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Sample records for functional screening approach

  1. A multi-functional imaging approach to high-content protein interaction screening.

    Directory of Open Access Journals (Sweden)

    Daniel R Matthews

    Full Text Available Functional imaging can provide a level of quantification that is not possible in what might be termed traditional high-content screening. This is due to the fact that the current state-of-the-art high-content screening systems take the approach of scaling-up single cell assays, and are therefore based on essentially pictorial measures as assay indicators. Such phenotypic analyses have become extremely sophisticated, advancing screening enormously, but this approach can still be somewhat subjective. We describe the development, and validation, of a prototype high-content screening platform that combines steady-state fluorescence anisotropy imaging with fluorescence lifetime imaging (FLIM. This functional approach allows objective, quantitative screening of small molecule libraries in protein-protein interaction assays. We discuss the development of the instrumentation, the process by which information on fluorescence resonance energy transfer (FRET can be extracted from wide-field, acceptor fluorescence anisotropy imaging and cross-checking of this modality using lifetime imaging by time-correlated single-photon counting. Imaging of cells expressing protein constructs where eGFP and mRFP1 are linked with amino-acid chains of various lengths (7, 19 and 32 amino acids shows the two methodologies to be highly correlated. We validate our approach using a small-scale inhibitor screen of a Cdc42 FRET biosensor probe expressed in epidermoid cancer cells (A431 in a 96 microwell-plate format. We also show that acceptor fluorescence anisotropy can be used to measure variations in hetero-FRET in protein-protein interactions. We demonstrate this using a screen of inhibitors of internalization of the transmembrane receptor, CXCR4. These assays enable us to demonstrate all the capabilities of the instrument, image processing and analytical techniques that have been developed. Direct correlation between acceptor anisotropy and donor FLIM is observed for FRET

  2. Functional genomic screening approaches in mechanistic toxicology and potential future applications of CRISPR-Cas9.

    Science.gov (United States)

    Shen, Hua; McHale, Cliona M; Smith, Martyn T; Zhang, Luoping

    2015-01-01

    Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Chemical toxicants act by many different mechanisms, however, and the genes involved in adverse outcome pathways (AOPs) and AOP networks are not yet characterized. Functional genomic approaches can reveal both toxicity pathways and susceptibility genes, through knockdown or knockout of all non-essential genes in a cell of interest, and identification of genes associated with a toxicity phenotype following toxicant exposure. Screening approaches in yeast and human near-haploid leukemic KBM7 cells have identified roles for genes and pathways involved in response to many toxicants but are limited by partial homology among yeast and human genes and limited relevance to normal diploid cells. RNA interference (RNAi) suppresses mRNA expression level but is limited by off-target effects (OTEs) and incomplete knockdown. The recently developed gene editing approach called clustered regularly interspaced short palindrome repeats-associated nuclease (CRISPR)-Cas9, can precisely knock-out most regions of the genome at the DNA level with fewer OTEs than RNAi, in multiple human cell types, thus overcoming the limitations of the other approaches. It has been used to identify genes involved in the response to chemical and microbial toxicants in several human cell types and could readily be extended to the systematic screening of large numbers of environmental chemicals. CRISPR-Cas9 can also repress and activate gene expression, including that of non-coding RNA, with near-saturation, thus offering the potential to more fully characterize AOPs and AOP networks. Finally, CRISPR-Cas9 can generate complex animal models in which to conduct preclinical toxicity testing at the level of individual genotypes or haplotypes. Therefore, CRISPR-Cas9 is a powerful and flexible functional genomic screening approach that can be harnessed to provide

  3. G-centers in irradiated silicon revisited: A screened hybrid density functional theory approach

    KAUST Repository

    Wang, H.

    2014-05-13

    Electronic structure calculations employing screened hybrid density functional theory are used to gain fundamental insight into the interaction of carbon interstitial (Ci) and substitutional (Cs) atoms forming the CiCs defect known as G-center in silicon (Si). The G-center is one of the most important radiation related defects in Czochralski grown Si. We systematically investigate the density of states and formation energy for different types of CiCs defects with respect to the Fermi energy for all possible charge states. Prevalence of the neutral state for the C-type defect is established.

  4. G-centers in irradiated silicon revisited: A screened hybrid density functional theory approach

    Energy Technology Data Exchange (ETDEWEB)

    Wang, H.; Schwingenschlögl, U., E-mail: Udo.Schwingenschlogl@kaust.edu.sa [PSE Division, KAUST, Thuwal 23955-6900 (Saudi Arabia); Chroneos, A., E-mail: Alex.Chroneos@open.ac.uk [Engineering and Innovation, The Open University, Milton Keynes MK7 6AA (United Kingdom); Department of Materials, Imperial College, London SW7 2AZ (United Kingdom); Londos, C. A.; Sgourou, E. N. [University of Athens, Solid State Physics Section, Panepistimiopolis Zografos, Athens 157 84 (Greece)

    2014-05-14

    Electronic structure calculations employing screened hybrid density functional theory are used to gain fundamental insight into the interaction of carbon interstitial (C{sub i}) and substitutional (C{sub s}) atoms forming the C{sub i}C{sub s} defect known as G-center in silicon (Si). The G-center is one of the most important radiation related defects in Czochralski grown Si. We systematically investigate the density of states and formation energy for different types of C{sub i}C{sub s} defects with respect to the Fermi energy for all possible charge states. Prevalence of the neutral state for the C-type defect is established.

  5. Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

    Institute of Scientific and Technical Information of China (English)

    Sugunadevi SAKKIAH; Keun Woo LEE

    2012-01-01

    Aim:To identify the critical chemical features,with reliable geometric constraints,that contributes to the inhibition of butyrylcholinesterase (BChE) function.Methods:Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors.The generated pharmacophore model was validated using various techniques,such as Fischer's randomization method,test set,and decoy set.The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE.Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties,and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site.To find the reactivity of the hit compounds,frontier orbital analysis was carried out using density functional theory.Results:Based on its correlation coefficient (0.96),root mean square (RMS) deviation (1.01),and total cost (105.72),the quantitative hypothesis Hypo1 consisting of 2 HBA,1 Hy-Ali,and 1 Hy-Ar was selected as the best hypothesis.Thus,Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases.The hit compounds were filtered using ADMET,Lipinski's Rule of Five,and molecular docking to reduce the number of false positive results.Finally,33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site.To confirm the inhibitors' potencies,the orbital energies,such as HOMO and LUMO,of the hit compounds and 7 training set compounds were calculated.Among the 33 hit compounds,10 compounds with the highest HOMO values were selected,and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer.From the overall results,5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1.Conclusion:This study pinpoints important chemical

  6. Lung cancer: Morphological and functional approach to screening, staging and treatment planning.

    Science.gov (United States)

    Coche, Emmanuel; Lonneux, Max; Geets, Xavier

    2010-03-01

    Lung cancer is a major problem in public health and constitutes the leading cause of cancer-related mortality in the world. Lung cancer screening with low-dose computed tomography is promising but needs to overcome many difficulties, such as the large number of incidentally discovered nodules, the radiation dose delivered to the patient during a whole screening program and its cost. The ultimate target point represented by the reduction of lung cancer-related mortality needs to be proved in large, well-designed, randomized, multicenter, prospective trials. Lung cancer staging by morphological tools seems to be limited owing to the presence of metastases in normal-sized lymph nodes. In this context, multidetector computed tomography cannot be used alone but is useful in conjunction with molecular imaging and MRI. Today, flurodeoxglucose PET-CT appears to be the most accurate method for lung cancer staging and may prevent unnecessary thoracotomies. For treatment planning, flurodeoxglucose PET-CT is playing an increasing role in radiotherapy planning at the target selection and definition steps.

  7. New approach to beta cell function screening by nitric oxide assessment of obese individuals at the population level

    Directory of Open Access Journals (Sweden)

    Chaim EA

    2012-05-01

    Full Text Available Elinton Adami Chaim, Renata Cristina GobatoUniversity of Campinas (UNICAMP, Faculty of Medical Sciences, Department of Surgery, Cidade Universitária Zeferino Vaz, Barão Geraldo, BrazilBackground: Approximately 27% of Americans today are obese, and this condition increases the prevalence of metabolic syndrome and diabetes. The UK Prospective Diabetes Study suggests that loss of beta cell function can begin at least 10 years before diagnosis, and mean beta cell function is already less than 50% at diagnosis. The aim of this research was to assess the possibility of detecting loss of beta cell function in obese patients by a novel approach involving nitric oxide assessment using a combination of technologies.Materials and methods: One hundred and fifteen obese patients (93 women, 22 men of mean age 39 (range 17–62 years, who were candidates for bariatric surgery were included in the study, and underwent laboratory tests, including fasting blood glucose, fasting insulin plasma, and examination with the Electro Sensor complex. The Electro Sensor complex offers a new way to assess nitric oxide production using five technologies managed by software, ie, the galvanic skin response, photoelectrical plethysmography, heart rate variability analysis, bioimpedance analysis, and blood pressure oscillometric measurements. The homeostasis model assessment 2% beta cell function (HOMA2% β algorithm was calculated from fasting blood glucose and fasting insulin plasma using free software provided by The University of Oxford Diabetes Trial Unit. The Electro Sensor complex percent beta (ESC% β algorithm was calculated from the Electro Sensor complex data and statistical neural network. Statistical analysis was performed to correlate ESC% β and HOMA2% β using the coefficient of correlation and Spearman's coefficient of rank correlation. Receiver-operating characteristic curves were also constructed to determine the specificity and sensitivity of ESC% β in

  8. New approach to beta cell function screening by nitric oxide assessment of obese individuals at the population level.

    Science.gov (United States)

    Chaim, Elinton Adami; Gobato, Renata Cristina

    2012-01-01

    Approximately 27% of Americans today are obese, and this condition increases the prevalence of metabolic syndrome and diabetes. The UK Prospective Diabetes Study suggests that loss of beta cell function can begin at least 10 years before diagnosis, and mean beta cell function is already less than 50% at diagnosis. The aim of this research was to assess the possibility of detecting loss of beta cell function in obese patients by a novel approach involving nitric oxide assessment using a combination of technologies. One hundred and fifteen obese patients (93 women, 22 men) of mean age 39 (range 17-62) years, who were candidates for bariatric surgery were included in the study, and underwent laboratory tests, including fasting blood glucose, fasting insulin plasma, and examination with the Electro Sensor complex. The Electro Sensor complex offers a new way to assess nitric oxide production using five technologies managed by software, ie, the galvanic skin response, photoelectrical plethysmography, heart rate variability analysis, bioimpedance analysis, and blood pressure oscillometric measurements. The homeostasis model assessment 2% beta cell function (HOMA2% β) algorithm was calculated from fasting blood glucose and fasting insulin plasma using free software provided by The University of Oxford Diabetes Trial Unit. The Electro Sensor complex percent beta (ESC% β) algorithm was calculated from the Electro Sensor complex data and statistical neural network. Statistical analysis was performed to correlate ESC% β and HOMA2% β using the coefficient of correlation and Spearman's coefficient of rank correlation. Receiver-operating characteristic curves were also constructed to determine the specificity and sensitivity of ESC% β in detecting a HOMA2% β value coefficient of correlation between ESC% β and HOMA2% β was 0.72 (using log values) and the Spearman's coefficient of rank correlation (rho) was 0.799 (P beta cell function in the obese population on a large

  9. Approaching Corporate Social Responsibility through Kenneth Burke's Notions of Terministic Screens and Entitlement

    DEFF Research Database (Denmark)

    Kampf, Constance

    Approaching Corporate Social Responsibility through Kenneth Burke's Notions of Terministic Screens and Entitlement Kenneth Burke brings together the function of rhetoric as both a constitutive and interpretive process through his notions of terministic screens and entitlement.  Terministic screen...

  10. Pragmatic approaches to genetic screening.

    NARCIS (Netherlands)

    Mallia, P.; Have, H.A.M.J. ten

    2005-01-01

    Pragmatic approaches to genetic testing are discussed and appraised. Whilst there are various schools of pragmatism, the Deweyan approach seems to be the most appreciated in bioethics as it allows a historical approach indebted to Hegel. This in turn allows the pragmatist to specify and balance prin

  11. Functional Screening of Core Promoter Activity.

    Science.gov (United States)

    Even, Dan Y; Kedmi, Adi; Ideses, Diana; Juven-Gershon, Tamar

    2017-01-01

    The core promoter is the DNA sequence that recruits the basal transcription machinery and directs accurate initiation of transcription. It is an active contributor to gene expression that can be rationally designed to manipulate the levels of expression. Core promoter function can be analyzed using different experimental approaches. Here, we describe the qualitative and quantitative analysis of engineered core promoter functions using the EGFP reporter gene that is driven by distinct core promoters. Expression plasmids are transfected into different mammalian cell lines, and the resulting fluorescence is monitored by live cell imaging , as well as by flow cytometry. In order to verify that the transcriptional activity of the examined core promoters is indeed a function of their activity, as opposed to differences in DNA uptake, real-time quantitative PCR analysis is performed. Importantly, the described methodology for functional screening of core promoter activity has enabled the analysis of engineered potent core promoters for extended time periods.

  12. A combined array-based comparative genomic hybridization and functional library screening approach identifies mir-30d as an oncomir in cancer.

    Science.gov (United States)

    Li, Ning; Kaur, Sippy; Greshock, Joel; Lassus, Heini; Zhong, Xiaomin; Wang, Yanling; Leminen, Arto; Shao, Zhongjun; Hu, Xiaowen; Liang, Shun; Katsaros, Dionyssios; Huang, Qihong; Bützow, Ralf; Weber, Barbara L; Coukos, George; Zhang, Lin

    2012-01-01

    Oncomirs are microRNAs (miRNA) that acts as oncogenes or tumor suppressor genes. Efficient identification of oncomirs remains a challenge. Here we report a novel, clinically guided genetic screening approach for the identification of oncomirs, identifying mir-30d through this strategy. mir-30d regulates tumor cell proliferation, apoptosis, senescence, and migration. The chromosomal locus harboring mir-30d was amplified in more than 30% of multiple types of human solid tumors (n = 1,283). Importantly, higher levels of mir-30d expression were associated significantly with poor clinical outcomes in ovarian cancer patients (n = 330, P = 0.0016). Mechanistic investigations suggested that mir-30d regulates a large number of cancer-associated genes, including the apoptotic caspase CASP3. The guided genetic screening approach validated by this study offers a powerful tool to identify oncomirs that may have utility as biomarkers or targets for drug development.

  13. Screening Test Items for Differential Item Functioning

    Science.gov (United States)

    Longford, Nicholas T.

    2014-01-01

    A method for medical screening is adapted to differential item functioning (DIF). Its essential elements are explicit declarations of the level of DIF that is acceptable and of the loss function that quantifies the consequences of the two kinds of inappropriate classification of an item. Instead of a single level and a single function, sets of…

  14. GPCALMA: a Grid Approach to Mammographic Screening

    CERN Document Server

    Bagnasco, S; Cerello, P G; Delogu, P; Fantacci, M E; Torres, E L; Masala, G L; Oliva, P R; Retico, A; Stumbo, S

    2004-01-01

    The next generation of High Energy Physics experiments requires a GRID approach to a distributed computing system and the associated data management: the key concept is the "Virtual Organisation" (VO), a group of geographycally distributed users with a common goal and the will to share their resources. A similar approach is being applied to a group of Hospitals which joined the GPCALMA project (Grid Platform for Computer Assisted Library for MAmmography), which will allow common screening programs for early diagnosis of breast and, in the future, lung cancer. HEP techniques come into play in writing the application code, which makes use of neural networks for the image analysis and shows performances similar to radiologists in the diagnosis. GRID technologies will allow remote image analysis and interactive online diagnosis, with a relevant reduction of the delays presently associated to screening programs.

  15. A comprehensive platform for highly multiplexed mammalian functional genetic screens

    Directory of Open Access Journals (Sweden)

    Cheung-Ong Kahlin

    2011-05-01

    Full Text Available Abstract Background Genome-wide screening in human and mouse cells using RNA interference and open reading frame over-expression libraries is rapidly becoming a viable experimental approach for many research labs. There are a variety of gene expression modulation libraries commercially available, however, detailed and validated protocols as well as the reagents necessary for deconvolving genome-scale gene screens using these libraries are lacking. As a solution, we designed a comprehensive platform for highly multiplexed functional genetic screens in human, mouse and yeast cells using popular, commercially available gene modulation libraries. The Gene Modulation Array Platform (GMAP is a single microarray-based detection solution for deconvolution of loss and gain-of-function pooled screens. Results Experiments with specially constructed lentiviral-based plasmid pools containing ~78,000 shRNAs demonstrated that the GMAP is capable of deconvolving genome-wide shRNA "dropout" screens. Further experiments with a larger, ~90,000 shRNA pool demonstrate that equivalent results are obtained from plasmid pools and from genomic DNA derived from lentivirus infected cells. Parallel testing of large shRNA pools using GMAP and next-generation sequencing methods revealed that the two methods provide valid and complementary approaches to deconvolution of genome-wide shRNA screens. Additional experiments demonstrated that GMAP is equivalent to similar microarray-based products when used for deconvolution of open reading frame over-expression screens. Conclusion Herein, we demonstrate four major applications for the GMAP resource, including deconvolution of pooled RNAi screens in cells with at least 90,000 distinct shRNAs. We also provide detailed methodologies for pooled shRNA screen readout using GMAP and compare next-generation sequencing to GMAP (i.e. microarray based deconvolution methods.

  16. 3D pharmacophore-based virtual screening, docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2 (HER2) inhibitors.

    Science.gov (United States)

    Gogoi, Dhrubajyoti; Baruah, Vishwa Jyoti; Chaliha, Amrita Kashyap; Kakoti, Bibhuti Bhushan; Sarma, Diganta; Buragohain, Alak Kumar

    2016-12-21

    Human epidermal growth factor receptor 2 (HER2) is one of the four members of the epidermal growth factor receptor (EGFR) family and is expressed to facilitate cellular proliferation across various tissue types. Therapies targeting HER2, which is a transmembrane glycoprotein with tyrosine kinase activity, offer promising prospects especially in breast and gastric/gastroesophageal cancer patients. Persistence of both primary and acquired resistance to various routine drugs/antibodies is a disappointing outcome in the treatment of many HER2 positive cancer patients and is a challenge that requires formulation of new and improved strategies to overcome the same. Identification of novel HER2 inhibitors with improved therapeutics index was performed with a highly correlating (r=0.975) ligand-based pharmacophore model (Hypo1) in this study. Hypo1 was generated from a training set of 22 compounds with HER2 inhibitory activity and this well-validated hypothesis was subsequently used as a 3D query to screen compounds in a total of four databases of which two were natural product databases. Further, these compounds were analyzed for compliance with Veber's drug-likeness rule and optimum ADMET parameters. The selected compounds were then subjected to molecular docking and Density Functional Theory (DFT) analysis to discern their molecular interactions at the active site of HER2. The findings thus presented would be an important starting point towards the development of novel HER2 inhibitors using well-validated computational techniques.

  17. Identification of novel histone deacetylase 1 inhibitors by combined pharmacophore modeling, 3D-QSAR analysis, in silico screening and Density Functional Theory (DFT) approaches

    Science.gov (United States)

    Choubey, Sanjay K.; Mariadasse, Richard; Rajendran, Santhosh; Jeyaraman, Jeyakanthan

    2016-12-01

    Overexpression of HDAC1, a member of Class I histone deacetylase is reported to be implicated in breast cancer. Epigenetic alteration in carcinogenesis has been the thrust of research for few decades. Increased deacetylation leads to accelerated cell proliferation, cell migration, angiogenesis and invasion. HDAC1 is pronounced as the potential drug target towards the treatment of breast cancer. In this study, the biochemical potential of 6-aminonicotinamide derivatives was rationalized. Five point pharmacophore model with one hydrogen-bond acceptor (A3), two hydrogen-bond donors (D5, D6), one ring (R12) and one hydrophobic group (H8) was developed using 6-aminonicotinamide derivatives. The pharmacophore hypothesis yielded a 3D-QSAR model with correlation-coefficient (r2 = 0.977, q2 = 0.801) and it was externally validated with (r2pred = 0.929, r2cv = 0.850 and r2m = 0.856) which reveals the statistical significance of the model having high predictive power. The model was then employed as 3D search query for virtual screening against compound libraries (Zinc, Maybridge, Enamine, Asinex, Toslab, LifeChem and Specs) in order to identify novel scaffolds which can be experimentally validated to design future drug molecule. Density Functional Theory (DFT) at B3LYP/6-31G* level was employed to explore the electronic features of the ligands involved in charge transfer reaction during receptor ligand interaction. Binding free energy (ΔGbind) calculation was done using MM/GBSA which defines the affinity of ligands towards the receptor.

  18. Integration a functional approach

    CERN Document Server

    Bichteler, Klaus

    1998-01-01

    This book covers Lebesgue integration and its generalizations from Daniell's point of view, modified by the use of seminorms. Integrating functions rather than measuring sets is posited as the main purpose of measure theory. From this point of view Lebesgue's integral can be had as a rather straightforward, even simplistic, extension of Riemann's integral; and its aims, definitions, and procedures can be motivated at an elementary level. The notion of measurability, for example, is suggested by Littlewood's observations rather than being conveyed authoritatively through definitions of (sigma)-algebras and good-cut-conditions, the latter of which are hard to justify and thus appear mysterious, even nettlesome, to the beginner. The approach taken provides the additional benefit of cutting the labor in half. The use of seminorms, ubiquitous in modern analysis, speeds things up even further. The book is intended for the reader who has some experience with proofs, a beginning graduate student for example. It might...

  19. Extended screened exchange functional derived from transcorrelated density functional theory

    Science.gov (United States)

    Umezawa, Naoto

    2017-09-01

    We propose a new formulation of the correlation energy functional derived from the transcorrelated method in use in density functional theory (TC-DFT). An effective Hamiltonian, HTC, is introduced by a similarity transformation of a many-body Hamiltonian, H , with respect to a complex function F: HTC=1/F H F . It is proved that an expectation value of HTC for a normalized single Slater determinant, Dn, corresponds to the total energy: E [n ] = ⟨Ψn|H |Ψn ⟩ /⟨Ψn|Ψn ⟩ = ⟨Dn|HTC|Dn ⟩ under the two assumptions: (1) The electron density n (r ) associated with a trial wave function Ψn = DnF is v -representable and (2) Ψn and Dn give rise to the same electron density n (r ). This formulation, therefore, provides an alternative expression of the total energy that is useful for the development of novel correlation energy functionals. By substituting a specific function for F, we successfully derived a model correlation energy functional, which resembles the functional form of the screened exchange method. The proposed functional, named the extended screened exchange (ESX) functional, is described within two-body integrals and is parametrized for a numerically exact correlation energy of the homogeneous electron gas. The ESX functional does not contain any ingredients of (semi-)local functionals and thus is totally free from self-interactions. The computational cost for solving the self-consistent-field equation is comparable to that of the Hartree-Fock method. We apply the ESX functional to electronic structure calculations for a solid silicon, H- ion, and small atoms. The results demonstrate that the TC-DFT formulation is promising for the systematic improvement of the correlation energy functional.

  20. Unconventional screening approaches for antibiotic discovery

    National Research Council Canada - National Science Library

    Farha, Maya A; Brown, Eric D

    2015-01-01

    .... Nevertheless, a paucity of new antibacterial drugs in discovery and development pipelines using traditional approaches has prompted a variety of unconventional and disruptive strategies for antibacterial drug discovery...

  1. Structure-based approach to pharmacophore identification, in silico screening, and three-dimensional quantitative structure-activity relationship studies for inhibitors of Trypanosoma cruzi dihydrofolate reductase function

    Energy Technology Data Exchange (ETDEWEB)

    Schormann, N.; Senkovich, O.; Walker, K.; Wright, D.L.; Anderson, A.C.; Rosowsky, A.; Ananthan, S.; Shinkre, B.; Velu, S.; Chattopadhyay, D. (UAB); (Connecticut); (Southern Research); (DFCI)

    2009-07-10

    We have employed a structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) approach to predict the biochemical activity for inhibitors of T. cruzi dihydrofolate reductase-thymidylate synthase (DHFR-TS). Crystal structures of complexes of the enzyme with eight different inhibitors of the DHFR activity together with the structure in the substrate-free state (DHFR domain) were used to validate and refine docking poses of ligands that constitute likely active conformations. Structural information from these complexes formed the basis for the structure-based alignment used as input for the QSAR study. Contrary to indirect ligand-based approaches the strategy described here employs a direct receptor-based approach. The goal is to generate a library of selective lead inhibitors for further development as antiparasitic agents. 3D-QSAR models were obtained for T. cruzi DHFR-TS (30 inhibitors in learning set) and human DHFR (36 inhibitors in learning set) that show a very good agreement between experimental and predicted enzyme inhibition data. For crossvalidation of the QSAR model(s), we have used the 10% leave-one-out method. The derived 3D-QSAR models were tested against a few selected compounds (a small test set of six inhibitors for each enzyme) with known activity, which were not part of the learning set, and the quality of prediction of the initial 3D-QSAR models demonstrated that such studies are feasible. Further refinement of the models through integration of additional activity data and optimization of reliable docking poses is expected to lead to an improved predictive ability.

  2. Physiological functioning of Lagerstroemia speciosa L. under heavy roadside traffic: an approach to screen potential species for abatement of urban air pollution.

    Science.gov (United States)

    Singh, H; Savita; Sharma, R; Sinha, S; Kumar, M; Kumar, P; Verma, A; Sharma, S K

    2017-05-01

    The mitigation potential of avenue tree species needs a sound understanding, especially for landscape planning or planting tree species on roadside, especially in city limits where there is huge traffic due to more number of vehicles. A preliminary study was conducted to investigate the impact of heavy traffic movement and pollution thereof on physiological functioning of Lagerstroemia speciosa trees planted on roadside in terms of carbon absorption, mitigation potential and adaptive behavior. Trees on roadside exhibited reduced carbon assimilation (36.7 ± 2.4%) and transpiration rate (42.14 ± 2.9%), decreased stomatal conductance (66.85 ± 3.87%), increased stomatal resistance (212.2 ± 11.25%), more leaf thickness (40.54 ± 3.25) and water use efficiency (9.4 ± 0.87%), and changes in lead (179.31 ± 10.24%) and proline (15.61 ± 1.92%) concentration in leaf tissues when compared to less traffic area (FRI campus). The impacts were also witnessed in the form of enhanced vapour pressure deficit of air (63.18 ± 4.94%) and leaf (45.72 ± 3.25%), and air temperature (3.2 ± 0.16%) and leaf temperature (9.0 ± 0.82%) along roadside trees. It was inferred that heavy traffic movements interrupt the physiological functioning of trees due to alteration in the surrounding environment as compared to non-traffic areas. The present study provides baseline information to further explore and identify the potential avenue tree species having significant mitigation potential and adaptive efficiency to heavy traffic movements for improving urban environment.

  3. Functional genomic and high-content screening for target discovery and deconvolution

    Science.gov (United States)

    Heynen-Genel, Susanne; Pache, Lars; Chanda, Sumit K

    2014-01-01

    Introduction Functional genomic screens apply knowledge gained from the sequencing of the human genome toward rapid methods of identifying genes involved in cellular function based on a specific phenotype. This approach has been made possible through the use of advances in both molecular biology and automation. The utility of this approach has been further enhanced through the application of image-based high content screening, an automated microscopy and quantitative image analysis platform. These approaches can significantly enhance acquisition of novel targets for drug discovery. Areas covered Both the utility and potential issues associated with functional genomic screening approaches are discussed along with examples that illustrate both. The considerations for high content screening applied to functional genomics are also presented. Expert opinion Functional genomic and high content screening are extremely useful in the identification of new drug targets. However, the technical, experimental, and computational parameters have an enormous influence on the results. Thus, although new targets are identified, caution should be applied toward interpretation of screening data in isolation. Genomic screens should be viewed as an integral component of a target identification campaign that requires both the acquisition of orthogonal data, as well as a rigorous validation strategy. PMID:22860749

  4. Big screens with small RNAs : loss of function genetic screens to identify novel cancer genes

    NARCIS (Netherlands)

    Mullenders, J.

    2009-01-01

    This thesis described the construction and screening of one of the first large scale RNAi libraries for use in human cells. Functional genetic screens with this library have led to the identification of novel cancer genes. These cancer genes function in several pathways including the p53 tumor suppr

  5. Unconventional screening approaches for antibiotic discovery.

    Science.gov (United States)

    Farha, Maya A; Brown, Eric D

    2015-09-01

    The dramatic rise in microbial drug resistance in recent years has led to ongoing searches for novel drugs to add to the armory against infectious disease. Nevertheless, a paucity of new antibacterial drugs in discovery and development pipelines using traditional approaches has prompted a variety of unconventional and disruptive strategies for antibacterial drug discovery. Herein, we review recent nontraditional approaches that have been piloted for early drug discovery efforts. These unique methodologies open new avenues for finding the next generation of antimicrobials. © 2015 New York Academy of Sciences.

  6. Screening and surveillance approaches in familial pancreatic cancer.

    Science.gov (United States)

    Canto, Marcia Irene

    2008-07-01

    Screening and surveillance for pancreatic cancer and its precursors is a relatively new indication for endoscopic ultrasound. It provides an alternative approach to the ineffective treatment of mostly incurable symptomatic pancreatic cancer. It is currently reserved for individuals with an increased risk for pancreatic ductal adenocarcinoma, such as those who have inherited genetic syndromes (eg, patients who have Peutz-Jeghers syndrome or hereditary pancreatitis, germline mutation carriers of p16 and BRCA2) and at-risk relatives of patients who have familial pancreatic cancer. This article discusses the rationale for performing screening and surveillance, the types of patients who are eligible for screening, the diagnostic modalities and technique for screening, the diagnostic yield of screening, and the ongoing research.

  7. A primer on using pooled shRNA libraries for functional genomic screens

    Institute of Scientific and Technical Information of China (English)

    Guang Hu; Ji Luo

    2012-01-01

    The discovery of RNA interference (RNAi) has revolutionized genetic analysis in mammalian cells.Loss-of-function RNAi screens enable rapid,functional annotation of the genome.Of the various RNAi approaches,pooled shRNA libraries have received considerable attention because of their versatility.A number of genome-wide shRNA libraries have been constructed against the human and mouse genomes,and these libraries can be readily applied to a variety of screens to interrogate the function of human and mouse genes in an unbiased fashion.We provide an introduction to the technical aspects of using pooled shRNA libraries for genetic screens.

  8. Combinatorial and high-throughput screening approaches for strain engineering.

    Science.gov (United States)

    Liu, Wenshan; Jiang, Rongrong

    2015-03-01

    Microbes have long been used in the industry to produce valuable biochemicals. Combinatorial engineering approaches, new strain engineering tools derived from inverse metabolic engineering, have started to attract attention in recent years, including genome shuffling, error-prone DNA polymerase, global transcription machinery engineering (gTME), random knockout/overexpression libraries, ribosome engineering, multiplex automated genome engineering (MAGE), customized optimization of metabolic pathways by combinatorial transcriptional engineering (COMPACTER), and library construction of "tunable intergenic regions" (TIGR). Since combinatorial approaches and high-throughput screening methods are fundamentally interconnected, color/fluorescence-based, growth-based, and biosensor-based high-throughput screening methods have been reviewed. We believe that with the help of metabolic engineering tools and new combinatorial approaches, plus effective high-throughput screening methods, researchers will be able to achieve better results on improving microorganism performance under stress or enhancing biochemical yield.

  9. Molecular approaches to screen bioactive compounds from endophytic fungi

    Directory of Open Access Journals (Sweden)

    M Vasundhara

    2016-11-01

    Full Text Available Endophytic fungi are capable of producing plant associated metabolites and their analogs with therapeutic value. In order to identify the potential endophytic isolates producing bioactive compounds, one need to screen all isolated endophytes, which may run into hundreds. Isolation of endophytic fungi is relatively a simple process; but screening of the isolated fungi for required metabolite production is a cumbersome process. Endophytic fungi producing plant associated metabolites may contain genes involved in the entire biosynthetic pathway(s. Therefore, ascertaining the presence of key enzymes of a particular biosynthetic pathway could serve as a molecular marker for screening of these endophytes to produce that metabolite. In absence of entire biosynthetic pathways in endophytic fungi, plant genes associated with that metabolic pathway could serve as markers. This review focuses on the impact of molecular approaches to screen the endophytic fungi for the production of bioactive compounds. An attempt has been made on screening of anticancer compounds like taxol (paclitaxel, podophyllotoxin and camptothecin using molecular markers. The advantages of molecular approaches over conventional methods to screen endophytic fungi and also identification of endophytic fungi are also discussed.

  10. Molecular Approaches to Screen Bioactive Compounds from Endophytic Fungi.

    Science.gov (United States)

    Vasundhara, M; Kumar, Anil; Reddy, M Sudhakara

    2016-01-01

    Endophytic fungi are capable of producing plant associated metabolites and their analogs with therapeutic value. In order to identify the potential endophytic isolates producing bioactive compounds, one need to screen all isolated endophytes, which may run into hundreds. Isolation of endophytic fungi is relatively a simple process; but screening of the isolated fungi for required metabolite production is a cumbersome process. Endophytic fungi producing plant associated metabolites may contain genes involved in the entire biosynthetic pathway(s). Therefore, ascertaining the presence of key enzymes of a particular biosynthetic pathway could serve as a molecular marker for screening of these endophytes to produce that metabolite. In absence of entire biosynthetic pathways in endophytic fungi, plant genes associated with that metabolic pathway could serve as markers. This review focuses on the impact of molecular approaches to screen the endophytic fungi for the production of bioactive compounds. An attempt has been made on screening of anticancer compounds like taxol (paclitaxel), podophyllotoxin, and camptothecin using molecular markers. The advantages of molecular approaches over conventional methods to screen endophytic fungi and also identification of endophytic fungi are discussed.

  11. A multi-substrate approach for functional metagenomics-based screening for (hemi)cellulases in two wheat straw-degrading microbial consortia unveils novel thermoalkaliphilic enzymes

    NARCIS (Netherlands)

    Maruthamuthu, Mukil; Jiménez Avella, Diego; Stevens, Patricia; van Elsas, Jan Dirk

    2016-01-01

    BACKGROUND: Functional metagenomics is a promising strategy for the exploration of the biocatalytic potential of microbiomes in order to uncover novel enzymes for industrial processes (e.g. biorefining or bleaching pulp). Most current methodologies used to screen for enzymes involved in plant biomas

  12. A simple screened exact-exchange approach for excitonic properties in solids

    OpenAIRE

    Yang, Zeng-hui; Sottile, Francesco; Ullrich, Carsten A.

    2015-01-01

    We present a screened exact-exchange (SXX) method for the efficient and accurate calculation of the optical properties of solids, where the screening is achieved through the zero-wavevector limit of the inverse dielectric function. The SXX approach can be viewed as a simplification of the Bethe-Salpeter equation (BSE) or, in the context of time-dependent density-functional theory, as a first step towards a new class of hybrid functionals for the optical properties of solids. SXX performs well...

  13. Adapting CRISPR/Cas9 for functional genomics screens.

    Science.gov (United States)

    Malina, Abba; Katigbak, Alexandra; Cencic, Regina; Maïga, Rayelle Itoua; Robert, Francis; Miura, Hisashi; Pelletier, Jerry

    2014-01-01

    The use of CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) for targeted genome editing has been widely adopted and is considered a "game changing" technology. The ease and rapidity by which this approach can be used to modify endogenous loci in a wide spectrum of cell types and organisms makes it a powerful tool for customizable genetic modifications as well as for large-scale functional genomics. The development of retrovirus-based expression platforms to simultaneously deliver the Cas9 nuclease and single guide (sg) RNAs provides unique opportunities by which to ensure stable and reproducible expression of the editing tools and a broad cell targeting spectrum, while remaining compatible with in vivo genetic screens. Here, we describe methods and highlight considerations for designing and generating sgRNA libraries in all-in-one retroviral vectors for such applications.

  14. Infant metabolic screening: a total quality management approach.

    Science.gov (United States)

    Forsberg, S A

    1997-01-01

    The principles of total quality management (TQM) were used to improve the infant metabolic screening program in a large urban hospital. Three quality indicators needed improvement; unsatisfactory specimen quality, delayed delivery to the state laboratory for testing, and specimen slips missing the date of collection. A multidisciplinary team identified the root causes of the poor quality and implemented remedies. Dramatic improvement in three infant screening indicators occurred within a 4-month period. Evaluation of the three indicators continued for the following 3-year period. Quality improvement programs that involve a multidisciplinary approach benefit the patient and staff and may reduce costs.

  15. Substrate Activity Screening (SAS) and Related Approaches in Medicinal Chemistry.

    Science.gov (United States)

    Gladysz, Rafaela; Lambeir, Anne-Marie; Joossens, Jurgen; Augustyns, Koen; Van der Veken, Pieter

    2016-03-04

    Substrate activity screening (SAS) was presented a decade ago by Ellman and co-workers as a straightforward methodology for the identification of fragment-sized building blocks for enzyme inhibitors. Ever since, SAS and variations derived from it have been successfully applied to the discovery of inhibitors of various families of enzymatically active drug targets. This review covers key achievements and challenges of SAS and related methodologies, including the modified substrate activity screening (MSAS) approach. Special attention is given to the kinetic and thermodynamic aspects of these methodologies, as a thorough understanding thereof is crucial for successfully transforming the identified fragment-sized hits into potent inhibitors.

  16. A novel approach to glaucoma screening and education in Nepal

    Directory of Open Access Journals (Sweden)

    Rens Ger V

    2008-10-01

    Full Text Available Abstract Background Glaucoma is a major cause of blindness worldwide and an increasingly significant global health problem. Glaucoma prevention and management efforts have been challenging due to inherent difficulty in developing a simple and cost-effective screening plan, limited access to health care and educational resources, poverty, and inadequate knowledge of the disease, particularly in developing countries. Starting in 2004 the Tilganga Eye Centre in Kathmandu, Nepal has provided targeted glaucoma screening, treatment, and education through a combination of clinical outreach programs and educational activities for patients. Methods A simple, age-based glaucoma screening algorithm was incorporated into three one-day cataract screening clinics. Using this algorithm, patients who were newly diagnosed with glaucoma were referred to TEC, where medication and surgery were provided free of charge through private donor funding. In addition, we describe two ongoing educational programs for increasing glaucoma awareness: an annual Glaucoma Awareness Week (which includes free screening, treatment, and counseling, and a repeating lecture series which generates new counselors. Results From 2004 to 2007 screening at the annual Glaucoma Awareness Week resulted in the diagnosis of 120 individuals with glaucoma, or 7.6% of total registrants. Attendance increased annually with a trend toward an increasing number of returning patients but a decreasing percentage of newly diagnosed patients, though the absolute numbers have remained relatively stable (range 21 to 38. Data from the three one-day screening clinics in 2006 show that approximately 2 to 4% of patients 50 years of age or older per clinic were newly diagnosed with POAG. Conclusion This multi-faceted approach appears to successfully identify individuals with glaucoma and provide treatment to those who would otherwise not be able to afford it. While more data is needed to validate this model

  17. 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.

  18. Functional-based screening methods for lipases, esterases, and phospholipases in metagenomic libraries.

    Science.gov (United States)

    Reyes-Duarte, Dolores; Ferrer, Manuel; García-Arellano, Humberto

    2012-01-01

    The use of metagenomic techniques for enzyme discovery constitutes a powerful approach. Functional screens, in contrast to sequence homology search, enable us to select enzymes based on their activity. It is noteworthy that they additionally guarantee the identification of genes coding for enzymes that exhibited no sequence similarity to known counterparts from public databases and that even do not match any putative catalytic residues, involved in the selected catalytic function. Therefore, this strategy not only provides new enzymes for new biotechnological applications, but also allows functional assignment of many proteins, found in abundance in the databases, currently designated as "hypothetical" or "conserved hypothetical" proteins. In the past decade, there has been an exponential increase in the design of functional screening programmes, the majority of them established for hydrolases and oxidoreductases. Here, functional screening methods that guarantee the greatest enzyme diversity, for mining esterases and lipases, are described.

  19. An evolutionary approach to Function.

    Science.gov (United States)

    Lord, Phillip

    2010-06-22

    Understanding the distinction between function and role is vexing and difficult. While it appears to be useful, in practice this distinction is hard to apply, particularly within biology. I take an evolutionary approach, considering a series of examples, to develop and generate definitions for these concepts. I test them in practice against the Ontology for Biomedical Investigations (OBI). Finally, I give an axiomatisation and discuss methods for applying these definitions in practice. The definitions in this paper are applicable, formalizing current practice. As such, they make a significant contribution to the use of these concepts within biomedical ontologies.

  20. An evolutionary approach to Function

    Directory of Open Access Journals (Sweden)

    Lord Phillip

    2010-06-01

    Full Text Available Abstract Background Understanding the distinction between function and role is vexing and difficult. While it appears to be useful, in practice this distinction is hard to apply, particularly within biology. Results I take an evolutionary approach, considering a series of examples, to develop and generate definitions for these concepts. I test them in practice against the Ontology for Biomedical Investigations (OBI. Finally, I give an axiomatisation and discuss methods for applying these definitions in practice. Conclusions The definitions in this paper are applicable, formalizing current practice. As such, they make a significant contribution to the use of these concepts within biomedical ontologies.

  1. Functional analysis screening for problem behavior maintained by automatic reinforcement.

    Science.gov (United States)

    Querim, Angie C; Iwata, Brian A; Roscoe, Eileen M; Schlichenmeyer, Kevin J; Ortega, Javier Virués; Hurl, Kylee E

    2013-01-01

    A common finding in previous research is that problem behavior maintained by automatic reinforcement continues to occur in the alone condition of a functional analysis (FA), whereas behavior maintained by social reinforcement typically is extinguished. Thus, the alone condition may represent an efficient screening procedure when maintenance by automatic reinforcement is suspected. We conducted a series of 5-min alone (or no-interaction) probes for 30 cases of problem behavior and compared initial predictions of maintenance or extinction to outcomes obtained in subsequent FAs. Results indicated that data from the screening procedure accurately predicted that problem behavior was maintained by automatic reinforcement in 21 of 22 cases and by social reinforcement in 7 of 8 cases. Thus, results of the screening accurately predicted the function of problem behavior (social vs. automatic reinforcement) in 28 of 30 cases.

  2. The iBeetle large-scale RNAi screen reveals gene functions for insect development and physiology.

    Science.gov (United States)

    Schmitt-Engel, Christian; Schultheis, Dorothea; Schwirz, Jonas; Ströhlein, Nadi; Troelenberg, Nicole; Majumdar, Upalparna; Dao, Van Anh; Grossmann, Daniela; Richter, Tobias; Tech, Maike; Dönitz, Jürgen; Gerischer, Lizzy; Theis, Mirko; Schild, Inga; Trauner, Jochen; Koniszewski, Nikolaus D B; Küster, Elke; Kittelmann, Sebastian; Hu, Yonggang; Lehmann, Sabrina; Siemanowski, Janna; Ulrich, Julia; Panfilio, Kristen A; Schröder, Reinhard; Morgenstern, Burkhard; Stanke, Mario; Buchhholz, Frank; Frasch, Manfred; Roth, Siegfried; Wimmer, Ernst A; Schoppmeier, Michael; Klingler, Martin; Bucher, Gregor

    2015-07-28

    Genetic screens are powerful tools to identify the genes required for a given biological process. However, for technical reasons, comprehensive screens have been restricted to very few model organisms. Therefore, although deep sequencing is revealing the genes of ever more insect species, the functional studies predominantly focus on candidate genes previously identified in Drosophila, which is biasing research towards conserved gene functions. RNAi screens in other organisms promise to reduce this bias. Here we present the results of the iBeetle screen, a large-scale, unbiased RNAi screen in the red flour beetle, Tribolium castaneum, which identifies gene functions in embryonic and postembryonic development, physiology and cell biology. The utility of Tribolium as a screening platform is demonstrated by the identification of genes involved in insect epithelial adhesion. This work transcends the restrictions of the candidate gene approach and opens fields of research not accessible in Drosophila.

  3. New approach to folding with the Coulomb wave function

    Energy Technology Data Exchange (ETDEWEB)

    Blokhintsev, L. D.; Savin, D. A. [Skobeltsyn Institute of Nuclear Physics, Lomonosov Moscow State University, Moscow 119991 (Russian Federation); Kadyrov, A. S. [Department of Physics, Astronomy and Medical Radiation Sciences, Curtin University, GPO Box U1987, Perth 6845 (Australia); Mukhamedzhanov, A. M. [Cyclotron Institute, Texas A and M University, College Station, Texas 77843 (United States)

    2015-05-15

    Due to the long-range character of the Coulomb interaction theoretical description of low-energy nuclear reactions with charged particles still remains a formidable task. One way of dealing with the problem in an integral-equation approach is to employ a screened Coulomb potential. A general approach without screening requires folding of kernels of the integral equations with the Coulomb wave. A new method of folding a function with the Coulomb partial waves is presented. The partial-wave Coulomb function both in the configuration and momentum representations is written in the form of separable series. Each term of the series is represented as a product of a factor depending only on the Coulomb parameter and a function depending on the spatial variable in the configuration space and the momentum variable if the momentum representation is used. Using a trial function, the method is demonstrated to be efficient and reliable.

  4. Simple screened exact-exchange approach for excitonic properties in solids

    Science.gov (United States)

    Yang, Zeng-hui; Sottile, Francesco; Ullrich, Carsten A.

    2015-07-01

    We present a screened exact-exchange (SXX) method for the efficient and accurate calculation of the optical properties of solids, where the screening is achieved through the zero-wave-vector limit of the inverse dielectric function. The SXX approach can be viewed as a simplification of the Bethe-Salpeter equation (BSE) or, in the context of time-dependent density-functional theory, as a first step towards a new class of hybrid functionals for the optical properties of solids. SXX performs well for bound excitons and continuum spectra in both small-gap semiconductors and large-gap insulators, with a computational cost much lower than that of the BSE.

  5. Microfluidic Screening of Electrophoretic Mobility Shifts Elucidates Riboswitch Binding Function

    OpenAIRE

    Karns, Kelly; Vogan, Jacob M.; Qin, Qian; Hickey, Scott F.; Wilson, Stephen C.; Hammond, Ming C.; Herr, Amy E.

    2013-01-01

    Riboswitches are RNA sensors that change conformation upon binding small molecule metabolites, in turn modulating gene expression. Our understanding of riboswitch regulatory function would be accelerated by a high throughput, quantitative screening tool capable of measuring riboswitch-ligand binding. We introduce a microfluidic mobility shift assay that enables precise and rapid quantitation of ligand binding and subsequent riboswitch conformational change. In 0.3% of the time required for be...

  6. A new CAD approach for improving efficacy of cancer screening

    Science.gov (United States)

    Zheng, Bin; Qian, Wei; Li, Lihua; Pu, Jiantao; Kang, Yan; Lure, Fleming; Tan, Maxine; Qiu, Yuchen

    2015-03-01

    Since performance and clinical utility of current computer-aided detection (CAD) schemes of detecting and classifying soft tissue lesions (e.g., breast masses and lung nodules) is not satisfactory, many researchers in CAD field call for new CAD research ideas and approaches. The purpose of presenting this opinion paper is to share our vision and stimulate more discussions of how to overcome or compensate the limitation of current lesion-detection based CAD schemes in the CAD research community. Since based on our observation that analyzing global image information plays an important role in radiologists' decision making, we hypothesized that using the targeted quantitative image features computed from global images could also provide highly discriminatory power, which are supplementary to the lesion-based information. To test our hypothesis, we recently performed a number of independent studies. Based on our published preliminary study results, we demonstrated that global mammographic image features and background parenchymal enhancement of breast MR images carried useful information to (1) predict near-term breast cancer risk based on negative screening mammograms, (2) distinguish between true- and false-positive recalls in mammography screening examinations, and (3) classify between malignant and benign breast MR examinations. The global case-based CAD scheme only warns a risk level of the cases without cueing a large number of false-positive lesions. It can also be applied to guide lesion-based CAD cueing to reduce false-positives but enhance clinically relevant true-positive cueing. However, before such a new CAD approach is clinically acceptable, more work is needed to optimize not only the scheme performance but also how to integrate with lesion-based CAD schemes in the clinical practice.

  7. High-content screening of functional genomic libraries.

    Science.gov (United States)

    Rines, Daniel R; Tu, Buu; Miraglia, Loren; Welch, Genevieve L; Zhang, Jia; Hull, Mitchell V; Orth, Anthony P; Chanda, Sumit K

    2006-01-01

    Recent advances in functional genomics have enabled genome-wide genetic studies in mammalian cells. These include the establishment of high-throughput transfection and viral propagation methodologies, the production of large-scale cDNA and siRNA libraries, and the development of sensitive assay detection processes and instrumentation. The latter has been significantly facilitated by the implementation of automated microscopy and quantitative image analysis, collectively referred to as high-content screening (HCS), toward cell-based functional genomics application. This technology can be applied to whole genome analysis of discrete molecular and phenotypic events at the level of individual cells and promises to significantly expand the scope of functional genomic analyses in mammalian cells. This chapter provides a comprehensive guide for curating and preparing function genomics libraries and performing HCS at the level of the genome.

  8. Approaches to Pendent Groups' Functionalization of Polyimide

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Pendent groups' functionalization of polyimide is an optimum approach to improve its processability and achieve functionalized polyimide materials. There are two types of modification routes for pendent groups functionalization of polyimide: monomer route and macromolecular route. In this paper, various approaches for pendent groups' functionalization of polyimide are introduced. At the same time, a new method to achieve functional polyimide materials without decreasing its thermal stability and mechanical properties is mentioned.

  9. Diagnostic Approach to Functional Recovery

    DEFF Research Database (Denmark)

    Havsteen, Inger; Madsen, Kristoffer H; Christensen, Hanne Krarup

    2013-01-01

    a substantial capacity to reorganize after a focal ischemic (or hemorrhagic) brain lesion. This functional reorganization contributes to functional recovery after stroke. Functional magnetic resonance imaging (fMRI) provides a valuable tool to capture the spatial and temporal activity changes in response......, only up to 20-25% of patients are eligible to causal treatment. Further, care in a specialized stroke unit improves prognosis in all patients independent of age and stroke severity. Even when it is not possible to prevent tissue loss, the surviving brain areas of functional brain networks have...... to an acute ischemic lesion. Task-related as well as resting-state fMRI have been successfully applied to elucidate post-stroke remodeling of functional brain networks. This includes regional changes in neuronal activation as well as distributed changes in functional brain connectivity. Since fMRI is readily...

  10. Discovery of novel drug targets and their functions using phenotypic screening of natural products.

    Science.gov (United States)

    Chang, Junghwa; Kwon, Ho Jeong

    2016-03-01

    Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

  11. Symbolic Tensor Calculus -- Functional and Dynamic Approach

    CERN Document Server

    Woszczyna, A; Czaja, W; Golda, Z A

    2016-01-01

    In this paper, we briefly discuss the dynamic and functional approach to computer symbolic tensor analysis. The ccgrg package for Wolfram Language/Mathematica is used to illustrate this approach. Some examples of applications are attached.

  12. Screening and metamodeling of computer experiments with functional outputs. Application to thermal-hydraulic computations

    CERN Document Server

    Auder, Benjamin; Iooss, Bertrand; Marques, Michel

    2010-01-01

    To perform uncertainty, sensitivity or optimization analysis on scalar variables calculated by a cpu time expensive computer code, a widely accepted methodology consists in first identifying the most influential uncertain inputs (by screening techniques), and then in replacing the cpu time expensive model by a cpu inexpensive mathematical function, called a metamodel. This paper extends this methodology to the functional output case, for instance when the model output variables are curves. The screening approach is based on the analysis of variance and principal component analysis of output curves. The functional metamodeling consists in a curve classification step, a dimension reduction step, then a classical metamodeling step. An industrial nuclear reactor application (dealing with uncertainties in the pressurized thermal shock analysis) illustrates all these steps.

  13. Disseminating perinatal depression screening as a public health initiative: a train-the-trainer approach.

    Science.gov (United States)

    Segre, Lisa S; Brock, Rebecca L; O'Hara, Michael W; Gorman, Laura L; Engeldinger, Jane

    2011-08-01

    This case report describes the development and implementation of the Train-the-Trainer: Maternal Depression Screening Program (TTT), a novel approach to disseminating perinatal depression screening. We trained screeners according to a standard pyramid scheme of train-the-trainer programs: three experts trained representatives from health care agencies (the TTT trainers), who in turn trained their staff and implemented depression screening at their home agencies. The TTT trainers had little or no prior mental health experience so "enhanced" components were added to ensure thorough instruction. Although TTT was implemented primarily as a services project, we evaluated both the statewide dissemination and the screening rates achieved by TTT programs. Thirty-two social service or health agencies implemented maternal depression screening in 20 counties throughout Iowa; this reached 58.2% of the Iowa population. For the 16 agencies that provided screening data, the average screening rate (number of women screened/number eligible to be screened) for the first 3 months of screening was 73.2%, 80.5% and 79.0%. We compared screening rates of our TTT programs with those of Healthy Start, a program in which screening was established via an intensive consultation model. We found the screening rates in 62.5% of TTT agencies were comparable to those in Healthy Start. Our "enhanced" train-the-trainer method is a promising approach for broadly implementing depression-screening programs in agencies serving pregnant and postpartum women.

