data in order to create an operational very high-resolution analysis, but also to test the option of running in the future a very short-range forecast starting from these analyses (RUC or Rapid Update Cycle. The results, in terms of Root Mean Square Error, Mean Error and diurnal cycle of some surface variables such as 2 m temperature, 2 m relative humidity and 10 m wind intensity show a positive impact during the assimilation cycle which tends to dissipate a few hours after the end of it. Moreover, the 2 m temperature assimilation has a slightly positive or neutral impact on the vertical profiles of temperature, eventhough some calibration is needed for the precipitation field which is too much perturbed during the assimilation cycle, while it is unaffected in the forecast period. So the stability of the planetary boundary layer, on the one hand, has not been particularly improved by the new-data assimilation, but, on the other hand, it has not been destroyed

  15. Breast cancer screening in an era of personalized regimens: a conceptual model and National Cancer Institute initiative for risk-based and preference-based approaches at a population level.

    Science.gov (United States)

    Onega, Tracy; Beaber, Elisabeth F; Sprague, Brian L; Barlow, William E; Haas, Jennifer S; Tosteson, Anna N A; D Schnall, Mitchell; Armstrong, Katrina; Schapira, Marilyn M; Geller, Berta; Weaver, Donald L; Conant, Emily F

    2014-10-01

    Breast cancer screening holds a prominent place in public health, health care delivery, policy, and women's health care decisions. Several factors are driving shifts in how population-based breast cancer screening is approached, including advanced imaging technologies, health system performance measures, health care reform, concern for "overdiagnosis," and improved understanding of risk. Maximizing benefits while minimizing the harms of screening requires moving from a "1-size-fits-all" guideline paradigm to more personalized strategies. A refined conceptual model for breast cancer screening is needed to align women's risks and preferences with screening regimens. A conceptual model of personalized breast cancer screening is presented herein that emphasizes key domains and transitions throughout the screening process, as well as multilevel perspectives. The key domains of screening awareness, detection, diagnosis, and treatment and survivorship are conceptualized to function at the level of the patient, provider, facility, health care system, and population/policy arena. Personalized breast cancer screening can be assessed across these domains with both process and outcome measures. Identifying, evaluating, and monitoring process measures in screening is a focus of a National Cancer Institute initiative entitled PROSPR (Population-based Research Optimizing Screening through Personalized Regimens), which will provide generalizable evidence for a risk-based model of breast cancer screening, The model presented builds on prior breast cancer screening models and may serve to identify new measures to optimize benefits-to-harms tradeoffs in population-based screening, which is a timely goal in the era of health care reform. © 2014 American Cancer Society.

  16. Screening CO

    NARCIS (Netherlands)

    Ramírez, A.; Hagedoorn, S.; Kramers, L.; Wildenborg, T.; Hendriks, C.

    2010-01-01

    This paper describes the development and application of a methodology to screen and rank Dutch reservoirs suitable for long-term large scale CO2 storage. The screening focuses on off- and on-shore individual aquifers, gas and oil fields. In total 176 storage reservoirs have been taken int

  17. Effects of Application of Social Marketing Theory and the Health Belief Model in Promoting Cervical Cancer Screening among Targeted Women in Sisaket Province, Thailand.

    Science.gov (United States)

    Wichachai, Suparp; Songserm, Nopparat; Akakul, Theerawut; Kuasiri, Chanapong

    2016-01-01

    Cervical cancer is a major public health problem in Thailand, being ranked second only to breast cancer. Thai women have been reported to have a low rate of cervical cancer screening (27.7% of the 80% goal of WHO). We therefore aimed to apply the social marketing theory and health belief model in promoting cervical cancer screening in Kanthararom District, Sisaket Province. A total of 92 from 974 targeted women aged 3060 years were randomly divided into two groups. The experimental group underwent application of social marketing theory and a health belief model program promoting cervical cancer screening while the control group received normal services. Two research tools were used: (1) application of social marketing theory and health belief model program and (2) questionnaire used to evaluate perceptions of cervical cancer. Descriptive and inferential statistics including paired sample ttest and independent ttest were used to analyze the data. After the program had been used, the mean score of perception of cervical cancer of experimental group was at a higher level (x=4.09; S.D. =0.30), than in the control group (x=3.82; S.D. =0.20) with statistical significance (psocial marketing and the health belief model be used to promote cervical cancer screening in targeted women and it can be promoted as a guideline for other health services, especially in health promotion and disease prevention.

  18. Modelling the Costs and Effects of Selective and Universal Hospital Admission Screening for Methicillin-Resistant Staphylococcus aureus

    NARCIS (Netherlands)

    Hubben, Gijs; Bootsma, Martin; Luteijn, Michiel; Glynn, Diarmuid; Bishai, David; Bonten, Marc; Postma, Maarten

    2011-01-01

    Background: Screening at hospital admission for carriage of methicillin-resistant Staphylococcus aureus (MRSA) has been proposed as a strategy to reduce nosocomial infections. The objective of this study was to determine the long-term costs and health benefits of selective and universal screening fo

  19. A model-based cost-effectiveness analysis of osteoporosis screening and treatment strategy for postmenopausal Japanese women.

    Science.gov (United States)

    Yoshimura, M; Moriwaki, K; Noto, S; Takiguchi, T

    2017-02-01

    Although an osteoporosis screening program has been implemented as a health promotion project in Japan, its cost-effectiveness has yet to be elucidated fully. We performed a cost-effectiveness analysis and found that osteoporosis screening and treatment would be cost-effective for Japanese women over 60 years.

  20. Reducing Harms and Increasing Benefits of Screening for Cervical Cancer and Colorectal Cancer – A Model-based Approach

    NARCIS (Netherlands)

    S.K. Naber (Steffie)

    2017-01-01

    textabstractScreening is the systematic testing of asymptomatic individuals to identify disease or risk factors for disease. This enables the possibility to act earlier, e.g. by starting treatment of the disease earlier. Screening is especially valuable for diseases like cancer, where prognosis is

  1. Reducing Harms and Increasing Benefits of Screening for Cervical Cancer and Colorectal Cancer – A Model-based Approach

    NARCIS (Netherlands)

    S.K. Naber (Steffie)

    2017-01-01

    textabstractScreening is the systematic testing of asymptomatic individuals to identify disease or risk factors for disease. This enables the possibility to act earlier, e.g. by starting treatment of the disease earlier. Screening is especially valuable for diseases like cancer, where prognosis is b

  2. Ligand-Based Pharmacophore Modeling and Virtual Screening of RAD9 Inhibitors

    Directory of Open Access Journals (Sweden)

    Nirmal K. Prasad

    2013-01-01

    Full Text Available Human RAD9 is a key cell-cycle checkpoint protein that participates in DNA repair, activation of multiple cell cycle phase checkpoints, and apoptosis. Aberrant RAD9 expression has been linked to breast, lung, thyroid, skin, and prostate tumorigenesis. Overexpression of RAD9 interacts with BCL-2 proteins and blocks the binding sites of BCL-2 family proteins to interact with chemotherapeutic drugs and leads to drug resistance. Focusing on this interaction, the present study was designed to identify the interaction sites of RAD9 to bind BCL-2 protein and also to inhibit RAD9-BCL-2 interactions by designing novel small molecule inhibitors using pharmacophore modeling and to restore BCL-2 for interacting with anticancer drugs. The bioactive molecules of natural origin act as excellent leads for new drug development. Thus, in the present study, we used the compounds of natural origin like camptothecin, ascididemin, and Dolastatin and also compared them with synthetic molecule NSC15520. The results revealed that camptothecin can act as an effective inhibitor among all the ligands taken and can be used as an RAD9 inhibitor. The amino acids ARG45 and ALA134 of RAD9 protein are interacting commonly with the drugs and BCL-2 protein.

  3. Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools.

    Science.gov (United States)

    Odermatt, Alex; Strajhar, Petra; Engeli, Roger T

    2016-04-01

    In the modern world, humans are exposed during their whole life to a large number of synthetic chemicals. Some of these chemicals have the potential to disrupt endocrine functions and contribute to the development and/or progression of major diseases. Every year approximately 1000 novel chemicals, used in industrial production, agriculture, consumer products or as pharmaceuticals, are reaching the market, often with limited safety assessment regarding potential endocrine activities. Steroids are essential endocrine hormones, and the importance of the steroidogenesis pathway as a target for endocrine disrupting chemicals (EDCs) has been recognized by leading scientists and authorities. Cell lines have a prominent role in the initial stages of toxicity assessment, i.e. for mechanistic investigations and for the medium to high throughput analysis of chemicals for potential steroidogenesis disrupting activities. Nevertheless, the users have to be aware of the limitations of the existing cell models in order to apply them properly, and there is a great demand for improved cell-based testing systems and protocols. This review intends to provide an overview of the available cell lines for studying effects of chemicals on gonadal and adrenal steroidogenesis, their use and limitations, as well as the need for future improvements of cell-based testing systems and protocols.

  4. Screening of Catalysts for Hydrodeoxygenation of Phenol as Model Compound for Bio-oil

    DEFF Research Database (Denmark)

    Mortensen, Peter Mølgaard; Grunwaldt, Jan-Dierk; Jensen, Peter Arendt

    2013-01-01

    in that order. Nickel was the only active non-noble metal catalyst. For nickel, also the effect of support was investigated and ZrO2 was found to perform best. Pt/C, Ni/CeO2, and Ni/CeO2-ZrO2 were the most active catalysts for the initial hydrogenation of phenol to cyclohexanol, but were not very active...... effectively be described by a kinetic model involving a two-step reaction were phenol initially was hydrogenated to cyclohexanol and then subsequently deoxygenated to cyclohexane. Among reduced noble metal catalysts ruthenium, palladium, and platinum were all found to be active, with decreasing activity...... for the subsequent deoxygenation step. Overall, the order of activity of the best performing HDO catalysts was: Ni/ZrO2 > Ni-V2O5/ZrO2 > Ni-V2O5/SiO2 > Ru/C > Ni/Al2O3 > Ni/SiO2 >> Pd/C > Pt/C. The choice of support influenced the activity significantly. Nickel was found to be practically inactive for HDO of phenol...

  5. Light Quarks in the Screened Dyon-Anti-Dyon Coulomb Liquid Model II

    CERN Document Server

    Liu, Yizhuang; Zahed, Ismail

    2015-01-01

    We discuss an extension of the dyon-anti-dyon liquid model that includes light quarks in the dense center symmetric Coulomb phase. In this work, like in our previous one, we use the simplest color SU(2) group. We start with a single fermion flavor $N_f=1$ and explicitly map the theory onto a 3-dimensional quantum effective theory with a fermion that is only U$_V(1)$ symmetric. We use it to show that the dense center symmetric plasma develops, in the mean field approximation, a nonzero chiral condensate, although the ensuing Goldstone mode is massive due to the U$_A(1)$ axial-anomaly. We estimate the chiral condensate and $\\sigma,\\eta$ meson masses for $N_f=1$. We then extend our analysis to several flavors $N_f>1$ and colors $N_c>2$ and show that center symmetry and spontaneous chiral symmetry breaking disappear simultaneously when $x=N_f/N_c\\geq 2$ in the dense plasma phase. A reorganization of the dense plasma phase into a gas of dyon-antidyon molecules restores chiral symmetry, but may preserve center symm...

  6. Alcohol, Sex, and Screens: Modeling Media Influence on Adolescent Alcohol and Sex Co-Occurrence.

    Science.gov (United States)

    Bleakley, Amy; Ellithorpe, Morgan E; Hennessy, Michael; Khurana, Atika; Jamieson, Patrick; Weitz, Ilana

    2017-02-26

    Alcohol use and sexual behavior are important risk behaviors in adolescent development, and combining the two is common. The reasoned action approach (RAA) is used to predict adolescents' intention to combine alcohol use and sexual behavior based on exposure to alcohol and sex combinations in popular entertainment media. We conducted a content analysis of mainstream (n = 29) and Black-oriented movies (n = 34) from 2014 and 2013-2014, respectively, and 56 television shows (2014-2015 season). Content analysis ratings featuring character portrayals of both alcohol and sex within the same five-minute segment were used to create exposure measures that were linked to online survey data collected from 1,990 adolescents ages 14 to 17 years old (50.3% Black, 49.7% White; 48.1% female). Structural equation modeling (SEM) and group analysis by race were used to test whether attitudes, norms, and perceived behavioral control mediated the effects of media exposure on intention to combine alcohol and sex. Results suggest that for both White and Black adolescents, exposure to media portrayals of alcohol and sex combinations is positively associated with adolescents' attitudes and norms. These relationships were stronger among White adolescents. Intention was predicted by attitude, norms, and control, but only the attitude-intention relationship was different by race group (stronger for Whites).

  7. A consensus development conference model for establishing health policy for surveillance and screening of antimicrobial-resistant organisms.

    Science.gov (United States)

    Buick, Steve; Joffe, A Mark; Taylor, Geoffrey; Conly, John

    2015-04-01

    The Canadian Consensus Development Conference on Surveillance and Screening for Antimicrobial-Resistant Organisms (AROs) was sponsored by the Alberta Ministry of Health to provide evidence to update policies for ARO screening in acute care settings. A rigorous evidence-based literature review completed before the conference concluded that that neither universal nor targeted screening of patients was associated with a reduction in hospital-acquired ARO colonization, infection, morbidity, or mortality. Leading international clinicians, scientists, academics, policy makers, and administrators presented current evidence and clinical experience, focusing on whether and how hospitals should screen patients for AROs as part of broader ARO control strategies. An unbiased and independent "jury" with a broad base of expertise from complementary disciplines considered the evidence and released a consensus statement of 22 recommendations. Policy highlights included developing an integrated "One Health" strategy, fully resourcing basic infection control practices, not performing universal screening, and focusing original research to determine what works.

  8. Human Umbilical Cord Blood-Derived Neural Stem Cell Line as a Screening Model for Toxicity.

    Science.gov (United States)

    Patnaik, Rajashree; Padhy, Rabindra Nath

    2017-04-01

    The aim was to investigate whether a human neural stem cell (NSC) line derived from human umbilical cord blood (hUCB) can be used for toxicity study. Toxicity of both neurotoxic environmental xenobiotics, methyl mercury chloride (CH3HgCl), lead acetate (CH3COOPb), and chlorpyrifos (CP), and non-neurotoxic insecticide, dichlorvos, as well as non-neurotoxic drugs, theophylline and acetaminophen were assessed. Additionally, differentiation of neuronal and glial cell lines derived from hUCB was elucidated. It was observed that CH3HgCl was more toxic to human NSCs in comparison to CH3COOPb and CP. The minimum inhibitory concentration (MIC) value against NSCs was 3, 10, and 300 mg/L, in each staining process, acridine orange/ethidium bromide (AO/EB) staining, 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay, and Hoechst staining, for CH3HgCl, CP, and CH3COOPb, respectively. CH3HgCl had the LC25 value as 10.0, 14.4, and 12.7 mg/L, by staining method mentioned in succession. CP had the LC25 value as 21.9, 23.7, and 18.4 mg/L; similarly, CH3COOPb had LC25 values, successively as 616.9, 719.2, and 890.3 mg/L. LC50 values ranged from 18.2 to 21.7 mg/L for CH3HgCl, 56.4 to 60.2 mg/L for CP, and 1000 to 1460.1 for CH3COOPb. Theophylline, acetaminophen, and dichlorvos had no impact on the viability of NSCs. This work justified that hUCB-NSC model can be used for toxicity study.

  9. Development and application of a screening model for evaluating bioenhanced dissolution in DNAPL source zones

    Science.gov (United States)

    Phelan, Thomas J.; Abriola, Linda M.; Gibson, Jenny L.; Smits, Kathleen M.; Christ, John A.

    2015-12-01

    In-situ bioremediation, a widely applied treatment technology for source zones contaminated with dense non-aqueous phase liquids (DNAPLs), has proven economical and reasonably efficient for long-term management of contaminated sites. Successful application of this remedial technology, however, requires an understanding of the complex interaction of transport, mass transfer, and biotransformation processes. The bioenhancement factor, which represents the ratio of DNAPL mass transfer under microbially active conditions to that which would occur under abiotic conditions, is commonly used to quantify the effectiveness of a particular bioremediation remedy. To date, little research has been directed towards the development and validation of methods to predict bioenhancement factors under conditions representative of real sites. This work extends an existing, first-order, bioenhancement factor expression to systems with zero-order and Monod kinetics, representative of many source-zone scenarios. The utility of this model for predicting the bioenhancement factor for previously published laboratory and field experiments is evaluated. This evaluation demonstrates the applicability of these simple bioenhancement factors for preliminary experimental design and analysis, and for assessment of dissolution enhancement in ganglia-contaminated source zones. For ease of application, a set of nomographs is presented that graphically depicts the dependence of bioenhancement factor on physicochemical properties. Application of these nomographs is illustrated using data from a well-documented field site. Results suggest that this approach can successfully capture field-scale, as well as column-scale, behavior. Sensitivity analyses reveal that bioenhanced dissolution will critically depend on in-situ biomass concentrations.

  10. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

    Directory of Open Access Journals (Sweden)

    Chuang Chih-Kuang

    2011-01-01

    Full Text Available Abstract Background Alzheimer's disease (AD is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. Methods In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5 program based on a set of known AChE inhibitors. Results The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. Conclusions The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.

  11. A touch-screen based paired-associates learning (PAL) task for the rat may provide a translatable pharmacological model of human cognitive impairment.

    Science.gov (United States)

    Talpos, John C; Aerts, Nancy; Fellini, Laetitia; Steckler, Thomas

    2014-07-01

    The use of touch-screen equipped operant boxes is an increasingly popular approach for modeling human cognition in the rodent. However little data is currently available describing the effects of pharmacological manipulations on touch-screen based tasks. Owing to the relationship between performance on visual-spatial paired associates learning (PAL) with schizophrenia and Alzheimer's disease one task of specific interest is the touch-screen PAL task developed for rodents (J. Talpos et al., 2009). The goal of this study was to profile a range of the commonly used pharmacological models of schizophrenia and Alzheimer's disease to investigate the sensitivity of PAL to these models of disease. Male Lister hooded rats were trained on PAL until stable performance was obtained. The effects of PCP, ketamine, amphetamine, LSD, scopolamine, and biperiden (recently proposed as an alternative to scopolamine) were then tested on animals performing the PAL task. While all compounds influenced responding during PAL, only PCP and amphetamine impaired performance with minimal changes in secondary measures (response latencies, trials completed). Surprisingly ketamine did not cause a change in percent correct despite being an NMDA antagonist, indicating that not all NMDA antagonists are equal in the touch-screen platform. This finding is in agreement with existing literature showing differential effects of NMDA antagonists on a wide variety of behavioral assays include tasks of attention, memory, and cognitive flexibility (Gilmour et al., 2009; Dix et al., 2010; Smith et al., 2011). Moreover biperiden showed no benefit when compared to scopolamine, highlighting the current lack of an effective pharmacological model of cholinergic dysfunction in the touch-screen platform. These data demonstrate that performance on PAL can be disrupted by common pharmacological disease models, suggesting that PAL may have the sensitivity to serve as a translational test for the study of cognition in

  12. micro-RNA screening and prediction model construction for diagnosis of salt-sensitive essential hypertension.

    Science.gov (United States)

    Qi, Han; Liu, Zheng; Liu, Bin; Cao, Han; Sun, Weiping; Yan, Yuxiang; Zhang, Ling

    2017-04-01

    Commonly used tests for diagnosis of salt-sensitive hypertension (SSH) are complex and time-consuming, so new methods are required. Many studies have demonstrated roles for miRNAs in hypertension; however, the diagnostic value of miRNAs has yet to be determined for human SSH. In this study, we examined miRNA expression profiles by initial high-throughput miRNA sequencing of samples from patients with salt-sensitive and salt-resistant hypertension (SSH and SRH, respectively; n = 6, both groups), followed by validation by quantitative real-time polymerase chain reaction (qRT-PCR) in a larger cohort (n = 91). We also evaluated differences in baseline characteristics (e.g., age, sex, body mass index, consumption of specific foods) between the SSH and SRH groups. Of 36 miRNAs identified as differentially expressed between SSH and SRH groups by RNA-Seq, 8 were analyzed by qRT-PCR. There were significant differences in the expression levels of hsa-miR-361-5p and hsa-miR-362-5p between the 2 groups (P = .023 and.049, respectively). In addition, there were significant differences in sauce and poultry consumption between the 2 groups (P = .004 and.001, respectively). The areas under the curve (AUC) determined by receptor operating characteristic (ROC) analysis for hsa-miR-361-5p and all 8 miRNAs were 0.793 (95% CI, 0.698-0.888; sensitivity = 73.9%, specificity = 74.4%; P < .001) and 0.836 (95% CI, 0.749-0.922; sensitivity = 80.4%, specificity = 81.4%; P < .001), respectively, when sauce and poultry consumption were included in the models. Assay feasibility and economic considerations make hsa-miR-361-5p combined with the dietary factors the preferred markers for diagnosis of SSH.

  13. Screening for supra-additive effects of cytotoxic drugs and gamma irradiation in an in vitro model for hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lambert, B. [Ghent Univ. Hosptial, Nuclear Medicine Div., Ghent (Belgium)]. E-mail: bieke.lambert@Ugent.be; De Ridder, L. [Ghent Univ., Dept. of Histology, Anatomy, and Embryology, Ghent (Belgium); Slegers, G. [Ghent Univ., Dept. of Radiopharmacy, Ghent (Belgium); De Gelder, V. [Ghent Univ., Dept. of Medical Physics, Ghent (Belgium); Dierckx, R.A. [Ghent Univ. Hosptial, Nuclear Medicine Div., Ghent (Belgium); Thierens, H. [Ghent Univ., Dept. of Medical Physics, Ghent (Belgium)

    2004-02-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. A wide variety of treatment modalities is available for palliative therapy of HCC, although there is no strong evidence that these treatments can have a significant impact on survival. The aim of this work was to screen cytotoxic drugs relevant in the treatment of HCC for enhancement of the effect of irradiation in an in vitro model. As the majority of patients presenting with HCC suffer reduced liver function, attention was paid to low-dose effects of the cytotoxic drugs tested. To reflect this situation in vivo, multicellular tumor aggregates or 'spheroids' of HepG2 cells were cultured and exposed to gamma irradiation alone or in combination with cisplatin for 4 h, gemcitabin for 4 or 24 h, or 5-fluorouracil for 4 h. In one experiment, the spheroids were cultured for 4 weeks in multiwell plates that allowed adhesion. Measurement of two-dimensional spheroid outgrowth was made every week for each spheroid. This kind of growth depends on the proliferation and motility of the cells that form the spheroid. In a second experiment, toxicity was evaluated by comparative growth curves by means of a three-dimensional growth assay and by histology. Supra-additive effects lasting for 4 weeks were observed for all drugs tested in combination with a gamma irradiation of 10 Gy. (author)

  14. Information needs and preferences of low and high literacy consumers for decisions about colorectal cancer screening: utilizing a linguistic model

    Science.gov (United States)

    Smith, Sian K; Trevena, Lyndal; Nutbeam, Don; Barratt, Alexandra; McCaffery, Kirsten J

    2008-01-01

    Abstract Context  The use of written decision aids (DAs) in clinical practice has proliferated. However, few DAs have been developed for low literacy users, despite this group having low knowledge about healthcare and lacking involvement in health decisions. Objective  To explore the information needs and understanding of adults with varying literacy in relation to colorectal cancer screening, and to consider their responses to two versions of a decision aid. Participants  Thirty‐three men and women aged 45–74 years were recruited from Adult Basic Education classes (n = 17) and University Continuing Education programs (n = 16). Methods  We used qualitative methods (in‐depth, semi‐structured interviews) to compare and contrast the views of adults with lower and higher literacy levels, to gain a better understanding of how people with lower literacy value and interpret specific DA content and components; and determine whether needs and preferences are specific to lower literacy groups or generic across the broad literacy spectrum. Results  Regardless of literacy perspective, participants’ interpretations of the DA were shaped by their prior knowledge and expectations, as well as their values and preferences. This influenced perceptions of the DAs role in supporting informed decision making. A linguistic theoretical model was applied to interpret the findings. This facilitated considerations beyond the traditional focus on the readability of materials. Conclusion  Decision aids developers may find it useful to apply alternative approaches (linguistic) when creating DAs for consumers of varying literacy. PMID:18494957

  15. Response to an abnormal ovarian cancer-screening test result: test of the social cognitive processing and cognitive social health information processing models.