  14. Contact-based ligand-clustering approach for the identification of active compounds in virtual screening

    Directory of Open Access Journals (Sweden)

    Mantsyzov AB

    2012-09-01

    Full Text Available Alexey B Mantsyzov,1 Guillaume Bouvier,2 Nathalie Evrard-Todeschi,1 Gildas Bertho11Université Paris Descartes, Sorbonne, Paris, France; 2Institut Pasteur, Paris, FranceAbstract: Evaluation of docking results is one of the most important problems for virtual screening and in silico drug design. Modern approaches for the identification of active compounds in a large data set of docked molecules use energy scoring functions. One of the general and most significant limitations of these methods relates to inaccurate binding energy estimation, which results in false scoring of docked compounds. Automatic analysis of poses using self-organizing maps (AuPosSOM represents an alternative approach for the evaluation of docking results based on the clustering of compounds by the similarity of their contacts with the receptor. A scoring function was developed for the identification of the active compounds in the AuPosSOM clustered dataset. In addition, the AuPosSOM efficiency for the clustering of compounds and the identification of key contacts considered as important for its activity, were also improved. Benchmark tests for several targets revealed that together with the developed scoring function, AuPosSOM represents a good alternative to the energy-based scoring functions for the evaluation of docking results.Keywords: scoring, docking, virtual screening, CAR, AuPosSOM

  15. Accessing autonomic function can early screen metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Kan Sun

    Full Text Available BACKGROUND: Clinical diagnosis of the metabolic syndrome is time-consuming and invasive. Convenient instruments that do not require laboratory or physical investigation would be useful in early screening individuals at high risk of metabolic syndrome. Examination of the autonomic function can be taken as a directly reference and screening indicator for predicting metabolic syndrome. METHODOLOGY AND PRINCIPAL FINDINGS: The EZSCAN test, as an efficient and noninvasive technology, can access autonomic function through measuring electrochemical skin conductance. In this study, we used EZSCAN value to evaluate autonomic function and to detect metabolic syndrome in 5,887 participants aged 40 years or older. The EZSCAN test diagnostic accuracy was analyzed by receiver operating characteristic curves. Among the 5,815 participants in the final analysis, 2,541 were diagnosed as metabolic syndrome and the overall prevalence was 43.7%. Prevalence of the metabolic syndrome increased with the elevated EZSCAN risk level (p for trend <0.0001. Moreover, EZSCAN value was associated with an increase in the number of metabolic syndrome components (p for trend <0.0001. Compared with the no risk group (EZSCAN value 0-24, participants at the high risk group (EZSCAN value: 50-100 had a 2.35 fold increased risk of prevalent metabolic syndrome after the multiple adjustments. The area under the curve of the EZSCAN test was 0.62 (95% confidence interval [CI], 0.61-0.64 for predicting metabolic syndrome. The optimal operating point for the EZSCAN value to detect a high risk of prevalent metabolic syndrome was 30 in this study, while the sensitivity and specificity were 71.2% and 46.7%, respectively. CONCLUSIONS AND SIGNIFICANCE: In conclusion, although less sensitive and accurate when compared with the clinical definition of metabolic syndrome, we found that the EZSCAN test is a good and simple screening technique for early predicting metabolic syndrome.

  16. Soil eukaryotic functional diversity, a metatranscriptomic approach.

    Science.gov (United States)

    Bailly, Julie; Fraissinet-Tachet, Laurence; Verner, Marie-Christine; Debaud, Jean-Claude; Lemaire, Marc; Wésolowski-Louvel, Micheline; Marmeisse, Roland

    2007-11-01

    To appreciate the functional diversity of communities of soil eukaryotic micro-organisms we evaluated an experimental approach based on the construction and screening of a cDNA library using polyadenylated mRNA extracted from a forest soil. Such a library contains genes that are expressed by each of the different organisms forming the community and represents its metatranscriptome. The diversity of the organisms that contributed to this library was evaluated by sequencing a portion of the 18S rDNA gene amplified from either soil DNA or reverse-transcribed RNA. More than 70% of the sequences were from fungi and unicellular eukaryotes (protists) while the other most represented group was the metazoa. Calculation of richness estimators suggested that more than 180 species could be present in the soil samples studied. Sequencing of 119 cDNA identified genes with no homologues in databases (32%) and genes coding proteins involved in different biochemical and cellular processes. Surprisingly, the taxonomic distribution of the cDNA and of the 18S rDNA genes did not coincide, with a marked under-representation of the protists among the cDNA. Specific genes from such an environmental cDNA library could be isolated by expression in a heterologous microbial host, Saccharomyces cerevisiae. This is illustrated by the functional complementation of a histidine auxotrophic yeast mutant by two cDNA originating possibly from an ascomycete and a basidiomycete fungal species. Study of the metatranscriptome has the potential to uncover adaptations of whole microbial communities to local environmental conditions. It also gives access to an abundant source of genes of biotechnological interest.

  17. Functional Movement Screen (FMS) - kompleksowy system oceny funkcjonalnej pacjenta = Functional Movement Screen (FMS) - a comprehensive system for the functional evaluation of the patient

    OpenAIRE

    Kochański, Bartosz; Plaskiewicz, Anna; Kałużny, Krystian; Dylewska, Monika; Płoszaj, Ola; Hagner-Derengowska, Magdalena; Zukow, Walery

    2015-01-01

    Kochański Bartosz, Plaskiewicz Anna, Kałużny Krystian, Dylewska Monika, Płoszaj Ola, Hagner-Derengowska Magdalena, Zukow Walery. Functional Movement Screen (FMS) - kompleksowy system oceny funkcjonalnej pacjenta = Functional Movement Screen (FMS) - a comprehensive system for the functional evaluation of the patient. Journal of Education, Health and Sport. 2015;5(4):90-101. ISSN 2391-8306. DOI: 10.5281/zenodo.16626 http://ojs.ukw.edu.pl/index.php/johs/article/view/2015%3B5%284%29...

  18. Performance on the Functional Movement Screen in older active adults

    Institute of Scientific and Technical Information of China (English)

    Ulrike H. Mitchell; A. Wayne Johnson; Pat R. Vehrs; J. Brent Feland; Sterling C. Hilton

    2016-01-01

    Background: The Functional Movement Screen (FMS™) has become increasingly popular for identifying functional limitations in basic functional movements. This exploratory and descriptive study was undertaken to confirm feasibility of performing the FMS™ in older active adults, assess prevalence of asymmetries and to evaluate the relationship between functional movement ability, age, physical activity levels and body mass index (BMI). Methods: This is an observational study;97 men (n=53) and women (n=44) between the ages of 52 and 83 participated. BMI was computed and self-reported physical activity levels were obtained. Subjects were grouped by age (5-year intervals), BMI (normal, over-weight, and obese) and sex. Each participant’s performance on the FMS™was digitally recorded for later analysis. Results: The youngest age group (50–54 years) scored highest in all seven tests and the oldest age group (75+) scored lowest in most of the tests compared to all other age groups. The subjects in the“normal weight”group performed no different than those who were in the“overweight”group;both groups performed better than the“obese”group. Of the 97 participants 54 had at least one asymmetry. The pairwise correlations between the total FMS™score and age (r=−0.531), BMI (r=−0.270), and the measure of activity level (r=0.287) were significant (p<0.01 for all). Conclusion: FMS™scores decline with increased BMI, increased age, and decreased activity level. The screen identifies range of motion-and strength-related asymmetries. The FMS™can be used to assess functional limitations and asymmetries. Future research should evaluate if a higher total FMS™score is related to fewer falls or injuries in the older population.

  19. Functional screening of an asthma QTL in YAC transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Symula, Derek J.; Frazer, Kelly A.; Ueda, Yukihiko; Denefle, Patrice; Stevens, Mary E.; Wang, Zhi-En; Locksley, Richard; Rubin, Edward M.

    1999-07-02

    While large numbers of quantitative trait loci (QTLs) contributing to genetically complex conditions have been discovered, few causative genes have been identified. This is mainly due to the large size of QTLs and the subtle connection between genotype and quantitative phenotype associated with these conditions. While large numbers of quantitative trait loci (QTLs) contributing to genetically complex conditions have been discovered, few causative genes have been identified. This is mainly due to the large size of QTLs and the subtle connection between genotype and quantitative phenotype associated with these conditions. To screen for genes contributing to an asthma QTL mapped to human chromosome 5q33, the authors characterized a panel of large-insert 5q31 transgenics based on studies demonstrating that altering gene dosage frequently affects quantitative phenotypes normally influenced by that gene. This panel of human YAC transgenics, propagating a one megabase interva2048 chromosome 5q31 containing 23 genes, was screened for quantitative changes in several asthma-associated phenotypes. Multiple independent transgenic lines with altered IgE response to antigen treatment shared a 180 kb region containing 5 genes, including human interleukin 4 (IL4) and interleukin 13 (IL13), which induce IgE class switching in B cells5. Further analysis of these mice and mice transgenic for only murine Il4 and Il13 demonstrated that moderate changes in murine Il4 and Il13 expression affect asthma-associated phenotypes in vivo. This functional screen of large-insert transgenics enabled them to sift through multiple genes in the 5q3 asthma QTL without prior consideration of assumed individual gene function and identify genes that influence the QTL phenotype in vivo.

  20. Broad target chemical screening approach used as tool for rapid assessment of groundwater quality

    NARCIS (Netherlands)

    ter Laak, T.L.; Puijker, L.M.; van Leerdam, J.A.; Raat, K.J.; Kolkman, A.; de Voogt, P.; van Wezel, A.P.

    2012-01-01

    The chemical water quality is often assessed by screening for a limited set of target chemicals. This ‘conventional’ target analysis approach inevitably misses chemicals present in the samples. In this study a ‘broad’ target screening approach for water quality assessment using high resolution and a

  1. A first approach to a neuropsychological screening tool using eye-tracking for bedside cognitive testing based on the Edinburgh Cognitive and Behavioural ALS Screen.

    Science.gov (United States)

    Keller, Jürgen; Krimly, Amon; Bauer, Lisa; Schulenburg, Sarah; Böhm, Sarah; Aho-Özhan, Helena E A; Uttner, Ingo; Gorges, Martin; Kassubek, Jan; Pinkhardt, Elmar H; Abrahams, Sharon; Ludolph, Albert C; Lulé, Dorothée

    2017-08-01

    Reliable assessment of cognitive functions is a challenging task in amyotrophic lateral sclerosis (ALS) patients unable to speak and write. We therefore present an eye-tracking based neuropsychological screening tool based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a standard screening tool for cognitive deficits in ALS. In total, 46 ALS patients and 50 healthy controls matched for age, gender and education were tested with an oculomotor based and a standard paper-and-pencil version of the ECAS. Significant correlation between both versions was observed for ALS patients and healthy controls in the ECAS total score and in all of its ALS-specific domains (all r > 0.3; all p eye-tracking version of the ECAS reliably distinguished between ALS patients and healthy controls in the ECAS total score (p eye-tracking based ECAS version is a promising approach for assessing cognitive deficits in ALS patients who are unable to speak or write.

  2. Calculations of properties of screened He-like systems using correlated wave functions.

    Science.gov (United States)

    Dai, S T; Solovyova, A; Winkler, P

    2001-07-01

    The purpose of the present study is twofold. First, the techniques of correlated wave functions for two-electron systems have been extended to obtain results for P and D states in a screening environment, and in particular for Debye screening. In these calculations, the satisfaction of both the quantum virial theorem and a related sum rule has been enforced and found to provide a high degree of stability of the solutions. Second, in order to facilitate the general use of correlated wave functions in combination with sum rule stability criteria, a rather systematic computational approach to this notoriously cumbersome method has been developed and thoroughly discussed here. Accurate calculations for few-electron systems are of interest to plasma diagnostics; in particular, when inaccuracies in binding energies are drastically magnified as they occur in exponents of Boltzmann factors.

  3. Functional movement screen scores in a group of running athletes.

    Science.gov (United States)

    Loudon, Janice K; Parkerson-Mitchell, Amy J; Hildebrand, Laurie D; Teague, Connie

    2014-04-01

    The purpose of this study was to determine the mean values of the functional movement screen (FMS) in a group of long-distance runners. The secondary aims were to investigate whether the FMS performance differed between sexes and between young and older runners. Forty-three runners, 16 women (mean age = 33.5 years, height = 165.2 cm, weight = 56.3 kg, and body mass index [BMI] = 20.6) and 27 men (mean age = 39.3 years, height = 177.6 cm, weight = 75.8 kg, and BMI = 24.2) performed the FMS. All the runners were injury-free and ran >30 km·wk. Independent t-tests were performed on the composite scores to examine the differences between men and women and also between young (40 years). Contingency tables (2 × 2) were developed for each of the 7 screening tests to further look at the differences in groups for each single test. The χ values were calculated to determine significant differences. Statistical significance was set at p ≤ 0.05. There was no significant difference in the composite score between women and men. There were significant differences between the sexes in the push-up and straight leg test scores, with the women scoring better on each test. A significant difference was found in the composite scores between younger and older runners (p score differences were found for the squat, hurdle step, and in-line lunge tests with the younger runners scoring better. This study provided mean values for the FMS in a cohort of long-distance runners. These values can be used as a reference for comparing FMST scores in other runners who are screened with this tool.

  4. Primary health care approach for prevention, screening and ...

    African Journals Online (AJOL)

    (IGT) or impaired fasting glucose (IFG), screening of high-risk individuals has merit. During ... a precedent for effectively altering lifestyle in patients with a high risk for .... syndrome, a family history of Type 2 diabetes, a history of gestational.

  5. The Wisconsin approach to newborn screening for severe combined immunodeficiency.

    Science.gov (United States)

    Verbsky, James; Thakar, Monica; Routes, John

    2012-03-01

    Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable with hematopoietic cell transplantation if detected early. Population-based screening for SCID using the T-cell receptor excision circle (TREC) assay began in Wisconsin in 2008; 5 infants with SCID or other forms of severe T-cell lymphopenia (TCL) have been detected, and no infants with SCID have been missed. This review will provide an overview of the TREC screening assay and an update of the findings from Wisconsin on all infants screened from January 1, 2008, until December 31, 2010. Importantly, we give practical recommendations regarding newborn population-based screening using the TREC assay, including the evaluation and care of infants detected.

  6. Molecular Approaches to Screen Bioactive Compounds from Endophytic Fungi

    OpenAIRE

    Vasundhara, M.; Anil Kumar; M. Sudhakara Reddy

    2016-01-01

    Endophytic fungi are capable of producing plant associated metabolites and their analogs with therapeutic value. In order to identify the potential endophytic isolates producing bioactive compounds, one need to screen all isolated endophytes, which may run into hundreds. Isolation of endophytic fungi is relatively a simple process; but screening of the isolated fungi for required metabolite production is a cumbersome process. Endophytic fungi producing plant associated metabolites may contain...

  7. Microfluidic screening of electrophoretic mobility shifts elucidates riboswitch binding function.

    Science.gov (United States)

    Karns, Kelly; Vogan, Jacob M; Qin, Qian; Hickey, Scott F; Wilson, Stephen C; Hammond, Ming C; Herr, Amy E

    2013-02-27

    Riboswitches are RNA sensors that change conformation upon binding small molecule metabolites, in turn modulating gene expression. Our understanding of riboswitch regulatory function would be accelerated by a high-throughput, quantitative screening tool capable of measuring riboswitch-ligand binding. We introduce a microfluidic mobility shift assay that enables precise and rapid quantitation of ligand binding and subsequent riboswitch conformational change. In 0.3% of the time required for benchtop assays (3.2 versus 1020 min), we screen and validate five candidate SAM-I riboswitches isolated from thermophilic and cryophilic bacteria. The format offers enhanced resolution of conformational change compared to slab gel formats, quantitation, and repeatability for statistical assessment of small mobility shifts, low reagent consumption, and riboswitch characterization without modification of the aptamer structure. Appreciable analytical sensitivity coupled with high-resolution separation performance allows quantitation of equilibrium dissociation constants (K(d)) for both rapidly and slowly interconverting riboswitch-ligand pairs as validated through experiments and modeling. Conformational change, triplicate mobility shift measurements, and K(d) are reported for both a known and a candidate SAM-I riboswitch with comparison to in-line probing assay results. The microfluidic mobility shift assay establishes a scalable format for the study of riboswitch-ligand binding that will advance the discovery and selection of novel riboswitches and the development of antibiotics to target bacterial riboswitches.

  8. A partial ordering approach for functional diversity.

    Science.gov (United States)

    Ricotta, Carlo; Szeidl, Laszlo; Moretti, Marco; Blasi, Carlo

    2011-09-01

    Functional diversity is generally regarded as the constituent of biological diversity that considers how the species functional traits affect ecosystem processes. Due to its ecological relevance, a number of indices of functional diversity have been proposed to date based on distinct objectives and motivations. Such proliferation of indices can be at least partially overcome by a more fundamental mathematical approach. In this paper we propose an intrinsic ordering approach for abundance-weighted measures of functional diversity that is similar to the Lorenz curves used by ecologists for ordering evenness measures. We then discuss the relevance of a number of functional diversity indices that have a behavior compatible with the proposed partial ordering.

  9. An efficient RNA interference screening strategy for gene functional analysis

    Directory of Open Access Journals (Sweden)

    Chang Chih-Hung

    2012-09-01

    Full Text Available Abstract Background RNA interference (RNAi is commonly applied in genome-scale gene functional screens. However, a one-on-one RNAi analysis that targets each gene is cost-ineffective and laborious. Previous studies have indicated that siRNAs can also affect RNAs that are near-perfectly complementary, and this phenomenon has been termed an off-target effect. This phenomenon implies that it is possible to silence several genes simultaneously with a carefully designed siRNA. Results We propose a strategy that is combined with a heuristic algorithm to design suitable siRNAs that can target multiple genes and a group testing method that would reduce the number of required RNAi experiments in a large-scale RNAi analysis. To verify the efficacy of our strategy, we used the Orchid expressed sequence tag data as a case study to screen the putative transcription factors that are involved in plant disease responses. According to our computation, 94 qualified siRNAs were sufficient to examine all of the predicated 229 transcription factors. In addition, among the 94 computer-designed siRNAs, an siRNA that targets both TF15 (a previously identified transcription factor that is involved in the plant disease-response pathway and TF21 was introduced into orchids. The experimental results showed that this siRNA can simultaneously silence TF15 and TF21, and application of our strategy successfully confirmed that TF15 is involved in plant defense responses. Interestingly, our second-round analysis, which used an siRNA specific to TF21, indicated that TF21 is a previously unidentified transcription factor that is related to plant defense responses. Conclusions Our computational results showed that it is possible to screen all genes with fewer experiments than would be required for the traditional one-on-one RNAi screening. We also verified that our strategy is capable of identifying genes that are involved in a specific phenotype.

  10. Development of a Cargo Screening Process Simulator: A First Approach

    CERN Document Server

    Siebers, Peer-Olaf; Aickelin, Uwe

    2010-01-01

    The efficiency of current cargo screening processes at sea and air ports is largely unknown as few benchmarks exists against which they could be measured. Some manufacturers provide benchmarks for individual sensors but we found no benchmarks that take a holistic view of the overall screening procedures and no benchmarks that take operator variability into account. Just adding up resources and manpower used is not an effective way for assessing systems where human decision-making and operator compliance to rules play a vital role. Our aim is to develop a decision support tool (cargo-screening system simulator) that will map the right technology and manpower to the right commodity-threat combination in order to maximise detection rates. In this paper we present our ideas for developing such a system and highlight the research challenges we have identified. Then we introduce our first case study and report on the progress we have made so far.

  11. The distinguishable cluster approach from a screened Coulomb formalism.

    Science.gov (United States)

    Kats, Daniel

    2016-01-28

    The distinguishable cluster doubles equations have been derived starting from an effective screened Coulomb formalism and a particle-hole symmetric formulation of the Fock matrix. A perturbative triples correction to the distinguishable cluster with singles and doubles (DCSD) has been introduced employing the screened integrals. It is shown that the resulting DCSD(T) method is more accurate than DCSD for reaction energies and is less sensitive to the static correlation than coupled cluster with singles and doubles with a perturbative triples correction.

  12. An iterative approach of protein function prediction

    Directory of Open Access Journals (Sweden)

    Chi Xiaoxiao

    2011-11-01

    Full Text Available Abstract Background Current approaches of predicting protein functions from a protein-protein interaction (PPI dataset are based on an assumption that the available functions of the proteins (a.k.a. annotated proteins will determine the functions of the proteins whose functions are unknown yet at the moment (a.k.a. un-annotated proteins. Therefore, the protein function prediction is a mono-directed and one-off procedure, i.e. from annotated proteins to un-annotated proteins. However, the interactions between proteins are mutual rather than static and mono-directed, although functions of some proteins are unknown for some reasons at present. That means when we use the similarity-based approach to predict functions of un-annotated proteins, the un-annotated proteins, once their functions are predicted, will affect the similarities between proteins, which in turn will affect the prediction results. In other words, the function prediction is a dynamic and mutual procedure. This dynamic feature of protein interactions, however, was not considered in the existing prediction algorithms. Results In this paper, we propose a new prediction approach that predicts protein functions iteratively. This iterative approach incorporates the dynamic and mutual features of PPI interactions, as well as the local and global semantic influence of protein functions, into the prediction. To guarantee predicting functions iteratively, we propose a new protein similarity from protein functions. We adapt new evaluation metrics to evaluate the prediction quality of our algorithm and other similar algorithms. Experiments on real PPI datasets were conducted to evaluate the effectiveness of the proposed approach in predicting unknown protein functions. Conclusions The iterative approach is more likely to reflect the real biological nature between proteins when predicting functions. A proper definition of protein similarity from protein functions is the key to predicting

  13. A Unified Approach to Generalized Stirling Functions

    Institute of Scientific and Technical Information of China (English)

    Tianxiao HE

    2012-01-01

    Here presented is a unified approach to generalized Stirling functions by using generalized factorial functions,k-Gamma functions,generalized divided difference,and the unified expression of Stirling numbers defined in[16].Previous well-known Stirling functions introduced by Butzer and Hauss[4],Butzer,Kilbas,and Trujilloet[6]and others are included as particular cases of our generalization.Some basic properties related to our general pattern such as their recursive relations,generating functions,and asymptotic properties are discussed,which extend the corresponding results about the Stirling numbers shown in[21]to the defined Stirling functions.

  14. Analysis of radial basis function interpolation approach

    Institute of Scientific and Technical Information of China (English)

    Zou You-Long; Hu Fa-Long; Zhou Can-Can; Li Chao-Liu; Dunn Keh-Jim

    2013-01-01

    The radial basis function (RBF) interpolation approach proposed by Freedman is used to solve inverse problems encountered in well-logging and other petrophysical issues. The approach is to predict petrophysical properties in the laboratory on the basis of physical rock datasets, which include the formation factor, viscosity, permeability, and molecular composition. However, this approach does not consider the effect of spatial distribution of the calibration data on the interpolation result. This study proposes a new RBF interpolation approach based on the Freedman's RBF interpolation approach, by which the unit basis functions are uniformly populated in the space domain. The inverse results of the two approaches are comparatively analyzed by using our datasets. We determine that although the interpolation effects of the two approaches are equivalent, the new approach is more flexible and beneficial for reducing the number of basis functions when the database is large, resulting in simplification of the interpolation function expression. However, the predicted results of the central data are not sufficiently satisfied when the data clusters are far apart.

  15. Efficacy of the functional movement screen: a review.

    Science.gov (United States)

    Kraus, Kornelius; Schütz, Elisabeth; Taylor, William R; Doyscher, Ralf

    2014-12-01

    The aim of this review was to evaluate and synthesize the scientific literature of the functional movement screen (FMS)-driven research for scientists and strength and conditioning specialists. An additional purpose was to optimize the methodological quality of prospective studies. Relevant research was identified through using a manual and electronically database search. Thirty-four articles met the inclusion criteria and were read, abstracted, and coded for this review. The publications were classified into different stages of Bishops Applied Research Model for the Sport Sciences (ARMSS). Thirteen descriptive studies explored the main tasks in test development like factor structure, objectivity, and reliability. They can be classified to the second stage of Bishops Model (ARMSS stage 2). Twelve studies covered ability of FMS to predict sporting performance and injury risk (ARMSS stages 3 and 4). Seven studies investigated the effectiveness of the FMS in designing programs (ARMSS stages 6 and 8). In addition, 2 assessed norming data. On the descriptive level, results suggest that the FMS is a reliable screen, if the rater is educated and has solid experience (>100 trials). Factor analysis describes the FMS as a unitary construct, which is an argument against the FMS total score. Studies clearly illustrate its limited ability to predict athletic performance. On the contrary, to predict injury risk in team sports, the FMS total score is supported by moderate scientific evidence. The majority of the FMS based intervention programs showed an improvement on general motor quality. However, a randomized trial does not confirm that results. Hence, to implement the findings on field, a critical strength and conditioning specialist is crucial.

  16. Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening.

    Directory of Open Access Journals (Sweden)

    Rodrigo Quiroga

    Full Text Available Autodock Vina is a very popular, and highly cited, open source docking program. Here we present a scoring function which we call Vinardo (Vina RaDii Optimized. Vinardo is based on Vina, and was trained through a novel approach, on state of the art datasets. We show that the traditional approach to train empirical scoring functions, using linear regression to optimize the correlation of predicted and experimental binding affinities, does not result in a function with optimal docking capabilities. On the other hand, a combination of scoring, minimization, and re-docking on carefully curated training datasets allowed us to develop a simplified scoring function with optimum docking performance. This article provides an overview of the development of the Vinardo scoring function, highlights its differences with Vina, and compares the performance of the two scoring functions in scoring, docking and virtual screening applications. Vinardo outperforms Vina in all tests performed, for all datasets analyzed. The Vinardo scoring function is available as an option within Smina, a fork of Vina, which is freely available under the GNU Public License v2.0 from http://smina.sf.net. Precompiled binaries, source code, documentation and a tutorial for using Smina to run the Vinardo scoring function are available at the same address.

  17. Vinardo: A Scoring Function Based on Autodock Vina Improves Scoring, Docking, and Virtual Screening.

    Science.gov (United States)

    Quiroga, Rodrigo; Villarreal, Marcos A

    2016-01-01

    Autodock Vina is a very popular, and highly cited, open source docking program. Here we present a scoring function which we call Vinardo (Vina RaDii Optimized). Vinardo is based on Vina, and was trained through a novel approach, on state of the art datasets. We show that the traditional approach to train empirical scoring functions, using linear regression to optimize the correlation of predicted and experimental binding affinities, does not result in a function with optimal docking capabilities. On the other hand, a combination of scoring, minimization, and re-docking on carefully curated training datasets allowed us to develop a simplified scoring function with optimum docking performance. This article provides an overview of the development of the Vinardo scoring function, highlights its differences with Vina, and compares the performance of the two scoring functions in scoring, docking and virtual screening applications. Vinardo outperforms Vina in all tests performed, for all datasets analyzed. The Vinardo scoring function is available as an option within Smina, a fork of Vina, which is freely available under the GNU Public License v2.0 from http://smina.sf.net. Precompiled binaries, source code, documentation and a tutorial for using Smina to run the Vinardo scoring function are available at the same address.

  18. Function-Based Metagenomic Library Screening and Heterologous Expression Strategy for Genes Encoding Phosphatase Activity.

    Science.gov (United States)

    Villamizar, Genis A Castillo; Nacke, Heiko; Daniel, Rolf

    2017-01-01

    The release of phosphate from inorganic and organic phosphorus compounds can be mediated enzymatically. Phosphate-releasing enzymes, comprising acid and alkaline phosphatases, are recognized as useful biocatalysts in applications such as plant and animal nutrition, bioremediation and diagnostic analysis. Metagenomic approaches provide access to novel phosphatase-encoding genes. Here, we describe a function-based screening approach for rapid identification of genes conferring phosphatase activity from small-insert and large-insert metagenomic libraries derived from various environments. This approach bears the potential for discovery of entirely novel phosphatase families or subfamilies and members of known enzyme classes hydrolyzing phosphomonoester bonds such as phytases. In addition, we provide a strategy for efficient heterologous phosphatase gene expression.

  19. Screening for autism identifies behavioral disorders in children functional defecation disorders

    OpenAIRE

    Kuizenga-Wessel, Sophie; Di Lorenzo, Carlo; Nicholson, Lisa M.; Butter, Eric M.; Ratliff-Schaub, Karen L.; Marc A Benninga; Williams, Kent C.

    2016-01-01

    This study prospectively assessed whether positive screening surveys for autism spectrum disorders (ASDs) in children with functional defecation disorders (FDDs) accurately identify ASD. Parents of children (4–12 years) who met Rome III criteria for functional constipation (FC), FC with fecal incontinence (FI) and functional nonretentive FI (FNRFI) completed two ASD screening surveys. Children with positive screens were referred for psychological evaluation, and a year later, follow-up survey...

  20. Functional capacity evaluation: an empirical approach.

    Science.gov (United States)

    Jette, A M

    1980-02-01

    This paper presents an empirical approach to selecting activities of daily living (ADL) to assess the functional capacity of noninstitutionalized individuals with polyarticular disability. The results of structural analyses illustrate the feasibility of substantially reducing the task of assessing functional capacity with a subset of ADL items without sacrificing the comprehensiveness of the assessment. The analyses reveal 5 common functional categories: physical mobility, transfers, home chores, kitchen chores, and personal care, which account for over 50% of the variance in the data.

  1. Advanced Lung Cancer Screening: An Individualized Molecular Nanotechnology Approach

    Science.gov (United States)

    2014-08-01

    lung tumors in Asian populations than in the Baltimore region. Our plans for implementation of this panel for detection in plasma and sputum were...increase in amplifiable DNA, on average. Having developed an optimal panel and improved upon methods for processing the DNA as planned , we...CT Densitometry of Screening Participants CT scans were analyzed for emphysema using Pulmonary Workstation 2.0 software ( Vida Diagnosis, Iowa City

  2. Microfluidic Approaches for Manipulating, Imaging, and Screening C. elegans

    Directory of Open Access Journals (Sweden)

    Bhagwati P. Gupta

    2016-07-01

    Full Text Available The nematode C. elegans (worm is a small invertebrate animal widely used in studies related to fundamental biological processes, disease modelling, and drug discovery. Due to their small size and transparent body, these worms are highly suitable for experimental manipulations. In recent years several microfluidic devices and platforms have been developed to accelerate worm handling, phenotypic studies and screens. Here we review major tools and briefly discuss their usage in C. elegans research.

  3. Screening Twilight: critical approaches to a cinematic phenomenon

    OpenAIRE

    Clayton, Wickham; Harman, Sarah

    2014-01-01

    The Twilight saga, a series of five films adapted from Stephanie Meyer's four vampire novels, has been a sensation, both at the box office and through the attention it has won from its predominantly teenaged fans. This series has also been the subject of criticism and sometimes derision - often from critics and on occasion even from fans. However, it also offers rich opportunities for analytic and critical attention, which the contributors to Screening Twilight demonstrate with energy and sty...

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

    Directory of Open Access Journals (Sweden)

    Yoshiki eNakahara

    2015-10-01

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

  5. A Functional Approach to User Guides

    DEFF Research Database (Denmark)

    Nielsen, Sandro

    2007-01-01

    The functional approach opens up exciting new possibilities for theoretical and practical lexicography. It encourages lexicographers to adopt a new way of thinking when planning and compiling dictionaries and when discussing and developing new lexicographic principles. One area in which it impacts...... to fulfil the requirements of users. By applying the functional approach lexicographers are forced to reconsider the scope of the user guide. The user guide has traditionally centred on the structures of entries - and consequently on the word list - but its scope should be widened, so as to include all......-oriented and/or cognitive functions and relate the data in the entire dictionary, not merely the entries, to these functions. Finally, the lexicographers should consider the classes of language functions involved in writing user guides. In order to guide and instruct the user in the best way possible, user...

  6. A functional approach to the TMJ disorders.

    Science.gov (United States)

    Deodato, F; Cristiano, S; Trusendi, R; Giorgetti, R

    2003-01-01

    This manuscript describes our conservative approach to treatment of TMJ disorders. The method we use had been suggested by Rocabado - its aims are: joint distraction by the elimination of compression, restoration of physiologic articular rest, mobilization of the soft tissues, and whenever possible, to improve the condyle-disk-glenoid fossa relationship. To support these claims two clinical cases are presented where the non-invasive therapy was successful. The results obtained confirm the validity of this functional approach.

  7. Isolation of xylose isomerases by sequence- and function-based screening from a soil metagenomic library

    Directory of Open Access Journals (Sweden)

    Parachin Nádia

    2011-05-01

    Full Text Available Abstract Background Xylose isomerase (XI catalyses the isomerisation of xylose to xylulose in bacteria and some fungi. Currently, only a limited number of XI genes have been functionally expressed in Saccharomyces cerevisiae, the microorganism of choice for lignocellulosic ethanol production. The objective of the present study was to search for novel XI genes in the vastly diverse microbial habitat present in soil. As the exploitation of microbial diversity is impaired by the ability to cultivate soil microorganisms under standard laboratory conditions, a metagenomic approach, consisting of total DNA extraction from a given environment followed by cloning of DNA into suitable vectors, was undertaken. Results A soil metagenomic library was constructed and two screening methods based on protein sequence similarity and enzyme activity were investigated to isolate novel XI encoding genes. These two screening approaches identified the xym1 and xym2 genes, respectively. Sequence and phylogenetic analyses revealed that the genes shared 67% similarity and belonged to different bacterial groups. When xym1 and xym2 were overexpressed in a xylA-deficient Escherichia coli strain, similar growth rates to those in which the Piromyces XI gene was expressed were obtained. However, expression in S. cerevisiae resulted in only one-fourth the growth rate of that obtained for the strain expressing the Piromyces XI gene. Conclusions For the first time, the screening of a soil metagenomic library in E. coli resulted in the successful isolation of two active XIs. However, the discrepancy between XI enzyme performance in E. coli and S. cerevisiae suggests that future screening for XI activity from soil should be pursued directly using yeast as a host.

  8. [Partial lease squares approach to functional analysis].

    Science.gov (United States)

    Preda, C

    2006-01-01

    We extend the partial least squares (PLS) approach to functional data represented in our models by sample paths of stochastic process with continuous time. Due to the infinite dimension, when functional data are used as a predictor for linear regression and classification models, the estimation problem is an ill-posed one. In this context, PLS offers a simple and efficient alternative to the methods based on the principal components of the stochastic process. We compare the results given by the PLS approach and other linear models using several datasets from economy, industry and medical fields.

  9. Scanning probe and micropatterning approaches for biomolecular screening applications

    CERN Document Server

    Wilde, L M

    2002-01-01

    Force mapping using atomic force microscopy (AFM) allows for the simultaneous acquisition of topography and probe-sample interaction data. For example, AFM probes functionalised with an antigen can be employed to map the spatial distribution of recognition events on a substrate functionalised with the complementary specific antibody. However, this technique is currently limited to the detection of a single receptor-ligand species. Were the detection of multiple receptor-ligand interactions possible, AFM force mapping would offer greater scope as a sensitive tool for bioassay and screening applications. This thesis outlines developments in probe and substrate immobilisation methods to facilitate this process. We have developed an immobilisation strategy, which allows two antigen species, human serum albumin (HSA) and the beta subunit of human chorionic gonadotropin (beta hCG) to be simultaneously present on an AFM probe. Single point force spectroscopy results have revealed the ability of such probes to discri...

  10. An ENU-mutagenesis screen in the mouse: identification of novel developmental gene functions.

    Directory of Open Access Journals (Sweden)

    Carolien Wansleeben

    Full Text Available BACKGROUND: Mutagenesis screens in the mouse have been proven useful for the identification of novel gene functions and generation of interesting mutant alleles. Here we describe a phenotype-based screen for recessive mutations affecting embryonic development. METHODOLOGY/PRINCIPAL FINDINGS: Mice were mutagenized with N-ethyl-N-nitrosourea (ENU and following incrossing the offspring, embryos were analyzed at embryonic day 10.5. Mutant phenotypes that arose in our screen include cardiac and nuchal edema, neural tube defects, situs inversus of the heart, posterior truncation and the absence of limbs and lungs. We isolated amongst others novel mutant alleles for Dll1, Ptprb, Plexin-B2, Fgf10, Wnt3a, Ncx1, Scrib(Scrib, Scribbled homolog [Drosophila] and Sec24b. We found both nonsense alleles leading to severe protein truncations and mutants with single-amino acid substitutions that are informative at a molecular level. Novel findings include an ectopic neural tube in our Dll1 mutant and lung defects in the planar cell polarity mutants for Sec24b and Scrib. CONCLUSIONS/SIGNIFICANCE: Using a forward genetics approach, we have generated a number of novel mutant alleles that are linked to disturbed morphogenesis during development.

  11. Universal screening test based on analysis of circulating organ-enriched microRNAs: a novel approach to diagnostic screening.

    Science.gov (United States)

    Sheinerman, Kira S; Umansky, Samuil

    2015-03-01

    Early disease detection leads to more effective and cost-efficient treatment. It is especially important for cancer and neurodegenerative diseases, because progression of these pathologies leads to significant and frequently irreversible changes in underlying pathophysiological processes. At the same time, the development of specific screening tests for detection of each of the hundreds of human pathologies in asymptomatic stage may be impractical. Here, we discuss a recently proposed concept: the development of minimally invasive Universal Screening Test (UST) based on analysis of organ-enriched microRNAs in plasma and other bodily fluids. The UST is designed to detect the presence of a pathology in particular organ systems, organs, tissues or cell types without diagnosing a specific disease. Once the pathology is detected, more specific, and if necessary invasive and expensive, tests can be administered to precisely define the nature of the disease. Here, we discuss recent studies and analyze the data supporting the UST approach.

  12. Introducing linear functions: an alternative statistical approach

    Science.gov (United States)

    Nolan, Caroline; Herbert, Sandra

    2015-12-01

    The introduction of linear functions is the turning point where many students decide if mathematics is useful or not. This means the role of parameters and variables in linear functions could be considered to be `threshold concepts'. There is recognition that linear functions can be taught in context through the exploration of linear modelling examples, but this has its limitations. Currently, statistical data is easily attainable, and graphics or computer algebra system (CAS) calculators are common in many classrooms. The use of this technology provides ease of access to different representations of linear functions as well as the ability to fit a least-squares line for real-life data. This means these calculators could support a possible alternative approach to the introduction of linear functions. This study compares the results of an end-of-topic test for two classes of Australian middle secondary students at a regional school to determine if such an alternative approach is feasible. In this study, test questions were grouped by concept and subjected to concept by concept analysis of the means of test results of the two classes. This analysis revealed that the students following the alternative approach demonstrated greater competence with non-standard questions.

  13. Tailor-Made Pore Surface Engineering in Covalent Organic Frameworks: Systematic Functionalization for Performance Screening.

    Science.gov (United States)

    Huang, Ning; Krishna, Rajamani; Jiang, Donglin

    2015-06-10

    Imine-linked covalent organic frameworks (COFs) were synthesized to bear content-tunable, accessible, and reactive ethynyl groups on the walls of one-dimensional pores. These COFs offer an ideal platform for pore-wall surface engineering aimed at anchoring diverse functional groups ranging from hydrophobic to hydrophilic units and from basic to acidic moieties with controllable loading contents. This approach enables the development of various tailor-made COFs with systematically tuned porosities and functionalities while retaining the crystallinity. We demonstrate that this strategy can be used to efficiently screen for suitable pore structures for use as CO2 adsorbents. The pore-surface-engineered walls exhibit an enhanced affinity for CO2, resulting in COFs that can capture and separate CO2 with high performance.

  14. Consensus virtual screening approaches to predict protein ligands.

    Science.gov (United States)

    Kukol, Andreas

    2011-09-01

    In order to exploit the advantages of receptor-based virtual screening, namely time/cost saving and specificity, it is important to rely on algorithms that predict a high number of active ligands at the top ranks of a small molecule database. Towards that goal consensus methods combining the results of several docking algorithms were developed and compared against the individual algorithms. Furthermore, a recently proposed rescoring method based on drug efficiency indices was evaluated. Among AutoDock Vina 1.0, AutoDock 4.2 and GemDock, AutoDock Vina was the best performing single method in predicting high affinity ligands from a database of known ligands and decoys. The rescoring of predicted binding energies with the water/octanol partition coefficient did not lead to an improvement averaged over ten receptor targets. Various consensus algorithms were investigated and a simple combination of AutoDock and AutoDock Vina results gave the most consistent performance that showed early enrichment of known ligands for all receptor targets investigated. In case a number of ligands is known for a specific target, every method proposed in this study should be evaluated. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  15. Screening for Learning and Memory Mutations: A New Approach

    Science.gov (United States)

    Gallistel, C. R.; King, A. P.; Daniel, A. M.; Freestone, D.; Papachristos, E. B.; Balci, F.; Kheifets, A.; Zhang, J.; Su, X.; Schiff, G.; Kourtev, H.

    2010-01-01

    We describe a fully automated, live-in 24/7 test environment, with experimental protocols that measure the accuracy and precision with which mice match the ratio of their expected visit durations to the ratio of the incomes obtained from two hoppers, the progress of instrumental and classical conditioning (trials-to-acquisition), the accuracy and precision of interval timing, the effect of relative probability on the choice of a timed departure target, and the accuracy and precision of memory for the times of day at which food is available. The system is compact; it obviates the handling of the mice during testing; it requires negligible amounts of experimenter/technician time; and it delivers clear and extensive results from 3 protocols within a total of 7–9 days after the mice are placed in the test environment. Only a single 24-hour period is required for the completion of first protocol (the matching protocol), which is strong test of temporal and spatial estimation and memory mechanisms. Thus, the system permits the extensive screening of many mice in a short period of time and in limited space. The software is publicly available. PMID:20352069

  16. Discovering novel enzymes by functional screening of plurigenomic libraries from alga-associated Flavobacteriia and Gammaproteobacteria.

    Science.gov (United States)

    Martin, Marjolaine; Vandermies, Marie; Joyeux, Coline; Martin, Renée; Barbeyron, Tristan; Michel, Gurvan; Vandenbol, Micheline

    2016-01-01

    Alga-associated microorganisms, in the context of their numerous interactions with the host and the complexity of the marine environment, are known to produce diverse hydrolytic enzymes with original biochemistry. We recently isolated several macroalgal-polysaccharide-degrading bacteria from the surface of the brown alga Ascophyllum nodosum. These active isolates belong to two classes: the Flavobacteriia and the Gammaproteobacteria. In the present study, we constructed two "plurigenomic" (with multiple bacterial genomes) libraries with the 5 most interesting isolates (regarding their phylogeny and their enzymatic activities) of each class (Fv and Gm libraries). Both libraries were screened for diverse hydrolytic activities. Five activities, out of the 48 previously identified in the natural polysaccharolytic isolates, were recovered by functional screening: a xylanase (GmXyl7), a beta-glucosidase (GmBg1), an esterase (GmEst7) and two iota-carrageenases (Fvi2.5 and Gmi1.3). We discuss here the potential role of the used host-cell, the average DNA insert-sizes and the used restriction enzymes on the divergent screening yields obtained for both libraries and get deeper inside the "great screen anomaly". Interestingly, the discovered esterase probably stands for a novel family of homoserine o-acetyltransferase-like-esterases, while the two iota-carrageenases represent new members of the poorly known GH82 family (containing only 19 proteins since its description in 2000). These original results demonstrate the efficiency of our uncommon "plurigenomic" library approach and the underexplored potential of alga-associated cultivable microbiota for the identification of novel and algal-specific enzymes. Copyright © 2016 Elsevier GmbH. All rights reserved.

  17. A Multivariate Approach to Functional Neuro Modeling

    DEFF Research Database (Denmark)

    Mørch, Niels J.S.

    1998-01-01

    This Ph.D. thesis, A Multivariate Approach to Functional Neuro Modeling, deals with the analysis and modeling of data from functional neuro imaging experiments. A multivariate dataset description is provided which facilitates efficient representation of typical datasets and, more importantly...... and overall conditions governing the functional experiment, via associated micro- and macroscopic variables. The description facilitates an efficient microscopic re-representation, as well as a handle on the link between brain and behavior; the latter is achieved by hypothesizing variations in the micro...... a generalization theoretical framework centered around measures of model generalization error. - Only few, if any, examples of the application of generalization theory to functional neuro modeling currently exist in the literature. - Exemplification of the proposed generalization theoretical framework...

  18. The hunt for original microbial enzymes: an initiatory review on the construction and functional screening of (metagenomic libraries

    Directory of Open Access Journals (Sweden)

    Martin, M.

    2016-01-01

    Full Text Available Introduction. Discovering novel enzymes is of interest in both applied and basic science. Microbial enzymes, which are incredibly diverse and easy to produce, are increasingly sought by diverse approaches. Literature. This review first distinguishes culture-based from culture-independent methods, detailing within each group the advantages and drawbacks of sequence- and function-based methods. It then discusses the main factors affecting the success of endeavors to identify novel enzymes through construction and functional screening of genomic or metagenomic libraries: the sampled environment, how DNA is extracted and processed, the vector used (plasmid, cosmid, fosmid, BAC, or shuttle vector, the host cell chosen from the available prokaryotic and eukaryotic ones and the main screening steps. Conclusions. Library construction and screening can be tricky and requires expertise. Combining different strategies, such as working with cultivable and non-cultivable organisms, using sequence- and function-based approaches, or performing multihost screenings, is probably the best way to identify novel and diverse enzymes from an environmental sample.

  19. An analysis of differential item functioning by gender in the Learning Disability Screening Questionnaire (LDSQ).

    Science.gov (United States)

    Murray, Aja Louise; Booth, Tom; McKenzie, Karen

    2015-04-01

    The Learning Disability Screening Questionnaire (LDSQ; McKenzie & Paxton, 2006) was developed as a brief screen for intellectual disability. Although several previous studies have evaluated the LDSQ with respect to its utility as a clinical and research tool, no studies have considered the fairness of the test across males and females. In the current study we, therefore, used a multi-group item response theory approach to assess differential item functioning across gender in a sample of 211 males and 132 females assessed in clinical and forensic settings. Although the test did not show evidence of differential item functioning by gender, it was necessary to exclude one item due to estimation problems and to combine two very highly related items (concerning reading and writing ability) into a single literacy item Thus, in addition to being generally supportive of the utility of the LDSQ, our results also highlight possible areas of weakness in the tool and suggest possible amendments that could be made to test content to improve the test in future revisions. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Patxi San Martin-Uriz

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

  1. Estimating Function Approaches for Spatial Point Processes

    Science.gov (United States)

    Deng, Chong

    Spatial point pattern data consist of locations of events that are often of interest in biological and ecological studies. Such data are commonly viewed as a realization from a stochastic process called spatial point process. To fit a parametric spatial point process model to such data, likelihood-based methods have been widely studied. However, while maximum likelihood estimation is often too computationally intensive for Cox and cluster processes, pairwise likelihood methods such as composite likelihood, Palm likelihood usually suffer from the loss of information due to the ignorance of correlation among pairs. For many types of correlated data other than spatial point processes, when likelihood-based approaches are not desirable, estimating functions have been widely used for model fitting. In this dissertation, we explore the estimating function approaches for fitting spatial point process models. These approaches, which are based on the asymptotic optimal estimating function theories, can be used to incorporate the correlation among data and yield more efficient estimators. We conducted a series of studies to demonstrate that these estmating function approaches are good alternatives to balance the trade-off between computation complexity and estimating efficiency. First, we propose a new estimating procedure that improves the efficiency of pairwise composite likelihood method in estimating clustering parameters. Our approach combines estimating functions derived from pairwise composite likeli-hood estimation and estimating functions that account for correlations among the pairwise contributions. Our method can be used to fit a variety of parametric spatial point process models and can yield more efficient estimators for the clustering parameters than pairwise composite likelihood estimation. We demonstrate its efficacy through a simulation study and an application to the longleaf pine data. Second, we further explore the quasi-likelihood approach on fitting

  2. Functional genomics down under: RNAi screening in the Victorian Centre for Functional Genomics.

    Science.gov (United States)

    Thomas, Daniel W; Gould, Cathryn M; Handoko, Yanny; Simpson, Kaylene J

    2014-05-01

    The Victorian Centre for Functional Genomics (VCFG) is an RNAi screening facility housed at the Peter MacCallum Cancer Centre in Melbourne, Australia. The Peter Mac is Australia's largest dedicated Cancer Research Institute, home to a team of over 520 scientists that focus on understanding the genetic risk of cancer, the molecular events regulating cancer growth and dissemination and improving detection through new diagnostic tools (www.petermac.org). Peter Mac is a well recognised technology leader and established the VCFG with a view to enabling researchers Australia and New Zealand-wide access to cutting edge functional genomics technology, infrastructure and expertise. This review documents the technology platforms operated within the VCFG and provides insight into the workflows and analysis pipelines currently in operation.

  3. Innovative approaches to cervical cancer screening for sex trade workers: an international scoping review.

    Science.gov (United States)

    Thulien, Naomi S

    2014-03-01

    Female sex trade workers are among those at highest risk for developing and dying of cervical cancer, and yet many-particularly the most marginalized-are less likely than other women to be screened. This review summarizes global findings on innovative approaches to cervical cancer screening for female sex trade workers, highlights current gaps in the delivery of cervical cancer screening for female sex trade workers globally, and suggests areas for future research and policy development. A scoping review of peer-reviewed publications and grey literature was conducted. Medline (OVID), PubMed, EMBASE, and SCOPUS were searched for relevant studies written in English. There were no limitations placed on dates. Grey literature was identified by hand searching and through discussion with health care providers and community outreach workers currently working with sex trade workers. Twenty-five articles were deemed suitable for review. Articles detailing innovative ways for female sex trade workers to access cervical cancer screening were included. Articles about screening for sexually transmitted infections were also included if the findings could be generalized to screening for cervical cancer. Articles limited to exploring risk factors, knowledge, awareness, education, prevalence, and incidence of cervical cancer among sex trade workers were excluded from the review. Successful screening initiatives identified in the studies reviewed had unconventional hours of operation, understood the difference between street-based and venue-based sex trade workers, and/or used peers for outreach. Two significant gaps in health care service delivery were highlighted in this review: the limited use of unorthodox hours and the nearly exclusive practice of providing sexually transmitted infection screening for female sex trade workers without cervical cancer screening. In addition, although street-based (as opposed to venue-based) sex trade workers are likely at higher risk for

  4. Partition functions and graphs: A combinatorial approach

    CERN Document Server

    Solomon, A I; Duchamp, G; Horzela, A; Penson, K A; Solomon, Allan I.; Blasiak, Pawel; Duchamp, Gerard; Horzela, Andrzej; Penson, Karol A.

    2004-01-01

    Although symmetry methods and analysis are a necessary ingredient in every physicist's toolkit, rather less use has been made of combinatorial methods. One exception is in the realm of Statistical Physics, where the calculation of the partition function, for example, is essentially a combinatorial problem. In this talk we shall show that one approach is via the normal ordering of the second quantized operators appearing in the partition function. This in turn leads to a combinatorial graphical description, giving essentially Feynman-type graphs associated with the theory. We illustrate this methodology by the explicit calculation of two model examples, the free boson gas and a superfluid boson model. We show how the calculation of partition functions can be facilitated by knowledge of the combinatorics of the boson normal ordering problem; this naturally gives rise to the Bell numbers of combinatorics. The associated graphical representation of these numbers gives a perturbation expansion in terms of a sequen...

  5. Robust functional statistics applied to Probability Density Function shape screening of sEMG data.

    Science.gov (United States)

    Boudaoud, S; Rix, H; Al Harrach, M; Marin, F

    2014-01-01

    Recent studies pointed out possible shape modifications of the Probability Density Function (PDF) of surface electromyographical (sEMG) data according to several contexts like fatigue and muscle force increase. Following this idea, criteria have been proposed to monitor these shape modifications mainly using High Order Statistics (HOS) parameters like skewness and kurtosis. In experimental conditions, these parameters are confronted with small sample size in the estimation process. This small sample size induces errors in the estimated HOS parameters restraining real-time and precise sEMG PDF shape monitoring. Recently, a functional formalism, the Core Shape Model (CSM), has been used to analyse shape modifications of PDF curves. In this work, taking inspiration from CSM method, robust functional statistics are proposed to emulate both skewness and kurtosis behaviors. These functional statistics combine both kernel density estimation and PDF shape distances to evaluate shape modifications even in presence of small sample size. Then, the proposed statistics are tested, using Monte Carlo simulations, on both normal and Log-normal PDFs that mimic observed sEMG PDF shape behavior during muscle contraction. According to the obtained results, the functional statistics seem to be more robust than HOS parameters to small sample size effect and more accurate in sEMG PDF shape screening applications.