    Science.gov (United States)

    Andrykowski, Michael A; Pavlik, Edward J

    2011-04-01

    All cancer screening tests produce a proportion of abnormal results requiring follow up. Consequently, the cancer-screening setting is a natural laboratory for examining psychological and behavioural response to a threatening health-related event. This study tested hypotheses derived from the social cognitive processing and cognitive-social health information processing models in trying to understand response to an abnormal ovarian cancer (OC) screening test result. Women (n = 278) receiving an abnormal screening test result a mean of 7 weeks earlier were assessed prior to a repeat screening test intended to clarify their previous abnormal result. Measures of disposition (optimism, informational coping style), social environment (social support and constraint), emotional processing, distress, and benefit finding were obtained. Regression analyses indicated greater distress was associated with greater social constraint and emotional processing and a monitoring coping style in women with a family history of OC. Distress was unrelated to social support. Greater benefit finding was associated with both greater social constraint and support and greater distress. The primacy of social constraint in accounting for both benefit finding and distress was noteworthy and warrants further research on the role of social constraint in adaptation to stressful events.

  16. Quadruple screen test

    Science.gov (United States)

    Quad screen; Multiple marker screening; AFP plus; Triple screen test; AFP maternal; MSAFP; 4-marker screen; Down syndrome - quadruple; Trisomy 21 - quadruple; Turner syndrome - quadruple; Spina bifida - ...

  17. A genetic screen in zebrafish identifies the mutants vps18, nf2 and foie gras as models of liver disease.

    Science.gov (United States)

    Sadler, Kirsten C; Amsterdam, Adam; Soroka, Carol; Boyer, James; Hopkins, Nancy

    2005-08-01

    Hepatomegaly is a sign of many liver disorders. To identify zebrafish mutants to serve as models for hepatic pathologies, we screened for hepatomegaly at day 5 of embryogenesis in 297 zebrafish lines bearing mutations in genes that are essential for embryonic development. Seven mutants were identified, and three have phenotypes resembling different liver diseases. Mutation of the class C vacuolar protein sorting gene vps18 results in hepatomegaly associated with large, vesicle-filled hepatocytes, which we attribute to the failure of endosomal-lysosomal trafficking. Additionally, these mutants develop defects in the bile canaliculi and have marked biliary paucity, suggesting that vps18 also functions to traffic vesicles to the hepatocyte apical membrane and may play a role in the development of the intrahepatic biliary tree. Similar findings have been reported for individuals with arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, which is due to mutation of another class C vps gene. A second mutant, resulting from disruption of the tumor suppressor gene nf2, develops extrahepatic choledochal cysts in the common bile duct, suggesting that this gene regulates division of biliary cells during development and that nf2 may play a role in the hyperplastic tendencies observed in biliary cells in individuals with choledochal cysts. The third mutant is in the novel gene foie gras, which develops large, lipid-filled hepatocytes, resembling those in individuals with fatty liver disease. These mutants illustrate the utility of zebrafish as a model for studying liver development and disease, and provide valuable tools for investigating the molecular pathogenesis of congenital biliary disorders and fatty liver disease.

  18. Toxicology screen

    Science.gov (United States)

    Toxicology screening is most often done using a blood or urine sample. However, it may be done soon after the person swallowed the medication, using stomach contents taken through gastric lavage (stomach pumping) or after vomiting.

  19. Hypertension screening

    Science.gov (United States)

    Foulke, J. M.

    1975-01-01

    An attempt was made to measure the response to an announcement of hypertension screening at the Goddard Space Center, to compare the results to those of previous statistics. Education and patient awareness of the problem were stressed.

  20. Hypertension screening

    Science.gov (United States)

    Foulke, J. M.

    1975-01-01

    An attempt was made to measure the response to an announcement of hypertension screening at the Goddard Space Center, to compare the results to those of previous statistics. Education and patient awareness of the problem were stressed.

  1. Bottomonium suppression at sNN=2.76 TeV using a model based on color screening and gluonic dissociation with collisional damping

    Science.gov (United States)

    Ganesh, S.; Mishra, M.

    2013-10-01

    We present a model to explain the bottomonium suppression in Pb+Pb collisions at midrapidity obtained from Large Hadron Collider (LHC) energy, sNN=2.76 TeV. The model consists of two decoupled mechanisms, namely, color screening during bottomonium production followed by gluon induced dissociation along with collisional damping. The quasiparticle model (QPM) is used as equation of state (EOS) for the quark-gluon plasma (QGP) medium. The feed-down from higher Υ states, such as Υ(1P), Υ(2S), and Υ(2P), dilated formation times for bottomonium states, and viscous effect of the QGP medium are other ingredients included in the current formulation. We further assume that the QGP is expanding according to (1+1)-dimensional Bjorken's boost invariant scaling law. The net suppression (in terms of pT integrated survival probability) for bottomonium states at midrapidity is obtained as a function of centrality, and the result is then compared both quantitatively and qualitatively with the recent LHC experimental data in the midrapidity region recently published by the CMS Collaboration. We find that the current model, based on Debye color screening plus gluonic dissociation along with collisional damping, better describes the centrality dependence of bottomonium suppression at LHC energy as compared to the color screening model alone.

  2. HCC screening; HCC-Screening

    Energy Technology Data Exchange (ETDEWEB)

    Albrecht, T. [Charite-Unversitaetsmedizin,Freie Universitaet und Humboldt-Universitaet zu Berlin, Klinik und Hochschulambulanz fuer Radiologie und Nuklearmedizin,Campus Benjamin Franklin, Berlin (Germany)

    2008-01-15

    Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed tumour diseases throughout the world. In the vast majority of cases those affected are high-risk patients with chronic viral hepatitis and/or liver cirrhosis, which means there is a clearly identifiable target group for HCC screening. With resection, transplantation, and interventional procedures for local ablation, following early diagnosis curative treatment options are available with which 5-year survival rates of over 60% can be reached. Such early diagnosis is a reality only in a minority of patients, however, and in the majority of cases the disease is already in an advanced stage at diagnosis. One of the objects of HCC screening is diagnosis in an early stage when curative treatment is still possible. Precisely this is achieved by screening, so that the proportion of patients treated with curative intent is decisively higher. There is not yet any clear evidence as to whether this leads to a lowering of the mortality of HCC. As lower mortality is the decisive indicator of success for a screening programme the benefit of HCC screening has so far been neither documented nor refuted. Nonetheless, in large regions of the world it is the practice for high-risk patients to undergo HCC screening in the form of twice-yearly ultrasound examination and determination of AFP. (orig.) [German] Das hepatozellulaere Karzinom (HCC) ist eine der weltweit haeufigsten Tumorerkrankungen. Es tritt in der grossen Mehrzahl der Faelle bei Hochrisikopatienten mit chronischer Virushepatitis bzw. Leberzirrhose auf, woraus sich eine klar identifizierbare Zielgruppe fuer das HCC-Screening ergibt. Mit der Resektion, der Transplantation und interventionellen lokal ablativen Verfahren stehen bei rechtzeitiger Diagnosestellung kurative Therapieoptionen zur Verfuegung, die 5-Jahres-Ueberlebensraten von >60% erreichen. Diese rechtzeitige Diagnosestellung erfolgt jedoch nur bei einer Minderzahl der Patienten, waehrend die

  3. Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus

    Science.gov (United States)

    Bhaskar, Baki Vijaya; Babu, Tirumalasetty Muni Chandra; Reddy, Netala Vasudeva; Rajendra, Wudayagiri

    2016-01-01

    Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane α-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds. PMID:27757014

  4. Large-scale microfluidics providing high-resolution and high-throughput screening of Caenorhabditis elegans poly-glutamine aggregation model

    Science.gov (United States)

    Mondal, Sudip; Hegarty, Evan; Martin, Chris; Gökçe, Sertan Kutal; Ghorashian, Navid; Ben-Yakar, Adela

    2016-10-01

    Next generation drug screening could benefit greatly from in vivo studies, using small animal models such as Caenorhabditis elegans for hit identification and lead optimization. Current in vivo assays can operate either at low throughput with high resolution or with low resolution at high throughput. To enable both high-throughput and high-resolution imaging of C. elegans, we developed an automated microfluidic platform. This platform can image 15 z-stacks of ~4,000 C. elegans from 96 different populations using a large-scale chip with a micron resolution in 16 min. Using this platform, we screened ~100,000 animals of the poly-glutamine aggregation model on 25 chips. We tested the efficacy of ~1,000 FDA-approved drugs in improving the aggregation phenotype of the model and identified four confirmed hits. This robust platform now enables high-content screening of various C. elegans disease models at the speed and cost of in vitro cell-based assays.

  5. From Omics to Drug Metabolism and High Content Screen of Natural Product in Zebrafish: A New Model for Discovery of Neuroactive Compound

    Directory of Open Access Journals (Sweden)

    Ming Wai Hung

    2012-01-01

    Full Text Available The zebrafish (Danio rerio has recently become a common model in the fields of genetics, environmental science, toxicology, and especially drug screening. Zebrafish has emerged as a biomedically relevant model for in vivo high content drug screening and the simultaneous determination of multiple efficacy parameters, including behaviour, selectivity, and toxicity in the content of the whole organism. A zebrafish behavioural assay has been demonstrated as a novel, rapid, and high-throughput approach to the discovery of neuroactive, psychoactive, and memory-modulating compounds. Recent studies found a functional similarity of drug metabolism systems in zebrafish and mammals, providing a clue with why some compounds are active in zebrafish in vivo but not in vitro, as well as providing grounds for the rationales supporting the use of a zebrafish screen to identify prodrugs. Here, we discuss the advantages of the zebrafish model for evaluating drug metabolism and the mode of pharmacological action with the emerging omics approaches. Why this model is suitable for identifying lead compounds from natural products for therapy of disorders with multifactorial etiopathogenesis and imbalance of angiogenesis, such as Parkinson's disease, epilepsy, cardiotoxicity, cerebral hemorrhage, dyslipidemia, and hyperlipidemia, is addressed.

  6. In vitro neuropeptide Y mRNA expressing model for screening essences that may affect appetite using Rolf B1.T cells.

    Science.gov (United States)

    Chen, Shiau-Wei; Wu, Po-Ju; Chiang, Been-Huang

    2012-08-15

    Neuropeptide Y (NPY) is the most important appetite regulator. This study aimed to establish an in vitro NPY mRNA expression model for screening essences to determine if they are an appetite stimulator or inhibitor. We cultured the olfactory nerve cells Rolf B1.T for 2 days and then treated the cells with the known appetite inhibitor limonene and stimulator linalool. It was found that linalool could significantly stimulate NPY mRNA expression in 10 min, and limonene had the opposite effect. Similar results were also found in primary olfactory ensheathing cells isolated from rats. Further clinical trials using human subjects found that, when 10 min of treatment was applied, linalool indeed increased the serum NPY level in human peripheral blood. Limonene, on the other hand, decreased the serum NPY level. Thus, NPY mRNA expression in Rolf B1.T cells could be used as an in vitro model for screening essences that may affect appetite.

  7. Allergic sensitization: screening methods

    DEFF Research Database (Denmark)

    Ladics, Gregory S.; Fry, Jeremy; Goodman, Richard

    2014-01-01

    Experimental in silico, in vitro, and rodent models for screening and predicting protein sensitizing potential are discussed, including whether there is evidence of new sensitizations and allergies since the introduction of genetically modified crops in 1996, the importance of linear versus...... of infection; (f) role of the gut microbiota; (g) influence of the structure and physicochemical properties of the protein; and (h) the genetic background and physiology of consumers. The consensus view is that sensitization screening models are not yet validated to definitively predict the de novo sensitizing...

  8. A partnership model to improve population health screening for noncommunicable conditions and their common risk factors, Qazvin, Islamic Republic of Iran.

    Science.gov (United States)

    Alikhani, S; Damari, B

    2017-02-01

    Early findings and management of health conditions are among the key functions of health care systems. We developed a partnership framework to establish an extended primary health care-based selective screening service for the entire population of a small town as a key project of Qazvin Health Plan, Qazvin, Islamic Republic of Iran. Eight scientific associations and a diverse technical taskforce extensively reviewed evidence to adapt the grade A and B preventive recommendations of the American Preventive Service Taskforce. A list of 15 priority health conditions was identified and screening protocols were developed accordingly. Then strategies for working with private sector providers for better health care were applied to form our partnership model through which we ensured provision of screening services in 3 areas: service provision, quality and costs. Six private medical offices and a laboratory cooperated with the public health centre of the town to screen eligible residents. Preliminary analysis of the results suggests that the framework has successfully engaged private care providers.

  9. Development of a cell-based high-throughput peroxisome proliferator-activated receptors (PPARs) screening model and its application for evaluation of the extracts from Rhizoma Coptis.

    Science.gov (United States)

    Xia, Zhi-Ning; Lin, Ye-Xin; Guo, Li-Xia; Yang, Feng-Qing; Xu, Pan; Zhang, Yong-Lan; Liu, Jian-Hui

    2013-01-01

    To date, peroxisome proliferator-activated receptors (PPARs) are becoming the new therapeutic targets for the treatment of metabolic diseases, such as Type 2 diabetes, obesity, and cardiovascular disease. In this study, a cell-based high-throughput PPARs (PPARα/β/γ) model was developed for the screening of PPARs agonists. The screening conditions were evaluated through analyzing the expression value of luciferase. Finally, 24 h of drug acting time, 5 times of the dilution factor of luciferase zymolyte, and about 2 × 10(4) cells/ well on HeLa cells in 96-well plates were used, respectively. Furthermore, the quality of high-throughput screening (HTS) in stability and reliability was evaluated by the Z'-factor. Additionally, different extracts of Rhizoma Coptis and berberine were tested by the developed method. The results suggested that both the EtOAc extract and berberine were able to activate PPARα/β/γ, and Rhizoma Coptis contains potential natural agonists of PPARs besides berberine. In conclusion, the developed HTS assay is a simple, rapid, stable, and specific method for the screening of PPARs natural agonists.

  10. Magnetization of type-II superconductors in the form of short cylinders and the screening supercurrent distribution in the Bean model

    Science.gov (United States)

    Kuz'michev, N. D.; Fedchenko, A. A.

    2012-05-01

    The simplest analytical form of the screening supercurrent distribution is found, and the magnetization of type-II (hard) superconductors in the form of finite-length cylinders and disks (pellets) is calculated. Calculations are carried out in terms of the Bean model taking into account the curvature of magnetic field lines. From this distribution, the total magnetic field intensity and the magnetization hysteresis loop are calculated for such samples in different cases.

  11. Multiple receptor-ligand based pharmacophore modeling and molecular docking to screen the selective inhibitors of matrix metalloproteinase-9 from natural products

    Science.gov (United States)

    Gao, Qi; Wang, Yijun; Hou, Jiaying; Yao, Qizheng; Zhang, Ji

    2017-07-01

    Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP-001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC50 value was estimated to be only 13.4 µM, showing the strongly inhibitory activity of NP-000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future.

  12. Esophageal Cancer Screening

    Science.gov (United States)

    ... Esophageal Cancer Prevention Esophageal Cancer Screening Research Esophageal Cancer Screening (PDQ®)–Patient Version What is screening? Go to ... the esophagus and the stomach). Being overweight . Esophageal Cancer Screening Key Points Tests are used to screen for ...

  13. Use of risk projection models to estimate mortality and incidence from radiation-induced breast cancer in screening programs

    Energy Technology Data Exchange (ETDEWEB)

    Ramos, M [Chemical and Nuclear Engineering Department, Polytechnic University of Valencia, Camino de Vera s/n 46022 Valencia (Spain); Ferrer, S [Chemical and Nuclear Engineering Department, Polytechnic University of Valencia, Camino de Vera s/n 46022 Valencia (Spain); Villaescusa, J I [Radiation Protection Service, Hospital Universitario La Fe, Avda Campanar, 21 46009 Valencia (Spain); Verdu, G [Chemical and Nuclear Engineering Department, Polytechnic University of Valencia, Camino de Vera s/n 46022 Valencia (Spain); Salas, M D [Public Health General Direction, Conselleria de Sanitat de Valencia, C/Micer Masco, 31 46021 Valencia (Spain); Cuevas, M D [Assistential Service General Direction, Conselleria de Sanitat de Valencia, C/Micer Masco, 31 46021 Valencia (Spain)

    2005-02-07

    The authors report on a method to calculate radiological risks, applicable to breast screening programs and other controlled medical exposures to ionizing radiation. In particular, it has been applied to make a risk assessment in the Valencian Breast Cancer Early Detection Program (VBCEDP) in Spain. This method is based on a parametric approach, through Markov processes, of hazard functions for radio-induced breast cancer incidence and mortality, with mean glandular breast dose, attained age and age-at-exposure as covariates. Excess relative risk functions of breast cancer mortality have been obtained from two different case-control studies exposed to ionizing radiation, with different follow-up time: the Canadian Fluoroscopy Cohort Study (1950-1987) and the Life Span Study (1950-1985 and 1950-1990), whereas relative risk functions for incidence have been obtained from the Life Span Study (1958-1993), the Massachusetts tuberculosis cohorts (1926-1985 and 1970-1985), the New York post-partum mastitis patients (1930-1981) and the Swedish benign breast disease cohort (1958-1987). Relative risks from these cohorts have been transported to the target population undergoing screening in the Valencian Community, a region in Spain with about four and a half million inhabitants. The SCREENRISK software has been developed to estimate radiological detriments in breast screening. Some hypotheses corresponding to different screening conditions have been considered in order to estimate the total risk associated with a woman who takes part in all screening rounds. In the case of the VBCEDP, the total radio-induced risk probability for fatal breast cancer is in a range between [5 x 10{sup -6}, 6 x 10{sup -4}] versus the natural rate of dying from breast cancer in the Valencian Community which is 9.2 x 10{sup -3}. The results show that these indicators could be included in quality control tests and could be adequate for making comparisons between several screening programs.

  14. SCREEN CUISINE

    National Research Council Canada - National Science Library

    Heather Baysa

    2010-01-01

    ... from the legendary restaurant; the World's First FoodTruck Drive-In Movie on Saturday, where the city's finest food-truck vendors park for the screenings; and the Brooklyn Burger W Beer Garden on Sunday, serving up hearty burgers and brews while you watch Anat Baron's Beer Wars. Tonight at 7, Water Taxi Beach, South Street Seaport.fest...

  15. Airport Screening

    Science.gov (United States)

    ... must be limited to a safe level. An American National Standards Institute/Health Physics Society industry standard states that the maxi- mum ... that does not directly damage DNA. 2 References American National ... Physics Society. Radiation safety for personnel security screening systems ...

  16. Computational Analysis and In silico Predictive Modeling for Inhibitors of PhoP Regulon in S. typhi on High-Throughput Screening Bioassay Dataset.

    Science.gov (United States)

    Kaur, Harleen; Ahmad, Mohd; Scaria, Vinod

    2016-03-01

    There is emergence of multidrug-resistant Salmonella enterica serotype typhi in pandemic proportions throughout the world, and therefore, there is a necessity to speed up the discovery of novel molecules having different modes of action and also less influenced by the resistance formation that would be used as drug for the treatment of salmonellosis particularly typhoid fever. The PhoP regulon is well studied and has now been shown to be a critical regulator of number of gene expressions which are required for intracellular survival of S. enterica and pathophysiology of disease like typhoid. The evident roles of two-component PhoP-/PhoQ-regulated products in salmonella virulence have motivated attempts to target them therapeutically. Although the discovery process of biologically active compounds for the treatment of typhoid relies on hit-finding procedure, using high-throughput screening technology alone is very expensive, as well as time consuming when performed on large scales. With the recent advancement in combinatorial chemistry and contemporary technique for compounds synthesis, there are more and more compounds available which give ample growth of diverse compound library, but the time and endeavor required to screen these unfocused massive and diverse library have been slightly reduced in the past years. Hence, there is demand to improve the high-quality hits and success rate for high-throughput screening that required focused and biased compound library toward the particular target. Therefore, we still need an advantageous and expedient method to prioritize the molecules that will be utilized for biological screens, which saves time and is also inexpensive. In this concept, in silico methods like machine learning are widely applicable technique used to build computational model for high-throughput virtual screens to prioritize molecules for advance study. Furthermore, in computational analysis, we extended our study to identify the common enriched

  17. In silico Screening and Evaluation of the Anticonvulsant Activity of Docosahexaenoic Acid-Like Molecules in Experimental Models of Seizures.

    Science.gov (United States)

    Gharibi Loron, Ali; Sardari, Soroush; Narenjkar, Jamshid; Sayyah, Mohammad

    2017-01-01

    Resistance to antiepileptic drugs and the intolerability in 20-30% of the patients raises demand for developing new drugs with improved efficacy and safety. Acceptable anticonvulsant activity, good tolerability, and inexpensiveness of docosahexaenoic acid (DHA) make it as a good candidate for designing and development of the new anticonvulsant medications. Ten DHA-based molecules were screened based on in silico screening of DHA-like molecules by root-mean-square deviation of atomic positions, the biological activity score of Professional Association for SQL Server, and structural requirements suggested by pharmacophore design. Anticonvulsant activity was tested against clonic seizures induced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) and tonic seizures induced by maximal electroshock (MES, 50 mA, 50 Hz, 1 ms duration) by intracerebroventricular (i.c.v.) injection of the screened compounds to mice. Among screened compounds, 4-Phenylbutyric acid, 4-Biphenylacetic acid, phenylacetic acid, and 2-Phenylbutyric acid showed significant protective activity in pentylenetetrazole test with ED50 values of 4, 5, 78, and 70 mM, respectively. In MES test, shikimic acid and 4-tert-Butylcyclo-hexanecarboxylic acid showed significant activity with ED50 values 29 and 637 mM, respectively. Effective compounds had no mortality in mice up to the maximum i.c.v. injectable dose of 1 mM. Common electrochemical features and three-dimensional spatial structures of the effective compounds suggest the involvement of the anticonvulsant mechanisms similar to the parent compound DHA.

  18. Establishment of the model of white blood cell membrane chromatography and screening of antagonizing TLR4 receptor component from Atractylodes macrocephala Koidz

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    A model of white blood cell membrane chromatography (WB-CMC) was established to screen active component from Atractylodes macrocephala Koidz. The component can antagonize Toll-like receptor 4 (TLR4) and inhibit inflammatory reaction. In the model of WB-CMC, cell membrane stationary phase (CMSP) was prepared by immobilizing the rabbit white blood cell membrane (WBCM) onto the surface of silica carrier and taxinol was used as a model molecule. The active component which can act on WBCM and its receptor (such as TLR4) as an effective target in A. macrocephala was determined by using a replacement experiment. The anti-inflammatory effects of the active component were tested by using pharmacological methods in vivo. The results indicated that the retention characteristics of atractylenolide I as active component was similar to that of taxinol in the model of WB-CMC. And so, atractylenolide I acted on the WBCM and TLR4 and its anti-inflammatory activity was related with antagonizing TLR4. Therefore, the interaction between the active component and WBCM and its receptor can be simulated by the model of WB-CMC in vitro. This model can be used to screen active components and to study effective characteristics for acting on definite targets.