  6. An ENU-mutagenesis screen in the mouse: identification of novel developmental gene functions

    NARCIS (Netherlands)

    Wansleeben, C.; van Gurp, L.; Feitsma, H.; Kroon, C.; Rieter, E.; Verberne, M.; Guryev, V.; Cuppen, E.; Meijlink, F.

    2011-01-01

    BACKGROUND: Mutagenesis screens in the mouse have been proven useful for the identification of novel gene functions and generation of interesting mutant alleles. Here we describe a phenotype-based screen for recessive mutations affecting embryonic development. METHODOLOGY/PRINCIPAL FINDINGS: Mice we

  7. Functional Metagenomics: Construction and High-Throughput Screening of Fosmid Libraries for Discovery of Novel Carbohydrate-Active Enzymes.

    Science.gov (United States)

    Ufarté, Lisa; Bozonnet, Sophie; Laville, Elisabeth; Cecchini, Davide A; Pizzut-Serin, Sandra; Jacquiod, Samuel; Demanèche, Sandrine; Simonet, Pascal; Franqueville, Laure; Veronese, Gabrielle Potocki

    2016-01-01

    Activity-based metagenomics is one of the most efficient approaches to boost the discovery of novel biocatalysts from the huge reservoir of uncultivated bacteria. In this chapter, we describe a highly generic procedure of metagenomic library construction and high-throughput screening for carbohydrate-active enzymes. Applicable to any bacterial ecosystem, it enables the swift identification of functional enzymes that are highly efficient, alone or acting in synergy, to break down polysaccharides and oligosaccharides.

  8. Bacteria-based in vivo peptide library screening using biopanning approach.

    Science.gov (United States)

    Choi, Ji-Hyeon; Park, Sang-Hyun

    2011-10-01

    Traditionally, library screening has been performed to identify biologically active agents including small molecules or peptides that inhibit target proteins or molecules with therapeutic interests. Due to its chemical nature, library screening is usually performed under in vitro environments using purified proteins and molecules. However, active agents identified from in vitro screenings often fail to exhibit biological activities in cells. To overcome this inherent limitation, we have developed an in vivo peptide library screening system that allows for the identification of dissociative inhibitors of protein interactions of interest. The screening is based on the reconstitution of the cI repressor from bacteriophage lambda with high-density expression peptide library and is entirely performed in bacteria cells. Furthermore, to enhance the efficacy and sensitivity of the screening, a multiple-round biopanning approach was employed for amplification and enrichment of positive peptides. Overall, this in vivo screening should provide a fast and efficient tool for identification of biologically active peptide molecules against target protein assembly.

  9. Screening for EIA in India: enhancing effectiveness through ecological carrying capacity approach.

    Science.gov (United States)

    Rajaram, T; Das, Ashutosh

    2011-01-01

    Developing countries across the world have embraced the policy of high economic growth as a means to reduce poverty. This economic growth largely based on industrial output is fast degrading the ecosystems, jeopardizing their long term sustainability. Environmental Impact Assessment (EIA) has long been recognized as a tool which can help in protecting the ecosystems and aid sustainable development. The Screening guidelines for EIA reflect the level of commitment the nation displays towards tightening its environmental protection system. The paper analyses the screening process for EIA in India and dissects the rationale behind the exclusions and thresholds set in the screening process. The screening process in India is compared with that of the European Union with the aim of understanding the extent of deviations from a screening approach in the context of better economic development. It is found that the Indian system excludes many activities from the purview of screening itself when compared to the EU. The constraints responsible for these exclusions are discussed and the shortcomings of the current command and control system of environmental management in India are also explained. It is suggested that an ecosystem carrying capacity based management system can provide significant inputs to enhance the effectiveness of EIA process from screening to monitoring.

  10. An Automated Microscale Thermophoresis Screening Approach for Fragment-Based Lead Discovery.

    Science.gov (United States)

    Linke, Pawel; Amaning, Kwame; Maschberger, Melanie; Vallee, Francois; Steier, Valerie; Baaske, Philipp; Duhr, Stefan; Breitsprecher, Dennis; Rak, Alexey

    2016-04-01

    Fragment-based lead discovery has proved to be an effective alternative to high-throughput screenings in identifying chemical matter that can be developed into robust lead compounds. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. In order to minimize the time and costs of screening, optimal combinations of biophysical techniques with maximal information content, sensitivity, and robustness are needed. Here we describe an approach utilizing automated microscale thermophoresis (MST) affinity screening to identify fragments active against MEK1 kinase. MST identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods. Furthermore, MST also provided information about ligand-induced aggregation and protein denaturation. The technique delivered a large number of binders while reducing experimentation time and sample consumption, demonstrating the potential of MST to execute and maximize the efficacy of fragment screening campaigns.

  11. A new approach to data evaluation in the non-target screening of organic trace substances in water analysis.

    Science.gov (United States)

    Müller, Alexander; Schulz, Wolfgang; Ruck, Wolfgang K L; Weber, Walter H

    2011-11-01

    Non-target screening via high performance liquid chromatography-mass spectrometry (HPLC-MS) has gained increasingly in importance for monitoring organic trace substances in water resources targeted for the production of drinking water. In this article a new approach for evaluating the data from non-target HPLC-MS screening in water is introduced and its advantages are demonstrated using the supply of drinking water as an example. The crucial difference between this and other approaches is the comparison of samples based on compounds (features) determined by their full scan data. In so doing, we take advantage of the temporal, spatial, or process-based relationships among the samples by applying the set operators, UNION, INTERSECT, and COMPLEMENT to the features of each sample. This approach regards all compounds, detectable by the used analytical method. That is the fundamental meaning of non-target screening, which includes all analytical information from the applied technique for further data evaluation. In the given example, in just one step, all detected features (1729) of a landfill leachate sample could be examined for their relevant influences on water purification respectively drinking water. This study shows that 1721 out of 1729 features were not relevant for the water purification. Only eight features could be determined in the untreated water and three of them were found in the final drinking water after ozonation. In so doing, it was possible to identify 1-adamantylamine as contamination of the landfill in the drinking water at a concentration in the range of 20 ng L(-1). To support the identification of relevant compounds and their transformation products, the DAIOS database (Database-Assisted Identification of Organic Substances) was used. This database concept includes some functions such as product ion search to increase the efficiency of the database query after the screening. To identify related transformation products the database function

  12. An Empirical, Functional approach to Depth Damages

    Directory of Open Access Journals (Sweden)

    Lehman Will

    2016-01-01

    Full Text Available In order to compute direct damages to structures and contents, the United States Army Corps of Engineers (USACE has traditionally relied on relationships that define damage for a given depth. These relationships are described using paired data relationships of depth and damage. Generally, the curves utilized are based on an Elicitation of Experts (EoE. This paper will present an alternative methodology which takes empirical data of damage and depth, stratified by building classifications, and use Non Linear Least Squares Estimation to fit a parameterized function to compute depth-damage estimates. The general function will be described, and the parameters will be discussed. Parameters include foundation height, ground elevation, percent damages below ground, number of stories, height of stories, maximum damage as a percent, and the beginning elevation for damage. The advantages of this approach include the ability to utilize empirical data, and the ability to change parameters based on building practices across the world. Additionally, the paper will illustrate a bootstrapping approach to the empirical data to assist in describing confidence limits around the parameterized functional depth damage relationship. A Figure (Figure 1 is provided to illustrate the output of the process.

  13. Assessment of Appropriateness of Screening Community-Dwelling Older People to Prevent Functional Decline

    NARCIS (Netherlands)

    Drewes, Yvonne M.; Gussekloo, Jacobijn; van der Meer, Victor; Rigter, Henk; Dekker, Janny H.; Goumans, Marleen J. B. M.; Metsemakers, Job F. M.; van Overbeek, Riki; de Rooij, Sophia E.; Schers, Henk J.; Schuurmans, Marieke J.; Sturmans, Ferd; de Vries, Kerst; Westendorp, Rudi G. J.; Wind, Annet W.; Assendelft, Willem J. J.

    2012-01-01

    OBJECTIVES: To identify appropriate screening conditions, stratified according to age and vulnerability, to prevent functional decline in older people. DESIGN: A RAND/University of California at Los Angeles appropriateness method. SETTING: The Netherlands. PARTICIPANTS: A multidisciplinary panel of

  14. Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.

    Science.gov (United States)

    Mendes-Pereira, Ana M; Sims, David; Dexter, Tim; Fenwick, Kerry; Assiotis, Ioannis; Kozarewa, Iwanka; Mitsopoulos, Costas; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J; Ashworth, Alan

    2012-02-21

    Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.

  15. Self-encoding Functional Resin Applying for Combinatorial Chemistry and High Throughput Screening

    Institute of Scientific and Technical Information of China (English)

    DU Lei; CHEN Tong-sheng

    2004-01-01

    A novel solid phase organic synthesis resin was synthesized for combinatorial high-throughput screening,which based on FTIR spectra self-encoding functional resin technology. A new deconvolution strategy termed position encoding deconvolution had illustrated and was compared with some popular combinatorial deconvolution strategies in efficiency and information content. The mimic high throughput screening of hexapeptide library successfully proved the applying of the self-encoding functional resin technology and the position encoding deconvolution strategy.

  16. Self-consistent Green's function approaches

    CERN Document Server

    Barbieri, Carlo

    2016-01-01

    We present the fundamental techniques and working equations of many-body Green's function theory for calculating ground state properties and the spectral strength. Green's function methods closely relate to other polynomial scaling approaches discussed in chapters~8 and ~10. However, here we aim directly at a global view of the many-fermion structure. We derive the working equations for calculating many-body propagators, using both the Algebraic Diagrammatic Construction technique and the self-consistent formalism at finite temperature. Their implementation is discussed, as well as the the inclusion of three-nucleon interactions. The self-consistency feature is essential to guarantee thermodynamic consistency. The paring and neutron matter models introduced in previous chapters are solved and compared with the other methods in this book.

  17. Distribution function approach to redshift space distortions

    CERN Document Server

    Seljak, Uros

    2011-01-01

    We develop a phase space distribution function approach to redshift space distortions (RSD), in which the redshift space density can be written as a sum over velocity moments of the distribution function. These moments are density weighted and their lowest orders are density, momentum density, and stress energy density. The series expansion is convergent on large scales. We perform an expansion of these velocity moments into helicity modes, which are eigenmodes under rotation around the axis of Fourier mode direction, generalizing the scalar, vector, tensor decomposition of perturbations to an arbitrary order. We show that only equal helicity moments correlate and derive the angular dependence of the individual contributions to the redshift space power spectrum in terms of angle mu between wave vector and line of sight. We show that the dominant term of mu^2 dependence on large scales is the cross-correlation between the density and scalar part of momentum density, which can be related to the time derivative ...

  18. New approach for high-throughput screening of drug activity on Plasmodium liver stages.

    NARCIS (Netherlands)

    Gego, A.; Silvie, O.; Franetich, J.F.; Farhati, K.; Hannoun, L.; Luty, A.J.F.; Sauerwein, R.W.; Boucheix, C.; Rubinstein, E.; Mazier, D.

    2006-01-01

    Plasmodium liver stages represent potential targets for antimalarial prophylactic drugs. Nevertheless, there is a lack of molecules active on these stages. We have now developed a new approach for the high-throughput screening of drug activity on Plasmodium liver stages in vitro, based on an

  19. Cost-effectiveness of screening programs for Chlamydia trachomatis - A population-based dynamic approach

    NARCIS (Netherlands)

    Welte, R; Kretzschmar, M; Leidl, R; Van den Hoek, A; Jager, JC; Postma, MJ

    2000-01-01

    Background: Models commonly used for the economic assessment of chamydial screening programs do not consider population effects. Goal: To develop a novel dynamic approach for the economic evaluation of chlamydial prevention measures and to determine the cost-effectiveness of a general practitioner-b

  20. New approach for high-throughput screening of drug activity on Plasmodium liver stages.

    NARCIS (Netherlands)

    Gego, A.; Silvie, O.; Franetich, J.F.; Farhati, K.; Hannoun, L.; Luty, A.J.F.; Sauerwein, R.W.; Boucheix, C.; Rubinstein, E.; Mazier, D.

    2006-01-01

    Plasmodium liver stages represent potential targets for antimalarial prophylactic drugs. Nevertheless, there is a lack of molecules active on these stages. We have now developed a new approach for the high-throughput screening of drug activity on Plasmodium liver stages in vitro, based on an infrare

  1. An industrial engineering approach to laboratory automation for high throughput screening

    OpenAIRE

    Menke, Karl C.

    2000-01-01

    Across the pharmaceutical industry, there are a variety of approaches to laboratory automation for high throughput screening. At Sphinx Pharmaceuticals, the principles of industrial engineering have been applied to systematically identify and develop those automated solutions that provide the greatest value to the scientists engaged in lead generation.

  2. Cost-effectiveness of screening programs for Chlamydia trachomatis - A population-based dynamic approach

    NARCIS (Netherlands)

    Welte, R; Kretzschmar, M; Leidl, R; Van den Hoek, A; Jager, JC; Postma, MJ

    2000-01-01

    Background: Models commonly used for the economic assessment of chamydial screening programs do not consider population effects. Goal: To develop a novel dynamic approach for the economic evaluation of chlamydial prevention measures and to determine the cost-effectiveness of a general

  3. A Culturally Relevant and Responsive Approach to Screening for Perinatal Depression

    Science.gov (United States)

    Price, Sarah Kye; Handrick, Sandii Leland

    2009-01-01

    Objectives: This study presents the design, implementation, and evaluation of a culturally relevant and responsive approach to screening for perinatal depression in low-income, predominantly African American women. Method: The study details the development of the community-informed instrument and subsequent evaluation of its psychometric…

  4. Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach.

    Directory of Open Access Journals (Sweden)

    Mathias Beig

    Full Text Available With the goal to identify novel trypanothione reductase (TR inhibitors, we performed a combination of in vitro and in silico screening approaches. Starting from a highly diverse compound set of 2,816 compounds, 21 novel TR inhibiting compounds could be identified in the initial in vitro screening campaign against T. cruzi TR. All 21 in vitro hits were used in a subsequent similarity search-based in silico screening on a database containing 200,000 physically available compounds. The similarity search resulted in a data set containing 1,204 potential TR inhibitors, which was subjected to a second in vitro screening campaign leading to 61 additional active compounds. This corresponds to an approximately 10-fold enrichment compared to the initial pure in vitro screening. In total, 82 novel TR inhibitors with activities down to the nM range could be identified proving the validity of our combined in vitro/in silico approach. Moreover, the four most active compounds, showing IC50 values of <1 μM, were selected for determining the inhibitor constant. In first on parasites assays, three compounds inhibited the proliferation of bloodstream T. brucei cell line 449 with EC50 values down to 2 μM.

  5. Tele-cytology: An innovative approach for cervical cancer screening in resource-poor settings

    Directory of Open Access Journals (Sweden)

    Sandeep Singh

    2016-01-01

    Full Text Available Carcinoma cervix remains a leading cause of cancer mortality among women in countries lacking any screening program. The existing screening policy and approach via conventional cytology centered mainly in Tertiary Care Center, is totally unaffordable to Indian women, especially in the remote areas. This suggests the need of depolarizing the resources via generating the near real time modalities which could be used at the door step of the needy ones. For any screening modality to be effective it should be adequately sensitive, specific, reproducible, cheap, simple, affordable, and the most important is should be real time to ensure wide coverage and curtail loss to follow-up. Incorporating telecytology as a screening tool could make the dream come true. Telecytology is the interpretation of cytology material at a distance using digital images. Use of mobile telecytology unit housed in a van carrying satellite equipment and the automated image capturing systems is the central theme behind this idea. The imaging equipment would be carrying out the imaging of Papanicolaou smears prepared at the screening site and sending the images to the central laboratories situated at some tertiary care level. This concept could overcome the hindrance of trained cytology infrastructure in the resource poor settings and could provide an efficient and economical way of screening patients. There is possibility that the designed approach may not detect the entire women positive for the disease but if the desired objective was to diagnose as many cases as possible in resource poor setting, then this process offers an advantage over no screening at all.

  6. 'Psychotropics caught in a trap' - adopting a screening approach to specific needs.

    Science.gov (United States)

    Kempf, Jürgen; Traber, Jessica; Auwärter, Volker; Huppertz, Laura M

    2014-10-01

    In the field of forensic toxicology, numerous strategies using different types of LC-MS platforms have been developed to set up an ultimate comprehensive screening method. Despite all this research, the question for the detection of a dedicated set of substances arises quite often in daily routine work. In this project, a screening method for the detection of psychotropic drugs based on the open library concept of a recently developed LC-MS(n) screening approach was developed and the effectiveness of a heated ESI-source was evaluated. To set up an individual spectral library all available data of psychotropics from the Toxtyper™ library was transferred to a new library format and complemented by MS, MS(2) and MS(3) data of additional psychotropic compounds. Precursor masses and retention time information of the library were used to trigger data dependent acquisition of MS(n)-spectra. Serum samples were analysed after alkaline liquid-liquid extraction on a Dionex RSLC (Acclaim™ C18 100×2.1C) coupled to a Bruker amaZon speed ion trap. A conventional ESI-source and an ionBooster™ source (IB) were used for ionization. All other LC and MS parameters were adopted from the original screening approach. Identification and result reporting was carried out by a fully automated software script. This screening method finally contains the individual precursor mass and retention time of 105 psychotropic substances and metabolites. Method evaluation was performed using pooled serum samples fortified with 12 different mixtures containing a total of 99 compounds at low therapeutic concentrations (cLOW and 2×cLOW). The customized method (ESI/IB) led to a higher rate of identifications (92%) - especially at low concentration levels (cLOW) - as the comprehensive screening approach (87%). Results from routine analysis with known intake of psychotropic drugs were confirmed with positive findings, if the concentration range was above or around the assumed limit of detection from

  7. Combining in silico and in cerebro approaches for virtual screening and pose prediction in SAMPL4.

    Science.gov (United States)

    Voet, Arnout R D; Kumar, Ashutosh; Berenger, Francois; Zhang, Kam Y J

    2014-04-01

    The SAMPL challenges provide an ideal opportunity for unbiased evaluation and comparison of different approaches used in computational drug design. During the fourth round of this SAMPL challenge, we participated in the virtual screening and binding pose prediction on inhibitors targeting the HIV-1 integrase enzyme. For virtual screening, we used well known and widely used in silico methods combined with personal in cerebro insights and experience. Regular docking only performed slightly better than random selection, but the performance was significantly improved upon incorporation of additional filters based on pharmacophore queries and electrostatic similarities. The best performance was achieved when logical selection was added. For the pose prediction, we utilized a similar consensus approach that amalgamated the results of the Glide-XP docking with structural knowledge and rescoring. The pose prediction results revealed that docking displayed reasonable performance in predicting the binding poses. However, prediction performance can be improved utilizing scientific experience and rescoring approaches. In both the virtual screening and pose prediction challenges, the top performance was achieved by our approaches. Here we describe the methods and strategies used in our approaches and discuss the rationale of their performances.

  8. Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse.

    Science.gov (United States)

    DiTommaso, Tia; Jones, Lynelle K; Cottle, Denny L; Gerdin, Anna-Karin; Vancollie, Valerie E; Watt, Fiona M; Ramirez-Solis, Ramiro; Bradley, Allan; Steel, Karen P; Sundberg, John P; White, Jacqueline K; Smyth, Ian M

    2014-10-01

    The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP). A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1), while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1). The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation.

  9. Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse.

    Directory of Open Access Journals (Sweden)

    Tia DiTommaso

    2014-10-01

    Full Text Available The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP. A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1, while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1. The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation.

  10. Quantum anharmonic oscillator: The airy function approach

    Energy Technology Data Exchange (ETDEWEB)

    Maiz, F., E-mail: fethimaiz@gmail.com [King Khalid University, Faculty of Science, Physics Department, PO Box 9004, Abha 61413, Asseer (Saudi Arabia); University of Cartage, Nabeul Engineering Preparatory Institute, Merazka, 8000 Nabeul (Tunisia); AlFaify, S. [King Khalid University, Faculty of Science, Physics Department, PO Box 9004, Abha 61413, Asseer (Saudi Arabia)

    2014-05-15

    New and simple numerical method is being reported to solve anharmonic oscillator problems. The method is setup to approach the real potential V(x) of the anharmonic oscillator system as a piecewise linear potential u(x) and to solve the Schrödinger equation of the system using the Airy function. Then, solutions continuity conditions lead to the energy quantification condition, and consequently, the energy eigenvalues. For testing purpose, the method was applied on the sextic and octic oscillators systems. The proposed method is found to be realistic, computationally simple, and having high degrees of accuracy. In addition, it can be applied to any form of potential. The results obtained by the proposed method were seen closely agreeing with results reached by other complicated methods.

  11. DVT prophylaxis after TKA: routine anticoagulation vs risk screening approach - a randomized study.

    Science.gov (United States)

    Kulshrestha, Vikas; Kumar, Santhosh

    2013-12-01

    The American College of Chest Physicians (ACCP) recommended routine anticoagulation for thromboprophylaxis in patients undergoing lower limb arthroplasty. We compared results of routine anticoagulation Vs risk stratified approach for Deep Venous Thrombosis (DVT) prophylaxis after TKA in terms of symptomatic DVT and wound complications. Nine hundred TKAs done in 673 patients were randomized after DVT risk screening to routine anticoagulation (n = 450) or to risk stratification (n = 450) and selective anticoagulation. 194 patients in the risk screening group received only Aspirin. Primary outcome was symptomatic DVT and wound complication. This randomized study showed that the symptomatic DVT rates after TKA were similar whether patients were routinely anticoagulated or selectively anticoagulated after risk screening. However there was a significantly higher incidence of wound complications (P < 0.014) after routine anticoagulation.

  12. FINDSITE(X): a structure-based, small molecule virtual screening approach with application to all identified human GPCRs.

    Science.gov (United States)

    Zhou, Hongyi; Skolnick, Jeffrey

    2012-06-01

    We have developed FINDSITE(X), an extension of FINDSITE, a protein threading based algorithm for the inference of protein binding sites, biochemical function and virtual ligand screening, that removes the limitation that holo protein structures (those containing bound ligands) of a sufficiently large set of distant evolutionarily related proteins to the target be solved; rather, predicted protein structures and experimental ligand binding information are employed. To provide the predicted protein structures, a fast and accurate version of our recently developed TASSER(VMT), TASSER(VMT)-lite, for template-based protein structural modeling applicable up to 1000 residues is developed and tested, with comparable performance to the top CASP9 servers. Then, a hybrid approach that combines structure alignments with an evolutionary similarity score for identifying functional relationships between target and proteins with binding data has been developed. By way of illustration, FINDSITE(X) is applied to 998 identified human G-protein coupled receptors (GPCRs). First, TASSER(VMT)-lite provides updates of all human GPCR structures previously modeled in our lab. We then use these structures and the new function similarity detection algorithm to screen all human GPCRs against the ZINC8 nonredundant (TC identity > 30% to the target from the binding data library) on a 168 human GPCR set with known binding data, the average enrichment factor in the top 1% of the compound library (EF(0.01)) is 22.7, whereas EF(0.01) by FINDSITE is 7.1. For virtual screening when just the target and its native ligands are excluded, the average EF(0.01) reaches 41.4. We also analyze off-target interactions for the 168 protein test set. All predicted structures, virtual screening data and off-target interactions for the 998 human GPCRs are available at http://cssb.biology.gatech.edu/skolnick/webservice/gpcr/index.html .

  13. New approaches to cervical cancer screening in Latin America and the Caribbean.

    Science.gov (United States)

    Herrero, Rolando; Ferreccio, Catterina; Salmerón, Jorge; Almonte, Maribel; Sánchez, Gloria Ines; Lazcano-Ponce, Eduardo; Jerónimo, José

    2008-08-19

    Cervical cancer remains an important public health problem in the Latin America and Caribbean region (LAC), with an expected significant increase in disease burden in the next decades as a result of population ageing. Prophylactic human papillomavirus (HPV) vaccine is currently unaffordable in LAC countries. However, even if vaccination was implemented, an additional two decades will be required to observe its impact on HPV related disease and cancer. With some exceptions, cytology-based screening programs have been largely ineffective to control the problem in the region, and there is a need for new approaches to the organization of screening and for use of newly developed techniques. Several research groups in LAC have conducted research on new screening methods, some of which are summarized in this paper. A recommendation to reorganize screening programs is presented considering visual inspection for very low resource areas, improvement of cytology where it is operating successfully and HPV DNA testing followed by visual inspection with acetic acid (VIA) or cytology as soon as this method becomes technically and economically sustainable. This could be facilitated by the incorporation of new, low-cost HPV DNA testing methods and the use of self-collected vaginal specimens for selected groups of the population. An important requisite for screening based on HPV testing will be the quality assurance of the laboratory and the technique by validation and certification measures.

  14. A Novel Dual Expression Platform for High Throughput Functional Screening of Phage Libraries in Product like Format.

    Directory of Open Access Journals (Sweden)

    Xiaodong Xiao

    Full Text Available High throughput screenings of single chain Fv (scFv antibody phage display libraries are currently done as soluble scFvs produced in E.coli. Due to endotoxin contaminations from bacterial cells these preparations cannot be reliably used in mammalian cell based assays. The monovalent nature and lack of Fc in soluble scFvs prevent functional assays that are dependent on target cross linking and/or Fc functions. A convenient approach is to convert scFvs into scFv.Fc fusion proteins and express them in mammalian cell lines for screening. This approach is low throughput and is only taken after primary screening of monovalent scFvs that are expressed in bacteria. There is no platform at present that combines the benefits of both bacterial and mammalian expression system for screening phage library output. We have, therefore, developed a novel dual expression vector, called pSplice, which can be used to express scFv.Fc fusion proteins both in E.coli and mammalian cell lines. The hallmark of the vector is an engineered intron which houses the bacterial promoter and signal peptide for expression and secretion of scFv.Fc in E.coli. When the vector is transfected into a mammalian cell line, the intron is efficiently spliced out resulting in a functional operon for expression and secretion of the scFv.Fc fusion protein into the culture medium. By applying basic knowledge of mammalian introns and splisosome, we designed this vector to enable screening of phage libraries in a product like format. Like IgG, the scFv.Fc fusion protein is bi-valent for the antigen and possesses Fc effector functions. Expression in E.coli maintains the speed of the bacterial expression platform and is used to triage clones based on binding and other assays that are not sensitive to endotoxin. Triaged clones are then expressed in a mammalian cell line without the need for any additional cloning steps. Conditioned media from the mammalian cell line containing the fusion proteins

  15. Clickable SBA-15 to screen functional groups for adsorption of antibiotics.

    Science.gov (United States)

    Gao, Jinsuo; Zhang, Xueying; Xu, Shutao; Liu, Jian; Tan, Feng; Li, Xinyong; Qu, Zhenping; Zhang, Yaobin; Quan, Xie

    2014-03-01

    Pharmaceutical antibiotics, as emerging contaminants, are usually composed of several functional groups that endow them with the ability to interact with adsorbents through different interactions. This makes the preparation of adsorbents tedious and time-consuming to screen appropriate functionalized materials. Herein, we describe the synthesis of clickable SBA-15 and demonstrate its feasibility as a screening material for the adsorption of antibiotics based on similar adsorption trends on materials with similar functional groups obtained by a click reaction and cocondensation/grafting methods.

  16. The screening effects of the screened exchange hybrid functional in surface systems: A case study on the CO/Pt(111) problem

    Science.gov (United States)

    Li, H.; Gillen, R.; Robertson, J.

    2016-06-01

    The screened exchange (sX) hybrid functional has been widely used in computational material science. Although it has widely been studied in bulk systems, less is known about its functional behavior in surface systems which are crucial to many technologies such as materials synthesis and nano-electronic devices. Assessing the screening dependent functional behaviors in the surface systems is therefore important for its application in such systems. In this work, we investigate the screening effects of the sX in CO adsorption on Pt(111) surface. The differences between the sX and Heyd-Scuseria-Ernzerhof (HSE06) hybrid functionals, and the effects of screening parameters are studied. The screening has two effects: first, the HOMO-LUMO gap is screening dependent. This affects the site preference most significantly. In this work, atop adsorption of CO/Pt(111) is predicted by the hybrid functionals with screened exchange potential. The sX(1.44) gives the largest HOMO-LUMO gap for the isolated CO molecule. The adsorption energy difference between the atop and fcc site is also the largest by the sX(1.44) which is explained by the reduced metal d states to the CO 2π* state back-donation, with stronger effect for the fcc adsorption than for the atop adsorption; second, the adsorption energy is screening dependent. This can be seen by comparing the sX(2.38) and HSE06 which have different screening strengths. They show similar surface band structures for the CO adsorption but different adsorption energies, which is explained by the stronger CO 5σ state to the metal d states donation or the effectively screened Pauli repulsion. This work underlines the screening strength as a main difference between sX and HSE06, as well as an important hybrid functional parameter for surface calculation.

  17. Rational drug design of antineoplastic agents using 3D-QSAR, cheminformatic, and virtual screening approaches.

    Science.gov (United States)

    Vucicevic, Jelica; Nikolic, Katarina; Mitchell, John B O

    2017-07-12

    Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Inhibitors of the Yersinia protein tyrosine phosphatase through high throughput and virtual screening approaches.

    Science.gov (United States)

    Hu, Xin; Vujanac, Milos; Southall, Noel; Stebbins, C Erec

    2013-02-15

    The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia pestis and a potential antibacterial drug target. Here we report our studies of screening for small molecule inhibitors of YopH using both high throughput and in silico approaches. The identified inhibitors represent a diversity of chemotypes and novel pTyr mimetics, providing a starting point for further development and fragment-based design of multi-site binding inhibitors. We demonstrate that the applications of high throughput and virtual screening, when guided by structural binding mode analysis, is an effective approach for identifying potent and selective inhibitors of YopH and other protein phosphatases for rational drug design. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Should Nursing Home Residents be Screened for Thyroid Function?

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    Ferit Kerim Küçükler

    2016-03-01

    Full Text Available Purpose: Thyroid dysfunctions, especially subclinical forms, which are more frequently seen in older populations, have been linked to increased morbidity and mortality. In the literature, there are few reports of thyroid functions among nursing home residents. Our aim was to investigate whether nursing home residents constitute a priority group for the evaluation of thyroid function. Material and Method: Hundred and ninety-two participants were enrolled in the study, 108 of them were nursing home participant (NP and 84 were dwelling participants (CP. All of the participants were evaluated in terms of thyroid functions and thyroid ultrasonography. Results: In the NP group, 89.8% were euthyroid, 3.7% were found to have subclinical hypothyroidism, 0.9% had overt hypothyroidism, 4.6% had subclinical hyperthyroidism, and 0.9% had overt hyperthyroidism. The corresponding rates in CP group were 83.3%, 9.5%, 0.0%, 7.1%, and 0.0%, respectively. At least one thyroid nodule was present in 64.2% and 78.3% of subjects of NP and CP groups, respectively. Discussion: There was no statistical difference between the two groups in terms of distribution of thyroid dysfunction and thyroid nodules. According to our results, living in nursing home has not any important effect on thyroid dysfunction or nodule.

  20. Identification and validation of vesicant therapeutic targets using a high, throughput siRNA screening approach

    Science.gov (United States)

    2014-12-24

    CONTRACT NUMBER siRNA screening approach 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Ruff, AL, Beach, S, Lehman , J, Rothwell, C...Sarah Beach · John Lehman · Cristin Rothwell · James F. Dillman Received: 15 September 2014 / Accepted: 25 November 2014 / Published online: 24...Defense, or the US Government. A. L. Ruff (*) · S. Beach · J. Lehman · C. Rothwell · J. F. Dillman Cell and Molecular Biology Branch, Research

  1. Porocytosis: a new approach to synaptic function.

    Science.gov (United States)

    Kriebel, M E; Keller, B; Silver, R B; Fox, G Q; Pappas, G D

    2001-12-01

    We propose a new approach to address the question of how a single quantum of neurotransmitter is secreted from a presynaptic terminal whose clustered secretory vesicles are locally bathed in high levels of calcium ions [Proceedings of the Symposium on Bioelectrogenesis (1961) 297-309; The Physiology of Synapses (1964) Chapters 1, 4, 5, 6; How the Self Controls its Brain (1994) Chapters 1, 4, 5, 6; Science 256 (1992) 677-679]. This hypothesis, which we term 'porocytosis', posits that the post-synaptic quantal response results from transmitter secreted through an array of docked vesicle/secretory pore complexes. The transient increase in calcium ions, which results from the voltage activated calcium channels, stimulates the array of secretory pores to simultaneously flicker open to pulse transmitter. Porocytosis is consistent with the quantal nature of presynaptic secretion and transmission, and with available biochemical, morphological and physiological evidence. It explains the frequency dependency of quantal size as a function of the secretion process. It permits a signature amount of transmitter release for different frequencies allowing a given synapse to be employed in different behavioral responses. The porocytosis hypothesis permits fidelity of secretion and the seemingly apposed characteristic of synaptic plasticity. The dynamics inherent in an array insure a constant quantal size as a function of the number of units within the array. In this hypothesis, plasticity is a consequence of concurrent pre- and post-synaptic changes due to a change in array size. Changes in the number of docked vesicle-secretory pore complexes composing the array can explain facilitation, depletion, graded excitation-secretion and long term plasticity.

  2. Cell array-based intracellular localization screening reveals novel functional features of human chromosome 21 proteins

    Directory of Open Access Journals (Sweden)

    Kahlem Pascal

    2006-06-01

    Full Text Available Abstract Background Trisomy of human chromosome 21 (Chr21 results in Down's syndrome, a complex developmental and neurodegenerative disease. Molecular analysis of Down's syndrome, however, poses a particular challenge, because the aneuploid region of Chr21 contains many genes of unknown function. Subcellular localization of human Chr21 proteins may contribute to further understanding of the functions and regulatory mechanisms of the genes that code for these proteins. Following this idea, we used a transfected-cell array technique to perform a rapid and cost-effective analysis of the intracellular distribution of Chr 21 proteins. Results We chose 89 genes that were distributed over the majority of 21q, ranging from RBM11 (14.5 Mb to MCM3AP (46.6 Mb, with part of them expressed aberrantly in the Down's syndrome mouse model. Open reading frames of these genes were cloned into a mammalian expression vector with an amino-terminal His6 tag. All of the constructs were arrayed on glass slides and reverse transfected into HEK293T cells for protein expression. Co-localization detection using a set of organelle markers was carried out for each Chr21 protein. Here, we report the subcellular localization properties of 52 proteins. For 34 of these proteins, their localization is described for the first time. Furthermore, the alteration in cell morphology and growth as a result of protein over-expression for claudin-8 and claudin-14 genes has been characterized. Conclusion The cell array-based protein expression and detection approach is a cost-effective platform for large-scale functional analyses, including protein subcellular localization and cell phenotype screening. The results from this study reveal novel functional features of human Chr21 proteins, which should contribute to further understanding of the molecular pathology of Down's syndrome.

  3. Thermoplasmonics modeling: A Green's function approach

    Science.gov (United States)

    Baffou, Guillaume; Quidant, Romain; Girard, Christian

    2010-10-01

    We extend the discrete dipole approximation (DDA) and the Green’s dyadic tensor (GDT) methods—previously dedicated to all-optical simulations—to investigate the thermodynamics of illuminated plasmonic nanostructures. This extension is based on the use of the thermal Green’s function and a original algorithm that we named Laplace matrix inversion. It allows for the computation of the steady-state temperature distribution throughout plasmonic systems. This hybrid photothermal numerical method is suited to investigate arbitrarily complex structures. It can take into account the presence of a dielectric planar substrate and is simple to implement in any DDA or GDT code. Using this numerical framework, different applications are discussed such as thermal collective effects in nanoparticles assembly, the influence of a substrate on the temperature distribution and the heat generation in a plasmonic nanoantenna. This numerical approach appears particularly suited for new applications in physics, chemistry, and biology such as plasmon-induced nanochemistry and catalysis, nanofluidics, photothermal cancer therapy, or phase-transition control at the nanoscale.

  4. General Green's function formalism for layered systems: Wave function approach

    Science.gov (United States)

    Zhang, Shu-Hui; Yang, Wen; Chang, Kai

    2017-02-01

    The single-particle Green's function (GF) of mesoscopic structures plays a central role in mesoscopic quantum transport. The recursive GF technique is a standard tool to compute this quantity numerically, but it lacks physical transparency and is limited to relatively small systems. Here we present a numerically efficient and physically transparent GF formalism for a general layered structure. In contrast to the recursive GF that directly calculates the GF through the Dyson equations, our approach converts the calculation of the GF to the generation and subsequent propagation of a scattering wave function emanating from a local excitation. This viewpoint not only allows us to reproduce existing results in a concise and physically intuitive manner, but also provides analytical expressions of the GF in terms of a generalized scattering matrix. This identifies the contributions from each individual scattering channel to the GF and hence allows this information to be extracted quantitatively from dual-probe STM experiments. The simplicity and physical transparency of the formalism further allows us to treat the multiple reflection analytically and derive an analytical rule to construct the GF of a general layered system. This could significantly reduce the computational time and enable quantum transport calculations for large samples. We apply this formalism to perform both analytical analysis and numerical simulation for the two-dimensional conductance map of a realistic graphene p -n junction. The results demonstrate the possibility of observing the spatially resolved interference pattern caused by negative refraction and further reveal a few interesting features, such as the distance-independent conductance and its quadratic dependence on the carrier concentration, as opposed to the linear dependence in uniform graphene.

  5. In silico-screening approaches for lead generation: identification of novel allosteric modulators of human-erythrocyte pyruvate kinase.

    Science.gov (United States)

    Tripathi, Ashutosh; Safo, Martin K

    2012-01-01

    Identification of allosteric binding site modulators have gained increased attention lately for their potential to be developed as selective agents with a novel chemotype and targeting perhaps a new and unique binding site with probable fewer side effects. Erythrocyte pyruvate kinase (R-PK) is an important glycolytic enzyme that can be pharmacologically modulated through its allosteric effectors for the treatment of hemolytic anemia, sickle-cell anemia, hypoxia-related diseases, and other disorders arising from erythrocyte PK malfunction. An in-silico screening approach was applied to identify novel allosteric modulators of pyruvate kinase. A small-molecules database of the National Cancer Institute (NCI), was virtually screened based on structure/ligand-based pharmacophore. The virtual screening campaign led to the identification of several compounds with similar pharmacophoric features as fructose-1,6-bisphosphate (FBP), the natural allosteric activator of the kinase. The compounds were subsequently docked into the FBP-binding site using the programs FlexX and GOLD, and their interactions with the protein were analyzed with the energy-scoring function of HINT. Seven promising candidates were obtained from the NCI and subjected to kinetics analysis, which revealed both activators and inhibitors of the R-isozyme of PK (R-PK).

  6. Further investigation on MODIS solar diffuser screen vignetting function and its implementation in RSB calibration

    Science.gov (United States)

    Wang, Zhipeng; Xiong, Xiaoxiong; Barnes, Williams L.

    2011-10-01

    The MODIS high-gain ocean color bands (B8-B16) are calibrated with its solar diffuser screen (SDS) closed to avoid saturation so that the vignetting function (VF) of SDS is necessary for the calculation of the gain coefficients of these detectors. Since there was no pre-launch system level characterization of the VF, a series of yaw maneuvers were carried out at the mission beginning for both Terra and Aqua to enable its on-orbit characterization. Current VF was derived from the low-gain bands (B1-B7 & B17-B19) data and applied to high-gain ocean color bands calibration, with the assumption that all bands and detectors should share the same VF since it is wavelength independent. As expected, error exists and it was carried over into the calibrated gain coefficients of those bands that use the SDS for their on-orbit calibration. In this paper, an improved VF calculation approach, still using the yaw data as input, is presented. The new approach takes the frame-level mismatch between different detector's footprints on the solar diffuser (SD) into account so that a proper SD image frame adjustment is made when the VF of the low-gain bands is translated into high-gain bands VF. A new set of band-and-detector dependent VFs can be derived using this approach. The implementation of the new VF into calibration of high-gain bands gain coefficient has effectively reduced the undesired seasonal oscillations in its trending from up to Terra's 0.6% and Aqua's 1.0% to nearly 0.2%.

  7. The cognitive effects of trauma: reversal of alpha function and the formation of a beta screen.

    Science.gov (United States)

    Brown, Lawrence J

    2005-04-01

    Following a brief review of Freud's writings on trauma, the author discusses relevant theories of Bion, and in particular the concepts of the alpha function and the beta screen. A clinical example is presented in which the patient's relatively recent trauma in adulthood had become fused with prior related experiences, leading to a propensity for repeated enactments in analysis and a failure to learn from experience. Drawing on the analyst's alpha function, the patient was gradually able to use mentalization to transform her rigidly structured traumatic organization. The author highlights the roles of dreams/dream associations and of screen memories in the patient's analysis.

  8. Ecosystem Screening Approach for Pathogen-Associated Microorganisms Affecting Host Disease▿†

    Science.gov (United States)

    Galiana, Eric; Marais, Antoine; Mura, Catherine; Industri, Benoît; Arbiol, Gilles; Ponchet, Michel

    2011-01-01

    The microbial community in which a pathogen evolves is fundamental to disease outcome. Species interacting with a pathogen on the host surface shape the distribution, density, and genetic diversity of the inoculum, but the role of these species is rarely determined. The screening method developed here can be used to characterize pathogen-associated species affecting disease. This strategy involves three steps: (i) constitution of the microbial community, using the pathogen as a trap; (ii) community selection, using extracts from the pathogen as the sole nutrient source; and (iii) molecular identification and the screening of isolates focusing on their effects on the growth of the pathogen in vitro and host disease. This approach was applied to a soilborne plant pathogen, Phytophthora parasitica, structured in a biofilm, for screening the microbial community from the rhizosphere of Nicotiana tabacum (the host). Two of the characterized eukaryotes interfered with the oomycete cycle and may affect the host disease. A Vorticella species acted through a mutualistic interaction with P. parasitica, disseminating pathogenic material by leaving the biofilm. A Phoma species established an amensal interaction with P. parasitica, strongly suppressing disease by inhibiting P. parasitica germination. This screening method is appropriate for all nonobligate pathogens. It allows the definition of microbial species as promoters or suppressors of a disease for a given biotope. It should also help to identify important microbial relationships for ecology and evolution of pathogens. PMID:21742919

  9. Ecosystem screening approach for pathogen-associated microorganisms affecting host disease.

    Science.gov (United States)

    Galiana, Eric; Marais, Antoine; Mura, Catherine; Industri, Benoît; Arbiol, Gilles; Ponchet, Michel

    2011-09-01

    The microbial community in which a pathogen evolves is fundamental to disease outcome. Species interacting with a pathogen on the host surface shape the distribution, density, and genetic diversity of the inoculum, but the role of these species is rarely determined. The screening method developed here can be used to characterize pathogen-associated species affecting disease. This strategy involves three steps: (i) constitution of the microbial community, using the pathogen as a trap; (ii) community selection, using extracts from the pathogen as the sole nutrient source; and (iii) molecular identification and the screening of isolates focusing on their effects on the growth of the pathogen in vitro and host disease. This approach was applied to a soilborne plant pathogen, Phytophthora parasitica, structured in a biofilm, for screening the microbial community from the rhizosphere of Nicotiana tabacum (the host). Two of the characterized eukaryotes interfered with the oomycete cycle and may affect the host disease. A Vorticella species acted through a mutualistic interaction with P. parasitica, disseminating pathogenic material by leaving the biofilm. A Phoma species established an amensal interaction with P. parasitica, strongly suppressing disease by inhibiting P. parasitica germination. This screening method is appropriate for all nonobligate pathogens. It allows the definition of microbial species as promoters or suppressors of a disease for a given biotope. It should also help to identify important microbial relationships for ecology and evolution of pathogens.

  10. An siRNA screen for ATG protein depletion reveals the extent of the unconventional functions of the autophagy proteome in virus replication

    NARCIS (Netherlands)

    Mauthe, Mario; Langereis, Martijn; Jung, Jennifer; Zhou, Xingdong; Jones, Alex; Omta, Wienand; Tooze, Sharon A.; Stork, Bjoern; Paludan, Soren Riis; Ahola, Tero; Egan, Dave; Behrends, Christian; Mokry, Michal; de Haan, Cornelis; van Kuppeveld, Frank; Reggiori, Fulvio

    2016-01-01

    Autophagy is a catabolic process regulated by the orchestrated action of the autophagy-related (ATG) proteins. Recent work indicates that some of the ATG proteins also have autophagy-independent roles. Using an unbiased siRNA screen approach, we explored the extent of these unconventional functions

  11. The relationship of core strength and activation and performance on three functional movement screens.

    Science.gov (United States)

    Johnson, Caleb D; Whitehead, Paul N; Pletcher, Erin R; Faherty, Mallory S; Lovaleka, Mita T; Eagle, Shawn R; Keenan, Karen A

    2017-04-18

    Current measures of core stability utilized by clinicians and researchers suffer from several shortcomings. Three functional movement screens appear, at face-value, to be dependent on the ability to activate and control core musculature. These three screens may present a viable alternative to current measures of core stability. Thirty-nine subjects completed a deep squat, trunk stability push-up, and rotary stability screen. Scores on the three screens were summed to calculate a composite score (COMP). During the screens, muscle activity was collected to determine the length of time that the bilateral erector spinae, rectus abdominus, external oblique, and gluteus medius muscles were active. Strength was assessed for core muscles (trunk flexion/extension, trunk rotation, hip abduction/adduction) and accessory muscles (knee flexion/extension, and pectoralis major). Two ordinal logistic regression equations were calculated with COMP as the outcome variable, and: 1) core strength and accessory strength, 2) only core strength. The first model was significant in predicting COMP (p=.004) (Pearson's Chi-Square=149.132, p=.435; Nagelkerke's R-Squared=.369). The second model was significant in predicting COMP (p=.001) (Pearson's Chi Square=148.837, p=.488; Nagelkerke's R-Squared=.362). The core muscles were found to be active for the majority of screens, with percentages of "time active" for each muscle ranging from 54%-86%. In conclusion, performance on the three screens is predicted by core strength, even when accounting for "accessory" strength variables. Further, it appears the screens elicit wide-ranging activation of core muscles. While more investigation is needed, these screens, collectively, appear to be a good assessment of core strength.

  12. Effects of screen size on smartphone functionality and usability for stroke patients with hemiparalysis.

    Science.gov (United States)

    Jung, Nam-Hae; Chang, Moonyoung

    2016-04-01

    [Purpose] The effect of screen size on smartphone functionality and usability for patients with stroke, considering both the non-dominant and dominant hand smartphone usage, was investigated in this study. [Subjects and Methods] Thirteen patients with stroke participated in this study-five pre-non-dominant hand users and eight pre-dominant hand users. The smartphone screen sizes used were 4.2, 4.5, and 5.6 inches. Usability was assessed in terms of discomfort experienced during dragging operations, which was self-reported using a four-point Likert scale. Functionality was assessed in terms of completion time and the frequency of errors in the task requiring users to quickly touch numbers 0 through 9 in order on the keypad. [Results] For all three screen sizes, a significant difference between the dominant and non-dominant hands was found in usability, completion time, and frequency of errors. For dominant hand users, differences in usability and completion time were found among the three screen sizes. Among the three screen sizes, no difference in the frequency of errors was found in either of the groups. [Conclusion] This study will be useful as basic research on usability and functionality with stroke patients using only pre-non-dominant or pre-dominant hand.

  13. Application of microarray and functional-based screening methods for the detection of antimicrobial resistance genes in the microbiomes of healthy humans.

    Directory of Open Access Journals (Sweden)

    Roderick M Card

    Full Text Available The aim of this study was to screen for the presence of antimicrobial resistance genes within the saliva and faecal microbiomes of healthy adult human volunteers from five European countries. Two non-culture based approaches were employed to obviate potential bias associated with difficult to culture members of the microbiota. In a gene target-based approach, a microarray was employed to screen for the presence of over 70 clinically important resistance genes in the saliva and faecal microbiomes. A total of 14 different resistance genes were detected encoding resistances to six antibiotic classes (aminoglycosides, β-lactams, macrolides, sulphonamides, tetracyclines and trimethoprim. The most commonly detected genes were erm(B, blaTEM, and sul2. In a functional-based approach, DNA prepared from pooled saliva samples was cloned into Escherichia coli and screened for expression of resistance to ampicillin or sulphonamide, two of the most common resistances found by array. The functional ampicillin resistance screen recovered genes encoding components of a predicted AcrRAB efflux pump. In the functional sulphonamide resistance screen, folP genes were recovered encoding mutant dihydropteroate synthase, the target of sulphonamide action. The genes recovered from the functional screens were from the chromosomes of commensal species that are opportunistically pathogenic and capable of exchanging DNA with related pathogenic species. Genes identified by microarray were not recovered in the activity-based screen, indicating that these two methods can be complementary in facilitating the identification of a range of resistance mechanisms present within the human microbiome. It also provides further evidence of the diverse reservoir of resistance mechanisms present in bacterial populations in the human gut and saliva. In future the methods described in this study can be used to monitor changes in the resistome in response to antibiotic therapy.

  14. Color features as an approach for the automated screening of Salmonella strain

    Science.gov (United States)

    Trujillo, Alejandra Serrano; González, Viridiana Contreras; Andrade Rincón, Saulo E.; Palafox, Luis E.

    2016-11-01

    We present the implementation of a feature extraction approach for the automated screening of Salmonella sp., a task visually carried out by a microbiologist, where the resulting color characteristics of the culture media plate indicate the presence of this strain. The screening of Salmonella sp. is based on the inoculation and incubation of a sample on an agar plate, allowing the isolation of this strain, if present. This process uses three media: Xylose lysine deoxycholate, Salmonella Shigella, and Brilliant Green agar plates, which exhibit specific color characteristics over the colonies and over the surrounding medium for a presumed positive interpretation. Under a controlled illumination environment, images of plates are captured and the characteristics found over each agar are processed separately. Each agar is analyzed using statistical descriptors for texture, to determine the presence of colonies, followed by the extraction of color features. A comparison among the color features seen over the three media, according to the FDA Bacteriological Analytical Manual, determines the presence of Salmonella sp. on a given sample. The implemented process proves that the task addressed can be accomplished under an image processing approach, leading to the future validation and automation of additional screening processes.

  15. SCREENING APPROACHES FOR METHANE MITIGATING POTENTIAL OF TANNIN-CONTAINING PLANTS UNDER IN VITRO RUMEN ENVIRONMENT

    Directory of Open Access Journals (Sweden)

    A. Jayanegara

    2012-12-01

    Full Text Available The aim of the present study was to conduct univariate, bivariate and multivariate (principal component analysis, PCA approaches in the screening of tannin-containing plants from various collection sites for their CH4 mitigating properties. Plant samples were obtained from various collection sites in different countries, i.e. Indonesia (n = 27 species, Mongolia (n = 14, Switzerland (n = 16 and Germany (n = 3. The plants were incubated in vitro with buffered-rumen fluid at 39oC for 24 h. Total gas production was recorded as an indicator of feed quality and emission of CH4 was measured. Results showed that, based on bivariate screening, generally, plants possessed low CH4 production had low quality or low total gas production except Rhus typhina, i.e. 43 ml/200 mg DM. The loading plot of PCA showed that all phenolic fractions were in the opposite direction with CH4 and total gas production. Plants clustered together in reverse direction to that of CH4 were Bergenia crassifolia root and leaf, Swietenia mahagoni, Clidemia hirta, Peltiphyllum peltatum, Acacia villosa and R. typhina. It was conluded that, for tannin-containing plants, screenings based on univariate, bivariate and multivariate approaches in relation to ruminal CH4 emission led to similar results

  16. Multiplicity of experimental approaches to therapy for genetic muscle diseases and necessity for population screening.

    Science.gov (United States)

    Laing, Nigel G

    2008-01-01

    Currently a multiplicity of experimental approaches to therapy for genetic muscle diseases is being investigated. These include replacement of the missing gene, manipulation of the gene message, repair of the mutation, upregulation of an alternative gene and pharmacological interventions targeting a number of systems. A number of these approaches are in current clinical trials. There is considerable anticipation that perhaps more than one of the approaches will finally prove of clinical benefit, but there are many voices of caution. No matter which approaches might ultimately prove effective, there is a consensus that for most benefit to the patients it will be necessary to start treatment as early as possible. A consensus is also developing that the only way to do this is to implement population-based newborn screening to identify affected children shortly after birth. Population-based newborn screening is currently practised in very few places in the world and it brings with it implications for prevention rather than cure of genetic muscle diseases.