  19. Screening of different stress factors and development of growth/no growth models for Zygosaccharomyces rouxii in modified Sabouraud medium, mimicking intermediate moisture foods (IMF).

    Science.gov (United States)

    Vermeulen, A; Daelman, J; Van Steenkiste, J; Devlieghere, F

    2012-12-01

    The microbial stability of intermediate moisture foods (IMF) is linked with the possible growth of osmophilic yeast and xerophilic moulds. As most of these products have a long shelf life the assessment of the microbial stability is often an important hurdle in product innovation. In this study a screening of several Zygosaccharomyces rouxii strains towards individual stress factors was performed and growth/no growth models were developed, incorporating a(w), pH, acetic acid and ethanol concentrations. These stress factors are important for sweet IMF such as chocolate fillings, ganache, marzipan, etc. A comparison was made between a logistic regression model with and without the incorporation of time as an explanatory variable. Next to the model development, a screening of the effect of chemical preservatives (sorbate and benzoate) was performed, in combination with relevant stress factors within the experimental design of the model. The results of the study showed that the influence of the investigated environmental stress factors on the growth/no growth boundary of Z. rouxii is the most significant in the first 30-40 days of incubation. Incorporating time as an explanatory variable in the model had the advantage that the growth/no growth boundary could be predicted at each time between 0 and 60 days of incubation at 22 °C. However, the growth/no growth boundary enlarged significantly leading to a less accurate prediction on the growth probability of Z. rouxii. The developed models can be a useful tool for product developers of sweet IMF. Screening with chemical preservatives revealed that benzoic acid was much less active towards Z. rouxii than sorbic acid or a mixture of both acids. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Optimal screening for genetic diseases.

    Science.gov (United States)

    Nævdal, Eric

    2014-12-01

    Screening for genetic diseases is performed in many regions and/or ethnic groups where there is a high prevalence of possibly malign genes. The propagation of such genes can be considered a dynamic externality. Given that many of these diseases are untreatable and give rise to truly tragic outcomes, they are a source of societal concern, and the screening process should perhaps be regulated. This paper incorporates a standard model of genetic propagation into an economic model of dynamic management to derive cost benefit rules for optimal screening. The highly non-linear nature of genetic dynamics gives rise to perhaps surprising results that include discontinuous controls and threshold effects. One insight is that any screening program that is in place for any amount of time should screen all individuals in a target population. The incorporation of genetic models may prove to be useful to several emerging fields in economics such as genoeconomics, neuroeconomics and paleoeconomics.

  1. Developing and validating predictive decision tree models from mining chemical structural fingerprints and high–throughput screening data in PubChem

    Directory of Open Access Journals (Sweden)

    Bryant Stephen H

    2008-09-01

    Full Text Available Abstract Background Recent advances in high-throughput screening (HTS techniques and readily available compound libraries generated using combinatorial chemistry or derived from natural products enable the testing of millions of compounds in a matter of days. Due to the amount of information produced by HTS assays, it is a very challenging task to mine the HTS data for potential interest in drug development research. Computational approaches for the analysis of HTS results face great challenges due to the large quantity of information and significant amounts of erroneous data produced. Results In this study, Decision Trees (DT based models were developed to discriminate compound bioactivities by using their chemical structure fingerprints provided in the PubChem system http://pubchem.ncbi.nlm.nih.gov. The DT models were examined for filtering biological activity data contained in four assays deposited in the PubChem Bioassay Database including assays tested for 5HT1a agonists, antagonists, and HIV-1 RT-RNase H inhibitors. The 10-fold Cross Validation (CV sensitivity, specificity and Matthews Correlation Coefficient (MCC for the models are 57.2~80.5%, 97.3~99.0%, 0.4~0.5 respectively. A further evaluation was also performed for DT models built for two independent bioassays, where inhibitors for the same HIV RNase target were screened using different compound libraries, this experiment yields enrichment factor of 4.4 and 9.7. Conclusion Our results suggest that the designed DT models can be used as a virtual screening technique as well as a complement to traditional approaches for hits selection.

  2. A model of integrated lung and focused heart ultrasound as a new screening examination in infants at risk of respiratory or hemodynamic compromise

    Directory of Open Access Journals (Sweden)

    Yasser Elsayed

    2017-02-01

    Full Text Available Objective: This was a feasibility study to determine whether an edu­cational program conducted over 2 days followed by 25 performed studies under supervision equips physicians with the skills to accurately interpret and perform integrated lung ultrasound (LUS and focused heart ultrasound (FHUS as a screening exam in infants at risk of respiratory or hemodynamic compromise.Methods: We conducted a training course over 2 days (total of 16 hours to teach fellows how to interpret a pre-designed model of LUS and FHUS, as a screening exam for infants at risk of respiratory or hemodynamic compromise. Then trainees performed 25 cases with different neonatal lung and functional heart issues. The screening model included only the basic views required to evaluate common lung parenchymal and functional neonatal heart conditions in sick infants. The accuracy of interpretation during the course was assessed by Kappa.Results: The inter-rater agreement between all trainees and instructor improved on the second day of the course to Kappa 0.86 (95% CI: 0.72-0.97 for LUS views and 0.78 (95% CI: 0.69-0.91 for FHUS views. The inter-rater agreement between trainees themselves improved from Kappa 0.64 (95% CI: 0.47-0.81 for LUS on day one to 0.89 (95% CI: 0.81-0.96 on day two. And from 0.58 (95% CI: 0.44-0.73 on day one to 0.75 (95% CI: 0.68-0.84 on day two.Conclusion: Bedside screening, using integrated LUS and FHUS can be a useful adjunct to clinical examination in infants at risk of respiratory or hemodynamic compromise.

  3. Development of a model to assess the cost-effectiveness of gestational diabetes mellitus screening and lifestyle change for the prevention of type 2 diabetes mellitus.

    Science.gov (United States)

    Lohse, Nicolai; Marseille, Elliot; Kahn, James G

    2011-11-01

    Gestational diabetes mellitus (GDM) is increasingly recognized as an opportunity for early prevention of diabetes and other diseases over the lifespan, and may be responsible for up to 30% of cases of type 2 diabetes. A newly developed mathematical model (the GDModel) provides provisional estimates of the cost and health impact of various GDM screening and management choices, and calculates averted disability-adjusted life-years (DALYs). The model was piloted in 5 different healthcare facilities in India and Israel. Universal screening of pregnant women followed by postpartum lifestyle management yielded net savings of US$78 per woman with GDM in India and US$1945 per woman in Israel. The estimated DALYs averted were 2.33 in India and 3.10 in Israel. With lower GDM prevalence, intervention efficacy, and type 2 diabetes incidence, the intervention had a net cost in India, with a cost per DALY averted of US$11.32. This was far below the WHO definition of "very cost-effective," set at annual GDP per capita. The intervention in Israel remained cost-saving. GDM screening and postpartum lifestyle management are either cost-saving or have a net cost but an attractive cost-effectiveness ratio. Some input values are currently being refined. Nevertheless, the current findings of cost-savings or favorable cost-effectiveness are robust to a wide range of plausible input values, including highly unfavorable values. The GDModel will be further developed into a user-friendly tool that can guide policy-makers on decisions regarding GDM screening strategies and guidelines.

  4. Constructing and Validating High-Performance MIEC-SVM Models in Virtual Screening for Kinases: A Better Way for Actives Discovery.

    Science.gov (United States)

    Sun, Huiyong; Pan, Peichen; Tian, Sheng; Xu, Lei; Kong, Xiaotian; Li, Youyong; Dan Li; Hou, Tingjun

    2016-04-22

    The MIEC-SVM approach, which combines molecular interaction energy components (MIEC) derived from free energy decomposition and support vector machine (SVM), has been found effective in capturing the energetic patterns of protein-peptide recognition. However, the performance of this approach in identifying small molecule inhibitors of drug targets has not been well assessed and validated by experiments. Thereafter, by combining different model construction protocols, the issues related to developing best MIEC-SVM models were firstly discussed upon three kinase targets (ABL, ALK, and BRAF). As for the investigated targets, the optimized MIEC-SVM models performed much better than the models based on the default SVM parameters and Autodock for the tested datasets. Then, the proposed strategy was utilized to screen the Specs database for discovering potential inhibitors of the ALK kinase. The experimental results showed that the optimized MIEC-SVM model, which identified 7 actives with IC50 < 10 μM from 50 purchased compounds (namely hit rate of 14%, and 4 in nM level) and performed much better than Autodock (3 actives with IC50 < 10 μM from 50 purchased compounds, namely hit rate of 6%, and 2 in nM level), suggesting that the proposed strategy is a powerful tool in structure-based virtual screening.

  5. Sheet beam model for intense space-charge: with application to Debye screening and the distribution of particle oscillation frequencies in a thermal equilibrium beam

    Energy Technology Data Exchange (ETDEWEB)

    Lund, Steven M.; Friedman, Alex; Bazouin, Guillaume

    2011-01-10

    A one-dimensional Vlasov-Poisson model for sheet beams is reviewed and extended to provide a simple framework for analysis of space-charge effects. Centroid and rms envelope equations including image charge effects are derived and reasonable parameter equivalences with commonly employed 2D transverse models of unbunched beams are established. This sheet beam model is then applied to analyze several problems of fundamental interest. A sheet beam thermal equilibrium distribution in a continuous focusing channel is constructed and shown to have analogous properties to two- d three-dimensional thermal equilibrium models in terms of the equilibrium structure and Deybe screening properties. The simpler formulation for sheet beams is exploited to explicitly calculate the distribution of particle oscillation frequencies within a thermal equilibrium beam. It is shown that as space-charge intensity increases, the frequency distribution becomes broad, suggesting that beams with strong space-charge can have improved stability.

  6. A translation inhibitor identified in a Drosophila screen enhances the effect of ionizing radiation and taxol in mammalian models of cancer

    Directory of Open Access Journals (Sweden)

    Mara Gladstone

    2012-05-01

    We described previously a screening protocol in Drosophila melanogaster that allows us to identify small molecules that increase the killing effect of ionizing radiation in vivo in a multicellular context. The ability of this screen to identify agents that enhance the effect of radiation in human cancer models has been validated in published proof-of-concept studies. Here we describe an agent, identified by screening through two National Cancer Institute (NCI small molecule libraries in Drosophila, that increases the effect of radiation. This agent, Bouvardin (NSC 259968, inhibits the elongation step of protein synthesis. We find that Bouvardin enhances the killing effect of X-rays in both Drosophila larvae and in human cancer cells. More detailed analysis showed that Bouvardin also increases the effect of radiation in clonogenic assays and in human cancer xenografts in mice. Finally, we present data that Bouvardin can also increase the efficacy of taxol. Regulation of translation is important to cancer biology. Current therapies target every aspect of cancer cell proliferation from growth factor signaling to cell division, with the exception of translation elongation. Our identification of Bouvardin as an enhancer of radio- and chemo-therapeutic agents suggests that targeting this niche has the potential to improve existing cancer therapies.

  7. Adulteration screening of botanical materials by a sensitive and model-free approach using infrared spectroscopic imaging and two-dimensional correlation infrared spectroscopy

    Science.gov (United States)

    Chen, Jian-bo; Zhou, Qun; Sun, Su-qin

    2016-11-01

    Infrared (IR) spectroscopy is often used as a simple, fast, and green method for the adulteration screening of botanical materials for foods and herbs. However, the overlapping of absorption signals of various substances significantly decrease the sensitivity and specificity of IR spectroscopy in the detection of adulterated samples. In this research, a model-free approach is proposed for the sensitive and non-targeted screening of botanical materials adulterated by adding other plant materials. First, the spectra of the entities in the test sample are collected by near-infrared spectroscopic imaging and clustered by unsupervised pattern recognition methods. The sample may be adulterated if there are two or more clusters of the entities. Next, the entities of different clusters are characterized by mid-infrared spectroscopy to interpret the chemical compositions to determine the clustering is caused whether by adulteration or other reasons. Second derivative spectroscopy and two-dimensional correlation spectroscopy are often needed to resolve the overlapped bands mathematically or experimentally to find the characteristic signals to identify the authentic and adulterant entities. The feasibility of this approach was proved by the simulated adulterated sample of saffron. In conclusion, botanical materials adulterated by adding other plant materials can be detected by a simple, fast, sensitive, and green screening approach using IR spectroscopic imaging, two-dimensional correlation spectroscopy, and necessary chemometrics techniques.

  8. Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening

    Directory of Open Access Journals (Sweden)

    Yuthavong Yongyuth

    2011-10-01

    Full Text Available Abstract Background Plasmodium vivax is the most prevalent cause of human malaria in tropical regions outside the African continent. The lack of a routine continuous in vitro culture of this parasite makes it difficult to develop specific drugs for this disease. To facilitate the development of anti-P. vivax drugs, bacterial and yeast surrogate models expressing the validated P. vivax target dihydrofolate reductase-thymidylate synthase (DHFR-TS have been generated; however, they can only be used as primary screening models because of significant differences in enzyme expression level and in vivo drug metabolism between the surrogate models and P. vivax parasites. Methods Plasmodium falciparum and Plasmodium berghei parasites were transfected with DNA constructs bearing P. vivax dhfr-ts pyrimethamine sensitive (wild-type and pyrimethamine resistant (mutant alleles. Double crossover homologous recombination was used to replace the endogenous dhfr-ts of P. falciparum and P. berghei parasites with P. vivax homologous genes. The integration of Pvdhfr-ts genes via allelic replacement was verified by Southern analysis and the transgenic parasites lines validated as models by standard drug screening assays. Results Transgenic P. falciparum and P. berghei lines stably expressing PvDHFR-TS replacing the endogenous parasite DHFR-TS were obtained. Anti-malarial drug screening assays showed that transgenic parasites expressing wild-type PvDHFR-TS were pyrimethamine-sensitive, whereas transgenic parasites expressing mutant PvDHFR-TS were pyrimethamine-resistant. The growth and sensitivity to other types of anti-malarial drugs in the transgenic parasites were otherwise indistinguishable from the parental parasites. Conclusion With the permanent integration of Pvdhfr-ts gene in the genome, the transgenic Plasmodium lines expressing PvDHFR-TS are genetically stable and will be useful for screening anti-P. vivax compounds targeting PvDHFR-TS. A similar approach

  9. Editor's Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis.

    Science.gov (United States)

    Foley, Briana; Doheny, Daniel L; Black, Michael B; Pendse, Salil N; Wetmore, Barbara A; Clewell, Rebecca A; Andersen, Melvin E; Deisenroth, Chad

    2017-01-01

    The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue express endogenous isoforms of PPARG and represent a biologically relevant cell-type for evaluating activity of PPARG ligands. Here, a multi-endpoint approach based on a phenotypic adipogenesis assay was applied to screen a set of 60 chemical compounds identified in ToxCast Phase I as PPARG active (49) or inactive (11). Chemicals showing activity in the adipogenesis screen were further evaluated in a series of 4 orthogonal assays representing 7 different key events in PPARG-dependent adipogenesis, including gene transcription, protein expression, and adipokine secretion. An siRNA screen was also used to evaluate PPARG-dependence of the adipogenesis phenotype. A universal concentration-response design enabled inter-assay comparability and implementation of a weight-of-evidence approach for bioactivity classification. Collectively, a total of 14/49 (29%) prioritized chemicals were identified with moderate-to-strong activity for human adipogenesis. These results provide the first integrated screening approach of prioritized ToxCast chemicals in a human stem cell model of adipogenesis and provide insight into the capacity of PPARG-activating chemicals to modulate early life programming of adipose tissue.

  10. Editor’s Highlight: Screening ToxCast Prioritized Chemicals for PPARG Function in a Human Adipose-Derived Stem Cell Model of Adipogenesis

    Science.gov (United States)

    Foley, Briana; Doheny, Daniel L.; Black, Michael B.; Pendse, Salil N.; Wetmore, Barbara A.; Clewell, Rebecca A.; Andersen, Melvin E.; Deisenroth, Chad

    2017-01-01

    The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue express endogenous isoforms of PPARG and represent a biologically relevant cell-type for evaluating activity of PPARG ligands. Here, a multi-endpoint approach based on a phenotypic adipogenesis assay was applied to screen a set of 60 chemical compounds identified in ToxCast Phase I as PPARG active (49) or inactive (11). Chemicals showing activity in the adipogenesis screen were further evaluated in a series of 4 orthogonal assays representing 7 different key events in PPARG-dependent adipogenesis, including gene transcription, protein expression, and adipokine secretion. An siRNA screen was also used to evaluate PPARG-dependence of the adipogenesis phenotype. A universal concentration-response design enabled inter-assay comparability and implementation of a weight-of-evidence approach for bioactivity classification. Collectively, a total of 14/49 (29%) prioritized chemicals were identified with moderate-to-strong activity for human adipogenesis. These results provide the first integrated screening approach of prioritized ToxCast chemicals in a human stem cell model of adipogenesis and provide insight into the capacity of PPARG-activating chemicals to modulate early life programming of adipose tissue. PMID:27664422

  11. Breast cancer screening

    Science.gov (United States)

    Mammogram - breast cancer screening; Breast exam - breast cancer screening; MRI - breast cancer screening ... performed to screen women to detect early breast cancer when it is more likely to be cured. ...

  12. 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.

  13. 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.

  14. Integration of genetic virtual screening patterns and latent multivariate modeling techniques for QSAR optimization based on combinations and/or interactions between peptides and proteins

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Both the concept and the model of snug quantitative structure-activity relationship (QSAR) were pro-posed and developed for molecular design through constructing QSAR based on some known mode of receptor/ligand interactions. Many disadvantages of traditional models can be avoided by using the proposed method because the traditional models only determined upon molecular structural features in sample sets themselves. A genetic virtual screening of peptide/protein combinations (GVSPPC) is proposed for the first time by utilizing this idea to examine peptide/protein affinity activities. A genetic algorithm (GA) was developed for screening combinative targets with an interaction mode for virtual receptors. GVSPPC succeeds in disposing difficulties in rational QSAR,in order to search for the ligand/receptor interactions on conditions of unknown structures. Some bioactive oligo-/poly-peptide systems covering 58 angiotensin converting enzyme (ACE) inhibitors and 18 double site mutation residues in camel antibody protein cAb-Lys3 were investigated by GVSPPC with satisfactory results (R 2 cu>0.91,Q 2 cv > 0.86,ERMS=0.19-0.95),respectively,which demonstrates that GVSPPC is more inter-pretable in the ligand-receptor interaction than the traditional QSAR method.

  15. Integration of genetic virtual screening patterns and latent multivariate modeling techniques for QSAR optimization based on combinations and/or interactions between peptides and proteins

    Institute of Scientific and Technical Information of China (English)

    LI ZhiLiang; CHEN Gang; LI GenRong; TIAN FeiFei; WU ShiRong; YANG ShanBin; YANG ShengXi; ZHOU Yuan; ZHANG QiaoXia; QIN RenHui; MEI Hu

    2008-01-01

    Both the concept and the model of snug quantitative structure-activity relationship (QSAR) were pro-posed and developed for molecular design through constructing QSAR based on some known mode of receptor/ligand interactions. Many disadvantages of traditional models can be avoided by using the proposed method because the traditional models only determined upon molecular structural features in sample sets themselves. A genetic virtual screening of peptide/protein combinations (GVSPPC) is proposed for the first time by utilizing this idea to examine peptide/protein affinity activities. A genetic algorithm (GA) was developed for screening combinative targets with an interaction mode for virtual receptors. GVSPPC succeeds in disposing difficulties in rational QSAR, in order to search for the ligand/receptor interactions on conditions of unknown structures. Some bioactive oligo-/poly-peptide systems covering 58 angiotensin converting enzyme (ACE) inhibitors and 18 double site mutation residues in camel antibody protein cAb-Lys3 were investigated by GVSPPC with satisfactory results (Rcu2 > 0.91, Qcv2 0.86, ERMS = 0.19-0.95), respectively, which demonstrates that GVSPPC is more inter-pretable in the ligand-receptor interaction than the traditional QSAR method.

  16. Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues.

    Science.gov (United States)

    Gogoi, Dhrubajyoti; Chaliha, Amrita Kashyap; Sarma, Diganta; Kakoti, Bibhuti Bhusan; Buragohain, Alak Kumar

    2017-01-01

    Ligand and structure-based pharmacophore models were used to identify the important chemical features of butyrylcholinesterase (BChE) inhibitors. A training set of 16 known structurally diverse compounds with a wide range of inhibitory activity against BChE was used to develop a quantitative ligand-based pharmacophore (Hypo1) model to identify novel BChE inhibitors in virtual screening databases. A structure-based pharmacophore hypothesis (Phar1) was also developed with the ligand-binding site of BChE in consideration. Further, the models were validated using test set, Fisher's Randomization and Leave-one-out validation methods. Well-validated pharmacophore hypotheses were further used as 3D queries in virtual screening and 430 compounds were finally selected for molecular docking analysis. Subsequently, ADMET, DFT and chemical similarity search were employed to narrow down on seven compounds as potential drug candidates. Analogues of the best hit were further developed through a bioisosterism-guided approach to further generate a library of potential BChE inhibitors.

  17. Investigating ER-Associated Degradation with RNAi Screening - and Searching for Model Proteins to Do It with

    DEFF Research Database (Denmark)

    Jensen, Njal Winther

    is a sophisticated pathway that recognizes misfolded proteins and targets them for degradation by the 26S proteasome residing in the cytosol. More than 60 diseases including Alzheimer’s disease, Huntington’s disease and Parkinson’s disease have been linked to the ERAD pathway underscoring its crucial role...... for cellular homeostasis. The aim of this thesis has been to gain insight into ERAD. The experimental approach was RNAi screening, which is a fast and efficient method for initial evaluation of a large pool of genes. Since relatively few proteins routinely are used as ERAD substrates, the first goal...

  18. Dynamics Behavior Research on Variable Linear Vibration Screen with Flexible Screen Face

    OpenAIRE

    Changlong Du; Kuidong Gao; Jianping Li; Hao Jiang

    2014-01-01

    In order to enable the variable linear vibration screen with ideal movement behavior of screen surface and efficient screening capacity, five-freedom dynamic model and stability equations of the variable linear vibration screen were established based on power balance method and Hamilton principle. The motion behaviour of screen face was investigated, and − 0.10 m ≤ xf ≤ − 0.04 m was confirmed as the best range of exciting position. With analysis of stability equations, the stable requirement ...

  19. Predictive Accuracy of the PanCan Lung Cancer Risk Prediction Model -External Validation based on CT from the Danish Lung Cancer Screening Trial

    DEFF Research Database (Denmark)

    Winkler Wille, Mathilde M.; van Riel, Sarah J.; Saghir, Zaigham

    2015-01-01

    ; in fact opposing effects of sex were observed in the two cohorts. Thus, female sex appeared to lower the risk (p = 0.047 and p = 0.040) in the DLCST. Conclusions: High risk discrimination was validated in the DLCST cohort, mainly determined by nodule size. Age and family history of lung cancer were......Objectives: Lung cancer risk models should be externally validated to test generalizability and clinical usefulness. The Danish Lung Cancer Screening Trial (DLCST) is a population-based prospective cohort study, used to assess the discriminative performances of the PanCan models. Methods: From...... used to evaluate risk discrimination. Results: AUCs of 0.826–0.870 were found for DLCST data based on PanCan risk prediction models. In the DLCST, age and family history were significant predictors (p = 0.001 and p = 0.013). Female sex was not confirmed to be associated with higher risk of lung cancer...