  17. Expression of heterologous sigma factors enables functional screening of metagenomic and heterologous genomic libraries.

    Science.gov (United States)

    Gaida, Stefan M; Sandoval, Nicholas R; Nicolaou, Sergios A; Chen, Yili; Venkataramanan, Keerthi P; Papoutsakis, Eleftherios T

    2015-05-06

    A key limitation in using heterologous genomic or metagenomic libraries in functional genomics and genome engineering is the low expression of heterologous genes in screening hosts, such as Escherichia coli. To overcome this limitation, here we generate E. coli strains capable of recognizing heterologous promoters by expressing heterologous sigma factors. Among seven sigma factors tested, RpoD from Lactobacillus plantarum (Lpl) appears to be able of initiating transcription from all sources of DNA. Using the promoter GFP-trap concept, we successfully screen several heterologous and metagenomic DNA libraries, thus enlarging the genomic space that can be functionally sampled in E. coli. For an application, we show that screening fosmid-based Lpl genomic libraries in an E. coli strain with a chromosomally integrated Lpl rpoD enables the identification of Lpl genetic determinants imparting strong ethanol tolerance in E. coli. Transcriptome analysis confirms increased expression of heterologous genes in the engineered strain.

  18. Sniffer dogs as part of a bimodal bionic research approach to develop a lung cancer screening.

    Science.gov (United States)

    Boedeker, Enole; Friedel, Godehard; Walles, Thorsten

    2012-05-01

    Lung cancer (LC) continues to represent a heavy burden for health care systems worldwide. Epidemiological studies predict that its role will increase in the near future. While patient prognosis is strongly associated with tumour stage and early detection of disease, no screening test exists so far. It has been suggested that electronic sensor devices, commonly referred to as 'electronic noses', may be applicable to identify cancer-specific volatile organic compounds in the breath of patients and therefore may represent promising screening technologies. However, three decades of research did not bring forward a clinically applicable device. Here, we propose a new research approach by involving specially trained sniffer dogs into research strategies by making use of their ability to identify LC in the breath sample of patients.

  19. A Community Capacity-Enhancement Approach to Breast and Cervical Cancer Screening among Older Women of Color

    Science.gov (United States)

    Bullock, Karen; McGraw, Sarah A.

    2006-01-01

    In the Screening Older Minority Women project, the authors applied a community capacity-enhancement approach to promoting breast and cervical cancer screening among older women of color. Members of informal support networks were recruited for this health promotion intervention to empower Latina and African American women to engage in positive…

  20. Benchmarking of computational approaches for fast screening of lithium ion battery electrolyte solvents

    Science.gov (United States)

    Kim, Daejin; Guk, Hyein; Choi, Seung-Hoon; Chung, Dong Hyen

    2017-08-01

    Electrolyte solvents play an important role in lithium-ion batteries. Hence, investigation of the solvent is key to improving battery functionality. We performed benchmark calculations to suggest the best conditions for rapid screening of electrolyte candidates using semi-empirical (SEM) calculations and density functional theory (DFT). A wide selection of Hamiltonians, DFT levels, and basis sets were used for this benchmarking with typical electrolyte solvents. The most efficient condition for reducing computational costs and time is VWN/DNP+ for DFT levels and PM3 for SEM Hamiltonians.

  1. Introducing Linear Functions: An Alternative Statistical Approach

    Science.gov (United States)

    Nolan, Caroline; Herbert, Sandra

    2015-01-01

    The introduction of linear functions is the turning point where many students decide if mathematics is useful or not. This means the role of parameters and variables in linear functions could be considered to be "threshold concepts". There is recognition that linear functions can be taught in context through the exploration of linear…

  2. Loss-of-function screen in rhabdomyosarcoma identifies CRKL-YES as a critical signal for tumor growth.

    Science.gov (United States)

    Yeung, C L; Ngo, V N; Grohar, P J; Arnaldez, F I; Asante, A; Wan, X; Khan, J; Hewitt, S M; Khanna, C; Staudt, L M; Helman, L J

    2013-11-21

    To identify novel signaling pathways necessary for rhabdomyosarcoma (RMS) survival, we performed a loss-of-function screen using an inducible small hairpin RNA (shRNA) library in an alveolar and an embryonal RMS cell line. This screen identified CRKL expression as necessary for growth of alveolar RMS and embryonal RMS both in vitro and in vivo. We also found that CRKL was uniformly highly expressed in both RMS cell lines and tumor tissue. As CRKL is a member of the CRK adapter protein family that contains an SH2 and two SH3 domains and is involved in signal transduction from multiple tyrosine kinase receptors, we evaluated CRKL interaction with multiple tyrosine kinase receptor signaling pathways in RMS cells. While we saw no interaction of CRKL with IGFIR, MET or PI3KAKT/mTOR pathways, we determined that CRKL signaling was associated with SRC family kinase (SFK) signaling, specifically with YES kinase. Inhibition of SFK signaling with dasatinib or another SFK inhibitor, sarcatinib, suppressed RMS cell growth in vitro and in vivo. These data identify CRKL as a novel critical component of RMS growth. This study also demonstrates the use of functional screening to identify a potentially novel therapeutic target and treatment approach for these highly aggressive pediatric cancers.

  3. State of the Art High-Throughput Approaches to Genotoxicity: Flow Micronucleus, Ames II, GreenScreen and Comet

    Science.gov (United States)

    State of the Art High-Throughput Approaches to Genotoxicity: Flow Micronucleus, Ames II, GreenScreen and Comet (Presented by Dr. Marilyn J. Aardema, Chief Scientific Advisor, Toxicology, Dr. Leon Stankowski, et. al. (6/28/2012)

  4. The effects of screening and intervention of subclinical hypothyroidism on pregnancy outcomes: a prospective multicenter single-blind, randomized, controlled study of thyroid function screening test during pregnancy.

    Science.gov (United States)

    Ma, Liangkun; Qi, Hong; Chai, Xiaofeng; Jiang, Fang; Mao, Su; Liu, Juntao; Zhang, Shaoqin; Lian, Xiaolan; Sun, Xiujing; Wang, Danhua; Ren, Jie; Yan, Qi

    2016-01-01

    To evaluate the effect of subclinical hypothyroidism (SCH) screening and intervention on pregnancy outcomes and explore the significance of thyroid function during early pregnancy. Pregnant women were recruited from Peking Union Medical College Hospital (screening group for measuring thyroid function and thyroid antibody in early pregnancy) and Haidian Maternal & Child Health Hospital (control group whose serum was stored and measured shortly after delivery) from July 2011 to December 2012. Thyrotropin levels 2.5-10 mIU/L and free T4 levels in normal range were considered SCH. Some of the screening group were treated with levothyroxine and adjusted. The others did not take medicine but kept a regular follow-up visit to doctors after antenatal clinic. The pregnancy outcomes and complications were compared. 1671 women (675 in screening group and 996 in control group) were recruited. 419 (167 from screening group) women was diagnosed as SCH. In screening group, 105 SCH and 4 hypothyroid women received thyroid hormone replacement therapy. The miscarriage and fetal macrosomia risks were lower, and cesarean was higher in screening group than control. Screening and intervention of SCH can significantly reduce the incidence rate of miscarriage.

  5. Screening for plant transporter function by expressing a normalized Arabidopsis full-length cDNA library in Xenopus oocytes

    Directory of Open Access Journals (Sweden)

    Halkier Barbara A

    2006-10-01

    Full Text Available Abstract Background We have developed a functional genomics approach based on expression cloning in Xenopus oocytes to identify plant transporter function. We utilized the full-length cDNA databases to generate a normalized library consisting of 239 full-length Arabidopsis thaliana transporter cDNAs. The genes were arranged into a 96-well format and optimized for expression in Xenopus oocytes by cloning each coding sequence into a Xenopus expression vector. Results Injection of 96 in vitro transcribed cRNAs from the library in pools of columns and rows into oocytes and subsequent screening for glucose uptake activity identified three glucose transporters. One of these, AtSTP13, had not previously been experimentally characterized. Conclusion Expression of the library in Xenopus oocytes, combined with uptake assays, has great potential in assignment of plant transporter function and for identifying membrane transporters for the many plant metabolites where a transporter has not yet been identified.

  6. Functional approaches in translation studies in Germany Functional approaches in translation studies in Germany

    Directory of Open Access Journals (Sweden)

    Paul Kussmaul

    2008-04-01

    Full Text Available In the early phase of translation studies in Germany, contrastive linguistics played a major role. I shall briefly describe this approach so that the functional approach will become clearer by contrast. Influenced by the representatives of stylistique comparée, Vinay/Darbelnet (1968 Wolfram Wilss, for instance, in his early work (1971, 1977 makes frequent use of the notion transposition (German “Ausdrucksverschiebung“, cf. also Catford’s (1965 term shift. As a whole, of course, Wilss’ work has a much broader scope. More recently, he has investigated the role of cognition (1988 and the various factors in translator behaviour (1996. Nevertheless, transposition is still a very important and useful notion in describing the translation process. The need for transpositions arises when there is no possibility of formal one-to-one correspondence between source and target-language structures. The basic idea is that whenever there is a need for transposition, we are faced with a translation problem. In the early phase of translation studies in Germany, contrastive linguistics played a major role. I shall briefly describe this approach so that the functional approach will become clearer by contrast. Influenced by the representatives of stylistique comparée, Vinay/Darbelnet (1968 Wolfram Wilss, for instance, in his early work (1971, 1977 makes frequent use of the notion transposition (German “Ausdrucksverschiebung“, cf. also Catford’s (1965 term shift. As a whole, of course, Wilss’ work has a much broader scope. More recently, he has investigated the role of cognition (1988 and the various factors in translator behaviour (1996. Nevertheless, transposition is still a very important and useful notion in describing the translation process. The need for transpositions arises when there is no possibility of formal one-to-one correspondence between source and target-language structures. The basic idea is that whenever there is a need for

  7. In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity.

    Science.gov (United States)

    Boisvert, Annie; Jones, Steven; Issop, Leeyah; Erythropel, Hanno C; Papadopoulos, Vassilios; Culty, Martine

    2016-10-01

    Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health.

  8. Density Functional Approach Based on Numerically Obtained Bridge Functional

    Institute of Scientific and Technical Information of China (English)

    ZHOUShi-Qi

    2002-01-01

    The ornstein-zenike equation is solved with the Rogers-Young approximation for bulk hard sphere fluid and Lennard-Jones fluid for several state points.Then the resulted bulk fluid radial distribution function combined with the test particle method is employed to determine numerically the function relationship of bridge functional as a function of indirect correlation function.It is found that all of the calculated points from different phase space state points for a same type of fluid collapse onto a same smooth curve.Then the numerically obtained curve is used to substitute the analytic expression of the bridge functional as a function of indirect correlation function required in the methodology [J.Chem.Phys,112(2000)8079] to determine the density distribution of non-uniform hard sphere fluid and Lennard-Jones fluid.The good agreement of theoretical predictions with the computer simulation data is obtained.The present numerical procedure incroporates the knowledge of bulk fluid radial distribution function into the constructing of the density functional approximation and makes the original methodology more accurate and more filexible for various interaction potential fluid.

  9. Change in renal function after sodium phosphate preparation for screening colonoscopy

    Institute of Scientific and Technical Information of China (English)

    Dong; Choon; Seol; Sung; Noh; Hong; Jeong; Hwan; Kim; In; Kyung; Sung; Hyung; Seok; Park; Jung; Hyun; Lee; Chan; Sup; Shim

    2010-01-01

    AIM:To investigate the changes in renal function at 12-24 mo in patients following sodium phosphate(NaP) preparation for screening colonoscopy.METHODS:We carried out a retrospective study on the results from patients who received health check-up services as part of an employer-provided wellness program performed between August 2006 and May 2008 and who were followed up for 12-24 mo.Prior to screening colonoscopy,224 patients underwent bowel cleansing with NaP(NaP group) and 113 patients with polyethylene gl...

  10. A Functional Analytic Approach to Group Psychotherapy

    Science.gov (United States)

    Vandenberghe, Luc

    2009-01-01

    This article provides a particular view on the use of Functional Analytical Psychotherapy (FAP) in a group therapy format. This view is based on the author's experiences as a supervisor of Functional Analytical Psychotherapy Groups, including groups for women with depression and groups for chronic pain patients. The contexts in which this approach…

  11. Angiography and coronary function, a clinical approach

    NARCIS (Netherlands)

    Stoel, Martin Gerrit

    2013-01-01

    Coronary angiography has the potential to determine coronary function in addition to merely showing coronary anatomy. In this thesis, we describe several facets of angiographic evaluation of coronary flow velocity and function. Measurement of the length of the coronary vessels by means of a guide

  12. SCREENING APPROACHES FOR METHANE MITIGATING POTENTIAL OF TANNIN-CONTAINING PLANTS UNDER IN VITRO RUMEN ENVIRONMENT

    Directory of Open Access Journals (Sweden)

    A. Jayanegara

    2014-10-01

    Full Text Available The aim of the present study was to conduct univariate, bivariate and multivariate (principalcomponent analysis, PCA approaches in the screening of tannin-containing plants from variouscollection sites for their CH4 mitigating properties. Plant samples were obtained from various collectionsites in different countries, i.e. Indonesia (n = 27 species, Mongolia (n = 14, Switzerland (n = 16 andGermany (n = 3. The plants were incubated in vitro with buffered-rumen fluid at 39oC for 24 h. Totalgas production was recorded as an indicator of feed quality and emission of CH4 was measured. Resultsshowed that, based on bivariate screening, generally, plants possessed low CH4 production had lowquality or low total gas production except Rhus typhina, i.e. 43 ml/200 mg DM. The loading plot of PCAshowed that all phenolic fractions were in the opposite direction with CH4 and total gas production.Plants clustered together in reverse direction to that of CH4 were Bergenia crassifolia root and leaf,Swietenia mahagoni, Clidemia hirta, Peltiphyllum peltatum, Acacia villosa and R. typhina. It wasconluded that, for tannin-containing plants, screenings based on univariate, bivariate and multivariateapproaches in relation to ruminal CH4 emission led to similar results.

  13. Antibacterial enzymes from the functional screening of metagenomic libraries hosted in Ralstonia metallidurans.

    Science.gov (United States)

    Iqbal, Hala A; Craig, Jeffrey W; Brady, Sean F

    2014-05-01

    Phenotype-based screening of bacterial metagenomic libraries provides an avenue for the discovery of novel genes, enzymes, and metabolites that have a variety of potential clinical and industrial uses. Here, we report the identification of a functionally diverse collection of antibacterially active enzymes from the phenotypic screening of 700 000 cosmid clones prepared from Arizona soil DNA and hosted in Ralstonia metallidurans. Environmental DNA clones surrounded by zones of growth inhibition in a bacterial overlay assay were found, through bioinformatics and functional analyses, to encode enzymes with predicted peptidase, lipase, and glycolytic activities conferring antibiosis. The antibacterial activities observed in our R. metallidurans-based assay could not be replicated with the same clones in screens using Escherichia coli as a heterologous host, suggesting that the large-scale screening of metagenomic libraries for antibiosis using phylogenetically diverse hosts should be a productive strategy for identifying enzymes with functionally diverse antibacterial activities. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    McGuire Michael J

    2012-01-01

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

  15. A high-throughput screening approach to discovering good forms of biologically inspired visual representation.

    Directory of Open Access Journals (Sweden)

    Nicolas Pinto

    2009-11-01

    Full Text Available While many models of biological object recognition share a common set of "broad-stroke" properties, the performance of any one model depends strongly on the choice of parameters in a particular instantiation of that model--e.g., the number of units per layer, the size of pooling kernels, exponents in normalization operations, etc. Since the number of such parameters (explicit or implicit is typically large and the computational cost of evaluating one particular parameter set is high, the space of possible model instantiations goes largely unexplored. Thus, when a model fails to approach the abilities of biological visual systems, we are left uncertain whether this failure is because we are missing a fundamental idea or because the correct "parts" have not been tuned correctly, assembled at sufficient scale, or provided with enough training. Here, we present a high-throughput approach to the exploration of such parameter sets, leveraging recent advances in stream processing hardware (high-end NVIDIA graphic cards and the PlayStation 3's IBM Cell Processor. In analogy to high-throughput screening approaches in molecular biology and genetics, we explored thousands of potential network architectures and parameter instantiations, screening those that show promising object recognition performance for further analysis. We show that this approach can yield significant, reproducible gains in performance across an array of basic object recognition tasks, consistently outperforming a variety of state-of-the-art purpose-built vision systems from the literature. As the scale of available computational power continues to expand, we argue that this approach has the potential to greatly accelerate progress in both artificial vision and our understanding of the computational underpinning of biological vision.

  16. Density Functional Approach Based on Numerically Obtained Bridge Functional

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shi-Qi

    2002-01-01

    The Ornstein Zernike equation is solved with the Rogers Young approximation for bulk hard sphere fluidand Lennard-Jones fluid for several state points. Then the resulted bulk fluid radial distribution function combinedwith the test particle method is employed to determine numerically the function relationship of bridge functional as afunction of indirect correlation function. It is found that all of the calculated points from different phase space statepoints for a same type of fluid collapse onto a same smooth curve. Then the numerically obtained curve is used tosubstitute the analytic expression of the bridge functional as a function of indirect correlation function required in themethodology [J. Chem. Phys. 112 (2000) 8079] to deterrnine the density distribution of non-uniform hard spherefluid and Lennard Jones fluid. The good agreement of theoretical predictions with the computer simulation data isobtained. The present numerical procedure incorporates the knowledge of bulk fluid radial distribution function intothe constructing of the density functional approximation and makes the original methodology more accurate and moreflexible for various interaction potential fluid.

  17. Assesment of The Efficacy of Thyroid Function Screening in Early Pregnancy

    Directory of Open Access Journals (Sweden)

    Muzaffer Temur

    2013-10-01

    Full Text Available Aim: To asses the efficacy of screening thyroid function during early pregnancy. Material and Method: One hundred and eighty five pregnant women who attended a secondary center for their first antenatal visits (6-12 weeks of gestation between May 2012 and August 2012 were divided into two groups comprising 94 women regarded as high-risk and 91 low-risk. Maternal serum concentrations of TSH, fT4 and fT3 were measured. The thyroid function of the study group was evaluated for euthyroidism, hypothyroidism, hyperthyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism according to TSH, fT3 and fT4 results. Analysis of data were performed, using the SPSS software version 11.5. In all tests, p<0.05 was accepted as statistically significant. Results: We screened thyroid function in 185 pregnant women, of whom 151 (81.62% were euthyroid and 34 (18.38%  had thyroid dysfunction, with 24 (12.98% in the high-risk group and 10 (5.4% in the low-risk group. When the results of thyroid function tests were evaluated as normal and abnormal, the most statistically significant characteristics for abnormal results were found to be history of antithyroid therapy and thyroid surgery (p=0.005, p=0.015. We would fail to spot about one third of thyroid dysfunctions if only high-risk women were screened. Discussion: Risk-stratified screening for maternal thyroid dysfunction during early pregnancy may led to neglected diagnoses of thyroid disorders. Results here indicated universal screening, but the debate regarding the targeting of high-risk cases seems set to continue into the future.

  18. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

    Science.gov (United States)

    Wang, Ching Y; Ai, Ni; Arora, Sonia; Erenrich, Eric; Nagarajan, Karthigeyan; Zauhar, Randy; Young, Douglas; Welsh, William J

    2006-12-01

    The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects. Large-scale in vitro and in vivo screening of chemicals to assess their estrogenic activity would demand a prodigious investment of time, labor, and money and would require animal testing on an unprecedented scale. Approaches in silico are increasingly recognized as playing a vital role in screening and prioritizing chemicals to extend limited resources available for experimental testing. Here, we evaluated a multistep procedure that is suitable for in silico (virtual) screening of large chemical databases to identify compounds exhibiting estrogenic activity. This procedure incorporates Shape Signatures, a novel computational tool that rapidly compares molecules on the basis of similarity in shape, polarity, and other bio-relevant properties. Using 4-hydroxy tamoxifen (4-OH TAM) and diethylstilbestrol (DES) as input queries, we employed this scheme to search a sample database of approximately 200,000 commercially available organic chemicals for matches (hits). Of the eight compounds identified computationally as potentially (anti)estrogenic, biological evaluation confirmed two as heretofore unknown estrogen antagonists. Subsequent radioligand binding assays confirmed that two of these three compounds exhibit antiestrogenic activities comparable to 4-OH TAM. Molecular modeling studies of these ligands docked inside the binding pocket of estrogen receptor alpha (ERalpha) elucidated key ligand-receptor interactions that corroborate these experimental findings. The present study demonstrates the utility of our computational scheme for this and

  19. Computational approaches to screen candidate ligands with anti- Parkinson's activity using R programming.

    Science.gov (United States)

    Jayadeepa, R M; Niveditha, M S

    2012-01-01

    It is estimated that by 2050 over 100 million people will be affected by the Parkinson's disease (PD). We propose various computational approaches to screen suitable candidate ligand with anti-Parkinson's activity from phytochemicals. Five different types of dopamine receptors have been identified in the brain, D1-D5. Dopamine receptor D3 was selected as the target receptor. The D3 receptor exists in areas of the brain outside the basal ganglia, such as the limbic system, and thus may play a role in the cognitive and emotional changes noted in Parkinson's disease. A ligand library of 100 molecules with anti-Parkinson's activity was collected from literature survey. Nature is the best combinatorial chemist and possibly has answers to all diseases of mankind. Failure of some synthetic drugs and its side effects have prompted many researches to go back to ancient healing methods which use herbal medicines to give relief. Hence, the candidate ligands with anti-Parkinson's were selected from herbal sources through literature survey. Lipinski rules were applied to screen the suitable molecules for the study, the resulting 88 molecules were energy minimized, and subjected to docking using Autodock Vina. The top eleven molecules were screened according to the docking score generated by Autodock Vina Commercial drug Ropinirole was computed similarly and was compared with the 11 phytochemicals score, the screened molecules were subjected to toxicity analysis and to verify toxic property of phytochemicals. R Programming was applied to remove the bias from the top eleven molecules. Using cluster analysis and Confusion Matrix two phytochemicals were computationally selected namely Rosmarinic acid and Gingkolide A for further studies on the disease Parkinson's.

  20. The great screen anomaly--a new frontier in product discovery through functional metagenomics.

    Science.gov (United States)

    Ekkers, David Matthias; Cretoiu, Mariana Silvia; Kielak, Anna Maria; Elsas, Jan Dirk van

    2012-02-01

    Functional metagenomics, the study of the collective genome of a microbial community by expressing it in a foreign host, is an emerging field in biotechnology. Over the past years, the possibility of novel product discovery through metagenomics has developed rapidly. Thus, metagenomics has been heralded as a promising mining strategy of resources for the biotechnological and pharmaceutical industry. However, in spite of innovative work in the field of functional genomics in recent years, yields from function-based metagenomics studies still fall short of producing significant amounts of new products that are valuable for biotechnological processes. Thus, a new set of strategies is required with respect to fostering gene expression in comparison to the traditional work. These new strategies should address a major issue, that is, how to successfully express a set of unknown genes of unknown origin in a foreign host in high throughput. This article is an opinionating review of functional metagenomic screening of natural microbial communities, with a focus on the optimization of new product discovery. It first summarizes current major bottlenecks in functional metagenomics and then provides an overview of the general metagenomic assessment strategies, with a focus on the challenges that are met in the screening for, and selection of, target genes in metagenomic libraries. To identify possible screening limitations, strategies to achieve optimal gene expression are reviewed, examining the molecular events all the way from the transcription level through to the secretion of the target gene product.

  1. Four Layered Approach to Non-Functional Requirements Analysis

    CERN Document Server

    Rao, A Ananda

    2012-01-01

    Identification of non-functional requirements is important for successful development and deployment of the software product. The acceptance of the software product by the customer depends on the non-functional requirements which are incorporated in the software. For this, we need to identify all the non-functional requirements required by all stakeholders. In the literature not many approaches are available for this purpose. Hence, we have proposed a four layered analysis approach for identification of non-functional requirements. The proposed layered approach has many advantages over non-layered approach. As part of this approach some rules are also proposed to be used in each layer. The approach is applied successfully on two case studies. The identified non-functional requirements are validated using a check list and in addition the completeness of the identified non-requirements is computed using a metric.

  2. Translation: Towards a Critical-Functional Approach

    Science.gov (United States)

    Sadeghi, Sima; Ketabi, Saeed

    2010-01-01

    The controversy over the place of translation in the teaching of English as a Foreign Language (EFL) is a thriving field of inquiry. Many older language teaching methodologies such as the Direct Method, the Audio-lingual Method, and Natural and Communicative Approaches, tended to either neglect the role of translation, or prohibit it entirely as a…

  3. Functional screening with a live cell imaging-based random cell migration assay.

    Science.gov (United States)

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Zovko, Sandra; de Bont, Hans; van de Water, Bob

    2011-01-01

    Cell migration, essential in cancer progression, is a complex process comprising a number of spatiotemporally regulated and well-coordinated mechanisms. In order to study (random) cell migration in the context of responses to various external cues (such as growth factors) or intrinsic cell signaling, a number of different tools and approaches have been developed. In order to unravel the key pathways and players involved in the regulation of (cancer) cell migration, a systematical mapping of the players/pathways is required. For this purpose, we developed a cell migration assay based on automatic high-throughput microscopy screen. This approach allows for screening of hundreds of genes, e.g., those encoding various kinases and phosphatases but can also be used for screening of drugs libraries. Moreover, we have developed an automatic analysis pipeline comprising of (a) automatic data acquisition (movie) and (b) automatic analysis of the acquired movies of the migrating cells. Here, we describe various facets of this approach. Since cell migration is essential in progression of cancer metastasis, we describe two examples of experiments performed on highly motile (metastatic) cancer cells.

  4. New Approach to Fractal Approximation of Vector-Functions

    Directory of Open Access Journals (Sweden)

    Konstantin Igudesman

    2015-01-01

    Full Text Available This paper introduces new approach to approximation of continuous vector-functions and vector sequences by fractal interpolation vector-functions which are multidimensional generalization of fractal interpolation functions. Best values of fractal interpolation vector-functions parameters are found. We give schemes of approximation of some sets of data and consider examples of approximation of smooth curves with different conditions.

  5. Efficacy of screening immune system function in at-risk newborns.

    Science.gov (United States)

    Pavlovski, Christopher J

    2014-01-01

    This paper explores the introduction of a screening test to highlight impaired immune system status for newborn infants and its efficacy as a preventative clinical measure. Moreover, it is suggested that screening of the infantile immune system has the potential to highlight susceptibility to a range of infant and childhood diseases, bestowing an opportunity to introduce early intervention to reduce the incidence of these diseases. Development of the neonatal immune system is an important health issue, implicated in many childhood problems such as allergies, infection, and autoimmunity. The neonate has a limited immune system and ability to combat bacteria. Depleted levels of the tripeptide reduced glutathione (GSH) have been linked to numerous conditions and its intracellular level is acknowledged as an indicator of immune system function. Introduction of an immune system screening programme for infants is formally reviewed and assessed. Several benefits are reported in the treatment of impaired immune systems, a trial screening programme is proposed for at-risk infants to gather further evidence as to its efficacy. Infants at risk of impaired immune system function include cystic fibrosis, premature infants, and low birth weight infants. The interventions include breastfeeding, milk banks, and appropriate formula to support the immune system.

  6. Functional renormalization group approach to neutron matter

    Directory of Open Access Journals (Sweden)

    Matthias Drews

    2014-11-01

    Full Text Available The chiral nucleon-meson model, previously applied to systems with equal number of neutrons and protons, is extended to asymmetric nuclear matter. Fluctuations are included in the framework of the functional renormalization group. The equation of state for pure neutron matter is studied and compared to recent advanced many-body calculations. The chiral condensate in neutron matter is computed as a function of baryon density. It is found that, once fluctuations are incorporated, the chiral restoration transition for pure neutron matter is shifted to high densities, much beyond three times the density of normal nuclear matter.

  7. 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.

  8. Certain Actions from the Functional Movement Screen Do Not Provide an Indication of Dynamic Stability

    Directory of Open Access Journals (Sweden)

    Lockie Robert G.

    2015-09-01

    Full Text Available Dynamic stability is an essential physical component for team sport athletes. Certain Functional Movement Screen (FMS exercises (deep squat; left- and right-leg hurdle step; left- and right-leg in-line lunge [ILL]; left- and right-leg active straight-leg raise; and trunk stability push-up [TSPU] have been suggested as providing an indication of dynamic stability. No research has investigated relationships between these screens and an established test of dynamic stability such as the modified Star Excursion Balance Test (mSEBT, which measures lower-limb reach distance in posteromedial, medial, and anteromedial directions, in team sport athletes. Forty-one male and female team sport athletes completed the screens and the mSEBT. Participants were split into high-, intermediate-, and low-performing groups according to the mean of the excursions when both the left and right legs were used for the mSEBT stance. Any between-group differences in the screens and mSEBT were determined via a one-way analysis of variance with Bonferroni post hoc adjustment (p < 0.05. Data was pooled for a correlation analysis (p < 0.05. There were no between-group differences in any of the screens, and only two positive correlations between the screens and the mSEBT (TSPU and right stance leg posteromedial excursion, r = 0.37; left-leg ILL and left stance leg posteromedial excursion, r = 0.46. The mSEBT clearly indicated participants with different dynamic stability capabilities. In contrast to the mSEBT, the selected FMS exercises investigated in this study have a limited capacity to identify dynamic stability in team sport athletes.

  9. Parental questionnaire as a screening instrument for motor function at age five

    DEFF Research Database (Denmark)

    Nordbye-Nielsen, Kirsten; Kesmodel, Ulrik Schiøler

    2014-01-01

    expressed concern about the child’s motor development had a sensitivity of 17.0% and a specificity of 93.9%. 
 Conclusion: A parental questionnaire used as a screening instrument to identify children with motor problems has a reasonable specificity, but a low sensitivity. The six questions can be used......Introduction: No standardised method is used to determine motor function in children in general practice in Denmark. Our aim was to evaluate the correlation between a parental questionnaire assessing motor function at the age of five years and the clinical test Movement Assessment Battery...... for Children (M-ABC), and to assess whether one or more questions could be used to screen for motor problems at the age of five years. Methods: This study was based on a parental questionnaire containing ten questions. The M-ABC was used as the gold standard. n = 755 children. The Mann-Whitney rank sum test...

  10. Genetic screens and functional genomics using CRISPR/Cas9 technology.

    Science.gov (United States)

    Hartenian, Ella; Doench, John G

    2015-04-01

    Functional genomics attempts to understand the genome by perturbing the flow of information from DNA to RNA to protein, in order to learn how gene dysfunction leads to disease. CRISPR/Cas9 technology is the newest tool in the geneticist's toolbox, allowing researchers to edit DNA with unprecedented ease, speed and accuracy, and representing a novel means to perform genome-wide genetic screens to discover gene function. In this review, we first summarize the discovery and characterization of CRISPR/Cas9, and then compare it to other genome engineering technologies. We discuss its initial use in screening applications, with a focus on optimizing on-target activity and minimizing off-target effects. Finally, we comment on future challenges and opportunities afforded by this technology.

  11. Cervical cancer screening and treatment of cervical intraepithelial neoplasia in female sex workers using “screen and treat” approach

    Directory of Open Access Journals (Sweden)

    Joshi S

    2015-05-01

    Full Text Available Smita Joshi,1 Vinay Kulkarni,2 Trupti Darak,2 Uma Mahajan,1 Yogesh Srivastava,3 Sanjay Gupta,3 Sumitra Krishnan,1 Mahesh Mandolkar,2 Alok Chandra Bharti31Hirabai Cowasji Jehangir Medical Research Institute (HCJMRI, Jehangir Hospital Premises, Pune, Maharashtra, India; 2Prayas Health Group, Amrita Clinic, Pune, India; 3Institute for Cytology and Preventive Oncology, Indian Council of Medical Research, New Delhi, IndiaObjective: Female sex workers (FSWs are at an increased risk of human immunodeficiency virus (HIV as well as human papillomavirus (HPV infections and thus have an increased risk of cervical intraepithelial neoplasia (CIN and cervical cancer. We evaluated the feasibility of “screen and treat approach” for cervical cancer prevention and the performance of different screening tests among FSWs.Methods: Women were screened using cytology, VIA (visual inspection with acetic acid, and VILI (visual inspection with Lugol’s iodine and underwent colposcopy, biopsy, and immediate treatment using cold coagulation, if indicated, at the same visit.Results: We screened 300 FSWs of whom 200 (66.67% were HIV uninfected and 100 (33.34% were HIV infected. The overall prevalence of CIN 2–3 lesions was 4.7%. But all women with CIN 2–3 lesions were HIV infected, and thus the prevalence of CIN 2–3 lesions in HIV-infected FSWs was 14/100 (14%, 95% confidence interval: 7.2–20.8. All of them screened positive by all three screening tests. Cold coagulation was well tolerated, with no appreciable side effects.Conclusion: Cervical cancer prevention by “screen and treat” approach using VIA, followed by ablative treatment, in this high-risk group of women is feasible and can be implemented through various targeted intervention programs. Keywords: cytology, VIA, VILI, CIN, cold coagulation, cervical cancer, HPV, FSWs

  12. 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

  13. Validation of nutritional screening tools against anthropometric and functional assessments among elderly people in selangor.

    Science.gov (United States)

    Suzana, Shahar; Siti Saifa, Hussain

    2007-03-01

    This cross sectional study was conducted to determine the validity of three screening tools, Mini Nutritional Assessment Short Form (MNA-SF), Malnutrition Risk Screening Tool for Community (MRST-C) and Malnutrition Risk Screening Tool for Hospital (MRST-H) among elderly people at health clinics. The screening tools were validated against anthropometric and functional assessments. The anthropometric assessments that were carried out included body weight, height, arm span, body mass index (BMI), calf circumference (CC) and mid upper arm circumference (MUAC). A set of questionnaire on manual dexterity, muscular strength, instrumental activities daily living (IADL) and cognitive status was used to assess functional abilities. A total of 156 subjects were recruited from rural (38 subjects) and urban (118 subjects) health clinics at Sabak Bernam and Cheras respectively. Subjects' age ranged from 60 to 83 years old, with 44.2% were men and 55.8% women. The prevalence of muscle wasting among the subjects assessed from MUAC and CC were both 7.0%. MNA-SF had the highest correlation with BMI (r = 0.497, pMNA-SF (93.2%), followed by MRST-H (52.5%) and MRST-C (25.8%). Specificity was the highest for MRST-H (97.3%), followed by MRST-C (90.8%) and MNA-SF (79.4%). Positive predictive value (PPV) for MRST-H, MNA-SF and MRST-C was 55.5%, 18.2% and 14.1%, respectively. In conclusion, among the screening tools being validated, MNA-SF is considered the most appropriate tool to be used in health clinics for identification of elderly individuals who are at high risk of malnutrition.

  14. MiRNA mimic screen for improved expression of functional neurotensin receptor from HEK293 cells.

    Science.gov (United States)

    Xiao, Su; Chen, Yu-Chi; Betenbaugh, Michael J; Martin, Scott E; Shiloach, Joseph

    2015-08-01

    Obtaining adequate quantities of functional mammalian membrane proteins has been a bottleneck in their structural and functional studies because the expression of these proteins from mammalian cells is relatively low. To explore the possibility of enhancing expression of these proteins using miRNA, a stable T-REx-293 cell line expressing the neurotensin receptor type 1 (NTSR1), a hard-to-express G protein-coupled receptor (GPCR), was constructed. The cell line was then subjected to human miRNA mimic library screening. In parallel, an HEK293 cell line expressing luciferase was also screened with the same human miRNA mimic library. Five microRNA mimics: hsa-miR-22-5p, hsa-miR-18a-5p, hsa-miR-22-3p, hsa-miR-429, and hsa-miR-2110were identified from both screens. They led to 48% increase in the expression of functional NTSR1 and to 239% increase of luciferase expression. These miRNAs were also effective in enhancing the expression of secretedglypican-3 hFc-fusion protein from HEK293 cells.The results indicate that these molecules may have a wide role in enhancing the production of proteins with biomedical interest.

  15. Effects of d-electrons in pseudopotential screened-exchange density functional calculations

    Science.gov (United States)

    Lee, Byounghak; Wang, Lin-Wang; Canning, Andrew

    2008-06-01

    We report a theoretical study on the role of shallow d states in the screened-exchange local density approximation (sX-LDA) band structure of binary semiconductor systems. We found that inaccurate pseudo-wave functions can lead to (1) an overestimation of the screened-exchange interaction between the localized d states and the delocalized higher energy s and p states, and (2) an underestimation of the screened-exchange interaction between the d states. The resulting sX-LDA band structures have substantially smaller band gaps compared with experiments. We correct the pseudo-wave functions of d states by including the semicore s and p states of the same shell in the valence states. The correction of pseudo-wave functions yields band gaps and d-state binding energies in good agreement with experiments and the full potential linearized augmented plane wave sX-LDA calculations. Compared with the quasiparticle GW method, our sX-LDA results shows not only similar quality on the band gaps but also much better d-state binding energies. Combined with its capability of ground-state structure calculation, the sX-LDA is expected to be a valuable theoretical tool for the II-VI and III-V (especially the III-N) bulk semiconductors and nanostructure studies.

  16. The Development of Meta-functional Approaches in Translation Studies

    Institute of Scientific and Technical Information of China (English)

    李菁菁

    2012-01-01

      Functional linguistics has exerted an increasing impact on modern linguistic studies. Functional approaches, especial⁃ly metafunctions have undergone a process of development and improvement. The affirmation of the metafunctions of lan⁃guage has aroused more and more scholars’concern on the“functional”facet of language, especially in Translation studies. The formation and improvement of functional approaches are introduced separately.

  17. Surface plasmon resonance biosensing: Approaches for screening and characterising antibodies for food diagnostics.

    Science.gov (United States)

    Yakes, B J; Buijs, J; Elliott, C T; Campbell, K

    2016-08-15

    Research in biosensing approaches as alternative techniques for food diagnostics for the detection of chemical contaminants and foodborne pathogens has increased over the last twenty years. The key component of such tests is the biorecognition element whereby polyclonal or monoclonal antibodies still dominate the market. Traditionally the screening of sera or cell culture media for the selection of polyclonal or monoclonal candidate antibodies respectively has been performed by enzyme immunoassays. For niche toxin compounds, enzyme immunoassays can be expensive and/or prohibitive methodologies for antibody production due to limitations in toxin supply for conjugate production. Automated, self-regenerating, chip-based biosensors proven in food diagnostics may be utilised as rapid screening tools for antibody candidate selection. This work describes the use of both single channel and multi-channel surface plasmon resonance (SPR) biosensors for the selection and characterisation of antibodies, and their evaluation in shellfish tissue as standard techniques for the detection of domoic acid, as a model toxin compound. The key advantages in the use of these biosensor techniques for screening hybridomas in monoclonal antibody production were the real time observation of molecular interaction and rapid turnaround time in analysis compared to enzyme immunoassays. The multichannel prototype instrument was superior with 96 analyses completed in 2h compared to 12h for the single channel and over 24h for the ELISA immunoassay. Antibodies of high sensitivity, IC50's ranging from 4.8 to 6.9ng/mL for monoclonal and 2.3-6.0ng/mL for polyclonal, for the detection of domoic acid in a 1min analysis time were selected. Although there is a progression for biosensor technology towards low cost, multiplexed portable diagnostics for the food industry, there remains a place for laboratory-based SPR instrumentation for antibody development for food diagnostics as shown herein.

  18. A kinome wide screen identifies novel kinases involved in regulation of monoamine transporter function

    DEFF Research Database (Denmark)

    Vuorenpää, Anne Elina; Ammendrup-Johnsen, Ina; Jorgensen, Trine N.

    2016-01-01

    cells (CAD) and rat chromocytoma (PC12) cells. Whereas SIK3 likely transcriptionally regulated expression of the three transfected transporters, depletion of PKA C-α was shown to decrease SERT function. Depletion of PrKX caused decreased surface expression and function of DAT without changing protein...... levels, suggesting that PrKX stabilizes the transporter at the cell surface. Summarized, our data provide novel insight into kinome regulation of the monoamine transporters and identifies PrKX as a yet unappreciated possible regulator of monoamine transporter function....... in regulation of monoamine transporter function and surface expression. A primary screen in HEK 293 cells stably expressing DAT or SERT with siRNAs against 573 human kinases revealed 93 kinases putatively regulating transporter function. All 93 hits, which also included kinases previously implicated...

  19. Repositioning approved drugs for the treatment of problematic cancers using a screening approach.

    Science.gov (United States)

    Varbanov, Hristo P; Kuttler, Fabien; Banfi, Damiano; Turcatti, Gerardo; Dyson, Paul J

    2017-01-01

    Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan.

  20. Synthetic biology approaches to improve biocatalyst identification in metagenomic library screening.

    Science.gov (United States)

    Guazzaroni, María-Eugenia; Silva-Rocha, Rafael; Ward, Richard John

    2015-01-01

    There is a growing demand for enzymes with improved catalytic performance or tolerance to process-specific parameters, and biotechnology plays a crucial role in the development of biocatalysts for use in industry, agriculture, medicine and energy generation. Metagenomics takes advantage of the wealth of genetic and biochemical diversity present in the genomes of microorganisms found in environmental samples, and provides a set of new technologies directed towards screening for new catalytic activities from environmental samples with potential biotechnology applications. However, biased and low level of expression of heterologous proteins in Escherichia coli together with the use of non-optimal cloning vectors for the construction of metagenomic libraries generally results in an extremely low success rate for enzyme identification. The bottleneck arising from inefficient screening of enzymatic activities has been addressed from several perspectives; however, the limitations related to biased expression in heterologous hosts cannot be overcome by using a single approach, but rather requires the synergetic implementation of multiple methodologies. Here, we review some of the principal constraints regarding the discovery of new enzymes in metagenomic libraries and discuss how these might be resolved by using synthetic biology methods.

  1. Discovery of new [Formula: see text] proteasome inhibitors using a knowledge-based computational screening approach.

    Science.gov (United States)

    Mehra, Rukmankesh; Chib, Reena; Munagala, Gurunadham; Yempalla, Kushalava Reddy; Khan, Inshad Ali; Singh, Parvinder Pal; Khan, Farrah Gul; Nargotra, Amit

    2015-11-01

    Mycobacterium tuberculosis bacteria cause deadly infections in patients [Corrected]. The rise of multidrug resistance associated with tuberculosis further makes the situation worse in treating the disease. M. tuberculosis proteasome is necessary for the pathogenesis of the bacterium validated as an anti-tubercular target, thus making it an attractive enzyme for designing Mtb inhibitors. In this study, a computational screening approach was applied to identify new proteasome inhibitor candidates from a library of 50,000 compounds. This chemical library was procured from the ChemBridge (20,000 compounds) and the ChemDiv (30,000 compounds) databases. After a detailed analysis of the computational screening results, 50 in silico hits were retrieved and tested in vitro finding 15 compounds with [Formula: see text] values ranging from 35.32 to 64.15 [Formula: see text]M on lysate. A structural analysis of these hits revealed that 14 of these compounds probably have non-covalent mode of binding to the target and have not reported for anti-tubercular or anti-proteasome activity. The binding interactions of all the 14 protein-inhibitor complexes were analyzed using molecular docking studies. Further, molecular dynamics simulations of the protein in complex with the two most promising hits were carried out so as to identify the key interactions and validate the structural stability.

  2. A Suggested Approach to Simplify and Improve Cervical Screening in the United States.

    Science.gov (United States)

    Schiffman, Mark; Wentzensen, Nicolas

    2016-01-01

    Cervical cancer prevention strategies in the United States have become complicated and even controversial, despite advanced understanding of carcinogenic human papillomavirus (HPV) infection as the necessary causal agent. Twenty years ago, etiologic and methodologic studies had already yielded 2 powerful preventive approaches. There are excellent vaccines to prevent the most carcinogenic types of HPV infection; reduced HPV endemicity will ultimately prevent a large fraction of cervical precancer and cancers. For prevention of cervical cancer in the interim, sensitive HPV tests that target women at risk of cancer, by detection of the DNA/RNA of approximately a dozen carcinogenic HPV types, permit early diagnosis and treatment of precancers.Although HPV vaccines and tests have continued to improve, implementation of these new HPV-based prevention methods has been relatively slow in the United States and in most places worldwide. Increasing vaccination rates is the clearest and most vital long-term priority. But, for decades to come, screening will also be important. To promote useful discussion, this commentary will raise some current critical issues in simplifying and speeding the rational introduction of HPV molecular methods into US cervical screening.

  3. Repositioning approved drugs for the treatment of problematic cancers using a screening approach

    Science.gov (United States)

    Kuttler, Fabien; Banfi, Damiano; Turcatti, Gerardo; Dyson, Paul J.

    2017-01-01

    Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan. PMID:28166232

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

    Science.gov (United States)

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

    2012-01-01

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

  5. An estimating function approach to linkage heterogeneity

    Indian Academy of Sciences (India)

    He Gao; Ying Zhou; Weijun Ma; Haidong Liu; Linan Zhao

    2013-12-01

    Testing linkage heterogeneity between two loci is an important issue in genetics. Currently, there are four methods (K-test, A-test, B-test and D-test) for testing linkage heterogeneity in linkage analysis, which are based on the likelihood-ratio test. Among them, the commonly used methods are the K-test and A-test. In this paper, we present a novel test method which is different from the above four tests, called G-test. The new test statistic is based on estimating function, possessing a theoretic asymptotic distribution, and therefore demonstrates its own advantages. The proposed test is applied to analyse a real pedigree dataset. Our simulation results also indicate that the G-test performs well in terms of power of testing linkage heterogeneity and outperforms the current methods to some degree.

  6. Discovery of novel ligands for mouse olfactory receptor MOR42-3 using an in silico screening approach and in vitro validation.

    Directory of Open Access Journals (Sweden)

    Selvan Bavan

    Full Text Available The ligands for many olfactory receptors remain largely unknown despite successful heterologous expression of these receptors. Understanding the molecular receptive range of olfactory receptors and deciphering the olfactory recognition code are hampered by the huge number of odorants and large number of olfactory receptors, as well as the complexity of their combinatorial coding. Here, we present an in silico screening approach to find additional ligands for a mouse olfactory receptor that allows improved definition of its molecular receptive range. A virtual library of 574 odorants was screened against a mouse olfactory receptor MOR42-3. We selected the top 20 candidate ligands using two different scoring functions. These 40 odorant candidate ligands were then tested in vitro using the Xenopus oocyte heterologous expression system and two-electrode voltage clamp electrophysiology. We experimentally confirmed 22 of these ligands. The candidate ligands were screened for both agonist and antagonist activity. In summary, we validated 19 agonists and 3 antagonists. Two of the newly identified antagonists were of low potency. Several previously known ligands (mono- and dicarboxylic acids are also confirmed in this study. However, some of the newly identified ligands were structurally dissimilar compounds with various functional groups belonging to aldehydes, phenyls, alkenes, esters and ethers. The high positive predictive value of our in silico approach is promising. We believe that this approach can be used for initial deorphanization of olfactory receptors as well as for future comprehensive studies of molecular receptive range of olfactory receptors.

  7. Functional Movement Screen Factorial Validity and Measurement Invariance Across Sex Among Collegiate Student-Athletes.

    Science.gov (United States)

    Gnacinski, Stacy L; Cornell, David J; Meyer, Barbara B; Arvinen-Barrow, Monna; Earl-Boehm, Jennifer E

    2016-12-01

    Gnacinski, SL, Cornell, DJ, Meyer, BB, Arvinen-Barrow, M, and Earl-Boehm, JE. Functional Movement Screen factorial validity and measurement invariance across sex among collegiate student-athletes. J Strength Cond Res 30(12): 3388-3395, 2016-The Functional Movement Screen (FMS) is a screening tool used to evaluate functional movement quality and subsequent musculoskeletal injury risk. Despite recent research on the factorial validity of the FMS, no confirmatory factor analysis (CFA) has been conducted to examine measurement invariance across sex among student-athletes. The primary purpose of the current study was to confirm the factor structure of the FMS measurement model in a collegiate student-athlete population. It was hypothesized that the 1-factor model would demonstrate better model fit than the recently proposed 2-factor model. The secondary purpose of the study was to examine FMS measurement invariance across sex using the previously identified measurement model. It was hypothesized that FMS measurement invariance would hold across sex. Male (n = 88) and female (n = 88) collegiate student-athletes completed FMS screening during the off-season. Factorial validity was examined using CFA procedures, and model parameters were estimated using maximum likelihood estimation. Measurement invariance was examined by comparison of fit indices between hierarchically constrained models. Results revealed support for both the 1- and the 2-factor models; however, the 2-factor model failed to fit the data significantly better than the 1-factor model. Results also indicated that measurement invariance did not hold across sex, indicating that the FMS sum score construct is not measured equivalently in male and female populations. Collectively, results provide evidence for the use of the unidimensional FMS sum score among collegiate student-athletes, yet prompt caution because it relates to the evaluation of sex differences in sum or movement pattern scores.

  8. Development of a screening approach for exploring cell factory potential through metabolic flux analysis and physiology

    DEFF Research Database (Denmark)

    Knudsen, Peter Boldsen; Nielsen, Kristian Fog; Thykær, Jette

    2012-01-01

    The recent developments within the field of metabolic engineering have significantly increased the speed by which fungal recombinant strains are being constructed, pushing focus towards physiological characterisation and analysis. This raises demand for a tool for diligent analysis of the recombi...... and work-load connected with screening and selection of potential cell factories with attractive properties, compared with more “traditional” methodologies where metabolic flux analysis is applied at a much later state in the characterisation process.......The recent developments within the field of metabolic engineering have significantly increased the speed by which fungal recombinant strains are being constructed, pushing focus towards physiological characterisation and analysis. This raises demand for a tool for diligent analysis...... on a Hamilton robotic system. This method aimed at characterising physiology at two levels: (1) An approach focusing on the traditional growth related parameters, i.e. growth rate, yield coefficients and extracellular metabolites. (2) 13C-labelling experiments, where metabolic fluxes are quantified...

  9. Detailed screening of the soil faunal diversity using a tiered DNA metabarcoding approach

    DEFF Research Database (Denmark)

    Groot, G.A. de; Geisen, S.; Costa, D.

    for automated identification of six different groups of soil fauna at high taxonomic detail, with a single integrated method. We adopted a tiered approach, in which a general eukaryotic marker is used to screen for the presence of different eukaryotic clades and a set of more specific markers is simultaneously...... analyzed to obtain high resolution data for six different groups: mites, collembola, enchytraeids, nematodes, earthworms and protists. New primer sets, as well as reference barcode datasets were established for several of them. Here, we show the results of two test runs based on 454 pyrosequencing...... results for DNA pools that contained different relative amounts of DNA of the six groups, we could show that for most markers the number of taxa of the targeted group recovered depended on the presence of DNA from non-targeted groups. In the second run we moved towards the analysis of actual soil (e...

  10. CE: Tuberculosis: A New Screening Recommendation and an Expanded Approach to Elimination in the United States.

    Science.gov (United States)

    Parmer, John; Allen, Leeanna; Walton, Wanda

    2017-08-01

    : Nurses play a critical role in the diagnosis and treatment of tuberculosis and in the prevention of tuberculosis transmission through infection control practices. To eliminate tuberculosis in the United States, however, an expanded approach to testing and treating people with latent tuberculosis infection must be implemented. Recently, the U.S. Preventive Services Task Force (USPSTF) issued a new recommendation statement on latent tuberculosis infection testing that expands nurses' opportunities to identify at-risk populations for tuberculosis prevention. In combination with newer testing methodologies and shorter treatment regimens, implementation of the USPSTF recommendation has the potential to remove previously existing barriers to screening and treatment of both patients and health care providers. This article provides a general overview of tuberculosis transmission, pathogenesis, and epidemiology; presents preventive care recommendations for targeted testing among high-risk groups; and discusses the USPSTF recommendation's applicability to public health and primary care practice in the United States.

  11. The Effect of Screen Size on Mobile Phone User Comprehension of Health Information and Application Structure: An Experimental Approach.