  20. In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening.

    Science.gov (United States)

    Chaudhari, Prashant; Bari, Sanjay

    2016-02-01

    c-KIT is a component of the platelet-derived growth factor receptor family, classified as type-III receptor tyrosine kinase. c-KIT has been reported to be involved in, small cell lung cancer, other malignant human cancers, and inflammatory and autoimmune diseases associated with mast cells. Available c-KIT inhibitors suffer from tribulations of growing resistance or cardiac toxicity. A combined in silico pharmacophore and structure-based virtual screening was performed to identify novel potential c-KIT inhibitors. In the present study, five molecules from the ZINC database were retrieved as new potential c-KIT inhibitors, using Schrödinger's Maestro 9.0 molecular modeling suite. An atom-featured 3D QSAR model was built using previously reported c-KIT inhibitors containing the indolin-2-one scaffold. The developed 3D QSAR model ADHRR.24 was found to be significant (R2 = 0.9378, Q2 = 0.7832) and instituted to be sufficiently robust with good predictive accuracy, as confirmed through external validation approaches, Y-randomization and GH approach [GH score 0.84 and Enrichment factor (E) 4.964]. The present QSAR model was further validated for the OECD principle 3, in that the applicability domain was calculated using a "standardization approach." Molecular docking of the QSAR dataset molecules and final ZINC hits were performed on the c-KIT receptor (PDB ID: 3G0E). Docking interactions were in agreement with the developed 3D QSAR model. Model ADHRR.24 was explored for ligand-based virtual screening followed by in silico ADME prediction studies. Five molecules from the ZINC database were obtained as potential c-KIT inhibitors with high in -silico predicted activity and strong key binding interactions with the c-KIT receptor.

  1. Application of zebrafish models in drug screening%斑马鱼模型在药物筛选中的应用

    Institute of Scientific and Technical Information of China (English)

    辛胜昌; 赵艳秋; 李松; 林硕; 仲寒冰

    2012-01-01

    斑马鱼具有子代数量多、体外受精、胚胎透明、可以做大规模遗传突变筛选等生物学特性,因此成为一种良好的脊椎动物模式生物.随着研究的深入,斑马鱼不仅应用于遗传学和发育生物学研究,而且拓展和延伸到疾病模型和药物筛选领域.作为一种整体动物模型,斑马鱼能够全面地检测评估化合物的活性和副作用,实现高内涵筛选.近年来,科学家们不断地发展出新的斑马鱼疾病模型和新的筛选技术,并找到了一批活性化合物.这些化合物大多数在哺乳动物模型中也有相似的效果,其中前列腺素E2(dmPGE2)和来氟米特(Leflunomide)已经进入临床实验,分别用来促进脐带血细胞移植后的增殖和治疗黑素瘤.这些成果显示了斑马鱼模型很适合用于药物筛选.文章概括介绍了斑马鱼模型的特点和近年来在疾病模型和药物筛选方面的进展,希望能够帮助人们了解斑马鱼在新药研发中的应用,并开展基于斑马鱼模型的药物筛选.%Due to its small size, fast external development, transparent embryos, and amenability to genetic analysis, zebrafish has become an ideal vertebrate animal model. In addition to studies in genetics and developmental biology, zebrafish has also been widely used in human disease modeling and drug screening. As a small whole-organism model, zebrafish can be used to comprehensively test and evaluate the activity and side effect of a compound at the same time, fulfilling high content screening. Recently, new zebrafish disease models and screening technologies have been developed. A number of active compounds were identified and most of them have similar functions in mammal models. One compound prostaglandin E2 has been subjected to clinical trial to test if it can promote the growth of umbilical cord blood units after transplantation. Another compound leflunomide has also been approved in clinical trial to cure melanoma in combination

  2. Dynamics Behavior Research on Variable Linear Vibration Screen with Flexible Screen Face

    Directory of Open Access Journals (Sweden)

    Changlong Du

    2014-08-01

    Full Text Available In order to enable the variable linear vibration screen with ideal movement behavior of screen surface and efficient screening capacity, five-freedom dynamic model and stability equations of the variable linear vibration screen were established based on power balance method and Hamilton principle. The motion behaviour of screen face was investigated, and − 0.10 m ≤ xf ≤ − 0.04 m was confirmed as the best range of exciting position. With analysis of stability equations, the stable requirement of vibration screen was obtained: the direction angle of exciting force should be 0 ≤ θ ≤ 45°. Screening processes of variable linear vibration screen with flexible screen face, variable linear vibration screen with fixed screen face and linear vibration screen were investigated and compared by numerical simulation method, the results show that variable linear vibration screen with flexible screen face have such characteristics as higher intensity of projection and efficient screening. The correctness of theoretical research and simulation research were verified through experiment, and all of the work would provide some guidance for designing and studying variable linear vibration screen with flexible screen face.

  3. Differentiation of AmpC beta-lactamase binders vs. decoys using classification kNN QSAR modeling and application of the QSAR classifier to virtual screening

    Science.gov (United States)

    Hsieh, Jui-Hua; Wang, Xiang S.; Teotico, Denise; Golbraikh, Alexander; Tropsha, Alexander

    2008-09-01

    The use of inaccurate scoring functions in docking algorithms may result in the selection of compounds with high predicted binding affinity that nevertheless are known experimentally not to bind to the target receptor. Such falsely predicted binders have been termed `binding decoys'. We posed a question as to whether true binders and decoys could be distinguished based only on their structural chemical descriptors using approaches commonly used in ligand based drug design. We have applied the k-Nearest Neighbor ( kNN) classification QSAR approach to a dataset of compounds characterized as binders or binding decoys of AmpC beta-lactamase. Models were subjected to rigorous internal and external validation as part of our standard workflow and a special QSAR modeling scheme was employed that took into account the imbalanced ratio of inhibitors to non-binders (1:4) in this dataset. 342 predictive models were obtained with correct classification rate (CCR) for both training and test sets as high as 0.90 or higher. The prediction accuracy was as high as 100% (CCR = 1.00) for the external validation set composed of 10 compounds (5 true binders and 5 decoys) selected randomly from the original dataset. For an additional external set of 50 known non-binders, we have achieved the CCR of 0.87 using very conservative model applicability domain threshold. The validated binary kNN QSAR models were further employed for mining the NCGC AmpC screening dataset (69653 compounds). The consensus prediction of 64 compounds identified as screening hits in the AmpC PubChem assay disagreed with their annotation in PubChem but was in agreement with the results of secondary assays. At the same time, 15 compounds were identified as potential binders contrary to their annotation in PubChem. Five of them were tested experimentally and showed inhibitory activities in millimolar range with the highest binding constant Ki of 135 μM. Our studies suggest that validated QSAR models could complement

  4. Debye screening

    Science.gov (United States)

    Brydges, David C.; Federbush, Paul

    1980-10-01

    The existence and exponential clustering of correlation functions for a classical coulomb system at low density or high temperature are proven using methods from constructive quantum field theory, the sine gordon transformation and the Glimm, Jaffe, Spencer expansion about mean field theory. This is a vindication of a belief of long standing among physicists, known as Debye screening. That is, because of special properties of the coulomb potential, the configurations of significant probability are those in which the long range parts of r -1 are mostly cancelled, leaving an effective exponentially decaying potential acting between charge clouds. This paper generalizes a previous paper of one of the authors in which these results were obtained for a special lattice system. The present treatment covers the continuous mechanics situation, with essentially arbitrary short range forces and charge species. Charge symmetry is not assumed.

  5. Investigation on the Flexural Creep Stiffness Behavior of PC-ABS Material Processed by Fused Deposition Modeling Using Response Surface Definitive Screening Design

    Science.gov (United States)

    Mohamed, Omar Ahmed; Masood, Syed Hasan; Bhowmik, Jahar Lal

    2017-03-01

    The resistance of polymeric materials to time-dependent plastic deformation is an important requirement of the fused deposition modeling (FDM) design process, its processed products, and their application for long-term loading, durability, and reliability. The creep performance of the material and part processed by FDM is the fundamental criterion for many applications with strict dimensional stability requirements, including medical implants, electrical and electronic products, and various automotive applications. Herein, the effect of FDM fabrication conditions on the flexural creep stiffness behavior of polycarbonate-acrylonitrile-butadiene-styrene processed parts was investigated. A relatively new class of experimental design called "definitive screening design" was adopted for this investigation. The effects of process variables on flexural creep stiffness behavior were monitored, and the best suited quadratic polynomial model with high coefficient of determination ( R 2) value was developed. This study highlights the value of response surface definitive screening design in optimizing properties for the products and materials, and it demonstrates its role and potential application in material processing and additive manufacturing.

  6. Investigation on the Flexural Creep Stiffness Behavior of PC-ABS Material Processed by Fused Deposition Modeling Using Response Surface Definitive Screening Design

    Science.gov (United States)

    Mohamed, Omar Ahmed; Masood, Syed Hasan; Bhowmik, Jahar Lal

    2016-12-01

    The resistance of polymeric materials to time-dependent plastic deformation is an important requirement of the fused deposition modeling (FDM) design process, its processed products, and their application for long-term loading, durability, and reliability. The creep performance of the material and part processed by FDM is the fundamental criterion for many applications with strict dimensional stability requirements, including medical implants, electrical and electronic products, and various automotive applications. Herein, the effect of FDM fabrication conditions on the flexural creep stiffness behavior of polycarbonate-acrylonitrile-butadiene-styrene processed parts was investigated. A relatively new class of experimental design called "definitive screening design" was adopted for this investigation. The effects of process variables on flexural creep stiffness behavior were monitored, and the best suited quadratic polynomial model with high coefficient of determination (R 2) value was developed. This study highlights the value of response surface definitive screening design in optimizing properties for the products and materials, and it demonstrates its role and potential application in material processing and additive manufacturing.

  7. The discovery of a novel and selective inhibitor of PTP1B over TCPTP: 3D QSAR pharmacophore modeling, virtual screening, synthesis, and biological evaluation.

    Science.gov (United States)

    Ma, Ying; Jin, Yuan-Yuan; Wang, Ye-Liu; Wang, Run-Ling; Lu, Xin-Hua; Kong, De-Xin; Xu, Wei-Ren

    2014-06-01

    Given the special role of insulin and leptin signaling in various biological responses, protein-tyrosine phosphatase-1B (PTP1B) was regarded as a novel therapeutic target for treating type 2 diabetes and obesity. However, owing to the highly conserved (sequence identity of about 74%) in active pocket, targeting PTP1B for drug discovery is a great challenge. In this study, we employed the software package Discovery Studio to develop 3D QSAR pharmacophore models for PTP1B and TCPTP inhibitors. It was further validated by three methods (cost analysis, test set prediction, and Fisher's test) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective PTP1B inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective inhibitor of PTP1B over TCPTP. After that, a most likely binding mode was proposed. Thus, the findings reported here may provide a new strategy in discovering selective PTP1B inhibitors.

  8. Color screening scenario for quarkonia suppression in a quasiparticle model compared with data obtained from experiments at the CERN SPS, BNL RHIC, and CERN LHC

    Science.gov (United States)

    Srivastava, P. K.; Mishra, M.; Singh, C. P.