    Science.gov (United States)

    Al Ghamdi, Ebtisam; Yunus, Faisal; Da'ar, Omar; El-Metwally, Ashraf; Khalifa, Mohamed; Aldossari, Bakheet; Househ, Mowafa

    2016-01-01

    This research analyzes the impact of mobile phone screen size on user comprehension of health information and application structure. Applying experimental approach, we asked randomly selected users to read content and conduct tasks on a commonly used diabetes mobile application using three different mobile phone screen sizes. We timed and tracked a number of parameters, including correctness, effectiveness of completing tasks, content ease of reading, clarity of information organization, and comprehension. The impact of screen size on user comprehension/retention, clarity of information organization, and reading time were mixed. It is assumed on first glance that mobile screen size would affect all qualities of information reading and comprehension, including clarity of displayed information organization, reading time and user comprehension/retention of displayed information, but actually the screen size, in this experimental research, did not have significant impact on user comprehension/retention of the content or on understanding the application structure. However, it did have significant impact on clarity of information organization and reading time. Participants with larger screen size took shorter time reading the content with a significant difference in the ease of reading. While there was no significant difference in the comprehension of information or the application structures, there were a higher task completion rate and a lower number of errors with the bigger screen size. Screen size does not directly affect user comprehension of health information. However, it does affect clarity of information organization, reading time and user's ability to recall information.

  12. Drug discovery for male subfertility using high-throughput screening: a new approach to an unsolved problem.

    Science.gov (United States)

    Martins da Silva, Sarah J; Brown, Sean G; Sutton, Keith; King, Louise V; Ruso, Halil; Gray, David W; Wyatt, Paul G; Kelly, Mark C; Barratt, Christopher L R; Hope, Anthony G

    2017-05-01

    Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform. Spermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016. A HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping. Of the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase

  13. Toward Intelligent Hemodynamic Monitoring: A Functional Approach

    Directory of Open Access Journals (Sweden)

    Pierre Squara

    2012-01-01

    Full Text Available Technology is now available to allow a complete haemodynamic analysis; however this is only used in a small proportion of patients and seems to occur when the medical staff have the time and inclination. As a result of this, significant delays occur between an event, its diagnosis and therefore, any treatment required. We can speculate that we should be able to collect enough real time information to make a complete, real time, haemodynamic diagnosis in all critically ill patients. This article advocates for “intelligent haemodynamic monitoring”. Following the steps of a functional analysis, we answered six basic questions. (1 What is the actual best theoretical model for describing haemodynamic disorders? (2 What are the needed and necessary input/output data for describing this model? (3 What are the specific quality criteria and tolerances for collecting each input variable? (4 Based on these criteria, what are the validated available technologies for monitoring each input variable, continuously, real time, and if possible non-invasively? (5 How can we integrate all the needed reliably monitored input variables into the same system for continuously describing the global haemodynamic model? (6 Is it possible to implement this global model into intelligent programs that are able to differentiate clinically relevant changes as opposed to artificial changes and to display intelligent messages and/or diagnoses?

  14. Conceptual modelling approach of mechanical products based on functional surface

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A modelling framework based on functional surface is presented to support conceptual design of mechanical products. The framework organizes product information in an abstract and multilevel manner. It consists of two mapping processes: function decomposition process and form reconstitution process. The steady mapping relationship from function to form (function-functional surface-form) is realized by taking functional surface as the middle layer. It farthest reduces the possibilities of combinatorial explosion that can occur during function decomposition and form reconstitution. Finally, CAD tools are developed and an auto-bender machine is applied to demonstrate the proposed approach.

  15. Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

    Directory of Open Access Journals (Sweden)

    Pathan AAK

    2016-05-01

    Full Text Available Akbar Ali Khan Pathan,1,2,* Bhavana Panthi,3,* Zahid Khan,1 Purushotham Reddy Koppula,4–6 Mohammed Saud Alanazi,1 Sachchidanand,3 Narasimha Reddy Parine,1 Mukesh Chourasia3,* 1Genome Research Chair (GRC, Department of Biochemistry, College of Science, King Saud University, 2Integrated Gulf Biosystems, Riyadh, Kingdom of Saudi Arabia; 3Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India; 4Department of Internal Medicine, School of Medicine, 5Harry S. Truman Memorial Veterans Affairs Hospital, 6Department of Radiology, School of Medicine, Columbia, MO, USA *These authors contributed equally to this work Objective: Kirsten rat sarcoma (K-Ras protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. Methods: In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. Results: Interestingly, the designed compounds exhibit a binding preference for the

  16. Improving adherence to alpha-1 antitrypsin deficiency screening guidelines using the pulmonary function laboratory

    Directory of Open Access Journals (Sweden)

    Luna Diaz LV

    2017-07-01

    Full Text Available Landy V Luna Diaz,1 Isabella Iupe,1 Bruno Zavala,1 Kira C Balestrini,1 Andrea Guerrero,1 Gregory Holt,1,2 Rafael Calderon-Candelario,1,2 Mehdi Mirsaeidi,1,2 Michael Campos1,21Miami Veterans Administration Medical Center, Miami, FL, 2Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami School of Medicine, Miami, FL, USAAlpha-1 antitrypsin deficiency (AATD is the only well-recognized genetic disorder associated with an increased risk of emphysema and COPD.1 Identifying AATD allows genetic counseling and the chance to offer specific augmentation therapy to slow emphysema progression. Despite specific recommendations from the World Health Organization, American Thoracic Society and European Respiratory Society to screen all patients with COPD and other at-risk conditions,2–4 testing rates are low (<15%.5We conducted a project to improve AATD screening at the Miami VA Medical Center using the pulmonary function test (PFT laboratory. We instructed the PFT personnel to perform reflex testing on all patients with pre-bronchodilator airflow obstruction (forced expiratory volume in 1 second/forced vital capacity <70% and then evaluated if the screening was appropriate according to guidelines. Trained PFT personnel explained AATD disease to patients and provided them with an informational brochure. After obtaining verbal consent, AATD screening was performed using dried blood spot kits provided by the Alpha-1 Foundation as part of the Florida Screening Program (noncommercial.6 The PFT lab director was the responsible physician of record, in charge of discussing positive results to patients and documenting results in the electronic medical record. The Miami Veterans Affairs Medical Center Institutional Review Board approved the protocol as a quality improvement project.

  17. Comparing Diagnostic Accuracy of Cognitive Screening Instruments: A Weighted Comparison Approach

    Directory of Open Access Journals (Sweden)

    A.J. Larner

    2013-03-01

    Full Text Available Background/Aims: There are many cognitive screening instruments available to clinicians when assessing patients' cognitive function, but the best way to compare the diagnostic utility of these tests is uncertain. One method is to undertake a weighted comparison which takes into account the difference in sensitivity and specificity of two tests, the relative clinical misclassification costs of true- and false-positive diagnosis, and also disease prevalence. Methods: Data were examined from four pragmatic diagnostic accuracy studies from one clinic which compared the Mini-Mental State Examination (MMSE with the Addenbrooke's Cognitive Examination-Revised (ACE-R, the Montreal Cognitive Assessment (MoCA, the Test Your Memory (TYM test, and the Mini-Mental Parkinson (MMP, respectively. Results: Weighted comparison calculations suggested a net benefit for ACE-R, MoCA, and MMP compared to MMSE, but a net loss for TYM test compared to MMSE. Conclusion: Routine incorporation of weighted comparison or other similar net benefit measures into diagnostic accuracy studies merits consideration to better inform clinicians of the relative value of cognitive screening instruments.

  18. mRAISE: an alternative algorithmic approach to ligand-based virtual screening

    Science.gov (United States)

    von Behren, Mathias M.; Bietz, Stefan; Nittinger, Eva; Rarey, Matthias

    2016-08-01

    Ligand-based virtual screening is a well established method to find new lead molecules in todays drug discovery process. In order to be applicable in day to day practice, such methods have to face multiple challenges. The most important part is the reliability of the results, which can be shown and compared in retrospective studies. Furthermore, in the case of 3D methods, they need to provide biologically relevant molecular alignments of the ligands, that can be further investigated by a medicinal chemist. Last but not least, they have to be able to screen large databases in reasonable time. Many algorithms for ligand-based virtual screening have been proposed in the past, most of them based on pairwise comparisons. Here, a new method is introduced called mRAISE. Based on structural alignments, it uses a descriptor-based bitmap search engine (RAISE) to achieve efficiency. Alignments created on the fly by the search engine get evaluated with an independent shape-based scoring function also used for ranking of compounds. The correct ranking as well as the alignment quality of the method are evaluated and compared to other state of the art methods. On the commonly used Directory of Useful Decoys dataset mRAISE achieves an average area under the ROC curve of 0.76, an average enrichment factor at 1 % of 20.2 and an average hit rate at 1 % of 55.5. With these results, mRAISE is always among the top performing methods with available data for comparison. To access the quality of the alignments calculated by ligand-based virtual screening methods, we introduce a new dataset containing 180 prealigned ligands for 11 diverse targets. Within the top ten ranked conformations, the alignment closest to X-ray structure calculated with mRAISE has a root-mean-square deviation of less than 2.0 Å for 80.8 % of alignment pairs and achieves a median of less than 2.0 Å for eight of the 11 cases. The dataset used to rate the quality of the calculated alignments is freely available at

  19. A Cell-Based Approach for the Biosynthesis/Screening of Cyclic Peptide Libraries against Bacterial Toxins

    Energy Technology Data Exchange (ETDEWEB)

    Camarero, J A; Kimura, R; Woo, Y; Cantor, J; Steenblock, E

    2007-10-24

    Available methods for developing and screening small drug-like molecules able to knockout toxins or pathogenic microorganisms have some limitations. In order to be useful, these new methods must provide high-throughput analysis and identify specific binders in a short period of time. To meet this need, we are developing an approach that uses living cells to generate libraries of small biomolecules, which are then screened inside the cell for activity. Our group is using this new, combined approach to find highly specific ligands capable of disabling anthrax Lethal Factor (LF) as proof of principle. Key to our approach is the development of a method for the biosynthesis of libraries of cyclic peptides, and an efficient screening process that can be carried out inside the cell.

  20. Functional screening identifies miRNAs influencing apoptosis and proliferation in colorectal cancer

    DEFF Research Database (Denmark)

    Christensen, Lise Lotte; Holm, Anja; Rantala, Juha

    2014-01-01

    MicroRNAs (miRNAs) play a critical role in many biological processes and are aberrantly expressed in human cancers. Particular miRNAs function either as tumor suppressors or oncogenes and appear to have diagnostic and prognostic significance. Although numerous miRNAs are dys-regulated in colorectal...... cancer (CRC) only a small fraction has been characterized functionally. Using high-throughput functional screening and miRNA profiling of clinical samples the present study aims at identifying miRNAs important for the control of cellular growth and/or apoptosis in CRC. The high-throughput functional...... analysis of transient and stable transfected CRC cell lines confirmed that miR-375 reduces cell viability through the induction of apoptotic death. We identified YAP1 as a direct miR-375 target in CRC and show that HELLS and NOLC1 are down-stream targets. Knock-down of YAP1 mimicked the phenotype induced...

  1. A functional genomics approach using metabolomics and in silico pathway analysis

    DEFF Research Database (Denmark)

    Förster, Jochen; Gombert, Andreas Karoly; Nielsen, Jens

    2002-01-01

    In the field of functional genomics increasing effort is being undertaken to analyze the function of orphan genes using metabolome data. Improved analytical equipment allows screening simultaneously for a high number of metabolites. Such metabolite profiles are analyzed using multivariate data...... analysis techniques and changes in the genotype will in many cases lead to different metabolite profiles. Here, a theoretical framework that may be applied to identify the function of orphan genes is presented. The approach is based on a combination of metabolome analysis combined with in silico pathway...... analysis. Pathway analysis may be carried out using convex analysis and a change in the active pathway structure of deletion mutants expressed in a different metabolite profile may disclose the function or the functional class of an orphan gene. The concept is illustrated using a simplified model...

  2. A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase.

    Directory of Open Access Journals (Sweden)

    Mutsuki Amano

    Full Text Available BACKGROUND: Protein kinases are major components of signal transduction pathways in multiple cellular processes. Kinases directly interact with and phosphorylate downstream substrates, thus modulating their functions. Despite the importance of identifying substrates in order to more fully understand the signaling network of respective kinases, efficient methods to search for substrates remain poorly explored. METHODOLOGY/PRINCIPAL FINDINGS: We combined mass spectrometry and affinity column chromatography of the catalytic domain of protein kinases to screen potential substrates. Using the active catalytic fragment of Rho-kinase/ROCK/ROK as the model bait, we obtained about 300 interacting proteins from the rat brain cytosol fraction, which included the proteins previously reported as Rho-kinase substrates. Several novel interacting proteins, including doublecortin, were phosphorylated by Rho-kinase both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: This method would enable identification of novel specific substrates for kinases such as Rho-kinase with high sensitivity.

  3. 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.

  4. Developing the specifications of an Open Angle Glaucoma screening intervention in the United Kingdom: a Delphi approach

    Directory of Open Access Journals (Sweden)

    Campbell Susan E

    2012-12-01

    Full Text Available Abstract Background Glaucoma is a leading cause of blindness. Early detection is advocated but there is insufficient evidence from randomized controlled trials (RCTs to inform health policy on population screening. Primarily, there is no agreed screening intervention. For a screening programme, agreement is required on the screening tests to be used, either individually or in combination, the person to deliver the test and the location where testing should take place. This study aimed to use ophthalmologists (who were experienced glaucoma subspecialists, optometrists, ophthalmic nurses and patients to develop a reduced set of potential screening tests and testing arrangements that could then be explored in depth in a further study of their feasibility for evaluation in a glaucoma screening RCT. Methods A two-round Delphi survey involving 38 participants was conducted. Materials were developed from a prior evidence synthesis. For round one, after some initial priming questions in four domains, specialists were asked to nominate three screening interventions, the intervention being a combination of the four domains; target population, (age and higher risk groups, site, screening test and test operator (provider. More than 250 screening interventions were identified. For round two, responses were condensed into 72 interventions and each was rated by participants on a 0-10 scale in terms of feasibility. Results Using a cut-off of a median rating of feasibility of ≥5.5 as evidence of agreement of intervention feasibility, six interventions were identified from round 2. These were initiating screening at age 50, with a combination of two or three screening tests (varying combinations of tonometry/measures of visual function/optic nerve damage organized in a community setting with an ophthalmic trained technical assistant delivering the tests. An alternative intervention was a ‘glaucoma risk score’ ascertained by questionnaire. The advisory panel

  5. Neonatal screening of hearing function by otoacustic emissions: A single center experience

    Directory of Open Access Journals (Sweden)

    Živić Ljubica

    2012-01-01

    Full Text Available Background/Aim. Nowadays development of techniques enables detection of hearing impairment in a very short time, immediately after birth by using otoacoustic emissions. They are low-pitched sounds produced in physiologically clear cochlea and can be recorded in cochlear outer meatus. By this method, complete data are found on a whole presynaptic auditory nervous system functioning that has mostly been affected by pathological changes making it a perfect screening test. Reliability and sensibility of this method is up to 98%. The aim of this study was to present the first results of systematic neonatal screening of hearing function by otoacoustic emissions in the Clinical Center Kragujevac (Kragujevac, Serbia. Methods. This prospective study of neonatal hearing screening function, initiated systematically by the 2008 at the Clinical Center Kragujevac, included full-term newborns and premature born ones, within the first 24 h after birth, using a DPOAEs interacoustics otoread-screener. Retesting was done after a month. Results. From January 1st, 2009 to December 1st, 2010, a total number of examined infants by this method was 1,994 out of which 1,778 were full-term and 216 were premature born. The test passing was higher in the group of full-term babies (92.5% than in the preterm ones (55.1%. No bilateral answers were recorded in premature born children compared to the full-term ones, of whom a larger number was with missing lateral responses. The results of re-examination test in the group of full-term born and premature newborns were 83.7%, and 61%, respectively. Conclusion. Deliberately provoked transient otoacoustic emission is an efficient method in testing hearing function in newborns, since it is non-invasive, rapid and objective. Its correlation with audibly evoked potentials is very high, which confirms its reliability.

  6. Differences in performance on the functional movement screen between chronic low back pain patients and healthy control subjects.

    Science.gov (United States)

    Ko, Min-Joo; Noh, Kyung-Hee; Kang, Min-Hyeok; Oh, Jae-Seop

    2016-07-01

    [Purpose] Differences in scores on the Functional Movement Screen between patients with chronic lower back pain and healthy control subjects were investigated. [Subjects and Methods] In all, 20 chronic lower back pain patients and 20 healthy control subjects were recruited. Chronic lower back pain patients and healthy controls performed the Functional Movement Screen (deep squat, hurdle step, inline lunge, shoulder mobility, active straight leg raise, trunk stability pushup, and rotary stability). The Mann-Whitney test was used to analyze differences in Functional Movement Screen scores between the two groups. [Results] Chronic lower back pain patients scored lower on the Functional Movement Screen total composite compared with healthy control subjects. Chronic lower back pain patients scored lower on Functional Movement Screen subtests including the deep squat, hurdle step, active straight leg raise, and rotary stability tests. [Conclusion] The deep squat, hurdle step, active straight leg raise, and rotary stability tasks of the Functional Movement Screen can be recommended as a functional assessment tools to identify functional deficits in chronic lower back pain patients.

  7. Genetic screening of functional properties of lactic acid bacteria in a fermented pearl millet slurry and in the metagenome of fermented starchy foods.

    Science.gov (United States)

    Turpin, Williams; Humblot, Christèle; Guyot, Jean-Pierre

    2011-12-01

    Lactic acid bacteria (LAB) (n = 152) in African pearl millet slurries and in the metagenomes of amylaceous fermented foods were investigated by screening 33 genes involved in probiotic and nutritional functions. All isolates belonged to six species of the genera Pediococcus and Lactobacillus, and Lactobacillus fermentum was the dominant species. We screened the isolates for the abilities to survive passage through the gastrointestinal tract and to synthesize folate and riboflavin. The isolates were also tested in vitro for their abilities to survive exposure to bile salts and to survive at pH 2. Because the ability to hydrolyze starch confers an ecological advantage on LAB that grow in starchy matrixes as well as improving the nutritional properties of the gruels, we screened for genes involved in starch metabolism. The results showed that genes with the potential ability to survive passage through the gastrointestinal tract were widely distributed among isolates and metagenomes, whereas in vitro tests showed that only a limited set of isolates, mainly those belonging to L. fermentum, could tolerate a low pH. In contrast, the wide distribution of genes associated with bile salt tolerance, in particular bsh, is consistent with the high frequency of tolerance to bile salts observed. Genetic screening revealed a potential for folate and riboflavin synthesis in both isolates and metagenomes, as well as high variability among genes related to starch metabolism. Genetic screening of isolates and metagenomes from fermented foods is thus a promising approach for assessing the functional potential of food microbiotas.

  8. Genetic Screening of Functional Properties of Lactic Acid Bacteria in a Fermented Pearl Millet Slurry and in the Metagenome of Fermented Starchy Foods▿

    Science.gov (United States)

    Turpin, Williams; Humblot, Christèle; Guyot, Jean-Pierre

    2011-01-01

    Lactic acid bacteria (LAB) (n = 152) in African pearl millet slurries and in the metagenomes of amylaceous fermented foods were investigated by screening 33 genes involved in probiotic and nutritional functions. All isolates belonged to six species of the genera Pediococcus and Lactobacillus, and Lactobacillus fermentum was the dominant species. We screened the isolates for the abilities to survive passage through the gastrointestinal tract and to synthesize folate and riboflavin. The isolates were also tested in vitro for their abilities to survive exposure to bile salts and to survive at pH 2. Because the ability to hydrolyze starch confers an ecological advantage on LAB that grow in starchy matrixes as well as improving the nutritional properties of the gruels, we screened for genes involved in starch metabolism. The results showed that genes with the potential ability to survive passage through the gastrointestinal tract were widely distributed among isolates and metagenomes, whereas in vitro tests showed that only a limited set of isolates, mainly those belonging to L. fermentum, could tolerate a low pH. In contrast, the wide distribution of genes associated with bile salt tolerance, in particular bsh, is consistent with the high frequency of tolerance to bile salts observed. Genetic screening revealed a potential for folate and riboflavin synthesis in both isolates and metagenomes, as well as high variability among genes related to starch metabolism. Genetic screening of isolates and metagenomes from fermented foods is thus a promising approach for assessing the functional potential of food microbiotas. PMID:22003019

  9. Functional screening identifies miRNAs influencing apoptosis and proliferation in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Lise Lotte Christensen

    Full Text Available MicroRNAs (miRNAs play a critical role in many biological processes and are aberrantly expressed in human cancers. Particular miRNAs function either as tumor suppressors or oncogenes and appear to have diagnostic and prognostic significance. Although numerous miRNAs are dys-regulated in colorectal cancer (CRC only a small fraction has been characterized functionally. Using high-throughput functional screening and miRNA profiling of clinical samples the present study aims at identifying miRNAs important for the control of cellular growth and/or apoptosis in CRC. The high-throughput functional screening was carried out in six CRC cell lines transfected with a pre-miR library including 319 synthetic human pre-miRs. Phenotypic alterations were evaluated by immunostaining of cleaved cPARP (apoptosis or MKI67 (proliferation. Additionally, TaqMan Human MicroRNA Array Set v2.0 was used to profile the expression of 667 miRNAs in 14 normal colon mucosa and 46 microsatellite stable stage II CRC patients. Among the miRNAs that induced growth arrest and apoptosis in the CRC cell lines, and at same time were dys-regulated in the clinical samples, miR-375 was selected for further analysis. Independent in vitro analysis of transient and stable transfected CRC cell lines confirmed that miR-375 reduces cell viability through the induction of apoptotic death. We identified YAP1 as a direct miR-375 target in CRC and show that HELLS and NOLC1 are down-stream targets. Knock-down of YAP1 mimicked the phenotype induced by miR-375 over-expression indicating that miR-375 most likely exerts its pro-apoptotic role through YAP1 and its anti-apoptotic down-stream targets BIRC5 and BCL2L1. Finally, in vivo analysis of mouse xenograft tumors showed that miR-375 expression significantly reduced tumor growth. We conclude that the high-throughput screening successfully identified miRNAs that induce apoptosis and/or inhibit proliferation in CRC cells. Finally, combining the

  10. AN ENERGY FUNCTION APPROACH FOR FINDING ROOTS OF CHARACTERISTIC EQUATION

    Directory of Open Access Journals (Sweden)

    Deepak Mishra

    2011-07-01

    Full Text Available In this paper, an energy function approach for finding roots of a characteristic equation has been proposed. Finding the roots of a characteristics equation is considered as an optimization problem. We demonstrated that this problem can be solved with the application of feedback type neural network. The proposed approach is fast and robust against variation of parameter.

  11. Defining mental disorder. Exploring the 'natural function' approach

    Directory of Open Access Journals (Sweden)

    Varga Somogy

    2011-01-01

    Full Text Available Abstract Due to several socio-political factors, to many psychiatrists only a strictly objective definition of mental disorder, free of value components, seems really acceptable. In this paper, I will explore a variant of such an objectivist approach to defining metal disorder, natural function objectivism. Proponents of this approach make recourse to the notion of natural function in order to reach a value-free definition of mental disorder. The exploration of Christopher Boorse's 'biostatistical' account of natural function (1 will be followed an investigation of the 'hybrid naturalism' approach to natural functions by Jerome Wakefield (2. In the third part, I will explore two proposals that call into question the whole attempt to define mental disorder (3. I will conclude that while 'natural function objectivism' accounts fail to provide the backdrop for a reliable definition of mental disorder, there is no compelling reason to conclude that a definition cannot be achieved.

  12. Functional screening of intracardiac cell transplants using two-photon fluorescence microscopy.

    Science.gov (United States)

    Tao, Wen; Soonpaa, Mark H; Field, Loren J; Chen, Peng-Sheng; Firulli, Anthony B; Shou, Weinian; Rubart, Michael

    2012-08-01

    Although the adult mammalian myocardium exhibits a limited ability to undergo regenerative growth, its intrinsic renewal rate is insufficient to compensate for myocyte loss during cardiac disease. Transplantation of donor cardiomyocytes or cardiomyogenic stem cells is considered a promising strategy for reconstitution of cardiac mass, provided the engrafted cells functionally integrate with host myocardium and actively contribute to its contractile force. The authors previously developed a two-photon fluorescence microscopy-based assay that allows in situ screening of donor cell function after intracardiac delivery of the cells. This report reviews the techniques of two-photon fluorescence microscopy and summarizes its application for quantifying the extent to which a variety of donor cell types stably and functionally couple with the recipient myocardium.

  13. Strain screening, fermentation, separation, and encapsulation for production of nattokinase functional food.

    Science.gov (United States)

    Wei, Xuetuan; Luo, Mingfang; Xie, Yuchun; Yang, Liangrong; Li, Haojian; Xu, Lin; Liu, Huizhou

    2012-12-01

    This study presents a novel and integrated preparation technology for nattokinase functional food, including strain screening, fermentation, separation, and encapsulation. To rapidly screen a nattokinase-productive strain, PCR-based screening method was combined with fibrinolytic activity-based method, and a high productive strain, Bacillus subtilis LSSE-22, was isolated from Chinese soybean paste. Reduction of poly-γ-glutamic acid (γ-PGA) concentration may contribute to separation of nattokinase and reduction of late-onset anaphylaxis risk. Chickpeas were confirmed as the favorable substrate for enhancement of nattokinase production and reduction of γ-PGA yield. Using cracked chickpeas, the nattokinase activity reached 356.25 ± 17.18 FU/g (dry weight), which is much higher than previous reports. To further reduce γ-PGA concentration, ethanol fractional extraction and precipitation were applied for separation of nattokinase. By extraction with 50 % and precipitation with 75 % ethanol solution, 4,000.58 ± 192.98 FU/g of nattokinase powders were obtained, and the activity recovery reached 89 ± 1 %, while γ-PGA recovery was reduced to 21 ± 2 %. To improve the nattokinase stability at acidic pH condition, the nattokinase powders were encapsulated, and then coated with methacrylic acid-ethyl acrylate copolymer. After encapsulation, the nattokinase was protected from being denatured under various acid conditions, and pH-responsible controlled release at simulated intestinal fluid was realized.

  14. An Integrated Microfluidic Processor for DNA-Encoded Combinatorial Library Functional Screening

    Science.gov (United States)

    2017-01-01

    DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits. DNA-encoded compound beads (10-μm diameter) displaying a photocleavable positive control inhibitor pepstatin A were mixed (1920 beads, 729 encoding sequences) with negative control beads (58 000 beads, 1728 encoding sequences) and screened for cathepsin D inhibition using a biochemical enzyme activity assay. The circuit sorted 1518 hit droplets for collection following 18 min incubation over a 240 min analysis. Visual inspection of a subset of droplets (1188 droplets) yielded a 24% false discovery rate (1166 pepstatin A beads; 366 negative control beads). Using template barcoding strategies, it was possible to count hit collection beads (1863) using next-generation sequencing data. Bead-specific barcodes enabled replicate counting, and the false discovery rate was reduced to 2.6% by only considering hit-encoding sequences that were observed on >2 beads. This work represents a complete distributable small molecule discovery platform, from microfluidic miniaturized automation to ultrahigh-throughput hit deconvolution by sequencing. PMID:28199790

  15. Negative regulators of insulin signaling revealed in a genome-wide functional screen.

    Directory of Open Access Journals (Sweden)

    Shih-Min A Huang

    Full Text Available BACKGROUND: Type 2 diabetes develops due to a combination of insulin resistance and beta-cell failure and current therapeutics aim at both of these underlying causes. Several negative regulators of insulin signaling are known and are the subject of drug discovery efforts. We sought to identify novel contributors to insulin resistance and hence potentially novel targets for therapeutic intervention. METHODOLOGY: An arrayed cDNA library encoding 18,441 human transcripts was screened for inhibitors of insulin signaling and revealed known inhibitors and numerous potential novel regulators. The novel hits included proteins of various functional classes such as kinases, phosphatases, transcription factors, and GTPase associated proteins. A series of secondary assays confirmed the relevance of the primary screen hits to insulin signaling and provided further insight into their modes of action. CONCLUSION/SIGNIFICANCE: Among the novel hits was PALD (KIAA1274, paladin, a previously uncharacterized protein that when overexpressed led to inhibition of insulin's ability to down regulate a FOXO1A-driven reporter gene, reduced upstream insulin-stimulated AKT phosphorylation, and decreased insulin receptor (IR abundance. Conversely, knockdown of PALD gene expression resulted in increased IR abundance, enhanced insulin-stimulated AKT phosphorylation, and an improvement in insulin's ability to suppress FOXO1A-driven reporter gene activity. The present data demonstrate that the application of arrayed genome-wide screening technologies to insulin signaling is fruitful and is likely to reveal novel drug targets for insulin resistance and the metabolic syndrome.

  16. A new age in functional genomics using CRISPR/Cas9 in arrayed library screening.

    Science.gov (United States)

    Agrotis, Alexander; Ketteler, Robin

    2015-01-01

    CRISPR technology has rapidly changed the face of biological research, such that precise genome editing has now become routine for many labs within several years of its initial development. What makes CRISPR/Cas9 so revolutionary is the ability to target a protein (Cas9) to an exact genomic locus, through designing a specific short complementary nucleotide sequence, that together with a common scaffold sequence, constitute the guide RNA bridging the protein and the DNA. Wild-type Cas9 cleaves both DNA strands at its target sequence, but this protein can also be modified to exert many other functions. For instance, by attaching an activation domain to catalytically inactive Cas9 and targeting a promoter region, it is possible to stimulate the expression of a specific endogenous gene. In principle, any genomic region can be targeted, and recent efforts have successfully generated pooled guide RNA libraries for coding and regulatory regions of human, mouse and Drosophila genomes with high coverage, thus facilitating functional phenotypic screening. In this review, we will highlight recent developments in the area of CRISPR-based functional genomics and discuss potential future directions, with a special focus on mammalian cell systems and arrayed library screening.

  17. A New Age in Functional Genomics Using CRISPR/Cas9 in Arrayed Library Screening

    Directory of Open Access Journals (Sweden)

    Alexander eAgrotis

    2015-09-01

    Full Text Available CRISPR technology has rapidly changed the face of biological research, such that precise genome editing has now become routine for many labs within several years of its initial development. What makes CRISPR/Cas9 so revolutionary is the ability to target a protein (Cas9 to an exact genomic locus, through designing a specific short complementary nucleotide sequence, that together with a common scaffold sequence, constitute the guide RNA bridging the protein and the DNA. Wild-type Cas9 cleaves both DNA strands at its target sequence, but this protein can also be modified to exert many other functions. For instance, by attaching an activation domain to catalytically inactive Cas9 and targeting a promoter region, it is possible to stimulate the expression of a specific endogenous gene. In principle, any genomic region can be targeted, and recent efforts have successfully generated pooled guide RNA libraries for coding and regulatory regions of human, mouse and Drosophila genomes with high coverage, thus facilitating functional phenotypic screening. In this review, we will highlight recent developments in the area of CRISPR-based functional genomics and discuss potential future directions, with a special focus on mammalian cell systems and arrayed library screening.

  18. A Phenotypic Based Target Screening Approach Delivers New Antitubercular CTP Synthetase Inhibitors.

    Science.gov (United States)

    Esposito, Marta; Szadocka, Sára; Degiacomi, Giulia; Orena, Beatrice S; Mori, Giorgia; Piano, Valentina; Boldrin, Francesca; Zemanová, Júlia; Huszár, Stanislav; Barros, David; Ekins, Sean; Lelièvre, Joel; Manganelli, Riccardo; Mattevi, Andrea; Pasca, Maria Rosalia; Riccardi, Giovanna; Ballell, Lluis; Mikušová, Katarína; Chiarelli, Laurent R

    2017-06-09

    Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds. To this purpose the publically available GlaxoSmithKline antimycobacterial compound set was assayed, uncovering a series of 4-(pyridin-2-yl)thiazole derivatives which efficiently inhibit the Mycobacterium tuberculosis PyrG enzyme activity, one of them showing low activity against the human CTP synthetase. The three best compounds were ATP binding site competitive inhibitors, with Ki values ranging from 3 to 20 μM, but did not show any activity against a small panel of different prokaryotic and eukaryotic kinases, thus demonstrating specificity for the CTP synthetases. Metabolic labeling experiments demonstrated that the compounds directly interfere not only with CTP biosynthesis, but also with other CTP dependent biochemical pathways, such as lipid biosynthesis. Moreover, using a M. tuberculosis pyrG conditional knock-down strain, it was shown that the activity of two compounds is dependent on the intracellular concentration of the CTP synthetase. All these results strongly suggest a role of PyrG as a target of these compounds, thus strengthening the value of this kind of approach for the identification of new scaffolds for drug development.

  19. Text Analysis: A Functional Linguistic Approach of News Introduction

    Institute of Scientific and Technical Information of China (English)

    刘锦凤

    2009-01-01

    The past several decades have witnessed a phenomenal growth in interest in text analysis, in which different kinds of approaches have been studied and applied in this field. This paper aims at analyzing the introduction of a cho-sen CNN News from a functional linguis.tic approach, which is mainly realized through cohesive means and textual infor-mation. The study shows that in written text, well-organized semantic cohesive means and textual information are of great significance for readers to follow the movement of an idea from one sentence to another. Therefore, functional approach plays a momentous role in the analysis of a text.

  20. DYNAMIC SCALING OF GROWING SURFACES WITH GROWTH INHOMOGENEITIES OF SCREENED COULOMBIC FUNCTION

    Institute of Scientific and Technical Information of China (English)

    TANG GANG; MA BEN-KUN

    2000-01-01

    The dynamic scaling properties of growing surfaces with growth inhomogeneities are studied by applying a dy namic renormalization-group analysis to the generalized Kardar-Parisi-Zhang(hereafter abbreviated to KPZ) equation, which contains an additional term of growth inhomogeneities. In a practical crystal growth process, these growth inho mogeneities can be induced by surface impurities and defects and are modeled by a screened Coulomb function in this paper. Our results show that the existence of the growth inhomogeneities can significantly change the dynamic scaling properties of a growing surface and can lead to a rougher surface.

  1. Kabat's Surface Terms in the $\\zeta$-Function approach

    CERN Document Server

    Iellici, D; Iellici, Devis; Moretti, Valter

    1997-01-01

    The thermal partition functions of photons in any covariant gauge and gravitons in the harmonic gauge, propagating in a Rindler wedge, are computed using a local zeta-function approach. The relation with the surface terms previously obtained by D. Kabat is studied. The results are discussed in relation to the quantum corrections to the black hole entropy.

  2. Kabat's Surface Terms in the Zeta-Function Approach

    Science.gov (United States)

    Iellici, D.; Moretti, V.

    The thermal partition functions of photons in any covariant gauge and gravitons in the harmonic gauge, propagating in a Rindler wedge, are computed using a local zeta-function approach. The relation with the surface terms previously obtained by D. Kabat is studied. The results are discussed in relation to the quantum corrections to the black hole entropy.

  3. Efficient wave-function matching approach for quantum transport calculations

    DEFF Research Database (Denmark)

    Sørensen, Hans Henrik Brandenborg; Hansen, Per Christian; Petersen, Dan Erik;

    2009-01-01

    The wave-function matching (WFM) technique has recently been developed for the calculation of electronic transport in quantum two-probe systems. In terms of efficiency it is comparable to the widely used Green's function approach. The WFM formalism presented so far requires the evaluation of all ...

  4. Using a Functional Approach in Assessing Written Texts.

    Science.gov (United States)

    Nunan, David

    It is argued that assessment of student writing can be enhanced by adoption of a functional approach to linguistic analysis; through their research, functional grammarians have provided language teachers with criteria for evaluating the extent to which learners have gained control of the grammatical and discourse features of a variety of…

  5. Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies

    Science.gov (United States)

    Carreño, Oriel; Corominas, Roser; Serra, Selma Angèlica; Sintas, Cèlia; Fernández-Castillo, Noèlia; Vila-Pueyo, Marta; Toma, Claudio; Gené, Gemma G; Pons, Roser; Llaneza, Miguel; Sobrido, María-Jesús; Grinberg, Daniel; Valverde, Miguel Ángel; Fernández-Fernández, José Manuel; Macaya, Alfons; Cormand, Bru

    2013-01-01

    Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing. PMID:24498617

  6. Differences in performance on the functional movement screen between chronic low back pain patients and healthy control subjects

    OpenAIRE

    Ko, Min-Joo; Noh, Kyung-Hee; Kang, Min-Hyeok; Oh, Jae-Seop

    2016-01-01

    [Purpose] Differences in scores on the Functional Movement Screen between patients with chronic lower back pain and healthy control subjects were investigated. [Subjects and Methods] In all, 20 chronic lower back pain patients and 20 healthy control subjects were recruited. Chronic lower back pain patients and healthy controls performed the Functional Movement Screen (deep squat, hurdle step, inline lunge, shoulder mobility, active straight leg raise, trunk stability pushup, and rotary stabil...

  7. Functional screening of metagenome and genome libraries for detection of novel flavonoid-modifying enzymes.

    Science.gov (United States)

    Rabausch, U; Juergensen, J; Ilmberger, N; Böhnke, S; Fischer, S; Schubach, B; Schulte, M; Streit, W R

    2013-08-01

    The functional detection of novel enzymes other than hydrolases from metagenomes is limited since only a very few reliable screening procedures are available that allow the rapid screening of large clone libraries. For the discovery of flavonoid-modifying enzymes in genome and metagenome clone libraries, we have developed a new screening system based on high-performance thin-layer chromatography (HPTLC). This metagenome extract thin-layer chromatography analysis (META) allows the rapid detection of glycosyltransferase (GT) and also other flavonoid-modifying activities. The developed screening method is highly sensitive, and an amount of 4 ng of modified flavonoid molecules can be detected. This novel technology was validated against a control library of 1,920 fosmid clones generated from a single Bacillus cereus isolate and then used to analyze more than 38,000 clones derived from two different metagenomic preparations. Thereby we identified two novel UDP glycosyltransferase (UGT) genes. The metagenome-derived gtfC gene encoded a 52-kDa protein, and the deduced amino acid sequence was weakly similar to sequences of putative UGTs from Fibrisoma and Dyadobacter. GtfC mediated the transfer of different hexose moieties and exhibited high activities on flavones, flavonols, flavanones, and stilbenes and also accepted isoflavones and chalcones. From the control library we identified a novel macroside glycosyltransferase (MGT) with a calculated molecular mass of 46 kDa. The deduced amino acid sequence was highly similar to sequences of MGTs from Bacillus thuringiensis. Recombinant MgtB transferred the sugar residue from UDP-glucose effectively to flavones, flavonols, isoflavones, and flavanones. Moreover, MgtB exhibited high activity on larger flavonoid molecules such as tiliroside.

  8. A genetic screen in Drosophila reveals novel cytoprotective functions of the autophagy-lysosome pathway.

    Directory of Open Access Journals (Sweden)

    Andrew M Arsham

    Full Text Available The highly conserved autophagy-lysosome pathway is the primary mechanism for breakdown and recycling of macromolecular and organellar cargo in the eukaryotic cell. Autophagy has recently been implicated in protection against cancer, neurodegeneration, and infection, and interest is increasing in additional roles of autophagy in human health, disease, and aging. To search for novel cytoprotective features of this pathway, we carried out a genetic mosaic screen for mutations causing increased lysosomal and/or autophagic activity in the Drosophila melanogaster larval fat body. By combining Drosophila genetics with live-cell imaging of the fluorescent dye LysoTracker Red and fixed-cell imaging of autophagy-specific fluorescent protein markers, the screen was designed to identify essential metazoan genes whose disruption causes increased flux through the autophagy-lysosome pathway. The screen identified a large number of genes associated with the protein synthesis and ER-secretory pathways (e.g. aminoacyl tRNA synthetases, Oligosaccharyl transferase, Sec61alpha, and with mitochondrial function and dynamics (e.g. Rieske iron-sulfur protein, Dynamin-related protein 1. We also observed that increased lysosomal and autophagic activity were consistently associated with decreased cell size. Our work demonstrates that disruption of the synthesis, transport, folding, or glycosylation of ER-targeted proteins at any of multiple steps leads to autophagy induction. In addition to illuminating cytoprotective features of autophagy in response to cellular damage, this screen establishes a genetic methodology for investigating cell biological phenotypes in live cells, in the context of viable wild type organisms.

  9. MSoS: A Multi-Screen-Oriented Web Page Segmentation Approach

    OpenAIRE

    Sarkis, Mira; Concolato, Cyril; Dufourd, Jean-Claude

    2015-01-01

    International audience; In this paper we describe a multiscreen-oriented approach for segmenting web pages. The segmentation is an automatic and hybrid visual and structural method. It aims at creating coherent blocks which have different functions determined by the multiscreen environment. It is also characterized by a dynamic adaptation to the page content. Experiments are conducted on a set of existing applications that contain multimedia elements, in particular YouTube and video player pa...

  10. Micro-TLC Approach for Fast Screening of Environmental Samples Derived from Surface and Sewage Waters.

    Science.gov (United States)

    Zarzycki, Paweł K; Slączka, Magdalena M; Włodarczyk, Elżbieta; Baran, Michał J

    2013-01-01

    In this work we demonstrated analytical capability of micro-planar (micro-TLC) technique comprising one and two-dimensional (2D) separation modes to generate fingerprints of environmental samples originated from sewage and ecosystems waters. We showed that elaborated separation and detection protocols are complementary to previously invented HPLC method based on temperature-dependent inclusion chromatography and UV-DAD detection. Presented 1D and 2D micro-TLC chromatograms of SPE (solid-phase extraction) extracts were optimized for fast and low-cost screening of water samples collected from lakes and rivers located in the area of Middle Pomerania in northern part of Poland. Moreover, we studied highly organic compounds loaded in the treated and untreated sewage waters obtained from municipal wastewater treatment plant "Jamno" near Koszalin City (Poland). Analyzed environmental samples contained number of substances characterized by polarity range from estetrol to progesterone as well as chlorophyll-related dyes previously isolated and pre-purified by simple SPE protocol involving C18 cartridges. Optimization of micro-TLC separation and quantification protocols of such samples were discussed from the practical point of view using simple separation efficiency criteria including total peaks number, log(product ΔhRF), signal intensity and peak asymmetry. Outcomes of the presented analytical approach, especially using detection involving direct fluorescence (UV366/Vis) and phosphomolybdic acid (PMA) visualization are compared with UV-DAD HPLC-generated data reported previously. Chemometric investigation based on principal components analysis revealed that SPE extracts separated by micro-TLC and detected under fluorescence and PMA visualization modes can be used for robust sample fingerprinting even after long-term storage of the extracts (up to 4 years) at subambient temperature (-20 °C). Such approach allows characterization of wide range of sample components that

  11. Quadratic function approaching method for magnetotelluric soundingdata inversion

    Energy Technology Data Exchange (ETDEWEB)

    Liangjun, Yan; Wenbao, Hu; Zhang, Keni

    2004-04-05

    The quadratic function approaching method (QFAM) is introduced for magnetotelluric sounding (MT) data inversion. The method takes the advantage of that quadratic function has single extreme value, which avoids leading to an inversion solution for local minimum and ensures the solution for global minimization of an objective function. The method does not need calculation of sensitivity matrix and not require a strict initial earth model. Examples for synthetic data and field measurement data indicate that the proposed inversion method is effective.

  12. Activation of dorsolateral prefrontal cortex in a dual neuropsychological screening test: an fMRI approach.

    Science.gov (United States)

    Tachibana, Atsumichi; Noah, J Adam; Bronner, Shaw; Ono, Yumie; Hirano, Yoshiyuki; Niwa, Masami; Watanabe, Kazuko; Onozuka, Minoru

    2012-05-28

    The Kana Pick-out Test (KPT), which uses Kana or Japanese symbols that represent syllables, requires parallel processing of discrete (pick-out) and continuous (reading) dual tasks. As a dual task, the KPT is thought to test working memory and executive function, particularly in the prefrontal cortex (PFC), and is widely used in Japan as a clinical screen for dementia. Nevertheless, there has been little neurological investigation into PFC activity during this test. We used functional magnetic resonance imaging (fMRI) to evaluate changes in the blood oxygenation level-dependent (BOLD) signal in young healthy adults during performance of a computerized KPT dual task (comprised of reading comprehension and picking out vowels) and compared it to its single task components (reading or vowel pick-out alone). Behavioral performance of the KPT degraded compared to its single task components. Performance of the KPT markedly increased BOLD signal intensity in the PFC, and also activated sensorimotor, parietal association, and visual cortex areas. In conjunction analyses, bilateral BOLD signal in the dorsolateral PFC (Brodmann's areas 45, 46) was present only in the KPT. Our results support the central bottleneck theory and suggest that the dorsolateral PFC is an important mediator of neural activity for both short-term storage and executive processes. Quantitative evaluation of the KPT with fMRI in healthy adults is the first step towards understanding the effects of aging or cognitive impairment on KPT performance.

  13. Activation of dorsolateral prefrontal cortex in a dual neuropsychological screening test: An fMRI approach

    Directory of Open Access Journals (Sweden)

    Tachibana Atsumichi

    2012-05-01

    Full Text Available Abstract Background The Kana Pick-out Test (KPT, which uses Kana or Japanese symbols that represent syllables, requires parallel processing of discrete (pick-out and continuous (reading dual tasks. As a dual task, the KPT is thought to test working memory and executive function, particularly in the prefrontal cortex (PFC, and is widely used in Japan as a clinical screen for dementia. Nevertheless, there has been little neurological investigation into PFC activity during this test. Methods We used functional magnetic resonance imaging (fMRI to evaluate changes in the blood oxygenation level-dependent (BOLD signal in young healthy adults during performance of a computerized KPT dual task (comprised of reading comprehension and picking out vowels and compared it to its single task components (reading or vowel pick-out alone. Results Behavioral performance of the KPT degraded compared to its single task components. Performance of the KPT markedly increased BOLD signal intensity in the PFC, and also activated sensorimotor, parietal association, and visual cortex areas. In conjunction analyses, bilateral BOLD signal in the dorsolateral PFC (Brodmann's areas 45, 46 was present only in the KPT. Conclusions Our results support the central bottleneck theory and suggest that the dorsolateral PFC is an important mediator of neural activity for both short-term storage and executive processes. Quantitative evaluation of the KPT with fMRI in healthy adults is the first step towards understanding the effects of aging or cognitive impairment on KPT performance.

  14. The development of an ICF-based clinical guideline and screening tool for the standardized assessment and evaluation of functioning after head and neck cancer treatment.

    Science.gov (United States)

    Kisser, Ulrich; Adderson-Kisser, Christine; Coenen, Michaela; Stier-Jarmer, Marita; Becker, Sven; Sabariego, Carla; Harréus, Ulrich

    2017-02-01

    The assessment and evaluation of functioning and quality of life after tumor treatment in head and neck cancer (HNC) are considered as essential aspects of clinical routine and studies. A huge number of instruments are available that have been designed to evaluate functioning and quality of life after HNC treatment. The diversity of these instruments in terms of content, response options and administration hinders the comparability of available studies and the performance of meta-analyses. The objective of this paper is to inform about the development of a screening tool for the standardized assessment and evaluation of functioning based on the International Classification of Functioning, Disability and Health (ICF) Core Set for HNC. We followed a multi-step approach including (1) preparatory studies to identify and preselect suitable instruments for the assessment of functioning, (2) a decision-making process to agree on an ICF-based clinical guideline including instruments assessing functioning and (3) the development of a computer-based standardized screening tool to assess and evaluate functioning based on this guideline in clinical routine. Twenty-one experts participated in a consensus meeting and decided on instruments to be included in an ICF-based clinical guideline and screening tool for the assessment and evaluation of functioning in HNC patients in cancer treatment. The chosen instruments cover all aspects of the ICF Core Set for HNC addressing therapy control, pain, food intake/swallowing, voice/speech/breathing, other somatic complaints and psychosocial aspects. The screening tool contains patient-reported outcome measures and a clinician's checklist. It has to be further tested in clinical practice.

  15. Identification of a novel NR2B-selective NMDA receptor antagonist using a virtual screening approach.

    Science.gov (United States)

    Mony, Laetitia; Triballeau, Nicolas; Paoletti, Pierre; Acher, Francine C; Bertrand, Hugues-Olivier

    2010-09-15

    We report the identification of a novel NR2B-selective NMDAR antagonist with an original scaffold, LSP10-0500. This compound was identified by a virtual high-throughput screening approach on the basis of a quantitative pharmacophore model of NR2B-specific NMDAR antagonists. A SAR study around LSP10-0500 is also described.

  16. Local-basis-function approach to computed tomography

    Science.gov (United States)

    Hanson, K. M.; Wecksung, G. W.

    1985-12-01

    In the local basis-function approach, a reconstruction is represented as a linear expansion of basis functions, which are arranged on a rectangular grid and possess a local region of support. The basis functions considered here are positive and may overlap. It is found that basis functions based on cubic B-splines offer significant improvements in the calculational accuracy that can be achieved with iterative tomographic reconstruction algorithms. By employing repetitive basis functions, the computational effort involved in these algorithms can be minimized through the use of tabulated values for the line or strip integrals over a single-basis function. The local nature of the basis functions reduces the difficulties associated with applying local constraints on reconstruction values, such as upper and lower limits. Since a reconstruction is specified everywhere by a set of coefficients, display of a coarsely represented image does not require an arbitrary choice of an interpolation function.

  17. An RNAi Screen To Identify Protein Phosphatases That Function Within the Drosophila Circadian Clock.

    Science.gov (United States)

    Agrawal, Parul; Hardin, Paul E

    2016-12-07

    Circadian clocks in eukaryotes keep time via cell-autonomous transcriptional feedback loops. A well-characterized example of such a transcriptional feedback loop is in Drosophila, where CLOCK-CYCLE (CLK-CYC) complexes activate transcription of period (per) and timeless (tim) genes, rising levels of PER-TIM complexes feed-back to repress CLK-CYC activity, and degradation of PER and TIM permits the next cycle of CLK-CYC transcription. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Previous behavioral screens identified several kinases that control CLK, PER, and TIM levels, subcellular localization, and/or activity, but two phosphatases that function within the clock were identified through the analysis of candidate genes from other pathways or model systems. To identify phosphatases that play a role in the clock, we screened clock cell-specific RNA interference (RNAi) knockdowns of all annotated protein phosphatases and protein phosphatase regulators in Drosophila for altered activity rhythms. This screen identified 19 protein phosphatases that lengthened or shortened the circadian period by ≥1 hr (p ≤ 0.05 compared to controls) or were arrhythmic. Additional RNAi lines, transposon inserts, overexpression, and loss-of-function mutants were tested to independently confirm these RNAi phenotypes. Based on genetic validation and molecular analysis, 15 viable protein phosphatases remain for future studies. These candidates are expected to reveal novel features of the circadian timekeeping mechanism in Drosophila that are likely to be conserved in all animals including humans.

  18. An RNAi Screen To Identify Protein Phosphatases That Function Within the Drosophila Circadian Clock

    Directory of Open Access Journals (Sweden)

    Parul Agrawal

    2016-12-01

    Full Text Available Circadian clocks in eukaryotes keep time via cell-autonomous transcriptional feedback loops. A well-characterized example of such a transcriptional feedback loop is in Drosophila, where CLOCK-CYCLE (CLK-CYC complexes activate transcription of period (per and timeless (tim genes, rising levels of PER-TIM complexes feed-back to repress CLK-CYC activity, and degradation of PER and TIM permits the next cycle of CLK-CYC transcription. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Previous behavioral screens identified several kinases that control CLK, PER, and TIM levels, subcellular localization, and/or activity, but two phosphatases that function within the clock were identified through the analysis of candidate genes from other pathways or model systems. To identify phosphatases that play a role in the clock, we screened clock cell-specific RNA interference (RNAi knockdowns of all annotated protein phosphatases and protein phosphatase regulators in Drosophila for altered activity rhythms. This screen identified 19 protein phosphatases that lengthened or shortened the circadian period by ≥1 hr (p ≤ 0.05 compared to controls or were arrhythmic. Additional RNAi lines, transposon inserts, overexpression, and loss-of-function mutants were tested to independently confirm these RNAi phenotypes. Based on genetic validation and molecular analysis, 15 viable protein phosphatases remain for future studies. These candidates are expected to reveal novel features of the circadian timekeeping mechanism in Drosophila that are likely to be conserved in all animals including humans.

  19. Design a usable protocol screening database: the user-centered approach.

    Science.gov (United States)

    Xie, Zhong; Suki, Dima; Graham, Susan; Sawaya, Raymond

    2005-01-01

    Patient eligibility screening is a very important component of clinical research. Data obtained from such a task can serve valuable purposes beyond the specific protocol they are generated for and therefore should be captured and stored. We applied a user-centered design framework to evaluate the existing screening process and database at the Neurosurgery Department, M. D. Anderson Cancer Center and to design and develop a usable protocol patient screening interface.

  20. Screening for haplotypic variability within Oesophagostomum bifurcum (Nematoda) employing a single-strand conformation polymorphism approach.