    2013-03-01

    We present a modified color screening model for J/ψ suppression in the quark-gluon plasma (QGP) using the quasiparticle model (QPM) as the equation of state (EOS). Other theoretical ingredients incorporated in the model are feed-down from higher resonances, namely, χc, and ψ', dilated formation time for quarkonia, and viscous effects of the QGP medium. By assuming further that the QGP is expanding with Bjorken's hydrodynamical expansion, the present model is used to analyze the centrality dependence of the J/ψ suppression in the mid-rapidity region and compare it with the data obtained from Super Proton Synchrotron, Relativistic Heavy Ion Collider, and Large Hadron Collider experiments. We find that the centrality dependence of the data for the survival probability at all energies is well reproduced by our model. We further compare our model predictions with the results obtained from the bag model EOS for QGP which has usually been used earlier in all such calculations.

  9. Virtual Screening of M3 Protein Antagonists for Finding a Model to Study the Gammaherpesvirus Damaged Immune System and Chemokine Related Diseases

    Directory of Open Access Journals (Sweden)

    Ibrahim Torktaz

    2013-12-01

    Full Text Available Introduction: M3 protein is a chemokine decoy receptor involved in pathogenesis of persistent infection with gammaherpesvirus and complications related to the latency of this pathogen. We proposed that antagonists of the M3 would provide a unique opportunity for studying new therapeutic strategies in disordered immune system, immune-deficient states and role of chemokines in pathogenesis development. Methods: Comparative modeling and fold recognition algorithms have been used for prediction of M3 protein 3-D model. Evaluation of the models using Q-mean and ProSA-web score, has led to choosing predicted model by fold recognition algorithm as the best model which was minimized regarding energy level using Molegro Virtual Docker 2011.4.3.0 (MVD software. Pockets and active sites of model were recognized using MVD cavity detection, and MetaPocket algorithms. Ten thousand compounds accessible on KEGG database were screened; MVD was used for computer simulated docking study; MolDock SE was selected as docking scoring function and final results were evaluated based on MolDock and Re-rank score. Results: Docking data suggested that prilocaine, which is generally applied as a topical anesthetic, binds strongly to 3-D model of M3 protein. Conclusion: This study proposes that prilocaine is a potential inhibitor of M3 protein and possibly has immune enhancing properties.

  10. Caenorhabditis elegans as a model for the screening of anthelminthic compounds: ultrastructural study of the effects of albendazole.

    Science.gov (United States)

    Sant'anna, Viviane; Vommaro, Rossiane C; de Souza, Wanderley

    2013-09-01

    This study investigated the effects of albendazole on the viability, morphology and ultrastructure of different life stages of Caenorhabditis elegans. The albendazole EC50 value after seven days of treatment was 18.43 μM. This concentration was very efficient against all the stages. Light and electron microscopy analysis showed damage to the body wall of the adults and larvae. An intense desquamation of the cuticle of larvae and of the surface of the eggs was observed, preventing their hatching and development. The main ultrastructural damage detected was the degeneration of the mitochondria in the noncontractile muscle of the body wall, which appeared as large vacuoles. This study reaffirmed the use of C. elegans as a screening system for compounds with potential anthelmintic activity and showed the effects of albendazole on the different life stages of these worms.

  11. Screening of the anticonvulsant activity of some plants from Fabaceae family in experimental seizure models in mice

    Directory of Open Access Journals (Sweden)

    S Sardari

    2011-10-01

    Full Text Available "n  Background and purpose of the study: Fabaceae is the third largest family of flowering plants. Lack of essential oils in the plants of this family can be an advantage in search for safe and effective medicines. In this study the anticonvulsant effect of the leaves of Albizzia julibrissin, Acacia juliflora, Acacia nubica and aerial parts of Astragalus obtusifolius was evaluated in pentylenetetrazole (PTZ and maximal electroshock (MES seizure tests. "n  Methods: The hydroalcoholic extracts of the plants were obtained by percolation. Different doses of the extracts were injected to the mice intraperitoneally (i.p. and occurrence of clonic seizures induced by PTZ (60 mg/kg, i.p. or tonic seizures induced by MES (50 mA, 50Hz, 1sec were monitored up to 30 min after administration. Acute toxicity of the extracts was also assessed. The safe and effective extract was then fractionated by dichloromethane and anticonvulsant activity of the fractions was determined. Finally, the constituents of the extract and the fractions were screened by thin layer chromatography. "n  Results: Among the extracts, only A. obtusifolius extract showed low toxicity and protective effect against clonic seizures with ED50 value of 3.97 g/kg. Fractionation of the extract led to increase in anticonvulsant activity and ED50 value of 2.86 g/kg was obtained for the aqueous fraction. Phytochemical screening revealed the presence of alkaloids, flavonoids, anthrones and saponins in the aqueous fraction. "n  Major conclusion: The presence of anticonvulsant compounds in A. obtusifolius suggests further activity-guided fractionation and analytical studies to find out the potential of this plant as a source of anticonvulsant agent.

  12. Screening in Hot Non-Abelian Plasma

    CERN Document Server

    Petreczky, P

    1999-01-01

    This thesis is devoted to the study of the screening masses in hot non-Abelian theories. Section 1 contain a brief introduction to the topic. In section 2 a detailed overview of the screening phenomena and their applications is given. In section 3 the screening masses are defined through the coupled gap equations. Section 4 deals with the determination of the screening masses of hot SU(2) gauge theory in the framework of the 3d lattice adjoint Higgs model considered as an effective theory. Finally in section 5 the screening masses of hot SU(2) Higgs model are examined.

  13. The potential of the essential fatty acid-deficient hairless rat as a psoriasis screening model for topical anti-proliferative drugs

    DEFF Research Database (Denmark)

    Jensen, Mette; Groth, L.; Holmer, G.

    2002-01-01

    , histology of the epidermis and fatty acid analysis of serum and skin. Immediately after the EFAD condition had been established, the animals were treated with dithranol ointment or different concentrations of calcipotriol solution. A reduction in epidermal thickness of 15-20% was seen after the treatment......The objective of this study was to establish essential fatty acid deficiency (EFAD) in hairless rats and investigate the potential of this model as a psoriasis screening model by testing the effects of calcipotriol and dithranol on differentiation and proliferation in the epidermis. Hairless rats...... were fed with a fat-free diet lacking linoleic acid. The EFAD condition was established within 8 weeks. In order to ensure that this condition had been established, several parameters were measured and observed, i.e. animal weight, water consumption, transepidermal water loss, clinical skin symptoms...

  14. Modelling the performance of the monogroove with screen heat pipe for use in the radiator of the solar dynamic power system of the NASA Space Station

    Science.gov (United States)

    Evans, Austin Lewis

    1987-01-01

    A computer code to model the steady-state performance of a monogroove heat pipe for the NASA Space Station is presented, including the effects on heat pipe performance of a screen in the evaporator section which deals with transient surges in the heat input. Errors in a previous code have been corrected, and the new code adds additional loss terms in order to model several different working fluids. Good agreement with existing performance curves is obtained. From a preliminary evaluation of several of the radiator design parameters it is found that an optimum fin width could be achieved but that structural considerations limit the thickness of the fin to a value above optimum.

  15. Per-residue energy decomposition pharmacophore model to enhance virtual screening in drug discovery: a study for identification of reverse transcriptase inhibitors as potential anti-HIV agents.

    Science.gov (United States)

    Cele, Favourite N; Ramesh, Muthusamy; Soliman, Mahmoud Es

    2016-01-01

    A novel virtual screening approach is implemented herein, which is a further improvement of our previously published "target-bound pharmacophore modeling approach". The generated pharmacophore library is based only on highly contributing amino acid residues, instead of arbitrary pharmacophores, which are most commonly used in the conventional approaches in literature. Highly contributing amino acid residues were distinguished based on free binding energy contributions obtained from calculation from molecular dynamic (MD) simulations. To the best of our knowledge; this is the first attempt in the literature using such an approach; previous approaches have relied on the docking score to generate energy-based pharmacophore models. However, docking scores are reportedly unreliable. Thus, we present a model for a per-residue energy decomposition, constructed from MD simulation ensembles generating a more trustworthy pharmacophore model, which can be applied in drug discovery workflow. This work is aimed at introducing a more rational approach to the field of drug design, rather than comparing the validity of this approach against those previously reported. We recommend additional computational and experimental work to further validate this approach. This approach was used to screen for potential reverse transcriptase inhibitors using the pharmacophoric features of compound GSK952. The complex was subjected to docking, thereafter, MD simulation confirmed the stability of the system. Experimentally determined inhibitors with known HIV-reverse transcriptase inhibitory activity were used to validate the protocol. Two potential hits (ZINC46849657 and ZINC54359621) showed a significant potential with regard to free binding energy. Reported results obtained from this work confirm that this new approach is favorable in the future of the drug design industry.

  16. An Enhanced Sampling Strategy for High-Dimensional Models: Do We Really Need to Maximize Sample Spread for Efficient Parameter Screening Using the Method of Morris?

    Science.gov (United States)

    Khare, Y. P.; Martinez, C. J.; Munoz-Carpena, R.

    2015-12-01

    Improved knowledge about fundamental physical processes, advances in computing power, and a focus on integrated modeling has resulted in complex environmental and water resources models. However, the high-dimensionality of these models adds to overall uncertainty and poses issues when evaluating them for sensitivity, parameter identification, and optimization through rigorous computer experiments. The parameter screening method of elementary effects (EE) offers a perfect blend of useful properties inherited from inexpensive one-at-a time methods and expensive global techniques. Since its development EE has undergone improvements largely on the sampling side with over seven sampling strategies developed during the last decade. These strategies can broadly be classified into trajectory-based and polytope-based schemes. Trajectory-based strategies are more widely used, conceptually simple, and generally use the principle of spreading the sample points in the input hyper-space as widely as possible through oversampling. Due to this their implementation have been found to be impractically time consuming for high-dimensional cases (when # input factors > 50, say). Here, we enhanced the Sampling for Uniformity (SU) (Khare et al., 2015), a trajectory-based EE sampling scheme founded on the dual principle of spread and uniformity. This new scheme - enhanced SU (eSU) is the same as SU except the manner in which intermediate trajectory points are formed. It was tested for sample uniformity, spread, sampling time, and screening efficiency. Experiments were repeated with combinations of the number of trajectories and oversampling size. Preliminary results indicate that eSU is superior to SU by some margin with respect to all four criteria. Interestingly, in the case of eSU oversampling size had no impact on any of the evaluation criteria except linear increament in sampling time. Pending further investigation, this has opened a new avenue to substantially bring down the

  17. Normative weight-adjusted models for the median levels of first trimester serum biomarkers for trisomy 21 screening in a specific ethnicity.

    Science.gov (United States)

    Kor-Anantakul, Ounjai; Suntharasaj, Thitima; Suwanrath, Chitkasaem; Hanprasertpong, Tharangrut; Pranpanus, Savitree; Pruksanusak, Ninlapa; Janwadee, Suthiraporn; Geater, Alan

    2017-01-01

    To establish normative weight-adjusted models for the median levels of first trimester serum biomarkers for trisomy 21 screening in southern Thai women, and to compare these reference levels with Caucasian-specific and northern Thai models. A cross-sectional study was conducted in 1,150 normal singleton pregnancy women to determine serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) concentrations in women from southern Thailand. The predicted median values were compared with published equations for Caucasians and northern Thai women. The best-fitting regression equations for the expected median serum levels of PAPP-A (mIU/L) and free β- hCG (ng/mL) according to maternal weight (Wt in kg) and gestational age (GA in days) were: [Formula: see text] and [Formula: see text] Both equations were selected with a statistically significant contribution (p< 0.05). Compared with the Caucasian model, the median values of PAPP-A were higher and the median values of free β-hCG were lower in the southern Thai women. And compared with the northern Thai models, the median values of both biomarkers were lower in southern Thai women. The study has successfully developed maternal-weight- and gestational-age-adjusted median normative models to convert the PAPP-A and free β-hCG levels into their Multiple of Median equivalents in southern Thai women. These models confirmed ethnic differences.

  18. Predictive accuracy of the PanCan lung cancer risk prediction