    Science.gov (United States)

    de Gruijter, J M; Polderman, A M; Zhu, X Q; Gasser, R B

    2002-06-01

    Genetic markers in the mitochondrial genome have proven useful for population genetic studies because of their maternal inheritance and relatively high evolutionary rates. In this study, we exploited the high resolution capacity of PCR-coupled single-strand conformation polymorphism (SSCP) to screen for sequence variation in part of the cytochrome c oxidase subunit 1 gene (p cox 1) among individuals of the parasitic nematode, Oesophagostomum bifurcum from human or Mona monkey hosts from Africa. SSCP analysis revealed distinct profiles among some of the individuals, and subsequent sequence analysis of representative samples defined 10 different haplotypes. For comparative purposes, the p cox 1 sequences for representatives of four other species of Oesophagostomum from livestock were included. While there were high levels (11.5-13.7%) of sequence difference among the latter species, there was no fixed nucleotide difference between O. bifurcum individuals from humans and those from monkeys. The data support the proposal that O. bifurcum from the two primate hosts represents a single species and that the haplotypic variability in p cox 1 represents population variation. The results reinforce the usefulness of the SSCP-sequencing approach for studying genetic variation in nematode populations using mitochondrial markers.

  1. Integrating experimental and analytic approaches to improve data quality in genome-wide RNAi screens.

    Science.gov (United States)

    Zhang, Xiaohua Douglas; Espeseth, Amy S; Johnson, Eric N; Chin, Jayne; Gates, Adam; Mitnaul, Lyndon J; Marine, Shane D; Tian, Jenny; Stec, Eric M; Kunapuli, Priya; Holder, Dan J; Heyse, Joseph F; Strulovici, Berta; Ferrer, Marc

    2008-06-01

    RNA interference (RNAi) not only plays an important role in drug discovery but can also be developed directly into drugs. RNAi high-throughput screening (HTS) biotechnology allows us to conduct genome-wide RNAi research. A central challenge in genome-wide RNAi research is to integrate both experimental and computational approaches to obtain high quality RNAi HTS assays. Based on our daily practice in RNAi HTS experiments, we propose the implementation of 3 experimental and analytic processes to improve the quality of data from RNAi HTS biotechnology: (1) select effective biological controls; (2) adopt appropriate plate designs to display and/or adjust for systematic errors of measurement; and (3) use effective analytic metrics to assess data quality. The applications in 5 real RNAi HTS experiments demonstrate the effectiveness of integrating these processes to improve data quality. Due to the effectiveness in improving data quality in RNAi HTS experiments, the methods and guidelines contained in the 3 experimental and analytic processes are likely to have broad utility in genome-wide RNAi research.

  2. Facebook Usage as Social Screening. Exploring the Approach of Admissions Officers from Management Colleges

    Directory of Open Access Journals (Sweden)

    Elena - Mădălina VĂTĂMĂNESCU

    2015-03-01

    Full Text Available The online social networks allow individuals to continuously create and model their self-presentations and representations. Facebook stands for a relevant example as people are given the uncensored opportunity to unfold their online selves according to their interests, preferences, goals and expectations. As a social networking site, Facebook is particularly used for reasons related to social documentation (social searching and maintaining preexisting close relationships (bonding social capital that imply knowledge of new information about persons met offline, and less for social exploration (social browsing that refers to using Facebook to initiate new contacts. The extant recent literature often approach the usage of Facebook as a pre-employment screening tool with a view to select the fittest candidates for the job. Still, there are few studies which address the professors’ endeavor to use social media, in general and Facebook, in particular, as a complementary criterion when selecting future students. At this level, Facebook profiles are liable to stand for cogent indicators for the prospects’ personalities and potential, for their predispositions and professional perspectives. Starting from this point, the current research aims at investigating the approaches on the aforementioned issue of several professors from Management colleges in Romania who are in charge of settling the evaluation reference points of the college admissions procedure. The research is the more relevant so as the future graduate managers should possess some key characteristics which may be anticipated or pre-assessed based on their Facebook profile cues. In order to test the subjects’ openness to consider the implications of Facebook usage as a thorough social documentation tool, nineteen in-depth interviews were conducted. The findings show that there is a high degree of skepticism towards using Facebook as a source of reliable information.

  3. Functional state modelling approach validation for yeast and bacteria cultivations

    Science.gov (United States)

    Roeva, Olympia; Pencheva, Tania

    2014-01-01

    In this paper, the functional state modelling approach is validated for modelling of the cultivation of two different microorganisms: yeast (Saccharomyces cerevisiae) and bacteria (Escherichia coli). Based on the available experimental data for these fed-batch cultivation processes, three different functional states are distinguished, namely primary product synthesis state, mixed oxidative state and secondary product synthesis state. Parameter identification procedures for different local models are performed using genetic algorithms. The simulation results show high degree of adequacy of the models describing these functional states for both S. cerevisiae and E. coli cultivations. Thus, the local models are validated for the cultivation of both microorganisms. This fact is a strong structure model verification of the functional state modelling theory not only for a set of yeast cultivations, but also for bacteria cultivation. As such, the obtained results demonstrate the efficiency and efficacy of the functional state modelling approach. PMID:26740778

  4. Functional state modelling approach validation for yeast and bacteria cultivations.

    Science.gov (United States)

    Roeva, Olympia; Pencheva, Tania

    2014-09-03

    In this paper, the functional state modelling approach is validated for modelling of the cultivation of two different microorganisms: yeast (Saccharomyces cerevisiae) and bacteria (Escherichia coli). Based on the available experimental data for these fed-batch cultivation processes, three different functional states are distinguished, namely primary product synthesis state, mixed oxidative state and secondary product synthesis state. Parameter identification procedures for different local models are performed using genetic algorithms. The simulation results show high degree of adequacy of the models describing these functional states for both S. cerevisiae and E. coli cultivations. Thus, the local models are validated for the cultivation of both microorganisms. This fact is a strong structure model verification of the functional state modelling theory not only for a set of yeast cultivations, but also for bacteria cultivation. As such, the obtained results demonstrate the efficiency and efficacy of the functional state modelling approach.

  5. Screened exchange hybrid density functional for accurate and efficient structures and interaction energies.

    Science.gov (United States)

    Brandenburg, Jan Gerit; Caldeweyher, Eike; Grimme, Stefan

    2016-06-21

    We extend the recently introduced PBEh-3c global hybrid density functional [S. Grimme et al., J. Chem. Phys., 2015, 143, 054107] by a screened Fock exchange variant based on the Henderson-Janesko-Scuseria exchange hole model. While the excellent performance of the global hybrid is maintained for small covalently bound molecules, its performance for computed condensed phase mass densities is further improved. Most importantly, a speed up of 30 to 50% can be achieved and especially for small orbital energy gap cases, the method is numerically much more robust. The latter point is important for many applications, e.g., for metal-organic frameworks, organic semiconductors, or protein structures. This enables an accurate density functional based electronic structure calculation of a full DNA helix structure on a single core desktop computer which is presented as an example in addition to comprehensive benchmark results.

  6. A CRISPR/Cas9 Functional Screen Identifies Rare Tumor Suppressors

    Science.gov (United States)

    Katigbak, Alexandra; Cencic, Regina; Robert, Francis; Sénécha, Patrick; Scuoppo, Claudio; Pelletier, Jerry

    2016-01-01

    An enormous amount of tumor sequencing data has been generated through large scale sequencing efforts. The functional consequences of the majority of mutations identified by such projects remain an open, unexplored question. This problem is particularly complicated in the case of rare mutations where frequency of occurrence alone or prediction of functional consequences are insufficient to distinguish driver from passenger or bystander mutations. We combine genome editing technology with a powerful mouse cancer model to uncover previously unsuspected rare oncogenic mutations in Burkitt’s lymphoma. We identify two candidate tumor suppressors whose loss cooperate with MYC over-expression to accelerate lymphomagenesis. Our results highlight the utility of in vivo CRISPR/Cas9 screens combined with powerful mouse models to identify and validate rare oncogenic modifier events from tumor mutational data. PMID:27982060

  7. Service innovation: a comparison of two approaches for physical screening of psychiatric inpatients.

    Science.gov (United States)

    Harrison, Mark Richard; McMillan, Catherine Frances; Dickinson, Timothy

    2012-06-01

    Psychiatric medications have clear links to obesity, diabetes, dyslipidaemia, hypertension, hyperprolactinaemia and movement disorders. These disorders are a common cause of morbidity and mortality in psychiatric patients but physical screening by health services is often haphazard. We report the findings of an audit of physical screening across two hospital wards. Each ward undertook a process of service improvement. One ward modified the admissions proforma and the other developed a discharge screening clinic. The effectiveness of each of these interventions was then compared through a reaudit of practice across both wards. At baseline, screening was performed inconsistently and infrequently. On average, the modified admissions proforma increased screening rates by 4.7% compared to 30.7% for discharge screening clinics. The discharge screening clinic demonstrated statistically significant improvements in screening rates and effectively delivered health promotion advice. Discharge screening clinics are significantly more likely than improved admissions procedures to detect clinically significant abnormalities. If these abnormalities are detected and treated then the long-term physical health of psychiatric patients may be improved.

  8. Persuasive Interventions for Controversial Cancer Screening Recommendations: Testing a Novel Approach to Help Patients Make Evidence-Based Decisions.

    Science.gov (United States)

    Saver, Barry G; Mazor, Kathleen M; Luckmann, Roger; Cutrona, Sarah L; Hayes, Marcela; Gorodetsky, Tatyana; Esparza, Nancy; Bacigalupe, Gonzalo

    2017-01-01

    We wanted to evaluate novel decision aids designed to help patients trust and accept the controversial, evidence-based, US Preventive Services Task Force recommendations about prostate cancer screening (from 2012) and mammography screening for women aged 40 to 49 years (from 2009). We created recorded vignettes of physician-patient discussions about prostate cancer screening and mammography, accompanied by illustrative slides, based on principles derived from preceding qualitative work and behavioral science literature. We conducted a randomized crossover study with repeated measures with 27 men aged 50 to 74 years and 35 women aged 40 to 49 years. All participants saw a video intervention and a more traditional, paper-based decision aid intervention in random order. At entry and after seeing each intervention, they were surveyed about screening intentions, perceptions of benefits and harm, and decisional conflict. Changes in screening intentions were analyzed without regard to order of intervention after an initial analyses showed no evidence of an order effect. At baseline, 69% of men and 86% of women reported wanting screening, with 31% and 6%, respectively, unsure. Mean change on a 3-point, yes, unsure, no scale was -0.93 (P = <.001) for men and -0.50 (P = <.001) for women after seeing the video interventions vs 0.0 and -0.06 (P = .75) after seeing the print interventions. At the study end, 33% of men and 49% of women wanted screening, and 11% and 20%, respectively, were unsure. Our novel, persuasive video interventions significantly changed the screening intentions of substantial proportions of viewers. Our approach needs further testing but may provide a model for helping patients to consider and accept evidence-based, counterintuitive recommendations. © 2017 Annals of Family Medicine, Inc.

  9. Application of a cocktail approach to screen cytochrome P450 BM3 libraries for metabolic activity and diversity.

    Science.gov (United States)

    Reinen, Jelle; Postma, Geert; Tump, Cornelis; Bloemberg, Tom; Engel, Jasper; Vermeulen, Nico P E; Commandeur, Jan N M; Honing, Maarten

    2016-02-01

    In the present study, the validity of using a cocktail screening method in combination with a chemometrical data mining approach to evaluate metabolic activity and diversity of drug-metabolizing bacterial Cytochrome P450 (CYP) BM3 mutants was investigated. In addition, the concept of utilizing an in-house-developed library of CYP BM3 mutants as a unique biocatalytic synthetic tool to support medicinal chemistry was evaluated. Metabolic efficiency of the mutant library towards a selection of CYP model substrates, being amitriptyline (AMI), buspirone (BUS), coumarine (COU), dextromethorphan (DEX), diclofenac (DIC) and norethisterone (NET), was investigated. First, metabolic activity of a selection of CYP BM3 mutants was screened against AMI and BUS. Subsequently, for a single CYP BM3 mutant, the effect of co-administration of multiple drugs on the metabolic activity and diversity towards AMI and BUS was investigated. Finally, a cocktail of AMI, BUS, COU, DEX, DIC and NET was screened against the whole in-house CYP BM3 library. Different validated quantitative and qualitative (U)HPLC-MS/MS-based analytical methods were applied to screen for substrate depletion and targeted product formation, followed by a more in-depth screen for metabolic diversity. A chemometrical approach was used to mine all data to search for unique metabolic properties of the mutants and allow classification of the mutants. The latter would open the possibility of obtaining a more in-depth mechanistic understanding of the metabolites. The presented method is the first MS-based method to screen CYP BM3 mutant libraries for diversity in combination with a chemometrical approach to interpret results and visualize differences between the tested mutants.

  10. Social Media’s Function in Organizations: A Functional Analysis Approach

    Directory of Open Access Journals (Sweden)

    Amy Reitz

    2012-12-01

    Full Text Available System theorists believe that organizations that function as an open system have a greater chance of survival than organizations that function as a closed system due to the exchange of inputs and outputs between the organization and its publics. Public relations researchers have proposed adopting a dialogic approach to public relations where interaction between the organization and its publics are mutual, which is the underpinning to an open systems approach. This paper posits that organizations can function within an open systems approach to public relations by employing social media. Adoption of a functional approach is a fruitful way to look at the social functions various social media serve in the system of organizations and their publics. Research has considered the gratifications publics receive from social media; however, limited research has considered what social media do for the organization-public relationship system. It has been argued that organizations also have psychological and social motivations; therefore, applying a functional analysis approach might be a good of way determining what functions social media serve in the organization-public relationship system. Four functions are proposed in which social media may serve the system: maintenance of organizational identity, opportunity to build relationships with publics, ability to control issues management, and the chance to promote social corporate responsibility. Understanding social media’s role in the system can help practitioners identify the functions that may contribute to an open systems approach to public relations and ultimately an organization’s survival.

  11. Facilitating Structure-Function Studies of CFTR Modulator Sites with Efficiencies in Mutagenesis and Functional Screening.

    Science.gov (United States)

    Molinski, Steven V; Ahmadi, Saumel; Hung, Maurita; Bear, Christine E

    2015-12-01

    There are nearly 2000 mutations in the CFTR gene associated with cystic fibrosis disease, and to date, the only approved drug, Kalydeco, has been effective in rescuing the functional expression of a small subset of these mutant proteins with defects in channel activation. However, there is currently an urgent need to assess other mutations for possible rescue by Kalydeco, and further, definition of the binding site of such modulators on CFTR would enhance our understanding of the mechanism of action of such therapeutics. Here, we describe a simple and rapid one-step PCR-based site-directed mutagenesis method to generate mutations in the CFTR gene. This method was used to generate CFTR mutants bearing deletions (p.Gln2_Trp846del, p.Ser700_Asp835del, p.Ile1234_Arg1239del) and truncation with polyhistidine tag insertion (p.Glu1172-3Gly-6-His*), which either recapitulate a disease phenotype or render tools for modulator binding site identification, with subsequent evaluation of drug responses using a high-throughput (384-well) membrane potential-sensitive fluorescence assay of CFTR channel activity within a 1 wk time frame. This proof-of-concept study shows that these methods enable rapid and quantitative comparison of multiple CFTR mutants to emerging drugs, facilitating future large-scale efforts to stratify mutants according to their "theratype" or most promising targeted therapy.

  12. From equation to inequality using a function-based approach

    Science.gov (United States)

    Verikios, Petros; Farmaki, Vassiliki

    2010-06-01

    This article presents features of a qualitative research study concerning the teaching and learning of school algebra using a function-based approach in a grade 8 class, of 23 students, in 26 lessons, in a state school of Athens, in the school year 2003-2004. In this article, we are interested in the inequality concept and our aim is to investigate if and how our approach could facilitate students to comprehend inequality and to solve problems related to this concept. Data analysis showed that, in order to comprehend the new concept, the students should make a transition from equation to inequality. The role of the situation context proved decisive in this transition and in making sense of involved symbols. Also, students used function representations as problem-solving strategies in problems that included inequalities. However, the extension of the function-based approach in solving an abstract equation or inequality proved problematic for the students.

  13. Parental questionnaire as a screening instrument for motor function at age five.

    Science.gov (United States)

    Nordbye-Nielsen, Kirsten; Kesmodel, Ulrik Schiøler

    2014-12-01

    No standardised method is used to determine motor function in children in general practice in Denmark. Our aim was to evaluate the correlation between a parental questionnaire assessing motor function at the age of five years and the clinical test Movement Assessment Battery for Children (M-ABC), and to assess whether one or more questions could be used to screen for motor problems at the age of five years. This study was based on a parental questionnaire containing ten questions. The M-ABC was used as the gold standard. n = 755 children. The Mann-Whitney rank sum test, Pearson's χ(2)-test, logistic regression analyses and sensitivity and specificity were used to assess the correlation between the questionnaire and the M-ABC test. The best screening tool was six questions in combination: sensitivity 39.8%, specificity 87.1%. Asking if a health professional ever expressed concern about the childs motor development had a sensitivity of 17.0% and a specificity of 93.9%. A parental questionnaire used as a screening instrument to identify children with motor problems has a reasonable specificity, but a low sensitivity. The six questions can be used to identify children who do not have motor function difficulties with a relatively high certainty, and it can fairly well identify children with motor function problems. This study was primarily supported by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. Additional support was obtained from The Danish Health and Medicines Authority, the Lundbeck Foundation, Ludvig & Daara Elsass Foundation, the Augustinus Foundation, and Aase & Ejnar Danielsens Foundation. The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont

  14. 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.

  15. 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.

  16. Toward the discovery of functional transthyretin amyloid inhibitors: application of virtual screening methods.

    Science.gov (United States)

    Simões, Carlos J V; Mukherjee, Trishna; Brito, Rui M M; Jackson, Richard M

    2010-10-25

    Inhibition of amyloid fibril formation by stabilization of the native form of the protein transthyretin (TTR) is a viable approach for the treatment of familial amyloid polyneuropathy that has been gaining momentum in the field of amyloid research. The TTR stabilizer molecules discovered to date have shown efficacy at inhibiting fibrilization in vitro but display impairing issues of solubility, affinity for TTR in the blood plasma and/or adverse effects. In this study we present a benchmark of four protein- and ligand-based virtual screening (VS) methods for identifying novel TTR stabilizers: (i) two-dimensional (2D) similarity searches with chemical hashed, pharmacophore, and UNITY fingerprints, (ii) 3D searches based on shape, chemical, and electrostatic similarity, (iii) LigMatch, a new ligand-based method which uses multiple templates and combines 3D geometric hashing with a 2D preselection process, and (iv) molecular docking to consensus X-ray crystal structures of TTR. We illustrate the potential of the best-performing VS protocols to retrieve promising new leads by ranking a tailored library of 2.3 million commercially available compounds. Our predictions show that the top-scoring molecules possess distinctive features from the known TTR binders, holding better solubility, fraction of halogen atoms, and binding affinity profiles. To the best of our knowledge, this is the first attempt to rationalize the utilization of a large battery of in silico screening techniques toward the identification of a new generation of TTR amyloid inhibitors.

  17. Ion pair-reversed phase HPLC approach facilitates subcloning of PCR products and screening of recombinant colonies.

    Science.gov (United States)

    Shaw-Bruha, C M; Lamb, K A

    2000-04-01

    The isolation of a single DNA molecule for cloning is technically difficult, and the subsequent screening of colonies for recombinant DNA clones is time consuming. Ion pair-reversed phase HPLC (IP-RP-HPLC) analysis of nucleic acids improves the resolution and isolation of PCR products to be cloned. We demonstrate that PCR products analyzed and collected using the IP-RP-HPLC approach (WAVE DNA Fragment Analysis System) can be cloned directly into a plasmid vector. In addition, we demonstrate that when IP-RP-HPLC analysis is extended to the colony screening process, the time required for these procedures is reduced.

  18. Perspectives of Frailty and Frailty Screening: Protocol for a Collaborative Knowledge Translation Approach and Qualitative Study of Stakeholder Understandings and Experiences.

    Science.gov (United States)

    Archibald, Mandy M; Ambagtsheer, Rachel; Beilby, Justin; Chehade, Mellick J; Gill, Tiffany K; Visvanathan, Renuka; Kitson, Alison L

    2017-04-17

    Accompanying the unprecedented growth in the older adult population worldwide is an increase in the prevalence of frailty, an age-related clinical state of increased vulnerability to stressor events. This increased vulnerability results in lower social engagement and quality of life, increased dependency, and higher rates of morbidity, health service utilization and mortality. Early identification of frailty is necessary to guide implementation of interventions to prevent associated functional decline. Consensus is lacking on how to clinically recognize and manage frailty. It is unknown how healthcare providers and healthcare consumers understand and perceive frailty, whether or not they regard frailty as a public health concern; and information on the indirect and direct experiences of consumer and healthcare provider groups towards frailty are markedly limited. We will conduct a qualitative study of consumer, practice nurse, general practitioner, emergency department physician, and orthopedic surgeons' perspectives of frailty and frailty screening in metropolitan and non-metropolitan South Australia. We will use tailored combinations of semi-structured interviews and arts-based data collection methods depending on each stakeholder group, followed by inductive and iterative analysis of data using qualitative description. Using stakeholder driven approaches to understanding and addressing frailty and frailty screening in context is critical as the prevalence and burden of frailty is likely to increase worldwide. We will use the findings from the Perceptions of Frailty and Frailty Screening study to inform a context-driven identification, implementation and evaluation of a frailty-screening tool; drive awareness, knowledge, and skills development strategies across stakeholder groups; and guide future efforts to embed emerging knowledge about frailty and its management across diverse South Australian contexts using a collaborative knowledge translation approach

  19. An Epidemiological Approach to Screening Gifted Students Utilizing WISC-R Subtests.

    Science.gov (United States)

    Fineman, Carol A.; Carran, Deborah H.

    1986-01-01

    Full Wechsler Intelligence Scale for Children-Revised evaluations have become a drain on school resources. A screening formula for gifted students, utilizing three WISC-R subtests, was evaluated using traditional epidemiological techniques. The screen correctly detected the majority of gifted students and could have major implications in terms of…

  20. A practical approach to radiological evaluation of CT lung cancer screening examinations

    NARCIS (Netherlands)

    Xie, Xueqian; Heuvelmans, Marjolein A.; van Ooijen, Peter M. A.; Oudkerk, Matthijs; Vliegenthart, Rozemarijn

    2013-01-01

    Lung cancer is the most common cause of cancer-related death in the world. The Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON) was launched to investigate whether screening for lung cancer by low-dose multidetector computed tomography (CT) in high-risk patients will lead

  1. Developing New Tools for the in vivo Generation/Screening of Cyclic Peptide Libraries. A New Combinatorial Approach for the Detection of Bacterial Toxin Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Camarero, J A

    2006-11-28

    A new combinatorial approach for the biosynthesis and screening of small drug-like toxin inhibitors inside living cells is presented. This approach has been initially used as proof of principle for finding inhibitors against the LF factor from Bacillus anthracis. Key to our ''living combinatorial'' approach is the use of a living cell as a micro-chemical factory for both synthesis and screening of potential inhibitors for a given molecular recognition event (see Scheme 1). This powerful technique posses the advantage that both processes synthesis and screening happen inside the cell thus accelerating the whole screening/selection process.

  2. A practical approach to radiological evaluation of CT lung cancer screening examinations

    NARCIS (Netherlands)

    Xie, Xueqian; Heuvelmans, Marjolein A.; van Ooijen, Peter M. A.; Oudkerk, Matthijs; Vliegenthart, Rozemarijn

    2013-01-01

    Lung cancer is the most common cause of cancer-related death in the world. The Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON) was launched to investigate whether screening for lung cancer by low-dose multidetector computed tomography (CT) in high-risk patients will lead

  3. Interprofessional approach for teaching functional knee joint anatomy.

    Science.gov (United States)

    Meyer, Jakob J; Obmann, Markus M; Gießler, Marianne; Schuldis, Dominik; Brückner, Ann-Kathrin; Strohm, Peter C; Sandeck, Florian; Spittau, Björn

    2017-03-01

    Profound knowledge in functional and clinical anatomy is a prerequisite for efficient diagnosis in medical practice. However, anatomy teaching does not always consider functional and clinical aspects. Here we introduce a new interprofessional approach to effectively teach the anatomy of the knee joint. The presented teaching approach involves anatomists, orthopaedists and physical therapists to teach anatomy of the knee joint in small groups under functional and clinical aspects. The knee joint courses were implemented during early stages of the medical curriculum and medical students were grouped with students of physical therapy to sensitize students to the importance of interprofessional work. Evaluation results clearly demonstrate that medical students and physical therapy students appreciated this teaching approach. First evaluations of following curricular anatomy exams suggest a benefit of course participants in knee-related multiple choice questions. Together, the interprofessional approach presented here proves to be a suitable approach to teach functional and clinical anatomy of the knee joint and further trains interprofessional work between prospective physicians and physical therapists as a basis for successful healthcare management.

  4. Examining the Relationship Between the Functional Movement Screen and the Landing Error Scoring System in an Active, Male Collegiate Population.

    Science.gov (United States)

    Everard, Eoin M; Harrison, Andrew J; Lyons, Mark

    2017-05-01

    Everard, EM, Harrison, AJ, and Lyons, M. Examining the relationship between the functional movement screen and the landing error scoring system in an active, male collegiate population. J Strength Cond Res 31(5): 1265-1272, 2017-In recent years, there has been an increasing focus on movement screening as the principal aspect of preparticipation testing. Two of the most common movement screening tools are the Functional Movement Screen (FMS) and the Landing Error Scoring System (LESS). Several studies have examined the reliability and validity of these tools, but so far, there have been no studies comparing the results of these 2 screening tools against each other. Therefore, the purpose of this study was to determine the relationship between FMS scores and LESS scores. Ninety-eight male college athletes actively competing in sport (Gaelic games, soccer, athletics, boxing/mixed martial arts, Olympic weightlifting) participated in the study and performed the FMS and LESS screens. Both the 21-point and 100-point scoring systems were used to score the FMS. Spearman's correlation coefficients were used to determine the relationship between the 2 screening scores. The results showed a significant moderate correlation between FMS and LESS scores (rho 100 and 21 point = -0.528; -0.487; p < 0.001). In addition, r values of 0.26 and 0.23 indicate a poor shared variance between the 2 screens. The results indicate that performing well in one of the screens does not necessarily equate to performing well in the other. This has practical implications as it highlights that both screens may assess different movement patterns and should not be used as a substitute for each other.

  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. Exact response functions within the time-dependent Gutzwiller approach

    Science.gov (United States)

    Bünemann, J.; Wasner, S.; Oelsen, E. v.; Seibold, G.

    2015-02-01

    We investigate the applicability of the two existing versions of a time-dependent Gutzwiller approach (TDGA) beyond the frequently used limit of infinite spatial dimensions. To this end, we study the two-particle response functions of a two-site Hubbard model where we can compare the exact results and those derived from the TDGA. It turns out that only the more recently introduced version of the TDGA can be combined with a diagrammatic approach which allows for the evaluation of Gutzwiller wave functions in finite dimensions. For this TDGA method, we derive the time-dependent Lagrangian for general single-band Hubbard models.

  8. The functions of autobiographical memory: an integrative approach.

    Science.gov (United States)

    Harris, Celia B; Rasmussen, Anne S; Berntsen, Dorthe

    2014-01-01

    Recent research in cognitive psychology has emphasised the uses, or functions, of autobiographical memory. Theoretical and empirical approaches have focused on a three-function model: autobiographical memory serves self, directive, and social functions. In the reminiscence literature other taxonomies and additional functions have been postulated. We examined the relationships between functions proposed by these literatures, in order to broaden conceptualisations and make links between research traditions. In Study 1 we combined two measures of individual differences in the uses of autobiographical memory. Our results suggested four classes of memory functions, which we labelled Reflective, Generative, Ruminative, and Social. In Study 2 we tested relationships between our four functions and broader individual differences, and found conceptually consistent relationships. In Study 3 we found that memories cued by Generative and Social functions were more emotionally positive than were memories cued by Reflective and Ruminative functions. In Study 4 we found that reported use of Generative functions increased across the lifespan, while reported use of the other three functions decreased. Overall our findings suggest a broader view of autobiographical memory functions that links them to ways in which people make meaning of their selves, their environment, and their social world more generally.

  9. Systematic assessment of apraxia and functional predictions from the Birmingham Cognitive Screen.

    Science.gov (United States)

    Bickerton, Wai-Ling; Riddoch, M Jane; Samson, Dana; Balani, Alex Bahrami; Mistry, Bejal; Humphreys, Glyn W

    2012-05-01

    The validity and functional predictive values of the apraxia tests in the Birmingham Cognitive Screen (BCoS) were evaluated. BCoS was developed to identify patients with different forms of praxic deficit using procedures designed to be inclusive for patients with aphasia and/or spatial neglect. Observational studies were conducted from a university neuropsychological assessment centre and from acute and rehabilitation stroke care hospitals throughout an English region. Volunteers from referred patients with chronic acquired brain injuries, a consecutive hospital sample of patients within 3 months of stroke (n=635) and a population based healthy control sample (n=100) were recruited. The main outcome measures used were the Barthel Index, the Nottingham Extended Activities of Daily Living Scale as well as recovery from apraxia. There were high inter-rater reliabilities and correlations between the BCoS apraxia tasks and counterpart tests from the literature. The vast majority (88.3%) of the stroke survivors were able to complete the screen. Pantomime and gesture recognition tasks were more sensitive in differentiating between individuals with left hemisphere damage and right hemisphere damage whereas the Multistep Object Use test and the imitation task had higher functional correlates over and above effects of hemiplegia. Together, the initial scores of the four tasks enabled predictions with 75% accuracy, the recovery of apraxia and independence level at 9 months. As a model based assessment, BCoS offers a quick and valid way to detect apraxia and predict functional recovery. It enables early and informative assessment of most stroke patients for rehabilitation planning.

  10. Simple and practical screening approach to identify HIV-infected individuals with depression or at risk of developing depression

    DEFF Research Database (Denmark)

    Rodkjaer, L; Gabel, C; Laursen, T

    2016-01-01

    OBJECTIVES: Studies have shown that depression and other mental illnesses are under-diagnosed among HIV-infected individuals. The aim of this study was to evaluate the use of mental health history and questionnaire-based screening instruments to identify HIV-infected individuals at risk...... of depression. CONCLUSIONS: We suggest that the mental health of HIV-infected individuals should be reviewed and a "risk-flag" three-step approach should be used (1) to screen routinely with the two verbal questions suggested by the EACS, (2) to identify whether there is a risk of depression and then screen...... with the BDI-II, and (3) to identify whether there is still a risk and then perform a full evaluation and obtain an accurate psychiatric diagnosis by a psychiatrist....

  11. Generating function approach to reliability analysis of structural systems

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The generating function approach is an important tool for performance assessment in multi-state systems. Aiming at strength reliability analysis of structural systems, generating function approach is introduced and developed. Static reliability models of statically determinate, indeterminate systems and fatigue reliability models are built by constructing special generating functions, which are used to describe probability distributions of strength (resistance), stress (load) and fatigue life, by defining composite operators of generating functions and performance structure functions thereof. When composition operators are executed, computational costs can be reduced by a big margin by means of collecting like terms. The results of theoretical analysis and numerical simulation show that the generating function approach can be widely used for probability modeling of large complex systems with hierarchical structures due to the unified form, compact expression, computer program realizability and high universality. Because the new method considers twin loads giving rise to component failure dependency, it can provide a theoretical reference and act as a powerful tool for static, dynamic reliability analysis in civil engineering structures and mechanical equipment systems with multi-mode damage coupling.

  12. An Architectural Approach for Decoding and Distributing Functions in FPUs in a Functional Processor System

    CERN Document Server

    Nair, T R Gopalakrishnan; Krutthika, H K

    2010-01-01

    The main goal of this research is to develop the concepts of a revolutionary processor system called Functional Processor System. The fairly novel work carried out in this proposal concentrates on decoding of function pipelines and distributing it in FPUs as a part of scheduling approach. As the functional programs are super-level programs that entails requirements only at functional level, decoding of functions and distribution of functions in the heterogeneous functional processor units are a challenge. We explored the possibilities of segregation of the functions from the application program and distributing the functions on the relevant FPUs by using address mapping techniques. Here we pursue the perception of feeding the functions into the processor farm rather than the processor fetching the instructions or functions and executing it. This work is carried out at theoretical levels and it requires a long way to go in the realization of this work in hardware perhaps with a large industrial team with a pra...

  13. A Screening Questionnaire for Asperger Syndrome and Other High-Functioning Autism Spectrum Disorders in School Age Children.

    Science.gov (United States)

    Ehlers, Stephan; Gillberg, Christopher; Wing, Lorna

    1999-01-01

    Presents data on the High-Functioning Autism Spectrum Screening Questionnaire, a 27-item checklist for completion by lay informants when assessing symptoms characteristic of Asperger syndrome and other high-functioning autism spectrum disorders in children and adolescents with normal intelligence or mild mental retardation. Reliability and…

  14. Screening for DNA Alkylation Mono and Cross-Linked Adducts with a Comprehensive LC-MS(3) Adductomic Approach.

    Science.gov (United States)

    Stornetta, Alessia; Villalta, Peter W; Hecht, Stephen S; Sturla, Shana J; Balbo, Silvia

    2015-12-01

    A high-resolution/accurate-mass DNA adductomic approach was developed to investigate anticipated and unknown DNA adducts induced by DNA alkylating agents in biological samples. Two new features were added to a previously developed approach to significantly broaden its scope, versatility, and selectivity. First, the neutral loss of a base (guanine, adenine, thymine, or cytosine) was added to the original methodology's neutral loss of the 2'-deoxyribose moiety to allow for the detection of all DNA base adducts. Second, targeted detection of anticipated DNA adducts based on the reactivity of the DNA alkylating agent was demonstrated by inclusion of an ion mass list for data dependent triggering of MS(2) fragmentation events and subsequent MS(3) fragmentation. Additionally, untargeted screening of the samples, based on triggering of an MS(2) fragmentation event for the most intense ions of the full scan, was included for detecting unknown DNA adducts. The approach was tested by screening for DNA mono and cross-linked adducts in purified DNA and in DNA extracted from cells treated with PR104A, an experimental DNA alkylating nitrogen mustard prodrug currently under investigation for the treatment of leukemia. The results revealed the ability of this new DNA adductomic approach to detect anticipated and unknown PR104A-induced mono and cross-linked DNA adducts in biological samples. This methodology is expected to be a powerful tool for screening for DNA adducts induced by endogenous or exogenous exposures.

  15. Questionnaire of Executive Function for Dancers: An Ecological Approach

    Science.gov (United States)

    Wong, Alina; Rodriguez, Mabel; Quevedo, Liliana; de Cossio, Lourdes Fernandez; Borges, Ariel; Reyes, Alicia; Corral, Roberto; Blanco, Florentino; Alvarez, Miguel

    2012-01-01

    There is a current debate about the ecological validity of executive function (EF) tests. Consistent with the verisimilitude approach, this research proposes the Ballet Executive Scale (BES), a self-rating questionnaire that assimilates idiosyncratic executive behaviors of classical dance community. The BES was administrated to 149 adolescents,…

  16. From Equation to Inequality Using a Function-Based Approach

    Science.gov (United States)

    Verikios, Petros; Farmaki, Vassiliki

    2010-01-01

    This article presents features of a qualitative research study concerning the teaching and learning of school algebra using a function-based approach in a grade 8 class, of 23 students, in 26 lessons, in a state school of Athens, in the school year 2003-2004. In this article, we are interested in the inequality concept and our aim is to…

  17. From Equation to Inequality Using a Function-Based Approach

    Science.gov (United States)

    Verikios, Petros; Farmaki, Vassiliki

    2010-01-01

    This article presents features of a qualitative research study concerning the teaching and learning of school algebra using a function-based approach in a grade 8 class, of 23 students, in 26 lessons, in a state school of Athens, in the school year 2003-2004. In this article, we are interested in the inequality concept and our aim is to…

  18. Detection of Differential Item Functioning Using the Lasso Approach

    Science.gov (United States)

    Magis, David; Tuerlinckx, Francis; De Boeck, Paul

    2015-01-01

    This article proposes a novel approach to detect differential item functioning (DIF) among dichotomously scored items. Unlike standard DIF methods that perform an item-by-item analysis, we propose the "LR lasso DIF method": logistic regression (LR) model is formulated for all item responses. The model contains item-specific intercepts,…

  19. Carbon Nanofibers Functionalized with Active Screen Plasma-Deposited Metal Nanoparticles for Electrical Energy Storage Devices.

    Science.gov (United States)

    Corujeira Gallo, Santiago; Li, Xiaoying; Fütterer, Klaus; Charitidis, Constantinos A; Dong, Hanshan

    2017-07-12

    Supercapacitors are energy storage devices with higher energy densities than conventional capacitors but lower than batteries or fuel cells. There is a strong interest in increasing the volumetric and gravimetric capacitance of these devices to meet the growing demands of the electrical and electronic sectors. The capacitance depends largely on the electrode material, and carbon nanofibers (CNFs) have attracted much attention because of their relatively low cost, large surface area, and good electrical conductivity as well as chemical and thermal stability. The deposition of metal nanoparticles on CNFs is a promising way to increase their surface properties and, ultimately, the capacitance of the devices. In this study, nickel and silver nanoparticles were deposited on CNFs using the active screen plasma technology. The CNFs were characterized, and their electrochemical performance was assessed in a three-electrode cell. The results show significant improvements over the untreated CNFs, particularly after functionalization with silver nanoparticles.

  20. Computational screening of functionalized zinc porphyrins for dye sensitized solar cells

    DEFF Research Database (Denmark)

    Ørnsø, Kristian Baruël; García Lastra, Juan Maria; Thygesen, Kristian Sommer

    2013-01-01

    An efficient dye sensitized solar cell (DSSC) is one possible solution to meet the world's rapidly increasing energy demands and associated climate challenges. This requires inexpensive and stable dyes with well-positioned frontier energy levels for maximal solar absorption, efficient charge...... separation, and high output voltage. Here we demonstrate an extensive computational screening of zinc porphyrins functionalized with electron donating side groups and electron accepting anchoring groups. The trends in frontier energy levels versus side groups are analyzed and a no-loss DSSC level alignment...... quality is estimated. Out of the initial 1029 molecules, we find around 50 candidates with level alignment qualities within 5% of the optimal limit. We show that the level alignment of five zinc porphyrin dyes which were recently used in DSSCs with high efficiencies can be further improved by simple side...

  1. A method for rapidly screening functionality of actin mutants and tagged actins

    Directory of Open Access Journals (Sweden)

    Rommelaere Heidi

    2004-01-01

    Full Text Available Recombinant production and biochemical analysis of actin mutants has been hampered by the fact that actin has an absolute requirement for the eukaryotic chaperone CCT to reach its native state. We therefore have developed a method to rapidly screen the folding capacity and functionality of actin variants, by combining in vitro expression of labelled actin with analysis on native gels, band shift assays or copolymerization tests. Additionally, we monitor, using immuno-fluorescence, incorporation of actin variants in cytoskeletal structures in transfected cells. We illustrate the method by two examples. In one we show that tagged versions of actin do not always behave native-like and in the other we study some of the molecular defects of three &bgr;-actin mutants that have been associated with diseases.

  2. The Feynman-Vernon Influence Functional Approach in QED

    Science.gov (United States)

    Biryukov, Alexander; Shleenkov, Mark

    2016-10-01

    In the path integral approach we describe evolution of interacting electromagnetic and fermionic fields by the use of density matrix formalism. The equation for density matrix and transitions probability for fermionic field is obtained as average of electromagnetic field influence functional. We obtain a formula for electromagnetic field influence functional calculating for its various initial and final state. We derive electromagnetic field influence functional when its initial and final states are vacuum. We present Lagrangian for relativistic fermionic field under influence of electromagnetic field vacuum.

  3. A Comprehensive Approach for Pectin Chemical and Functional Characterization

    DEFF Research Database (Denmark)

    de Sousa, António Felipe Gomes Teixeira

    In this work, a comprehensive approach for the chemical and functional analysis of pectin was used in order to relate the different extraction conditions used to the polymer structure and the final functional (mainly gelling) properties. A wide range of methods were utilized including chemical...... and chromatographic characterization methods (HPAEC and HPSEC), rheological measurements of elasticity, and biological epitopes detection using carbohydrate microarrays. The end product of this study is expected to contribute to the knowledge of pectin polymeric conformation and structure-function properties as well...

  4. The Feynman-Vernon Influence Functional Approach in QED

    Directory of Open Access Journals (Sweden)

    Biryukov Alexander

    2016-01-01

    Full Text Available In the path integral approach we describe evolution of interacting electromagnetic and fermionic fields by the use of density matrix formalism. The equation for density matrix and transitions probability for fermionic field is obtained as average of electromagnetic field influence functional. We obtain a formula for electromagnetic field influence functional calculating for its various initial and final state. We derive electromagnetic field influence functional when its initial and final states are vacuum. We present Lagrangian for relativistic fermionic field under influence of electromagnetic field vacuum.

  5. Newer Approaches to Identify Potential Untoward Effects in Functional Foods.

    Science.gov (United States)

    Marone, Palma Ann; Birkenbach, Victoria L; Hayes, A Wallace

    2016-01-01

    Globalization has greatly accelerated the numbers and variety of food and beverage products available worldwide. The exchange among greater numbers of countries, manufacturers, and products in the United States and worldwide has necessitated enhanced quality measures for nutritional products for larger populations increasingly reliant on functionality. These functional foods, those that provide benefit beyond basic nutrition, are increasingly being used for their potential to alleviate food insufficiency while enhancing quality and longevity of life. In the United States alone, a steady import increase of greater than 15% per year or 24 million shipments, over 70% products of which are food related, is regulated under the Food and Drug Administration (FDA). This unparalleled growth has resulted in the need for faster, cheaper, and better safety and efficacy screening methods in the form of harmonized guidelines and recommendations for product standardization. In an effort to meet this need, the in vitro toxicology testing market has similarly grown with an anticipatory 15% increase between 2010 and 2015 of US$1.3 to US$2.7 billion. Although traditionally occupying a small fraction of the market behind pharmaceuticals and cosmetic/household products, the scope of functional food testing, including additives/supplements, ingredients, residues, contact/processing, and contaminants, is potentially expansive. Similarly, as functional food testing has progressed, so has the need to identify potential adverse factors that threaten the safety and quality of these products.

  6. Predictive screening for regulators of conserved functional gene modules (gene batteries in mammals

    Directory of Open Access Journals (Sweden)

    Sigvardsson Mikael

    2005-05-01

    Full Text Available Abstract Background The expression of gene batteries, genomic units of functionally linked genes which are activated by similar sets of cis- and trans-acting regulators, has been proposed as a major determinant of cell specialization in metazoans. We developed a predictive procedure to screen the mouse and human genomes and transcriptomes for cases of gene-battery-like regulation. Results In a screen that covered ~40 per cent of all annotated protein-coding genes, we identified 21 co-expressed gene clusters with statistically supported sharing of cis-regulatory sequence elements. 66 predicted cases of over-represented transcription factor binding motifs were validated against the literature and fell into three categories: (i previously described cases of gene battery-like regulation, (ii previously unreported cases of gene battery-like regulation with some support in a limited number of genes, and (iii predicted cases that currently lack experimental support. The novel predictions include for example Sox 17 and RFX transcription factor binding sites that were detected in ~10% of all testis specific genes, and HNF-1 and 4 binding sites that were detected in ~30% of all kidney specific genes respectively. The results are publicly available at http://www.wlab.gu.se/lindahl/genebatteries. Conclusion 21 co-expressed gene clusters were enriched for a total of 66 shared cis-regulatory sequence elements. A majority of these predictions represent novel cases of potential co-regulation of functionally coupled proteins. Critical technical parameters were evaluated, and the results and the methods provide a valuable resource for future experimental design.

  7. Loss of hippocampal function impairs pattern separation on a mouse touch-screen operant paradigm.

    Science.gov (United States)

    Josey, Megan; Brigman, Jonathan L

    2015-11-01

    The hippocampus is heavily involved in the learning and memory processes necessary to successfully encode environmental stimuli and representations over time. Impairment of hippocampal function is associated with numerous neuropsychiatric diseases and can lead to detriments in the quality of life. In order to take full advantage of preclinical models of these disorders, there is a need for the development of more refined measures of clinically relevant hippocampal behaviors. While arena-based navigation tasks have provided fundamental information regarding the role of the hippocampus in spatial memory, the development of automated operant variants have had mixed results. Recently, an automated touch-screen paradigm has been shown to be highly sensitive to hippocampal function in the rat and eliminated mediating strategies that arose in previous tasks. Here we show that mice with lesions encompassing the entire ventral portion of the dorsal hippocampus are impaired on pattern separation behavior using a delayed nonmatching-to-location (TUNL) adapted for mice. Lesioned mice readily acquired the task at control rates when separations were maximal and delay periods were short while decreasing separations significantly impaired lesion mice. However, in contrast to previously reported results in the rat, consistently increasing delays did not significantly impair performance in the lesion group. Presentation of a variable delay within a session significantly impaired performance in lesion mice across delay periods. The current results demonstrate the utility of a touch-screen paradigm for measuring hippocampal-dependent pattern separation in the mouse and establish the paradigm as an important platform for future studies in disease models.

  8. Associations between Functional Movement Screen scores and performance variables in surf athletes.

    Science.gov (United States)

    Ferreira da Silva, Bruno A; Clemente, Filipe M; Lourenço Martins, Fernando M

    2017-02-22

    Functional Movement Screen (FMS) have been used to assess the movement patterns in daily sports practice. Some associations between FMS scores and physical variables have been found in some sports. Nevertheless, no study was conducted in surf. Eighteen surf athletes (11 male) participated in the study (18.3 ± 6.3 y; 60.0 ± 9.6 kg; 168.6 ± 8.1 cm). All participants completed anthropometrics, Knee to Wall test, Functional Movement Screen, Isometric Knee Extension, Handgrip, Squat and Countermovement Jump. Based on that, this study investigated: 1) the variance of FMS scores between gender; 2) the association between FMS scores and physical variables of strength of upper and lower limbs, power of lower limbs and anthropometric variables; and 3) which FMS scores best explain the physical performance variables. The analysis of comparison between gender of each item of FMS showed significant statistical differences only in Trunk Stability Push-Up (p = 0.01, ES=0.141). Kendall's Tau b correlation test between FMS scores and physical variables, revealed significant associations. After performed the stepwise multiple linear regression FMS Deep Squat and Trunk Stability Push-Up explains 57% of Knee to Wall test - right side and the model is statistically significant (F(2. 15) = 13.097; p-value = 0.001). In Squat Jump (height) the results show that FMS Trunk Stability Push-Up explains 50.3% of this dimension and the model is statistically significant (F(1. 16) = 18.182; p-value = 0.001). FMS individual scores seems to better explain physical variables than total score. Only Trunk Stability Push-Up test seems to be a reliable indicator to predict physical performance in surf athletes.

  9. Routine prenatal screening for congenital heart disease: what can be expected? A decision-analytic approach

    NARCIS (Netherlands)

    E. Buskens (Erik); E.W. Steyerberg (Ewout); J. Hess (Jakob); J.W. Wladimiroff (Juriy); D.E. Grobbee (Diederick)

    1997-01-01

    textabstractOBJECTIVES: This study assessed the potential impact of fetal ultrasound screening on the number of newborns affected by cardiac anomalies. METHODS: A decision model was developed that included the prevalence and history of congenital heart disease, characte

  10. Routine prenatal screening for congenital heart disease: what can be expected? A decision-analytic approach

    NARCIS (Netherlands)

    E. Buskens (Erik); E.W. Steyerberg (Ewout); J. Hess (Jakob); J.W. Wladimiroff (Juriy); D.E. Grobbee (Diederick)

    1997-01-01

    textabstractOBJECTIVES: This study assessed the potential impact of fetal ultrasound screening on the number of newborns affected by cardiac anomalies. METHODS: A decision model was developed that included the prevalence and history of congenital heart disease, characte

  11. 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.

  12. Emerging approaches to probing ion channel structure and function

    Institute of Scientific and Technical Information of China (English)

    Wei-Guang Li; Tian-Le Xu

    2012-01-01

    Ion channels,as membrane proteins,are the sensors of the cell.They act as the first line of communication with the world beyond the plasma membrane and transduce changes in the external and internal environments into unique electrical signals to shape the responses of excitable cells.Because of their importance in cellular communication,ion channels have been intensively studied at the structural and functional levels.Here,we summarize the diverse approaches,including molecular and cellular,chemical,optical,biophysical,and computational,used to probe the structural and functional rearrangements that occur during channel activation (or sensitization),inactivation (or desensitization),and various forms of modulation.The emerging insights into the structure and function of ion channels by multidisciplinary approaches allow the development of new pharmacotherapies as well as new tools useful in controlling cellular activity.

  13. Web Page Segmentation for Small Screen Devices Using Tag Path Clustering Approach

    OpenAIRE

    Ms. S.Aruljothi; Mrs. S. Sivaranjani; Dr.S.Sivakumari

    2013-01-01

    The web pages breathing these days are developed to be displayed on a Desktop PCs and so viewing them on mobile web browsers is extremely tough. Since mobile devices have restricted resources, small screen device users need to scroll down and across the complicated sites persistently. To address the problem of resource limitation of small screen devices, a unique methodology of web page segmentation with tag path clustering is proposed, that reduces the memory space demand of the small hand-h...

  14. Modifying the Functional Movement Screen Deep Squat Test: The Effect of Foot and Arm Positional Variations.

    Science.gov (United States)

    McMillian, Danny J; Rynders, Zach G; Trudeau, Tyler R

    2016-04-01

    The functional movement screen (FMS) was developed as an evaluation tool for assessing the fundamental movement patterns believed to be prerequisites for functional activity. However, some of the FMS component movements, such as the deep overhead squat test (DST), likely represent novel motor challenges on which poor performance might reflect inexperience with the task rather than a movement impairment. The purpose of this study was to examine the effects of positional variations on DST scores in a population of young, healthy adults. We hypothesized that self-selecting foot positioning, removal of an overhead component, or changing both aspects of the DST would result in improvement in FMS scores. Twenty healthy subjects completed 4 squatting conditions in a counterbalanced sequence to eliminate carry over effects: DST, modified squat with hands at chest level and feet in the DST position (DSTO), modified squat with arms in the DST position and self-selected foot placement (DSTF), and modified squat with hands at chest level and self-selected foot placement (DSTB). A Friedman's analysis of variance and Wilcoxon signed-ranks' post hoc analysis revealed a significant difference between all squat conditions (p = 0.036), between DSTB-DST groups (p DST groups (p = 0.004), and DSTO-DSTB groups (p = 0.046). Each modified squat condition had an average score higher than the DST. These findings suggest that the FMS DST might underestimate an individual's ability to squat during functional tasks that involve self-selected foot and arm placement.

  15. Construction and screening of a functional metagenomic library to identify novel enzymes produced by Antarctic bacteria

    Institute of Scientific and Technical Information of China (English)

    Ignacio Ferrés; Vanesa Amarelle; Francisco Noya; Elena Fabiano

    2015-01-01

    A metagenomic fosmid library of approximately 52 000 clones was constructed to identify functional genes encoding cold-adapted enzymes. Metagenomic DNA was extracted from a sample of glacial meltwater, collected on the Antarctic Peninsula during the ANTARKOS XXIX Expedition during the austral summer of 2012–2013. Each clone contained an insert of about 35–40 kb, so the library represented almost 2 Gb of genetic information from metagenomic DNA. Activity-driven screening was used to detect the cold-adapted functions expressed by the library. Fifty lipase/esterase and two cellulase-producing clones were isolated, and two clones able to grow on Avicel® as the sole carbon source. Interestingly, three clones formed a brown precipitate in the presence of manganese (II). Accumulation of manganese oxides was determined with a leucoberbelin blue assay, indicating that these three clones had manganese-oxidizing activity. To the best of our knowledge, this is the first report of a manganese oxidase activity detected with a functional metagenomic strategy.

  16. Functional mutagenesis screens reveal the 'cap structure' formation in disulfide-bridge free TASK channels.

    Science.gov (United States)

    Goldstein, Matthias; Rinné, Susanne; Kiper, Aytug K; Ramírez, David; Netter, Michael F; Bustos, Daniel; Ortiz-Bonnin, Beatriz; González, Wendy; Decher, Niels

    2016-01-22

    Two-pore-domain potassium (K2P) channels have a large extracellular cap structure formed by two M1-P1 linkers, containing a cysteine for dimerization. However, this cysteine is not present in the TASK-1/3/5 subfamily. The functional role of the cap is poorly understood and it remained unclear whether K2P channels assemble in the domain-swapped orientation or not. Functional alanine-mutagenesis screens of TASK-1 and TRAAK were used to build an in silico model of the TASK-1 cap. According to our data the cap structure of disulfide-bridge free TASK channels is similar to that of other K2P channels and is most likely assembled in the domain-swapped orientation. As the conserved cysteine is not essential for functional expression of all K2P channels tested, we propose that hydrophobic residues at the inner leaflets of the cap domains can interact with each other and that this way of stabilizing the cap is most likely conserved among K2P channels.

  17. Rapid Discovery of Functional Small Molecule Ligands against Proteomic Targets through Library-Against-Library Screening.

    Science.gov (United States)

    Wu, Chun-Yi; Wang, Don-Hong; Wang, Xiaobing; Dixon, Seth M; Meng, Liping; Ahadi, Sara; Enter, Daniel H; Chen, Chao-Yu; Kato, Jason; Leon, Leonardo J; Ramirez, Laura M; Maeda, Yoshiko; Reis, Carolina F; Ribeiro, Brianna; Weems, Brittany; Kung, Hsing-Jien; Lam, Kit S

    2016-06-13

    Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the "library-against-library" screening approach and the resulting small molecule-protein domain interaction database may serve as a valuable tool for basic research and drug development.

  18. Repositioning the substrate activity screening (SAS) approach as a fragment-based method for identification of weak binders.

    Science.gov (United States)

    Gladysz, Rafaela; Cleenewerck, Matthias; Joossens, Jurgen; Lambeir, Anne-Marie; Augustyns, Koen; Van der Veken, Pieter

    2014-10-13

    Fragment-based drug discovery (FBDD) has evolved into an established approach for "hit" identification. Typically, most applications of FBDD depend on specialised cost- and time-intensive biophysical techniques. The substrate activity screening (SAS) approach has been proposed as a relatively cheap and straightforward alternative for identification of fragments for enzyme inhibitors. We have investigated SAS for the discovery of inhibitors of oncology target urokinase (uPA). Although our results support the key hypotheses of SAS, we also encountered a number of unreported limitations. In response, we propose an efficient modified methodology: "MSAS" (modified substrate activity screening). MSAS circumvents the limitations of SAS and broadens its scope by providing additional fragments and more coherent SAR data. As well as presenting and validating MSAS, this study expands existing SAR knowledge for the S1 pocket of uPA and reports new reversible and irreversible uPA inhibitor scaffolds.

  19. Statistical approach of functional profiling for a microbial community.

    Directory of Open Access Journals (Sweden)

    Lingling An

    Full Text Available Metagenomics is a relatively new but fast growing field within environmental biology and medical sciences. It enables researchers to understand the diversity of microbes, their functions, cooperation, and evolution in a particular ecosystem. Traditional methods in genomics and microbiology are not efficient in capturing the structure of the microbial community in an environment. Nowadays, high-throughput next-generation sequencing technologies are powerfully driving the metagenomic studies. However, there is an urgent need to develop efficient statistical methods and computational algorithms to rapidly analyze the massive metagenomic short sequencing data and to accurately detect the features/functions present in the microbial community. Although several issues about functions of metagenomes at pathways or subsystems level have been investigated, there is a lack of studies focusing on functional analysis at a low level of a hierarchical functional tree, such as SEED subsystem tree.A two-step statistical procedure (metaFunction is proposed to detect all possible functional roles at the low level from a metagenomic sample/community. In the first step a statistical mixture model is proposed at the base of gene codons to estimate the abundances for the candidate functional roles, with sequencing error being considered. As a gene could be involved in multiple biological processes the functional assignment is therefore adjusted by utilizing an error distribution in the second step. The performance of the proposed procedure is evaluated through comprehensive simulation studies. Compared with other existing methods in metagenomic functional analysis the new approach is more accurate in assigning reads to functional roles, and therefore at more general levels. The method is also employed to analyze two real data sets.metaFunction is a powerful tool in accurate profiling functions in a metagenomic sample.

  20. The accuracy of the functional movement screen to identify individuals with an elevated risk of musculoskeletal injury.

    Science.gov (United States)

    Krumrei, Kirk; Flanagan, Molly; Bruner, Josh; Durall, Chris

    2014-11-01

    Injuries are somewhat commonplace in highly active populations. One strategy for reducing injuries is to identify individuals with an elevated injury risk before participation so that remediative interventions can be provided. Preparticipation screenings have traditionally entailed strength and flexibility measures thought to be indicative of inflated injury risk. Some researchers, however, have suggested that functional movements/tasks should be assessed to help identify individuals with a high risk of future injury. One assessment tool used for this purpose is the Functional Movement Screen (FMS). The FMS generates a numeric score based on performance attributes during 7 dynamic tasks; this score is purported to reflect future injury risk. Expanding interest in the FMS has led researchers to investigate how accurately it can identify individuals with an increased risk of injury. Can the Functional Movement Screen accurately identify highly active individuals with an elevated risk of injury?

  1. The TSCA interagency testing committee`s approaches to screening and scoring chemicals and chemical groups: 1977-1983

    Energy Technology Data Exchange (ETDEWEB)

    Walker, J.D. [Environmental Protection Agency, Washington, DC (United States)

    1990-12-31

    This paper describes the TSCA interagency testing committee`s (ITC) approaches to screening and scoring chemicals and chemical groups between 1977 and 1983. During this time the ITC conducted five scoring exercises to select chemicals and chemical groups for detailed review and to determine which of these chemicals and chemical groups should be added to the TSCA Section 4(e) Priority Testing List. 29 refs., 1 fig., 2 tabs.

  2. An evolutionary computation approach to examine functional brain plasticity

    Directory of Open Access Journals (Sweden)

    Arnab eRoy

    2016-04-01

    Full Text Available One common research goal in systems neurosciences is to understand how the functional relationship between a pair of regions of interest (ROIs evolves over time. Examining neural connectivity in this way is well-suited for the study of developmental processes, learning, and even in recovery or treatment designs in response to injury. For most fMRI based studies, the strength of the functional relationship between two ROIs is defined as the correlation between the average signal representing each region. The drawback to this approach is that much information is lost due to averaging heterogeneous voxels, and therefore, the functional relationship between a ROI-pair that evolve at a spatial scale much finer than the ROIs remain undetected. To address this shortcoming, we introduce a novel evolutionary computation (EC based voxel-level procedure to examine functional plasticity between an investigator defined ROI-pair by simultaneously using subject-specific BOLD-fMRI data collected from two sessions seperated by finite duration of time. This data-driven procedure detects a sub-region composed of spatially connected voxels from each ROI (a so-called sub-regional-pair such that the pair shows a significant gain/loss of functional relationship strength across the two time points. The procedure is recursive and iteratively finds all statistically significant sub-regional-pairs within the ROIs. Using this approach, we examine functional plasticity between the default mode network (DMN and the executive control network (ECN during recovery from traumatic brain injury (TBI; the study includes 14 TBI and 12 healthy control subjects. We demonstrate that the EC based procedure is able to detect functional plasticity where a traditional averaging based approach fails. The subject-specific plasticity estimates obtained using the EC-procedure are highly consistent across multiple runs. Group-level analyses using these plasticity estimates showed an increase in

  3. Olfactory functions after transsphenoidal pituitary surgery: endoscopic versus microscopic approach.

    Science.gov (United States)

    Kahilogullari, Gokmen; Beton, Suha; Al-Beyati, Eyyub S M; Kantarcioglu, Ozlem; Bozkurt, Melih; Kantarcioglu, Emrah; Comert, Ayhan; Unlu, M Agahan; Meco, Cem

    2013-09-01

    Olfactory disturbances could be observed following transsphenoidal pituitary surgeries. To our knowledge, no previous comparative studies on olfactory functions after transsphenoidal endoscopic and microscopic approaches have been performed. Prospective study comparing olfactory functions between endoscopic and microscopic transsphenoidal pituitary surgery. Twenty-five patients operated on with the endoscopic approach and 25 patients operated on with the microscopic transsphenoidal approach have been evaluated. The Smell Diskettes Olfaction Test was used during the preoperative period, 1 month after the operation, and 6 months after the operation. In addition, the relationship between intraoperative cerebrospinal fluid leakage from the pituitary and postoperative synechiae formation with olfaction system was evaluated. The results were analyzed using the Friedman test, Mann-Whitney test, and Chi-Square test. In the endoscopic group, there were two hyposmic patients and no anosmic patients. In the microscopic group, there were 13 hyposmic patients and five anosmic patients. The data was statistically different between both groups (P microscopic group. There was no statistically significant difference between cerebrospinal fluid leakage and olfactory disturbances in both groups (P >0.05). Synechia was observed in nine patients in the microscopic group and in only one patient in the endoscopic group. There was a statistically significant difference between the presence of synechia and olfactory disturbances (P microscopic transsphenoidal approaches on the olfactory system during pituitary surgery. The obtained results indicate that an endoscopic approach seems to be more advantageous than a microscopic approach for protecting olfactory system and function. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  4. A novel imaging-based high-throughput screening approach to anti-angiogenic drug discovery.

    Science.gov (United States)

    Evensen, Lasse; Micklem, David R; Link, Wolfgang; Lorens, James B

    2010-01-01

    The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, high-throughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high-content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGF-switch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot high-throughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High

  5. Structure-based virtual screening of the nociceptin receptor: hybrid docking and shape-based approaches for improved hit identification.

    Science.gov (United States)

    Daga, Pankaj R; Polgar, Willma E; Zaveri, Nurulain T

    2014-10-27

    The antagonist-bound crystal structure of the nociceptin receptor (NOP), from the opioid receptor family, was recently reported along with those of the other opioid receptors bound to opioid antagonists. We recently reported the first homology model of the 'active-state' of the NOP receptor, which when docked with 'agonist' ligands showed differences in the TM helices and residues, consistent with GPCR activation after agonist binding. In this study, we explored the use of the active-state NOP homology model for structure-based virtual screening to discover NOP ligands containing new chemical scaffolds. Several NOP agonist and antagonist ligands previously reported are based on a common piperidine scaffold. Given the structure-activity relationships for known NOP ligands, we developed a hybrid method that combines a structure-based and ligand-based approach, utilizing the active-state NOP receptor as well as the pharmacophoric features of known NOP ligands, to identify novel NOP binding scaffolds by virtual screening. Multiple conformations of the NOP active site including the flexible second extracellular loop (EL2) loop were generated by simulated annealing and ranked using enrichment factor (EF) analysis and a ligand-decoy dataset containing known NOP agonist ligands. The enrichment factors were further improved by combining shape-based screening of this ligand-decoy dataset and calculation of consensus scores. This combined structure-based and ligand-based EF analysis yielded higher enrichment factors than the individual methods, suggesting the effectiveness of the hybrid approach. Virtual screening of the CNS Permeable subset of the ZINC database was carried out using the above-mentioned hybrid approach in a tiered fashion utilizing a ligand pharmacophore-based filtering step, followed by structure-based virtual screening using the refined NOP active-state models from the enrichment analysis. Determination of the NOP receptor binding affinity of a selected set

  6. Elements of a function analytic approach to probability.

    Energy Technology Data Exchange (ETDEWEB)

    Ghanem, Roger Georges (University of Southern California, Los Angeles, CA); Red-Horse, John Robert

    2008-02-01

    We first provide a detailed motivation for using probability theory as a mathematical context in which to analyze engineering and scientific systems that possess uncertainties. We then present introductory notes on the function analytic approach to probabilistic analysis, emphasizing the connections to various classical deterministic mathematical analysis elements. Lastly, we describe how to use the approach as a means to augment deterministic analysis methods in a particular Hilbert space context, and thus enable a rigorous framework for commingling deterministic and probabilistic analysis tools in an application setting.

  7. A novel approach for immunization, screening and characterization of selected scFv libraries using membrane fractions of tumor cells.

    Science.gov (United States)

    Tur, Mehmet Kemal; Rothe, Achim; Huhn, Michael; Goerres, Ute; Klimka, Alexander; Stöcker, Michael; Engert, Andreas; Fischer, Rainerr; Finner, Ricarda; Barth, Stefan

    2003-04-01

    Isolation of cell-surface specific antibodies prerequisites the functional expressing of antigens on intact cells, which are maintained routinely by cell culturing. However, long-term culturing of tumor cells could alter their antigen expression patterns and stable fixation of whole cells is not guaranteed on plastic surfaces during stringent screening procedures. We prepared functional breast cancer cell-membrane fractions that express surface molecules in their native conformation. Specific binding phages were isolated from phage antibody libraries constructed from the spleen messenger RNA of mice immunized with breast cancer cell-membrane fractions. After negative selection on non-mammary carcinoma cells and four rounds of positive selection on breast carcinoma cell lines, phage antibodies were enriched that bound specifically to breast cancer cell lines as confirmed by phage enzyme linked immunosorbent assay (ELISA) using 96-well plates coated with breast cancer cell membranes. The isolated phage antibodies were highly specific for the breast cancer cell line 8701-BC but not on other carcinoma such as the Hodgkin-derived cell line L540Cy as demonstrated by ELISA and flow cytometry. This report describes a rapid and more versatile method for isolating antibody fragments compared to whole cell screening procedures. One single membrane preparation can be stored for at least 15 months at -80 degrees C and used to immunize mice or for screening of antibody libraries. The selection and screening strategy used should be generally applicable to identify novel cell-surface antigens and their corresponding antibodies.

  8. Lihastasapainon arviointi Functional Movement Screen (FMS) -testipatteristolla : Kartoitus Lapin urheiluakatemian 16 - 19-vuotiaille maastohiihtäjille

    OpenAIRE

    Juotasniemi, Merja; Kivelä, Laura

    2014-01-01

    Opinnäytetyömme tavoitteena on kerätä tietoa Lapin urheiluakatemian 16 – 19-vuotiaiden maastohiihtäjien lihastasapainosta Functional Movement Screen (FMS) -testipatteristolla mitattuna. Tarkoituksena on mittausten kautta tuottaa tietoa, jota toimeksiantajamme Lapin urheiluakatemian valmentajat ja fysioterapeutit voivat hyödyntää valmennustyössään hiihtäjän kehittymisen tukemiseksi ja loukkaantumisten ennaltaehkäisemiseksi. Myös fysioterapia-ala voi hyötyä tiedosta Functional Movement Screen (...

  9. A screening questionnaire for Asperger syndrome and other high-functioning autism spectrum disorders in school age children.

    Science.gov (United States)

    Ehlers, S; Gillberg, C; Wing, L

    1999-04-01

    The high-functioning Autism Spectrum Screening Questionnaire (ASSQ) is a 27-item checklist for completion by lay informants when assessing symptoms characteristic of Asperger syndrome and other high-functioning autism spectrum disorders in children and adolescents with normal intelligence or mild mental retardation. Data for parent and teacher ratings in a clinical sample are presented along with various measures of reliability and validity. Optimal cutoff scores were estimated, using Receiver Operating Characteristic analysis. Findings indicate that the ASSQ is a useful brief screening device for the identification of autism spectrum disorders in clinical settings.

  10. A radial basis function network approach for the computation of inverse continuous time variant functions.

    Science.gov (United States)

    Mayorga, René V; Carrera, Jonathan

    2007-06-01

    This Paper presents an efficient approach for the fast computation of inverse continuous time variant functions with the proper use of Radial Basis Function Networks (RBFNs). The approach is based on implementing RBFNs for computing inverse continuous time variant functions via an overall damped least squares solution that includes a novel null space vector for singularities prevention. The singularities avoidance null space vector is derived from developing a sufficiency condition for singularities prevention that conduces to establish some characterizing matrices and an associated performance index.

  11. A novel approach for tuberculosis screening based on deep convolutional neural networks

    Science.gov (United States)

    Hwang, Sangheum; Kim, Hyo-Eun; Jeong, Jihoon; Kim, Hee-Jin

    2016-03-01

    Tuberculosis (TB) is one of the major global health threats especially in developing countries. Although newly diagnosed TB patients can be recovered with high cure rate, many curable TB patients in the developing countries are obliged to die because of delayed diagnosis, partly by the lack of radiography and radiologists. Therefore, developing a computer-aided diagnosis (CAD) system for TB screening can contribute to early diagnosis of TB, which results in prevention of deaths from TB. Currently, most CAD algorithms adopt carefully designed morphological features distinguishing different lesion types to improve screening performances. However, such engineered features cannot be guaranteed to be the best descriptors for TB screening. Deep learning has become a majority in machine learning society. Especially in computer vision fields, it has been verified that deep convolutional neural networks (CNN) is a very promising algorithm for various visual tasks. Since deep CNN enables end-to-end training from feature extraction to classification, it does not require objective-specific manual feature engineering. In this work, we designed CAD system based on deep CNN for automatic TB screening. Based on large-scale chest X-rays (CXRs), we achieved viable TB screening performance of 0.96, 0.93 and 0.88 in terms of AUC for three real field datasets, respectively, by exploiting the effect of transfer learning.

  12. Baby unplugged: a novel, market-based approach to reducing screen time and promoting healthy alternatives.

    Science.gov (United States)

    Hutton, John S

    2013-01-01

    The issue of electronic media use by young children is increasingly important in pediatrics, a major risk factor for numerous chronic conditions. Despite guidelines in place since 1999, screen time is on the rise, aided by new formats removing practically all barriers of use. Key drivers are technological allure, confusion about developmental readiness, and perception of educational value, fueled by potent marketing. This article describes the development of Baby Unplugged, a series of children's board books celebrating "old-school," screen-free childhood. Written by a pediatrician who also owns a children's bookstore, the books were inspired and informed by advocacy projects in the areas of media use and early literacy as a pediatric resident. They reinforce AAP Electronic Media Guidelines, notably discouraging screen-based media under 2 years old, largely by encouraging healthy, fun alternatives. Examples include Pets, Book, and Yard. Multi-sensorial exploration and parent-child engagement are emphasized in a non-prescriptive way, featuring gender and ethnic diversity and activities that are accessible and inexpensive. The author describes challenges faced by pediatricians providing anticipatory guidance for media use, given limited time and resources and the perception that we are out of touch. This is heightened by oft-deceptive marketing of screen-based products more likely to be perceived as "cool." Reach Out and Read is cited as an example of a successful, "cool" intervention, though limited to select populations. Baby Unplugged takes advocacy to the marketplace, where the screen time battle is being lost.

  13. A Novel Approach to Critical Congenital Heart Disease (CCHD Screening at Moderate Altitude

    Directory of Open Access Journals (Sweden)

    Erin Lueth

    2016-07-01

    Full Text Available The American Academy of Pediatrics (AAP has endorsed Critical Congenital Heart Disease (CCHD screening using pulse oximetry nationwide, but, however, acknowledges that altitude may impact failure rates and alternative algorithms may be required at high altitudes. We therefore evaluated a modified screening protocol at an altitude of 6200 feet with the hypothesis that modifications could decrease failure rates. We evaluated 2001 well, newborn infants ≥35 weeks gestation using a modified protocol, which included a lower saturation cutoff for the first screen (85% instead of the AAP recommended 90% and an oxygen hood intervention between the first two screens. Using our modified screening algorithm, we found a 0.3% failure rate, which was similar to the 0.2% sea-level rate and statistically different from the 1.1% rate identified in a recent study at similar altitude. Had the AAP protocol been used, the failure rate would have increased to 0.8%, which is similar to prior reports near this altitude. Echocardiograms were performed on failing newborns with no CCHD identified. A Birth Defects Registry Database review demonstrated one newborn with CCHD was missed after meeting AAP passing criteria. Overall, this study demonstrates that an alternative algorithm can be implemented at moderate altitude with decreased failure rate and comparable false negative rate.

  14. Value of phagocyte function screening for immunotoxicity of nanoparticles in vivo

    Directory of Open Access Journals (Sweden)

    Fröhlich E

    2015-05-01

    Full Text Available Eleonore Fröhlich Center for Medical Research, Medical University of Graz, Graz, Austria Abstract: Nanoparticles (NPs present in the environment and in consumer products can cause immunotoxic effects. The immune system is very complex, and in vivo studies are the gold standard for evaluation. Due to the increased amount of NPs that are being developed, cellular screening assays to decrease the amount of NPs that have to be tested in vivo are highly needed. Effects on the unspecific immune system, such as effects on phagocytes, might be suitable for screening for immunotoxicity because these cells mediate unspecific and specific immune responses. They are present at epithelial barriers, in the blood, and in almost all organs. This review summarizes the effects of carbon, metal, and metal oxide NPs used in consumer and medical applications (gold, silver, titanium dioxide, silica dioxide, zinc oxide, and carbon nanotubes and polystyrene NPs on the immune system. Effects in animal exposures through different routes are compared to the effects on isolated phagocytes. In addition, general problems in the testing of NPs, such as unknown exposure doses, as well as interference with assays are mentioned. NPs appear to induce a specific immunotoxic pattern consisting of the induction of inflammation in normal animals and aggravation of pathologies in disease models. The evaluation of particle action on several phagocyte functions in vitro may provide an indication on the potency of the particles to induce immunotoxicity in vivo. In combination with information on realistic exposure levels, in vitro studies on phagocytes may provide useful information on the health risks of NPs. Keywords: immunotoxicity, phagocytes, cytokines, respiratory burst, nitric oxide generation, phagocytosis

  15. Computational approaches for rational design of proteins with novel functionalities

    Directory of Open Access Journals (Sweden)

    Manish Kumar Tiwari

    2012-09-01

    Full Text Available Proteins are the most multifaceted macromolecules in living systems and have various important functions, including structural, catalytic, sensory, and regulatory functions. Rational design of enzymes is a great challenge to our understanding of protein structure and physical chemistry and has numerous potential applications. Protein design algorithms have been applied to design or engineer proteins that fold, fold faster, catalyze, catalyze faster, signal, and adopt preferred conformational states. The field of de novo protein design, although only a few decades old, is beginning to produce exciting results. Developments in this field are already having a significant impact on biotechnology and chemical biology. The application of powerful computational methods for functional protein designing has recently succeeded at engineering target activities. Here, we review recently reported de novo functional proteins that were developed using various protein design approaches, including rational design, computational optimization, and selection from combinatorial libraries, highlighting recent advances and successes.

  16. Computational approaches for rational design of proteins with novel functionalities.

    Science.gov (United States)

    Tiwari, Manish Kumar; Singh, Ranjitha; Singh, Raushan Kumar; Kim, In-Won; Lee, Jung-Kul

    2012-01-01

    Proteins are the most multifaceted macromolecules in living systems and have various important functions, including structural, catalytic, sensory, and regulatory functions. Rational design of enzymes is a great challenge to our understanding of protein structure and physical chemistry and has numerous potential applications. Protein design algorithms have been applied to design or engineer proteins that fold, fold faster, catalyze, catalyze faster, signal, and adopt preferred conformational states. The field of de novo protein design, although only a few decades old, is beginning to produce exciting results. Developments in this field are already having a significant impact on biotechnology and chemical biology. The application of powerful computational methods for functional protein designing has recently succeeded at engineering target activities. Here, we review recently reported de novo functional proteins that were developed using various protein design approaches, including rational design, computational optimization, and selection from combinatorial libraries, highlighting recent advances and successes.

  17. Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

    Science.gov (United States)

    Schneider, Nadine; Hindle, Sally; Lange, Gudrun; Klein, Robert; Albrecht, Jürgen; Briem, Hans; Beyer, Kristin; Claußen, Holger; Gastreich, Marcus; Lemmen, Christian; Rarey, Matthias

    2012-06-01

    The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.

  18. A transcription blocker isolated from a designed repeat protein combinatorial library by in vivo functional screen.

    Science.gov (United States)

    Tikhonova, Elena B; Ethayathulla, Abdul S; Su, Yue; Hariharan, Parameswaran; Xie, Shicong; Guan, Lan

    2015-01-28

    A highly diverse DNA library coding for ankyrin seven-repeat proteins (ANK-N5C) was designed and constructed by a PCR-based combinatorial assembly strategy. A bacterial melibiose fermentation assay was adapted for in vivo functional screen. We isolated a transcription blocker that completely inhibits the melibiose-dependent expression of α-galactosidase (MelA) and melibiose permease (MelB) of Escherichia coli by specifically preventing activation of the melAB operon. High-resolution crystal structural determination reveals that the designed ANK-N5C protein has a typical ankyrin fold, and the specific transcription blocker, ANK-N5C-281, forms a domain-swapped dimer. Functional tests suggest that the activity of MelR, a DNA-binding transcription activator and a member of AraC family of transcription factors, is inhibited by ANK-N5C-281 protein. All ANK-N5C proteins are expected to have a concave binding area with negative surface potential, suggesting that the designed ANK-N5C library proteins may facilitate the discovery of binders recognizing structural motifs with positive surface potential, like in DNA-binding proteins. Overall, our results show that the established library is a useful tool for the discovery of novel bioactive reagents.

  19. Functional Movement Screen Scores and Physical Performance among Youth Elite Soccer Players

    Directory of Open Access Journals (Sweden)

    Bruno Silva

    2017-02-01

    Full Text Available This study had two main objectives: (1 to determine if differences in Functional Movement Screen (FMS scores exist between two levels of competition; and (2 to analyze the association between FMS individual and overall scores and physical performance variables of lower-limb power (jumps, repeated sprint ability and shot speed. Twenty-two Under 16 (U16 and twenty-six Under 19 (U19 national competitive soccer players participated in this study. All participants were evaluated according to anthropometrics, FMS, jump performance, instep kick speed and anaerobic performance. There were no significant differences in the individual FMS scores between competitive levels. There were significant negative correlations between hurdle step (right and Running-based Anaerobic Sprint Test (RAST power average ( ρ = −0.293; p = 0.043 and RAST fatigue index (RAST FatIndex ( ρ = −0.340; p = 0.018. The hurdle step (left had a significant negative correlation to squat jump (SJ ( ρ = −0.369; p = 0.012. Rotary stability had a significant negative correlation to RAST fatigue index (Right: ρ = −0.311; p = 0.032. Left: ρ = −0.400; p = 0.005. The results suggest that individual FMS scores may be better discriminants of performance than FMS total score and established minimal association between FMS scores and physical variables. Based on that, FMS may be suitable for the purposes of determining physical function but not for discriminating physical performance.

  20. An Overview of Current Screening and Management Approaches for Prostate Cancer.

    Science.gov (United States)

    Akram, Omar N; Mushtaq, Gohar; Kamal, Mohammad Amjad

    2015-01-01

    Prostate cancer is the fourth leading cause of mortality in Australian men. The prevalence and incidence is increasing in both developed and developing nations, thus there is a need for better screening and management of this disorder. While there is no direct known cause of prostate cancer, management is largely focused on early detection and treatment strategies. Of particular concern is advanced prostate cancer which can manifest as castrate resistant prostate cancer characterized by therapy resistance. This short review outlines the global epidemiology of prostate cancer, clinical manifestations, risk factors, current screening strategies including first line clinical screening as well as the use of circulating biomarkers, and treatment of prostate cancer through mainstream therapeutics as well as the cutting edge peptide and nano-technology based therapeutics that are being implemented or in the process of development to overcome therapeutic obstacles in the treatment of prostate cancer.

  1. Design and analysis of a piezoelectric material based touch screen with additional pressure and its acceleration measurement functions

    Science.gov (United States)

    Chu, Xiang-Cheng; Liu, Jia-Yi; Gao, Ren-Long; Chang, Jie; Li, Long-Tu

    2013-12-01

    Touch screens are becoming more and more prevalent in everyday environments due to their convenience and humanized operation. In this paper, a piezoelectric material based touch screen is developed and investigated. Piezoelectric ceramics arrayed under the touch panel at the edges or corners are used as tactile sensors to measure the touch positioning point similarly to conventional touch screens. However, additional touch pressure and its acceleration performance can also be obtained to obtain a higher-level human-machine interface. The piezoelectric ceramics can also be added to a traditional touch screen structure, or they can be used independently to construct a novel touch screen with a high light transmittance approach to a transparent glass. The piezoelectric ceramics were processed from PZT piezoelectric ceramic powder into a round or rectangular shape. According to the varied touch position and physical press strength of a finger, or even a gloved hand or fingernail, the piezoelectric tactile sensors will have different output voltage responses. By calculating the ratio of different piezoelectric tactile sensors’ responses and summing up all piezoelectric tactile sensors’ output voltages, the touch point position, touch pressure and touch force acceleration can be detected. A prototype of such a touch screen is manufactured and its position accuracy, touch pressure and response speed are measured in detail. The experimental results show that the prototype has many advantages such as high light transmittance, low energy cost and high durability.

  2. Rational Design of Small-Molecule Stabilizers of Spermine Synthase Dimer by Virtual Screening and Free Energy-Based Approach

    Science.gov (United States)

    Zhang, Zhe; Martiny, Virginie; Lagorce, David; Ikeguchi, Yoshihiko; Alexov, Emil; Miteva, Maria A.

    2014-01-01

    Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now. PMID:25340632

  3. Rational design of small-molecule stabilizers of spermine synthase dimer by virtual screening and free energy-based approach.

    Directory of Open Access Journals (Sweden)

    Zhe Zhang

    Full Text Available Snyder-Robinson Syndrome (SRS is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS, which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now.

  4. Genetic and genomic approaches to understanding macrophage identity and function.

    Science.gov (United States)

    Glass, Christopher K

    2015-04-01

    A major goal of our laboratory is to understand the molecular mechanisms that underlie the development and functions of diverse macrophage phenotypes in health and disease. Recent studies using genetic and genomic approaches suggest a relatively simple model of collaborative and hierarchical interactions between lineage-determining and signal-dependent transcription factors that enable selection and activation of transcriptional enhancers that specify macrophage identity and function. In addition, we have found that it is possible to use natural genetic variation as a powerful tool for advancing our understanding of how the macrophage deciphers the information encoded by the genome to attain specific phenotypes in a context-dependent manner. Here, I will describe our recent efforts to extend genetic and genomic approaches to investigate the roles of distinct tissue environments in determining the phenotypes of different resident populations of macrophages.

  5. GREEN‘S FUNCTION APPROACH IN APPROXIMATE CONTROLLABILITY PROBLEMS

    Directory of Open Access Journals (Sweden)

    Avetisyan A. S.

    2016-06-01

    Full Text Available A mathematical approach based on Green‘s function approach allowing to construct controls providing approximate controllability is suggested in the present paper. Representing the solution of governing system via Green’s formula and substituting it in prescribed terminal conditions, we obtain control functions providing approximate controllability of the system under study in explicit form. Choosing appropriate controls, we can provide required accuracy of approximation for prescribed conditions. Examples illustrating the procedure are described. Particularly, infinite string, controlled by a concentrated force, semi-infinite rod heated by a point heat source, finite rod heated from its boundary and parameter optimization for electrical circuit are considered. Results of computsations are brought.

  6. Unified approach to partition functions of RNA secondary structures.

    Science.gov (United States)

    Bundschuh, Ralf

    2014-11-01

    RNA secondary structure formation is a field of considerable biological interest as well as a model system for understanding generic properties of heteropolymer folding. This system is particularly attractive because the partition function and thus all thermodynamic properties of RNA secondary structure ensembles can be calculated numerically in polynomial time for arbitrary sequences and homopolymer models admit analytical solutions. Such solutions for many different aspects of the combinatorics of RNA secondary structure formation share the property that the final solution depends on differences of statistical weights rather than on the weights alone. Here, we present a unified approach to a large class of problems in the field of RNA secondary structure formation. We prove a generic theorem for the calculation of RNA folding partition functions. Then, we show that this approach can be applied to the study of the molten-native transition, denaturation of RNA molecules, as well as to studies of the glass phase of random RNA sequences.

  7. New approach to equipment quality evaluation method with distinct functions

    Directory of Open Access Journals (Sweden)

    Milisavljević Vladimir M.

    2016-01-01

    Full Text Available The paper presents new approach for improving method for quality evaluation and selection of equipment (devices and machinery by applying distinct functions. Quality evaluation and selection of devices and machinery is a multi-criteria problem which involves the consideration of numerous parameters of various origins. Original selection method with distinct functions is based on technical parameters with arbitrary evaluation of each parameter importance (weighting. Improvement of this method, presented in this paper, addresses the issue of weighting of parameters by using Delphi Method. Finally, two case studies are provided, which included quality evaluation of standard boilers for heating and evaluation of load-haul-dump (LHD machines, to demonstrate applicability of this approach. Analytical Hierarchical Process (AHP is used as a control method.

  8. Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators

    Directory of Open Access Journals (Sweden)

    Lucía Pérez-Regidor

    2016-09-01

    Full Text Available This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field.

  9. Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators

    Science.gov (United States)

    Pérez-Regidor, Lucía; Zarioh, Malik; Ortega, Laura; Martín-Santamaría, Sonsoles

    2016-01-01

    This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR) modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful) contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field. PMID:27618029

  10. Web Page Segmentation for Small Screen Devices Using Tag Path Clustering Approach

    Directory of Open Access Journals (Sweden)

    Ms. S.Aruljothi

    2013-07-01

    Full Text Available The web pages breathing these days are developed to be displayed on a Desktop PCs and so viewing them on mobile web browsers is extremely tough. Since mobile devices have restricted resources, small screen device users need to scroll down and across the complicated sites persistently. To address the problem of resource limitation of small screen devices, a unique methodology of web page segmentation with tag path clustering is proposed, that reduces the memory space demand of the small hand-held devices. For segmenting web pages, both reappearance key patterns detection technique and page layout information are used to provide better segmentation accuracy.

  11. A probabilistic approach to delineating functional brain regions

    DEFF Research Database (Denmark)

    Kalbitzer, Jan; Svarer, Claus; Frokjaer, Vibe G

    2009-01-01

    The purpose of this study was to develop a reliable observer-independent approach to delineating volumes of interest (VOIs) for functional brain regions that are not identifiable on structural MR images. The case is made for the raphe nuclei, a collection of nuclei situated in the brain stem known...... to be densely packed with serotonin transporters (5-hydroxytryptaminic [5-HTT] system). METHODS: A template set for the raphe nuclei, based on their high content of 5-HTT as visualized in parametric (11)C-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile PET images, was created for 10...... healthy subjects. The templates were subsequently included in the region sets used in a previously published automatic MRI-based approach to create an observer- and activity-independent probabilistic VOI map. The probabilistic map approach was tested in a different group of 10 subjects and compared...

  12. Fuzzy set approach to quality function deployment: An investigation

    Science.gov (United States)

    Masud, Abu S. M.

    1992-01-01

    The final report of the 1992 NASA/ASEE Summer Faculty Fellowship at the Space Exploration Initiative Office (SEIO) in Langley Research Center is presented. Quality Function Deployment (QFD) is a process, focused on facilitating the integration of the customer's voice in the design and development of a product or service. Various input, in the form of judgements and evaluations, are required during the QFD analyses. All the input variables in these analyses are treated as numeric variables. The purpose of the research was to investigate how QFD analyses can be performed when some or all of the input variables are treated as linguistic variables with values expressed as fuzzy numbers. The reason for this consideration is that human judgement, perception, and cognition are often ambiguous and are better represented as fuzzy numbers. Two approaches for using fuzzy sets in QFD have been proposed. In both cases, all the input variables are considered as linguistic variables with values indicated as linguistic expressions. These expressions are then converted to fuzzy numbers. The difference between the two approaches is due to how the QFD computations are performed with these fuzzy numbers. In Approach 1, the fuzzy numbers are first converted to their equivalent crisp scores and then the QFD computations are performed using these crisp scores. As a result, the output of this approach are crisp numbers, similar to those in traditional QFD. In Approach 2, all the QFD computations are performed with the fuzzy numbers and the output are fuzzy numbers also. Both the approaches have been explained with the help of illustrative examples of QFD application. Approach 2 has also been applied in a QFD application exercise in SEIO, involving a 'mini moon rover' design. The mini moon rover is a proposed tele-operated vehicle that will traverse and perform various tasks, including autonomous operations, on the moon surface. The output of the moon rover application exercise is a

  13. FUZZY-DISTANCE FUNCTION APPROACH FOR MULTIPLE CRITERIA DECISION MAKING

    Directory of Open Access Journals (Sweden)

    Mayank Kumar

    2012-06-01

    Full Text Available In this paper, a method for decision making using fuzzy integral and distance function is presented. Case studies of multiple-response process with correlated responses are used to illustrate the effective application of the proposed approach. The efficacy of this method is compared with the existing methods of MCDM like TOPSIS and GRA. The proposed method is robust, requires less information and less complex as compared to many existing methods.

  14. A cultural research approach to instrument development: the case of breast and cervical cancer screening among Latino and Anglo women

    Science.gov (United States)

    Betancourt, Hector; Flynn, Patricia M.; Riggs, Matt; Garberoglio, Carlos

    2010-01-01

    To illustrate the implementation of a bottom-up approach to the study of culture in health disparities, this article describes the development of a cultural cancer screening scale (CCSS) using mixed methodologies. The aim was to identify cultural factors relevant to breast and cervical cancer screening, develop an instrument to assess them and examine its preliminary psychometric properties among Latin American (Latino) and non-Latino White (Anglo) women in Southern California. Seventy-eight Latino and Anglo women participated in semi-structured interviews, which were content coded based on Triandis' methods for the analysis of subjective culture. Based on the emerging cultural elements, items relevant to cancer screening were developed and pilot tested with 161 participants. After the instrument was refined, 314 Latino and Anglo women from various socioeconomic backgrounds completed the CCSS and data were factor analyzed resulting in five cultural factors: cancer screening fatalism, negative beliefs about health professionals, catastrophic disease expectations, symptomatic deterrents and sociocultural deterrents. The instrument demonstrated measurement equivalence, adequate reliability and predictive validity. The research and the CCSS are discussed in terms of implications for the study of culture in relation to health disparities and the development of evidence-based interventions with culturally diverse populations and their health professionals. PMID:20864605

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

    Science.gov (United States)

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

    2016-10-01

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

  16. Influence of approach velocity and mesh size on the entrainment and contact of a lowland river fish assemblage at a screened irrigation pump.

    Directory of Open Access Journals (Sweden)

    Craig A Boys

    Full Text Available Fish screens can help prevent the entrainment or injury of fish at irrigation diversions, but only when designed appropriately. Design criteria cannot simply be transferred between sites or pump systems and need to be developed using an evidence-based approach with the needs of local species in mind. Laboratory testing is typically used to quantify fish responses at intake screens, but often limits the number of species that can studied and creates artificial conditions not directly applicable to screens in the wild. In this study a field-based approach was used to assess the appropriateness of different screen design attributes for the protection of a lowland river fish assemblage at an experimental irrigation pump. Direct netting of entrained fish was used along with sonar technology to quantify the probability of screen contact for a Murray-Darling Basin (Australia fish species. Two approach velocities (0.1 and 0.5 m.sec(-1 and different sizes of woven mesh (5, 10 and 20 mm were evaluated. Smaller fish (<150 mm in the assemblage were significantly more susceptible to entrainment and screen contact, especially at higher approach velocities. Mesh size appeared to have little impact on screen contact and entrainment, suggesting that approach velocity rather than mesh size is likely to be the primary consideration when developing screens. Until the effects of screen contacts on injury and survival of these species are better understood, it is recommended that approach velocities not exceed 0.1 m.sec(-1 when the desire is to protect the largest range of species and size classes for lowland river fish assemblages in the Murray-Darling Basin. The field method tested proved to be a useful approach that could compliment laboratory studies to refine fish screen design and facilitate field validation.

  17. Comparing neural-network scoring functions and the state of the art: applications to common library screening.

    Science.gov (United States)

    Durrant, Jacob D; Friedman, Aaron J; Rogers, Kathleen E; McCammon, J Andrew

    2013-07-22

    We compare established docking programs, AutoDock Vina and Schrödinger's Glide, to the recently published NNScore scoring functions. As expected, the best protocol to use in a virtual-screening project is highly dependent on the target receptor being studied. However, the mean screening performance obtained when candidate ligands are docked with Vina and rescored with NNScore 1.0 is not statistically different than the mean performance obtained when docking and scoring with Glide. We further demonstrate that the Vina and NNScore docking scores both correlate with chemical properties like small-molecule size and polarizability. Compensating for these potential biases leads to improvements in virtual screen performance. Composite NNScore-based scoring functions suited to a specific receptor further improve performance. We are hopeful that the current study will prove useful for those interested in computer-aided drug design.

  18. PRISM offers a comprehensive genomic approach to transcription factor function prediction

    KAUST Repository

    Wenger, A. M.

    2013-02-04

    The human genome encodes 1500-2000 different transcription factors (TFs). ChIP-seq is revealing the global binding profiles of a fraction of TFs in a fraction of their biological contexts. These data show that the majority of TFs bind directly next to a large number of context-relevant target genes, that most binding is distal, and that binding is context specific. Because of the effort and cost involved, ChIP-seq is seldom used in search of novel TF function. Such exploration is instead done using expression perturbation and genetic screens. Here we propose a comprehensive computational framework for transcription factor function prediction. We curate 332 high-quality nonredundant TF binding motifs that represent all major DNA binding domains, and improve cross-species conserved binding site prediction to obtain 3.3 million conserved, mostly distal, binding site predictions. We combine these with 2.4 million facts about all human and mouse gene functions, in a novel statistical framework, in search of enrichments of particular motifs next to groups of target genes of particular functions. Rigorous parameter tuning and a harsh null are used to minimize false positives. Our novel PRISM (predicting regulatory information from single motifs) approach obtains 2543 TF function predictions in a large variety of contexts, at a false discovery rate of 16%. The predictions are highly enriched for validated TF roles, and 45 of 67 (67%) tested binding site regions in five different contexts act as enhancers in functionally matched cells.

  19. A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system.

    Science.gov (United States)

    Schlecht, Ulrich; Suresh, Sundari; Xu, Weihong; Aparicio, Ana Maria; Chu, Angela; Proctor, Michael J; Davis, Ronald W; Scharfe, Curt; St Onge, Robert P

    2014-04-05

    Copper is essential for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. We found that addition of copper (Cu) to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains. Cu's positive effect on respiratory growth was quantitatively reduced in deletion strains representing 73 different genes, the function of which identify increased iron uptake as a cause of the increase in growth rate. Conversely, these effects were enhanced in strains representing 93 genes. Many of these strains exhibited respiratory defects that were specifically rescued by supplementing the growth medium with Cu. Among the genes identified are known and direct regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Roughly half of the genes are conserved in man, and several of these are associated with Mendelian disorders, including the Cu-imbalance syndromes Menkes and Wilson's disease. We additionally demonstrate that pharmacological agents, including the approved drug disulfiram, can rescue Cu-deficiencies of both environmental and genetic origin. A functional screen in yeast has expanded the list of genes required for Cu-dependent fitness, revealing a complex cellular system with implications for human health. Respiratory fitness defects arising from perturbations in this system can be corrected with pharmacological agents that increase intracellular copper concentrations.

  20. A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses.

    Science.gov (United States)

    Verrier, Eloi R; Colpitts, Che C; Bach, Charlotte; Heydmann, Laura; Weiss, Amélie; Renaud, Mickaël; Durand, Sarah C; Habersetzer, François; Durantel, David; Abou-Jaoudé, Georges; López Ledesma, Maria M; Felmlee, Daniel J; Soumillon, Magali; Croonenborghs, Tom; Pochet, Nathalie; Nassal, Michael; Schuster, Catherine; Brino, Laurent; Sureau, Camille; Zeisel, Mirjam B; Baumert, Thomas F

    2016-01-01

    Chronic hepatitis B and D infections are major causes of liver disease and hepatocellular carcinoma worldwide. Efficient therapeutic approaches for cure are absent. Sharing the same envelope proteins, hepatitis B virus and hepatitis delta virus use the sodium/taurocholate cotransporting polypeptide (a bile acid transporter) as a receptor to enter hepatocytes. However, the detailed mechanisms of the viral entry process are still poorly understood. Here, we established a high-throughput infectious cell culture model enabling functional genomics of hepatitis delta virus entry and infection. Using a targeted RNA interference entry screen, we identified glypican 5 as a common host cell entry factor for hepatitis B and delta viruses. These findings advance our understanding of virus cell entry and open new avenues for curative therapies. As glypicans have been shown to play a role in the control of cell division and growth regulation, virus-glypican 5 interactions may also play a role in the pathogenesis of virus-induced liver disease and cancer. © 2015 by the American Association for the Study of Liver Diseases.

  1. A library screening approach identifies naturally occurring RNA sequences for a G-quadruplex binding ligand.

    Science.gov (United States)

    Mirihana Arachchilage, Gayan; Morris, Mark J; Basu, Soumitra

    2014-02-07

    An RNA G-quadruplex library was synthesised and screened against kanamycin A as the ligand. Naturally occurring G-quadruplex forming sequences that differentially bind to kanamycin A were identified and characterized. This provides a simple and effective strategy for identification of potential intracellular G-quadruplex targets for a ligand.

  2. A PROTEOMIC (SELDI-TOF-MS) APPROACH TO ESTROGEN AGONIST SCREENING

    Science.gov (United States)

    A small fish model and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI) were used to investigate plasma protein expression as a means to screen chemicals for estrogenic activity. Adult male sheepshead minnows (Cyprinodon variegatus) were place...

  3. Drug screening in biological fluids - The need for a systematic approach

    NARCIS (Netherlands)

    de Zeeuw, R.A

    1997-01-01

    In this paper the key steps towards drug screening in biological fluids are considered: (i) sample work up-isolation-concentration: (ii) differentiation-detection; (iii) identification. For (i) solid-phase extraction has very good potential; for (ii) thin-layer chromatography, gas chromatography and

  4. Optimization of enrichment for virtual ligand screening using an established FRED-Surflex approach

    NARCIS (Netherlands)

    Du, J.; Bleylevens, I.W.M.; Bitorina, A.V.; Nicolaes, G.A.F.

    2012-01-01

    Virtual ligand screening (VLS) is an in silico technology used for the productive and cost effective search for novel hit or lead compounds. VLS can be divided into rigid body docking (e.g. FRED) and flexible body docking (e.g. Surflex) procedures. Theoretically, rigid body docking VLS is fast but l

  5. High prevalence of tuberculosis in newly enrolled HIV patients in Zambia: need for enhanced screening approach.

    Science.gov (United States)

    Henostroza, G; Harris, J B; Chitambi, R; Siyambango, M; Turnbull, E R; Maggard, K R; Krüüner, A; Kapata, N; Reid, S E

    2016-08-01

    Tuberculosis (TB) remains a leading cause of morbidity and mortality in sub-Saharan Africa. In Zambia, smear microscopy and chest radiography (CXR) are the primary TB diagnostic tools, and most cases are not bacteriologically confirmed. We implemented enhanced screening to determine the TB burden among new human immunodeficiency virus (HIV) clinic enrollees. Consecutive adult HIV clinic enrollees were screened, regardless of symptoms. All underwent microscopy (Ziehl-Neelsen/fluorescence microscopy) on three sputum specimens, physical examination, and digital CXR. Sputum, blood and urine specimens were cultured. Xpert(®) MTB/RIF testing was performed retrospectively. From July 2011 to April 2012, 399 patients were enrolled. The median age was 34.4 years; body mass index was 20.8 kg/m(2), CD4 count was 202 cells/μl and 86% were symptomatic. Culture-confirmed TB was diagnosed in 72/399 (18%) patients; an additional 31/399 (8%) were culture-negative but diagnosed clinically. Symptom screening for any cough, fever, weight loss or night sweats had high sensitivity (95%) but low specificity (14%) for detecting culture-confirmed cases. Among culture-confirmed cases, 35/72 (49%) were missed clinically and detected only by culture. Xpert was 64% sensitive and 98% specific. High TB prevalence was found in Zambians newly enrolled into HIV care. Screening with sensitive diagnostics should be considered with culture when feasible in this population.

  6. Novel Scaffold Identification of mGlu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach.

    Science.gov (United States)

    Jang, Jae Wan; Cho, Nam-Chul; Min, Sun-Joon; Cho, Yong Seo; Park, Ki Duk; Seo, Seon Hee; No, Kyoung Tai; Pae, Ae Nim

    2016-02-01

    Metabotropic glutamate receptor 1 (mGluR1) is considered as an attractive drug target for neuropathic pain treatments. The hierarchical virtual screening approach for identifying novel scaffolds of mGluR1 allosteric modulators was performed using a homology model built with the dopamine D3 crystal structure as template. The mGluR1 mutagenesis data, conserved amino acid sequences across class A and class C GPCRs, and previously reported multiple sequence alignments of class C GPCRs to the rhodopsin template, were employed for the sequence alignment to overcome difficulties of model generation with low sequence identity of mGluR1 and dopamine D3. The structures refined by molecular dynamics simulations were employed for docking of Asinex commercial libraries after hierarchical virtual screening with pharmacophore and naïve Bayesian models. Five of 35 compounds experimentally evaluated using a calcium mobilization assay exhibited micromolar activities (IC50) with chemotype novelty that demonstrated the validity of our methods. A hierarchical structure and ligand-based virtual screening approach with homology model of class C GPCR based on dopamine D3 class A GPCR structure was successfully performed and applied to discover novel negative mGluR1 allosteric modulators.

  7. Zeta-function approach to Casimir energy with singular potentials

    CERN Document Server

    Khusnutdinov, N R

    2006-01-01

    In the framework of zeta-function approach the Casimir energy for three simple model system: single delta potential, step function potential and three delta potentials is analyzed. It is shown that the energy contains contributions which are peculiar to the potentials. It is suggested to renormalize the energy using the condition that the energy of infinitely separated potentials is zero which corresponds to subtraction all terms of asymptotic expansion of zeta-function. The energy obtained in this way obeys all physically reasonable conditions. It is finite in the Dirichlet limit and it may be attractive or repulsive depending on the strength of potential. The effective action is calculated and it is shown that the surface contribution appears. The renormalization of the effective action is discussed.

  8. 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.

  9. Density functional theory based screening of ternary alkali-transition metal borohydrides: A computational material design project

    DEFF Research Database (Denmark)

    Hummelshøj, Jens Strabo; Landis, David; Voss, Johannes

    2009-01-01

    We present a computational screening study of ternary metal borohydrides for reversible hydrogen storage based on density functional theory. We investigate the stability and decomposition of alloys containing 1 alkali metal atom, Li, Na, or K (M1); and 1 alkali, alkaline earth or 3d/4d transition...

  10. A Sleeping Beauty DNA transposon-based genetic sensor for functional screening of vitamin D3 analogues

    DEFF Research Database (Denmark)

    Staunstrup, Nicklas H; Sharma, Nynne; Bak, Rasmus O

    2011-01-01

    Analogues of vitamin D3 are extensively used in the treatment of various illnesses, such as osteoporosis, inflammatory skin diseases, and cancer. Functional testing of new vitamin D3 analogues and formulations for improved systemic and topical administration is supported by sensitive screening me...

  11. Density Functional Theory and Beyond for Band-Gap Screening: Performance for Transition-Metal Oxides and Dichalcogenides.

    Science.gov (United States)

    Li, Wenqing; Walther, Christian F J; Kuc, Agnieszka; Heine, Thomas

    2013-07-09

    The performance of a wide variety of commonly used density functionals, as well as two screened hybrid functionals (HSE06 and TB-mBJ), on predicting electronic structures of a large class of en vogue materials, such as metal oxides, chalcogenides, and nitrides, is discussed in terms of band gaps, band structures, and projected electronic densities of states. Contrary to GGA, hybrid functionals and GGA+U, both HSE06 and TB-mBJ are able to predict band gaps with an appreciable accuracy of 25% and thus allow the screening of various classes of transition-metal-based compounds, i.e., mixed or doped materials, at modest computational cost. The calculated electronic structures are largely unaffected by the choice of basis functions and software implementation, however, might be subject to the treatment of the core electrons.

  12. Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function

    Directory of Open Access Journals (Sweden)

    Yi Wang

    2016-01-01

    Full Text Available Sirtuin type 1 (SIRT1 belongs to the family of NAD+ dependent histone deacetylases and plays a critical role in cellular metabolism and response to oxidative stress. Traditional Chinese medicines (TCMs, as an important part of natural products, have been reported to exert protective effect against oxidative stress in mitochondria. In this study, we screened SIRT1 activators from TCMs and investigated their activities against mitochondrial damage. 19 activators were found in total by in vitro SIRT1 activity assay. Among those active compounds, four compounds, ginsenoside Rb2, ginsenoside F1, ginsenoside Rc, and schisandrin A, were further studied to validate the SIRT1-activation effects by liquid chromatography-mass spectrometry and confirm their activities against oxidative damage in H9c2 cardiomyocytes exposed to tert-butyl hydroperoxide (t-BHP. The results showed that those compounds enhanced the deacetylated activity of SIRT1, increased ATP content, and inhibited intracellular ROS formation as well as regulating the activity of Mn-SOD. These SIRT1 activators also showed moderate protective effects on mitochondrial function in t-BHP cells by recovering oxygen consumption and increasing mitochondrial DNA content. Our results suggested that those compounds from TCMs attenuated oxidative stress-induced mitochondrial damage in cardiomyocytes through activation of SIRT1.

  13. Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function

    Science.gov (United States)

    Wang, Yi; Liang, Xinying; Chen, Yaqi; Zhao, Xiaoping

    2016-01-01

    Sirtuin type 1 (SIRT1) belongs to the family of NAD+ dependent histone deacetylases and plays a critical role in cellular metabolism and response to oxidative stress. Traditional Chinese medicines (TCMs), as an important part of natural products, have been reported to exert protective effect against oxidative stress in mitochondria. In this study, we screened SIRT1 activators from TCMs and investigated their activities against mitochondrial damage. 19 activators were found in total by in vitro SIRT1 activity assay. Among those active compounds, four compounds, ginsenoside Rb2, ginsenoside F1, ginsenoside Rc, and schisandrin A, were further studied to validate the SIRT1-activation effects by liquid chromatography-mass spectrometry and confirm their activities against oxidative damage in H9c2 cardiomyocytes exposed to tert-butyl hydroperoxide (t-BHP). The results showed that those compounds enhanced the deacetylated activity of SIRT1, increased ATP content, and inhibited intracellular ROS formation as well as regulating the activity of Mn-SOD. These SIRT1 activators also showed moderate protective effects on mitochondrial function in t-BHP cells by recovering oxygen consumption and increasing mitochondrial DNA content. Our results suggested that those compounds from TCMs attenuated oxidative stress-induced mitochondrial damage in cardiomyocytes through activation of SIRT1. PMID:26981165

  14. A screened hybrid density functional study on energetic complexes: cobalt, nickel and copper carbohydrazide perchlorates.

    Science.gov (United States)

    Huang, Huisheng; Zhang, Tonglai; Zhang, Jianguo; Wang, Liqiong

    2010-07-15

    The molecular geometry, electronic structure, infrared spectra and thermochemical properties of cobalt and nickel tris(carbohydrazide) perchlorates (CoCP and NiCP) as well as copper bis(carbohydrazide) perchlorate (CuCP) were investigated using the Heyd-Scuseria-Ernzerhof (HSE) screened hybrid density functional. The results show that both perchlorate ions coordinate with the copper atom, and the interactions between copper and perchlorate are ionic, whereas all the metal-carbohydrazide interactions are covalent. Due to the delocalization from the sigma(N-H) bond orbital to the n*(M) antibond orbital, the amino stretching vibrations of these complexes show considerable red-shift compared with those of free carbohydrazide ligand. The calculated heats of reaction and formation indicate that the formations of these complexes are exothermic, and the order of their thermal stability is NiCP>CoCP>CuCP. These agree well with the experimental results. Finally, we find that there is a relationship between the energy gap and impact sensitivity.

  15. Calculation of point defects in rutile TiO2 by the Screened Exchange Hybrid Functional

    CERN Document Server

    Lee, Hsin-Yi; Robertson, John

    2012-01-01

    The formation energies of the oxygen vacancy and titanium interstitial in rutile TiO2 were calculated by the screened exchange (sX) hybrid density functional method, which gives a band gap of 3.1 eV, close to the experimental value. The O vacancy gives rise to a gap state lying 0.7 eV below the conduction band edge, whose charge density is localised around the two of three Ti atoms next to the vacancy. The Ti interstitial generates four defect states in the gap, whose unpaired electrons lie on the interstitial and the adjacent Ti 3d orbitals. The formation energy for the neutral O vacancy is 1.9 eV for the O-poor chemical potential, and similar to that of the neutral Ti interstitial, and has a lower formation energy for Ti interstitial under O-rich conditions. This indicates that both the O vacancy and Ti interstitial are relevant for oxygen deficiency in rutile TiO2 but the O vacancy will dominate under O-rich conditions. This resolves the questions about defect localisation and defect predominance in the li...

  16. Functional Screening of Antibiotic Resistance Genes from a Representative Metagenomic Library of Food Fermenting Microbiota

    Directory of Open Access Journals (Sweden)

    Chiara Devirgiliis

    2014-01-01

    Full Text Available Lactic acid bacteria (LAB represent the predominant microbiota in fermented foods. Foodborne LAB have received increasing attention as potential reservoir of antibiotic resistance (AR determinants, which may be horizontally transferred to opportunistic pathogens. We have previously reported isolation of AR LAB from the raw ingredients of a fermented cheese, while AR genes could be detected in the final, marketed product only by PCR amplification, thus pointing at the need for more sensitive microbial isolation techniques. We turned therefore to construction of a metagenomic library containing microbial DNA extracted directly from the food matrix. To maximize yield and purity and to ensure that genomic complexity of the library was representative of the original bacterial population, we defined a suitable protocol for total DNA extraction from cheese which can also be applied to other lipid-rich foods. Functional library screening on different antibiotics allowed recovery of ampicillin and kanamycin resistant clones originating from Streptococcus salivarius subsp. thermophilus and Lactobacillus helveticus genomes. We report molecular characterization of the cloned inserts, which were fully sequenced and shown to confer AR phenotype to recipient bacteria. We also show that metagenomics can be applied to food microbiota to identify underrepresented species carrying specific genes of interest.

  17. Integration of the functional movement screen into the National Hockey League Combine.

    Science.gov (United States)

    Rowan, Chip P; Kuropkat, Christiane; Gumieniak, Robert J; Gledhill, Norman; Jamnik, Veronica K

    2015-05-01

    The sport of ice hockey requires coordination of complex skills involving musculoskeletal and physiological abilities while simultaneously exposing players to a high risk for injury. The Functional Movement Screen (FMS) was developed to assess fundamental movement patterns that underlie both sport performance and injury risk. The top 111 elite junior hockey players from around the world took part in the 2013 National Hockey League Entry Draft Combine (NHL Combine). The FMS was integrated into the comprehensive medical and physiological fitness evaluations at the request of strength and conditioning coaches with affiliations to NHL teams. The inclusion of the FMS aimed to help develop strategies that could maximize its utility among elite hockey players and to encourage or inform further research in this field. This study evaluated the outcomes of integrating the FMS into the NHL Combine and identified any links to other medical plus physical and physiological fitness assessment outcomes. These potential associations may provide valuable information to identify elements of future training programs that are individualized to athletes' specific needs. The results of the FMS (total score and number of asymmetries identified) were significantly correlated to various body composition measures, aerobic and anaerobic fitness, leg power, timing of recent workouts, and the presence of lingering injury at the time of the NHL Combine. Although statistically significant correlations were observed, the implications of the FMS assessment outcomes remain difficult to quantify until ongoing assessment of FMS patterns, tracking of injuries, and hockey performance are available.

  18. Vertebrate embryos as tools for anti-angiogenic drug screening and function.

    Science.gov (United States)

    Beedie, Shaunna L; Diamond, Alexandra J; Fraga, Lucas Rosa; Figg, William D; Vargesson, Neil

    2016-11-22

    The development of new angiogenic inhibitors highlights a need for robust screening assays that adequately capture the complexity of vessel formation, and allow for the quantitative evaluation of the teratogenicity of new anti-angiogenic agents. This review discusses the use of screening assays in vertebrate embryos, specifically focusing upon chicken and zebrafish embryos, for the detection of anti-angiogenic agents.

  19. Combinatorial Density Functional Theory-Based Screening of Surface Alloys for the Oxygen Reduction Reaction

    DEFF Research Database (Denmark)

    Greeley, Jeffrey Philip; Nørskov, Jens Kehlet

    2009-01-01

    A density functional theory (DFT)-based, combinatorial search for improved oxygen reduction reaction (ORR) catalysts is presented. A descriptor-based approach to estimate the ORR activity of binary surface alloys, wherein alloying occurs only in the surface layer, is described, and rigorous......, potential-dependent computational tests of the stability of these alloys in aqueous, acidic environments are presented. These activity and stability criteria are applied to a database of DFT calculations on nearly 750 binary transition metal surface alloys; of these, many are predicted to be active...

  20. Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

    Energy Technology Data Exchange (ETDEWEB)

    Doherty, Kimberly R., E-mail: kimberly.doherty@quintiles.com; Talbert, Dominique R.; Trusk, Patricia B.; Moran, Diarmuid M.; Shell, Scott A.; Bacus, Sarah

    2015-05-15

    Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug-induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. - Highlights: • 24 drugs were tested for cardiac liability using an in vitro multi-parameter screen. • Changes in beating activity were the most sensitive in predicting cardiac risk. • Structural effects add in

  1. New approaches to screening infrastructure investments in multi-reservoir systems- Evaluating proposed dams in Ethiopia and Kenya

    Science.gov (United States)

    Harou, J. J.; Geressu, R. T.; Hurford, A. P.

    2014-12-01

    Two approaches have been used traditionally to screen infrastructure investments in multi-reservoir systems: scenario analysis of a few simulated designs and deterministic optimization, sometimes using hydro-economic models or screening optimization models. Simulation models realistically represent proposed water systems and can easily include multiple performance metrics; however each prospective system operating rules need to be formulated and simulated for each proposed design (time consuming. Optimization models have been used to overcome this burden. Screening optimization models use integer or non-linear programming and can be challenging to apply to large and/or multi-objective systems. Hydro-economic models that use deterministic (implicit stochastic) optimization must be modified to examine each different plan and they cannot always reproduce realistic or politically acceptable system operations. In this presentation we demonstrate the application of a new screening approach to multi-reservoir systems where operating rules and new assets (dams) are simultaneously optimized in a multi-criteria context. Results are not least cost investment plans that satisfy reliability or other engineering constraints, but rather Pareto-optimal sets of asset portfolios that work well under historical and/or future scenarios. This is achieved by using stakeholder-built simulation models linked to multi-criteria search algorithms (e.g. many objective evolutionary algorithms, MOEA). Typical output is demonstrated through two case-studies on the Tana and Blue Nile rivers where operating rules and reservoir assets are efficiently screened together considering stakeholder-defined metrics. The focus on the Tana system is how reservoir operating rules and new irrigation schemes should be co-managed to limit ecological damages. On the Nile system, we identify Blue Nile river reservoir capacities that least negatively impact downstream Nile nations. Limitations and new directions of

  2. Identification of potent Yes1 kinase inhibitors using a library screening approach.

    Science.gov (United States)

    Patel, Paresma R; Sun, Hongmao; Li, Samuel Q; Shen, Min; Khan, Javed; Thomas, Craig J; Davis, Mindy I

    2013-08-01

    Yes1 kinase has been implicated as a potential therapeutic target in a number of cancers including melanomas, breast cancers, and rhabdomyosarcomas. Described here is the development of a robust and miniaturized biochemical assay for Yes1 kinase that was applied in a high throughput screen (HTS) of kinase-focused small molecule libraries. The HTS provided 144 (17% hit rate) small molecule compounds with IC₅₀ values in the sub-micromolar range. Three of the most potent Yes1 inhibitors were then examined in a cell-based assay for inhibition of cell survival in rhabdomyosarcoma cell lines. Homology models of Yes1 were generated in active and inactive conformations, and docking of inhibitors supports binding to the active conformation (DFG-in) of Yes1. This is the first report of a large high throughput enzymatic activity screen for identification of Yes1 kinase inhibitors, thereby elucidating the polypharmacology of a variety of small molecules and clinical candidates.

  3. Promoting community practitioners' use of evidence-based approaches to increase breast cancer screening.

    Science.gov (United States)

    Leeman, Jennifer; Moore, Alexis; Teal, Randall; Barrett, Nadine; Leighton, Ashely; Steckler, Allan

    2013-07-01

    Many women do not get mammography screenings at the intervals recommended for early detection and treatment of breast cancer. The Guide to Community Preventive Services (Community Guide) recommends a range of evidence-based strategies to improve mammography rates. However, nurses and others working in community-based settings make only limited use of these strategies. We report on a dissemination intervention that partnered the University of North Carolina with the Susan G. Komen Triangle Affiliate to disseminate Community Guide breast cancer screening strategies to community organizations. The intervention was guided by social marketing and diffusion of innovation theory and was designed to provide evidence and support via Komen's existing relationships with grantee organizations. The present study reports the findings from a formative evaluation of the intervention, which included a content analysis of 46 grant applications pre- and post intervention and focus groups with 20 grant recipients. © 2013 Wiley Periodicals, Inc.

  4. Approaching Corporate Social Responsibility through Kenneth Burke's Notions of Terministic Screens and Entitlement

    DEFF Research Database (Denmark)

    Kampf, Constance

    summarizes Burke's essay, "Antinomies of Definition," from a Grammar of Motives as demonstrating that 'the intrinsic and the extrinsic can change places' "such that to define is always to contextualize and to uncover the absence of a solid ground for a claim to knowledge."2   So if the intrinsic...... allow for user agency, whereas entitlement appears to be focused more at the cultural level, with the agency shared by the 'tribe,' the language itself, and the context of situation.1 In other words, "terministic screens" appear to be extrinsic, while "entitlement" appears to be intrinsic.  Carmichael...... and extrinsic can change places, the interpretive process of "terministic screens" and the constitutive process of "entitlement" may well be reciprocal.  The implications of this reciprocity can be used as a basis for understanding the linguistic and cultural components of Corporate Social Responsibility...

  5. Screening for Hypertension Among Older Adults: A Primary Care “High Risk” Approach

    OpenAIRE

    John Jacob; Muliyil Jayaprakash; Balraj Vinohar

    2010-01-01

    Background: Recommendations for early detection and management of elevated blood pressure through opportunistic clinic-based screening may be inadequate for the rural population in India as access to health facilities is limited. Materials and Methods: Sixteen Health Aides (trained primary care workers) were trained to measure blood pressure using a standardized training procedure. Six of those assessed competent in initial evaluation were allotted a stratified random sample of about 150 per...

  6. Screening for hypertension among older adults: A primary care "High Risk" approach

    Directory of Open Access Journals (Sweden)

    John Jacob

    2010-01-01

    Full Text Available Background: Recommendations for early detection and management of elevated blood pressure through opportunistic clinic-based screening may be inadequate for the rural population in India as access to health facilities is limited. Materials and Methods: Sixteen Health Aides (trained primary care workers were trained to measure blood pressure using a standardized training procedure. Six of those assessed competent in initial evaluation were allotted a stratified random sample of about 150 persons each, 50 years or over, in the village under their care to measure blood pressures during their regular scheduled visits. Results: 14/16 of the health aides (83% met the stipulated criteria for the simulation study using a module from British Hypertension Society. In the field survey of 920 individuals where 20% of the population was evaluated by a blinded investigator, the weighted Kappa for agreement, using normal, pre-hypertension and hypertension as categories, ranged between 62% and 89%. Only 75/286 (25% of those detected to be hypertensive knew their status prior to the study. All those detected with hypertension were referred to a physician at a referral facility. 70% of those referred were evaluated at the referral facility and 64% of them initiated on treatment for hypertension within 3 months. Conclusion: Using primary care workers to screen for hypertension through the model suggested here will ensure that the population over 50 years of age will be screened once every 2 years without burdening the worker. This screening process will enable the health system to identify and cater to needs of this vulnerable population.

  7. Real-time screening tests for functional alignment of the trunk and lower extremities in adolescent – a systematic review

    DEFF Research Database (Denmark)

    Junge, Tina; Wedderkopp, Niels; Juul-Kristensen, Birgit

    2012-01-01

    mechanisms resulting in ACL injuries (Hewett, 2010). Prevention may therefore depend on identifying these potentially injury risk factors. Screening tools must thus include patterns of typical movements in sport and leisure time activities, consisting of high-load and multi-directional tests, focusing...... of knee alignment, there is a further need to evaluate reliability and validity of real-time functional alignment tests, before the can be used as screening tools for prevention of knee injuries among adolescents. Still the next step in this systematic review is to evaluate the quality and feasibility...

  8. A pharmacological screening approach for discovery of neuroprotective compounds in ischemic stroke.

    Directory of Open Access Journals (Sweden)

    Simret Beraki

    Full Text Available With the availability and ease of small molecule production and design continuing to improve, robust, high-throughput methods for screening are increasingly necessary to find pharmacologically relevant compounds amongst the masses of potential candidates. Here, we demonstrate that a primary oxygen glucose deprivation assay in primary cortical neurons followed by secondary assays (i.e. post-treatment protocol in organotypic hippocampal slice cultures and cortical neurons can be used as a robust screen to identify neuroprotective compounds with potential therapeutic efficacy. In our screen about 50% of the compounds in a library of pharmacologically active compounds displayed some degree of neuroprotective activity if tested in a pre-treatment toxicity assay but just a few of these compounds, including Carbenoxolone, remained active when tested in a post-treatment protocol. When further examined, Carbenoxolone also led to a significant reduction in infarction size and neuronal damage in the ischemic penumbra when administered six hours post middle cerebral artery occlusion in rats. Pharmacological testing of Carbenoxolone-related compounds, acting by inhibition of 11-β-hydroxysteroid dehydrogenase-1 (11β-HSD1, gave rise to similarly potent in vivo neuroprotection. This indicates that the increase of intracellular glucocorticoid levels mediated by 11β-HSD1 may be involved in the mechanism that exacerbates ischemic neuronal cell death, and inhibiting this enzyme could have potential therapeutic value for neuroprotective therapies in ischemic stroke and other neurodegenerative disorders associated with neuronal injury.

  9. Theology and Threshold: Victorian Approaches to Reviving Choir and Rood Screens

    Directory of Open Access Journals (Sweden)

    Ayla Lepine

    2017-04-01

    Full Text Available In 1851, A. W. N. Pugin published an influential treatise on rood screens, intending in his irrepressible polemical style to create further Gothic Revival momentum for inserting these iconographically complex and liturgically vital elements into Roman Catholic and Anglican churches throughout Britain and its empire. In the decades that followed, debates regarding ritual, aesthetics, materials, and Eucharistic theology surrounded the design, presence, and indeed absence of these screens. This interdisciplinary article on the borderlands between architectural history and theology explores what was at stake in the religious symbolism of a small number of diverse screens designed by George Gilbert Scott, George Frederick Bodley, and Ninian Comper, considering them in light of the key writing produced by Pugin at the mid-point of the nineteenth century, as well as by priest–architect Ernest Geldart in the century’s end. This study, together with its three short films that explore the screens’ meanings and histories in situ, charts shifts in theology and style as each architect offered innovative views through delicate latticework of stone, paint, and wood towards the Christian sacred epicentre of the Incarnation and the sacrifice of the Eucharist.

  10. In vivo functional expression of a screened P. aeruginosa chaperone-dependent lipase in E. coli

    Directory of Open Access Journals (Sweden)

    Wu Xiangping

    2012-09-01

    Full Text Available Abstract Background Microbial lipases particularly Pseudomonas lipases are widely used for biotechnological applications. It is a meaningful work to design experiments to obtain high-level active lipase. There is a limiting factor for functional overexpression of the Pseudomonas lipase that a chaperone is necessary for effective folding. As previously reported, several methods had been used to resolve the problem. In this work, the lipase (LipA and its chaperone (LipB from a screened strain named AB which belongs to Pseudomonas aeruginosa were overexpressed in E. coli with two dual expression plasmid systems to enhance the production of the active lipase LipA without in vitro refolding process. Results In this work, we screened a lipase-produced strain named AB through the screening procedure, which was identified as P. aeruginosa on the basis of 16S rDNA. Genomic DNA obtained from the strain was used to isolate the gene lipA (936 bp and lipase specific foldase gene lipB (1023 bp. One single expression plasmid system E. coli BL21/pET28a-lipAB and two dual expression plasmid systems E. coli BL21/pETDuet-lipA-lipB and E. coli BL21/pACYCDuet-lipA-lipB were successfully constructed. The lipase activities of the three expression systems were compared to choose the optimal expression method. Under the same cultured condition, the activities of the lipases expressed by E. coli BL21/pET28a-lipAB and E. coli BL21/pETDuet-lipA-lipB were 1300 U/L and 3200 U/L, respectively, while the activity of the lipase expressed by E. coli BL21/pACYCDuet-lipA-lipB was up to 8500 U/L. The lipase LipA had an optimal temperature of 30°C and an optimal pH of 9 with a strong pH tolerance. The active LipA could catalyze the reaction between fatty alcohols and fatty acids to generate fatty acid alkyl esters, which meant that LipA was able to catalyze esterification reaction. The most suitable fatty acid and alcohol substrates for esterification were octylic acid and hexanol

  11. Terminate lung cancer (TLC) study-A mixed-methods population approach to increase lung cancer screening awareness and low-dose computed tomography in Eastern Kentucky.

    Science.gov (United States)

    Cardarelli, Roberto; Reese, David; Roper, Karen L; Cardarelli, Kathryn; Feltner, Frances J; Studts, Jamie L; Knight, Jennifer R; Armstrong, Debra; Weaver, Anthony; Shaffer, Dana

    2017-02-01

    For low dose CT lung cancer screening to be effective in curbing disease mortality, efforts are needed to overcome barriers to awareness and facilitate uptake of the current evidence-based screening guidelines. A sequential mixed-methods approach was employed to design a screening campaign utilizing messages developed from community focus groups, followed by implementation of the outreach campaign intervention in two high-risk Kentucky regions. This study reports on rates of awareness and screening in intervention regions, as compared to a control region.

  12. A novel Bayesian approach to spectral function reconstruction

    CERN Document Server

    Burnier, Yannis

    2013-01-01

    We present a novel approach to the inference of spectral functions from Euclidean time correlator data that makes close contact with modern Bayesian concepts. Our method differs significantly from the maximum entropy method (MEM). A new set of axioms is postulated for the prior probability, leading to an improved expression, which is devoid of the asymptotically flat directions present in the Shanon-Jaynes entropy. Hyperparameters are integrated out explicitly, liberating us from the Gaussian approximations underlying the evidence approach of the MEM. We present a realistic test of our method in the context of the non-perturbative extraction of the heavy quark potential. Based on hard-thermal-loop correlator mock data, we establish firm requirements in the number of data points and their accuracy for a successful extraction of the potential from lattice QCD. An improved potential estimation from previously investigated quenched lattice QCD correlators is provided.

  13. An ecological approach to language development: an alternative functionalism.

    Science.gov (United States)

    Dent, C H

    1990-11-01

    I argue for a new functionalist approach to language development, an ecological approach. A realist orientation is used that locates the causes of language development neither in the child nor in the language environment but in the functioning of perceptual systems that detect language-world relationships and use them to guide attention and action. The theory requires no concept of innateness, thus avoiding problems inherent in either the innate ideas or the genes-as-causal-programs explanations of the source of structure in language. An ecological explanation of language is discussed in relation to concepts and language, language as representation, problems in early word learning, metaphor, and syntactic development. Finally, problems incurred in using the idea of innateness are summarized: History prior to the chosen beginning point is ignored, data on organism-environment mutuality are not collected, and the explanation claims no effect of learning, which cannot be tested empirically.

  14. Sensorimotor integration for functional recovery and the Bobath approach.

    Science.gov (United States)

    Levin, Mindy F; Panturin, Elia

    2011-04-01

    Bobath therapy is used to treat patients with neurological disorders. Bobath practitioners use hands-on approaches to elicit and reestablish typical movement patterns through therapist-controlled sensorimotor experiences within the context of task accomplishment. One aspect of Bobath practice, the recovery of sensorimotor function, is reviewed within the framework of current motor control theories. We focus on the role of sensory information in movement production, the relationship between posture and movement and concepts related to motor recovery and compensation with respect to this therapeutic approach. We suggest that a major barrier to the evaluation of the therapeutic effectiveness of the Bobath concept is the lack of a unified framework for both experimental identification and treatment of neurological motor deficits. More conclusive analysis of therapeutic effectiveness requires the development of specific outcomes that measure movement quality.

  15. The Navier-Stokes equations an elementary functional analytic approach

    CERN Document Server

    Sohr, Hermann

    2001-01-01

    The primary objective of this monograph is to develop an elementary and self-contained approach to the mathematical theory of a viscous, incompressible fluid in a domain of the Euclidean space, described by the equations of Navier-Stokes. Moreover, the theory is presented for completely general domains, in particular, for arbitrary unbounded, nonsmooth domains. Therefore, restriction was necessary to space dimensions two and three, which are also the most significant from a physical point of view. For mathematical generality, however, the linearized theory is expounded for general dimensions higher than one. Although the functional analytic approach developed here is, in principle, known to specialists, the present book fills a gap in the literature providing a systematic treatment of a subject that has been documented until now only in fragments. The book is mainly directed to students familiar with basic tools in Hilbert and Banach spaces. However, for the readers’ convenience, some fundamental properties...

  16. The ChemScreen project to design a pragmatic alternative approach to predict reproductive toxicity of chemicals.

    Science.gov (United States)

    van der Burg, Bart; Wedebye, Eva Bay; Dietrich, Daniel R; Jaworska, Joanna; Mangelsdorf, Inge; Paune, Eduard; Schwarz, Michael; Piersma, Aldert H; Kroese, E Dinant

    2015-08-01

    There is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use. The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner preferably using validated existing tools and place them in an innovative alternative testing strategy. In our approach we combined knowledge on critical processes affected by reproductive toxicants with knowledge on the mechanistic basis of such effects. We used in silico methods for prescreening chemicals for relevant toxic effects aiming at reduced testing needs. For those chemicals that need testing we have set up an in vitro screening panel that includes mechanistic high throughput methods and lower throughput assays that measure more integrative endpoints. In silico pharmacokinetic modules were developed for rapid exposure predictions via diverse exposure routes. These modules to match in vitro and in vivo exposure levels greatly improved predictivity of the in vitro tests. As a further step, we have generated examples how to predict reproductive toxicity of chemicals using available data. We have executed formal validations of panel constituents and also used more innovative manners to validate the test panel using mechanistic approaches. We are actively engaged in promoting regulatory acceptance of the tools developed as an essential step towards practical application, including case studies for read-across purposes. With this approach, a significant saving in animal use and associated costs seems very feasible. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. A Hybrid Intelligent Diagnosis Approach for Quick Screening of Alzheimer’s Disease Based on Multiple Neuropsychological Rating Scales

    Directory of Open Access Journals (Sweden)

    Ziming Yin

    2015-01-01

    Full Text Available Neuropsychological testing is an effective means for the screening of Alzheimer’s disease. Multiple neuropsychological rating scales should be used together to get subjects’ comprehensive cognitive state due to the limitation of a single scale, but it is difficult to operate in primary clinical settings because of the inadequacy of time and qualified clinicians. Aiming at identifying AD’s stages more accurately and conveniently in screening, we proposed a computer-aided diagnosis approach based on critical items extracted from multiple neuropsychological scales. The proposed hybrid intelligent approach combines the strengths of rough sets, genetic algorithm, and Bayesian network. There are two stages: one is attributes reduction technique based on rough sets and genetic algorithm, which can find out the most discriminative items for AD diagnosis in scales; the other is uncertain reasoning technique based on Bayesian network, which can forecast the probability of suffering from AD. The experimental data set consists of 500 cases collected by a top hospital in China and each case is determined by the expert panel. The results showed that the proposed approach could not only reduce items drastically with the same classification precision, but also perform better on identifying different stages of AD comparing with other existing scales.

  18. Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.

    Science.gov (United States)

    Kym, Philip R; Souers, Andrew J; Campbell, Thomas J; Lynch, John K; Judd, Andrew S; Iyengar, Rajesh; Vasudevan, Anil; Gao, Ju; Freeman, Jennifer C; Wodka, Dariusz; Mulhern, Mathew; Zhao, Gang; Wagaw, Seble H; Napier, James J; Brodjian, Sevan; Dayton, Brian D; Reilly, Regina M; Segreti, Jason A; Fryer, Ryan M; Preusser, Lee C; Reinhart, Glenn A; Hernandez, Lisa; Marsh, Kennan C; Sham, Hing L; Collins, Christine A; Polakowski, James S

    2006-04-06

    An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

  19. Matrix converter controlled with the direct transfer function approach

    DEFF Research Database (Denmark)

    Rodriguez, J.; Silva, E.; Blaabjerg, Frede

    2005-01-01

    Power electronics is an emerging technology. New power circuits are invented and have to be introduced into the power electronics curriculum. One of the interesting new circuits is the matrix converter (MC), and this paper analyses its working principles. A simple model is proposed to represent...... the power circuit, including the input filter. The power semiconductors are modelled as ideal bidirectional switches and the MC is controlled using a direct transfer function approach. The modulation strategy of the converter is explained in a complete and clear form. The commutation problem of two switches...

  20. Entanglement probabilities of polymers: a white noise functional approach

    Energy Technology Data Exchange (ETDEWEB)

    Bernido, Christopher C; Carpio-Bernido, M Victoria [Research Center for Theoretical Physics, Central Visayan Institute Foundation, Jagna, Bohol 6308 (Philippines)

    2003-04-18

    The entanglement probabilities for a highly flexible polymer to wind n times around a straight polymer are evaluated using white noise analysis. To introduce the white noise functional approach, the one-dimensional random walk problem is taken as an example. The polymer entanglement scenario, viewed as a random walk on a plane, is then treated and the entanglement probabilities are obtained for a magnetic flux confined along the straight polymer, and a case where an entangled polymer is subjected to the potential V = f-dot(s){theta}. In the absence of the magnetic flux and the potential V, the entanglement probabilities reduce to a result obtained by Wiegel.

  1. An information theoretic approach to the functional classification of neurons

    CERN Document Server

    Schneidman, E; Berry, M J; Schneidman, Elad; Bialek, William; Berry, Michael J.

    2002-01-01

    A population of neurons typically exhibits a broad diversity of responses to sensory inputs. The intuitive notion of functional classification is that cells can be clustered so that most of the diversity is captured in the identity of the clusters rather than by individuals within clusters. We show how this intuition can be made precise using information theory, without any need to introduce a metric on the space of stimuli or responses. Applied to the retinal ganglion cells of the salamander, this approach recovers classical results, but also provides clear evidence for subclasses beyond those identified previously. Further, we find that each of the ganglion cells is functionally unique, and that even within the same subclass only a few spikes are needed to reliably distinguish between cells.

  2. Current approaches on viral infection: proteomics and functional validations

    Directory of Open Access Journals (Sweden)

    Jie eZheng

    2012-11-01

    Full Text Available Viruses could manipulate cellular machinery to ensure their continuous survival and thus become parasites of living organisms. Delineation of sophisticated host responses upon virus infection is a challenging task. It lies in identifying the repertoire of host factors actively involved in the viral infectious cycle and characterizing host responses qualitatively and quantitatively during viral pathogenesis. Mass spectrometry based proteomics could be used to efficiently study pathogen-host interactions and virus-hijacked cellular signaling pathways. Moreover, direct host and viral responses upon infection could be further investigated by activity based functional validation studies. These approaches involve drug inhibition of secretory pathway, immunofluorescence staining, dominant negative mutation of protein target, real time PCR, small interfering siRNA-mediated knockdown, and molecular cloning studies. In this way, functional validation could gain novel insights into the high-content proteomic dataset in an unbiased and comprehensive way.

  3. 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.

  4. A Bayesian Approach to Calibrating High-Throughput Virtual Screening Results and Application to Organic Photovoltaic Materials

    CERN Document Server

    Pyzer-Knapp, Edward O; Aspuru-Guzik, Alan

    2015-01-01

    A novel approach for calibrating quantum-chemical properties determined as part of a high-throughput virtual screen to experimental analogs is presented. Information on the molecular graph is extracted through the use of extended connectivity fingerprints, and exploited using a Gaussian process to calibrate both electronic properties such as frontier orbital energies, and optical gaps and device properties such as short circuit current density, open circuit voltage and power conversion efficiency. The Bayesian nature of this process affords a value for uncertainty in addition to each calibrated value. This allows the researcher to gain intuition about the model as well as the ability to respect its bounds.

  5. Reconsidering prenatal screening: an empirical-ethical approach to understand moral dilemmas as a question of personal preferences.

    Science.gov (United States)

    García, E; Timmermans, D R M; van Leeuwen, E

    2009-07-01

    In contrast to most Western countries, routine offer of prenatal screening is considered problematic in the Netherlands. The main argument against offering it to every pregnant woman is that women would be brought into a moral dilemma when deciding whether to use screening or not. This paper explores whether the active offer of a prenatal screening test indeed confronts women with a moral dilemma. A qualitative study was developed, based on a randomised controlled trial that aimed to assess the decision-making process of women when confronted with a test offer. A sample of 59 women was interviewed about the different factors balanced in decision-making. Participants felt themselves caught between a need for knowledge and their unwillingness to take on responsibility. Conflict was reported between wishes, preferences and ethical views regarding parenthood; however, women did not seem to be caught in a choice between two or more ethical principles. Participants balanced the interests of the family against that of the fetus in line with their values and their personal circumstances. Therefore, we conclude that they are not so much faced with an ethical dilemma as conflicting interests. We propose that caregivers should provide the opportunity for the woman to discuss her wishes and doubts to facilitate her decision. This approach would help women to assess the meaning of testing within their parental duties towards their unborn child and their current offspring.

  6. The Navier-Stokes equations an elementary functional analytic approach

    CERN Document Server

    Sohr, Hermann

    2001-01-01

    The primary objective of this monograph is to develop an elementary and self­ contained approach to the mathematical theory of a viscous incompressible fluid in a domain 0 of the Euclidean space ]Rn, described by the equations of Navier­ Stokes. The book is mainly directed to students familiar with basic functional analytic tools in Hilbert and Banach spaces. However, for readers' convenience, in the first two chapters we collect without proof some fundamental properties of Sobolev spaces, distributions, operators, etc. Another important objective is to formulate the theory for a completely general domain O. In particular, the theory applies to arbitrary unbounded, non-smooth domains. For this reason, in the nonlinear case, we have to restrict ourselves to space dimensions n = 2,3 that are also most significant from the physical point of view. For mathematical generality, we will develop the lin­ earized theory for all n 2 2. Although the functional-analytic approach developed here is, in principle, known ...

  7. Functional proteomics screen enables enrichment of distinct cell types from human pancreatic islets.

    Directory of Open Access Journals (Sweden)

    Revital Sharivkin

    Full Text Available The current world-wide epidemic of diabetes has prompted attempts to generate new sources of insulin-producing cells for cell replacement therapy. An inherent challenge in many of these strategies is the lack of cell-surface markers permitting isolation and characterization of specific cell types from differentiating stem cell populations. Here we introduce an iterative proteomics procedure allowing tag-free isolation of cell types based on their function. Our method detects and associates specific cell-surface markers with particular cell functionality by coupling cell capture on antibody arrays with immunofluorescent labeling. Using this approach in an iterative manner, we discovered marker combinations capable of enriching for discrete pancreatic cell subtypes from human islets of Langerhans: insulin-producing beta cells (CD9high/CD56+, glucagon-producing alpha cells (CD9-/CD56+ and trypsin-producing acinar cells (CD9-/CD56-. This strategy may assist future beta cell research and the development of diagnostic tools for diabetes. It can also be applied more generally for function-based purification of desired cell types from other limited and heterogeneous biological samples.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Moy Richard L

    2008-07-01

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

  10. A combined approach exploring gene function based on Worm-Human Orthology

    Directory of Open Access Journals (Sweden)

    Johnsen Robert

    2005-05-01

    Full Text Available Abstract Background Many aspects of the nematode Caenorhabditis elegans biology are conserved between invertebrates and vertebrates establishing this particular organism as an excellent genetic model. Because of its small size, large populations and self-fertilization of the hermaphrodite, functional predictions carried out by genetic modifications as well as RNAi screens, can be rapidly tested. Results In order to explore the function of a set of C. elegans genes of unknown function, as well as their potential functional roles in the human genome, we performed a phylogenetic analysis to select the most probable worm orthologs. A total of 13 C. elegans genes were subjected to down- regulation via RNAi and characterization of expression profiles using GFP strains. Previously unknown distinct expression patterns were observed for four of the analyzed genes, as well as four visible RNAi phenotypes. In addition, subcellular protein over-expression profiles of the human orthologs for seven out of the thirteen genes using human cells were also analyzed. Conclusion By combining a whole-organism approach using C. elegans with complementary experimental work done on human cell lines, this analysis extends currently available information on the selected set of genes.

  11. A combined approach exploring gene function based on Worm-Human Orthology

    Science.gov (United States)

    Tamas, Ivica; Hodges, Emily; Dessi, Patrick; Johnsen, Robert; Vaz Gomes, Ana

    2005-01-01

    Background Many aspects of the nematode Caenorhabditis elegans biology are conserved between invertebrates and vertebrates establishing this particular organism as an excellent genetic model. Because of its small size, large populations and self-fertilization of the hermaphrodite, functional predictions carried out by genetic modifications as well as RNAi screens, can be rapidly tested. Results In order to explore the function of a set of C. elegans genes of unknown function, as well as their potential functional roles in the human genome, we performed a phylogenetic analysis to select the most probable worm orthologs. A total of 13 C. elegans genes were subjected to down- regulation via RNAi and characterization of expression profiles using GFP strains. Previously unknown distinct expression patterns were observed for four of the analyzed genes, as well as four visible RNAi phenotypes. In addition, subcellular protein over-expression profiles of the human orthologs for seven out of the thirteen genes using human cells were also analyzed. Conclusion By combining a whole-organism approach using C. elegans with complementary experimental work done on human cell lines, this analysis extends currently available information on the selected set of genes. PMID:15877817

  12. Experimental approach versus COSMO-RS assisted solvent screening for predicting the solubility of rapeseed oil

    Directory of Open Access Journals (Sweden)

    Sicaire Anne-Gaëlle

    2015-07-01

    Full Text Available Vegetable oils take a large part in industry for food and non-food applications. However the extraction process of oil from oilseeds includes a solvent extraction step using hexane. Despite its various advantages it presents numerous drawbacks; it is sourced from petroleum, it has a high flammability and it appears to be dangerous for health and environment (CMR2. This study presents a theoretical screening using COSMO-RS simulations of the relative solubility of vegetable oil constituents regarding several bio-based solvents as well as an experimental screening of the efficiency of these solvents. The aim is to correlate simulations and experiments and give a preliminary evaluation for the substitution of hexane by bio-based solvents for the extraction of vegetable oils. Differences between theory and practice have been noticed for several solvents such as terpenes that appeared to be good candidates in theory and that were in fact the solvents that gave the lowest extraction yield.

  13. A simple and rapid approach for screening of SARS-coronavirus genotypes: an evaluation study

    Directory of Open Access Journals (Sweden)

    Jin Yongjie

    2005-10-01

    Full Text Available Abstract Background The Severe Acute Respiratory Syndrome (SARS was a newly emerged infectious disease which caused a global epidemic in 2002–2003. Sequence analysis of SARS-coronavirus isolates revealed that specific genotypes predominated at different periods of the epidemic. This information can be used as a footprint for tracing the epidemiology of infections and monitor viral evolution. However, direct sequencing analysis of a large number of clinical samples is cumbersome and time consuming. We present here a simple and rapid assay for the screening of SARS-coronavirus genotypes based on the use of fluorogenic oligonucleotide probes for allelic discrimination. Methods Thirty SARS patients were recruited. Allelic discrimination assays were developed based on the use of fluorogenic oligonucleotide probes (TaqMan. Genotyping of the SARS-coronavirus isolates obtained from these patients were carried out by the allelic discrimination assays and confirmed by direct sequencing. Results Genotyping based on the allelic discrimination assays were fully concordant with direct sequencing. All of the 30 SARS-coronavirus genotypes studied were characteristic of genotypes previously documented to be associated with the latter part of the epidemic. Seven of the isolates contained a previously reported major deletion but in patients not epidemiologically related to the previously studied cohort. Conclusion We have developed a simple and accurate method for the characterization and screening of SARS-coronavirus genotypes. It is a promising tool for the study of epidemiological relationships between documented cases during an outbreak.

  14. Phenotypic screening approaches to develop Aurora kinase inhibitors: Drug Discovery perspectives

    Directory of Open Access Journals (Sweden)

    Carlos eMarugán

    2016-01-01

    Full Text Available Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins such as Aurora A and B. Current drugs which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules, have several side effects (neutropenia, alopecia, emesis. Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype.We will briefly describe two multiplexing technologies (high-content imaging, microarrays and flow cytometry and two key processes for drug discovery research (assay development and validation following our own published industry quality standards. We will further focus on high-content imaging as a useful tool for phenotypic screening and will provide a concrete example of high-content imaging assay to detect Aurora A or B selective inhibitors discriminating the off-target effects related to inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

  15. Combining a Ru(II) "Building Block" and Rapid Screening Approach to Identify DNA Structure-Selective "Light Switch" Compounds.

    Science.gov (United States)

    Wachter, Erin; Moyá, Diego; Glazer, Edith C

    2017-02-13

    A chemically reactive Ru(II) "building block", able to undergo condensation reactions with substituted diamines, was utilized to create a small library of luminescent "light switch" dipyrido-[3,2-a:2',3'-c] phenazine (dppz) complexes. The impact of substituent identity, position, and the number of substituents on the light switch effect was investigated. An unbiased, parallel screening approach was used to evaluate the selectivity of the compounds for a variety of different biomolecules, including protein, nucleosides, single stranded DNA, duplex DNA, triplex DNA, and G-quadruplex DNA. Combining these two approaches allowed for the identification of hit molecules that showed different selectivities for biologically relevant DNA structures, particularly triplex and quadruplex DNA.

  16. Adaptive Neuro-Fuzzy Inference System Approach for the Automatic Screening of Diabetic Retinopathy in Fundus Images

    Directory of Open Access Journals (Sweden)

    S. Kavitha

    2011-01-01

    Full Text Available Problem statement: Diabetic retinopathy is one of the most significant factors contributing to blindness and so early diagnosis and timely treatment is particularly important to prevent visual loss. Approach: An integrated approach for extraction of blood vessels and exudates detection was proposed to screen diabetic retinopathy. An automated classifier was developed based on Adaptive Neuro-Fuzzy Inference System (ANFIS to differentiate between normal and nonproliferative eyes from the quantitative assessment of monocular fundus images. Feature extraction was performed on the preprocessed fundus images. Structure of Blood vessels was extracted using Multiscale analysis. Hard Exudates were detected using CIE Color channel transformation, Entropy Thresholding and Improved Connected Component Analysis from the fundus images. Features like Wall to Lumen ratio in blood vessels, Texture, Homogeneity properties and area occupied by Hard Exudates, were given as input to ANFIS.ANFIS was trained with Back propagation in combination with the least squares method. Proposed method was evaluated on 200 real time images comprising 70 normal and 130 retinopathic eyes. Results and Conclusion: All of the results were validated with ground truths obtained from expert ophthalmologists. Quantitative performance of the method, detected exudates with an accuracy of 99.5%. Receiver operating characteristic curve evaluated for real time images produced better results compared to the other state of the art methods. ANFIS provides best classification and can be used as a screening tool in the analysis and diagnosis of retinal images.

  17. Direct and Evolutionary Approaches for Optimal Receiver Function Inversion

    Science.gov (United States)

    Dugda, Mulugeta Tuji

    Receiver functions are time series obtained by deconvolving vertical component seismograms from radial component seismograms. Receiver functions represent the impulse response of the earth structure beneath a seismic station. Generally, receiver functions consist of a number of seismic phases related to discontinuities in the crust and upper mantle. The relative arrival times of these phases are correlated with the locations of discontinuities as well as the media of seismic wave propagation. The Moho (Mohorovicic discontinuity) is a major interface or discontinuity that separates the crust and the mantle. In this research, automatic techniques to determine the depth of the Moho from the earth's surface (the crustal thickness H) and the ratio of crustal seismic P-wave velocity (Vp) to S-wave velocity (Vs) (kappa= Vp/Vs) were developed. In this dissertation, an optimization problem of inverting receiver functions has been developed to determine crustal parameters and the three associated weights using evolutionary and direct optimization techniques. The first technique developed makes use of the evolutionary Genetic Algorithms (GA) optimization technique. The second technique developed combines the direct Generalized Pattern Search (GPS) and evolutionary Fitness Proportionate Niching (FPN) techniques by employing their strengths. In a previous study, Monte Carlo technique has been utilized for determining variable weights in the H-kappa stacking of receiver functions. Compared to that previously introduced variable weights approach, the current GA and GPS-FPN techniques have tremendous advantages of saving time and these new techniques are suitable for automatic and simultaneous determination of crustal parameters and appropriate weights. The GA implementation provides optimal or near optimal weights necessary in stacking receiver functions as well as optimal H and kappa values simultaneously. Generally, the objective function of the H-kappa stacking problem

  18. Measuring functional connectivity in stroke: Approaches and considerations.

    Science.gov (United States)

    Siegel, Joshua S; Shulman, Gordon L; Corbetta, Maurizio

    2017-08-01

    Recent research has demonstrated the importance of global changes to the functional organization of brain network following stroke. Resting functional magnetic resonance imaging (R-fMRI) is a non-invasive tool that enables the measurement of functional connectivity (FC) across the entire brain while placing minimal demands on the subject. For these reasons, it is a uniquely appealing tool for studying the distant effects of stroke. However, R-fMRI studies rely on a number of premises that cannot be assumed without careful validation in the context of stroke. Here, we describe strategies to identify and mitigate confounds specific to R-fMRI research in cerebrovascular disease. Five main topics are discussed: (a) achieving adequate co-registration of lesioned brains, (b) identifying and removing hemodynamic lags in resting BOLD, (c) identifying other vascular disruptions that affect the resting BOLD signal, (d) selecting an appropriate control cohort, and (e) acquiring sufficient fMRI data to reliably identify FC changes. For each topic, we provide guidelines for steps to improve the interpretability and reproducibility of FC-stroke research. We include a table of confounds and approaches to identify and mitigate each. Our recommendations extend to any research using R-fMRI to study diseases that might alter cerebrovascular flow and dynamics or brain anatomy.

  19. Pediatrician's knowledge on the approach of functional constipation

    Directory of Open Access Journals (Sweden)

    Mario C. Vieira

    Full Text Available Abstract Objective: To evaluate the pediatrician's knowledge regarding the diagnostic and therapeutic approach of childhood functional constipation. Methods: A descriptive cross-sectional study was performed with the application of a self-administered questionnaire concerning a hypothetical clinical case of childhood functional constipation with fecal incontinence to physicians (n=297 randomly interviewed at the 36th Brazilian Congress of Pediatrics in 2013. Results: The majority of the participants were females, the mean age was 44.1 years, the mean time of professional practice was 18.8 years; 56.9% were Board Certified by the Brazilian Society of Pediatrics. Additional tests were ordered by 40.4%; including abdominal radiography (19.5%, barium enema (10.4%, laboratory tests (9.8%, abdominal ultrasound (6.7%, colonoscopy (2.4%, manometry and rectal biopsy (both 1.7%. The most common interventions included lactulose (26.6%, mineral oil (17.5%, polyethylene glycol (14.5%, fiber supplement (9.1% and milk of magnesia (5.4%. Nutritional guidance (84.8%, fecal disimpaction (17.2% and toilet training (19.5% were also indicated. Conclusions: Our results show that pediatricians do not adhere to current recommendations for the management of childhood functional constipation, as unnecessary tests were ordered and the first-line treatment was not prescribed.

  20. Pediatrician's knowledge on the approach of functional constipation

    Science.gov (United States)

    Vieira, Mario C.; Negrelle, Isadora Carolina Krueger; Webber, Karla Ulaf; Gosdal, Marjorie; Truppel, Sabine Krüger; Kusma, Solena Ziemer

    2016-01-01

    Abstract Objective: To evaluate the pediatrician's knowledge regarding the diagnostic and therapeutic approach of childhood functional constipation. Methods: A descriptive cross-sectional study was performed with the application of a self-administered questionnaire concerning a hypothetical clinical case of childhood functional constipation with fecal incontinence to physicians (n=297) randomly interviewed at the 36th Brazilian Congress of Pediatrics in 2013. Results: The majority of the participants were females, the mean age was 44.1 years, the mean time of professional practice was 18.8 years; 56.9% were Board Certified by the Brazilian Society of Pediatrics. Additional tests were ordered by 40.4%; including abdominal radiography (19.5%), barium enema (10.4%), laboratory tests (9.8%), abdominal ultrasound (6.7%), colonoscopy (2.4%), manometry and rectal biopsy (both 1.7%). The most common interventions included lactulose (26.6%), mineral oil (17.5%), polyethylene glycol (14.5%), fiber supplement (9.1%) and milk of magnesia (5.4%). Nutritional guidance (84.8%), fecal disimpaction (17.2%) and toilet training (19.5%) were also indicated. Conclusions: Our results show that pediatricians do not adhere to current recommendations for the management of childhood functional constipation, as unnecessary tests were ordered and the first-line treatment was not prescribed. PMID:27449075

  1. Finite frequency Seebeck coefficient of metals: A memory function approach

    Science.gov (United States)

    Bhalla, Pankaj; Kumar, Pradeep; Das, Nabyendu; Singh, Navinder

    2017-10-01

    We study the dynamical thermoelectric transport in metals subjected to the electron-impurity and the electron-phonon interactions using the memory function formalism. We introduce a generalized Drude form for the Seebeck coefficient in terms of thermoelectric memory function and calculate the latter in various temperature and frequency limits. In the zero frequency and high temperature limit, we find that our results are consistent with the experimental findings and with the traditional Boltzmann equation approach. In the low temperature limit, we find that the Seebeck coefficient is quadratic in temperature. In the finite frequency regime, we report new results: In the electron-phonon interaction case, we find that the Seebeck coefficient shows frequency independent behavior both in the high frequency regime (ω ≫ωD , where ωD is the Debye frequency) and in the low frequency regime (ω ≪ωD), whereas in the intermediate frequencies, it is a monotonically increasing function of frequency. In the case of the electron-impurity interaction, first it decays and then after passing through a minimum it increases with the increase in frequency and saturates at high frequencies.

  2. Can testing of six individual muscles represent a screening approach to upper limb neuropathic conditions?

    National Research Council Canada - National Science Library

    Jepsen, Jørgen Riis

    2014-01-01

    ... is reliable and that the outcome reflects symptoms. Since this approach may appear complicated and time consuming, this study deals with the value of an examination limited to manual testing of only six muscles...

  3. Assessment of Arteriovenous Shunt Pathway Function and Hypervolemia for Hemodialysis Patients by Using Integrated Rapid Screening System

    Directory of Open Access Journals (Sweden)

    Wei-Ling Chen

    2017-06-01

    Full Text Available Currently, the hemodialysis patients received body weight measurement by themselves, vital sign checking by nursing staffs before dialysis. Whenever, the arteriovenous routes with problems doubted, the patients needed to be referred to surgeon for vascular echography checking and then to be corrected. How to integrate these three tasks in one time is a very important issue. The project proposes to combine our previous study of audio-phono angiographic technology in detecting vascular stenosis with rapid screening system to evaluate dialysis patients’ arteriovenous routes function and their status of excess body fluids: inspecting and integrating the blood pressure, body weight, and fistula function work into a rapid screening system, and using the quantization of fistula phono angiography pitch to achieve assessing arteriovenous routes. Future hoping is developed a complete integrated intelligence system by combining the arteriovenous fistula signal processing with feature extraction with wireless sensor network technology.

  4. Real-time screening tests for functional alignment of the trunk and lower extremities in adolescent – a systematic review

    DEFF Research Database (Denmark)

    Junge, Tina; Wedderkopp, N; Juul-Kristensen, B

    2012-01-01

    mechanisms resulting in ACL injuries (Hewett, 2010). Prevention may therefore depend on identifying these potentially injury risk factors. Screening tools must thus include patterns of typical movements in sport and leisure time activities, consisting of high-load and multi-directional tests, focusing...... of knee alignment, there is a further need to evaluate reliability and validity of real-time functional alignment tests, before the can be used as screening tools for prevention of knee injuries among adolescents. Still the next step in this systematic review is to evaluate the quality and feasibility......Introduction The presence of neuromuscular imbalance (Hewett, 2010) or functional malalignment may be part of the increased rate of adolescent knee injuries, specifically the anterior cruciate ligament (ACL). Abnormal lateral trunk and knee abduction moment are possibly linked to the biomechanical...

  5. Headspace screening: A novel approach for fast quality assessment of the essential oil from culinary sage.

    Science.gov (United States)

    Cvetkovikj, Ivana; Stefkov, Gjoshe; Acevska, Jelena; Karapandzova, Marija; Dimitrovska, Aneta; Kulevanova, Svetlana

    2016-07-01

    Quality assessment of essential oil (EO) from culinary sage (Salvia officinalis L., Lamiaceae) is limited by the long pharmacopoeial procedure. The aim of this study was to employ headspace (HS) sampling in the quality assessment of sage EO. Different populations (30) of culinary sage were assessed using GC/FID/MS analysis of the hydrodistilled EO (pharmacopoeial method) and HS sampling directly from leaves. Compound profiles from both procedures were evaluated according to ISO 9909 and GDC standards for sage EO quality, revealing compliance for only 10 populations. Factors to convert HS values, for the target ISO and GDC components, into theoretical EO values were calculated. Statistical analysis revealed a significant relationship between HS and EO values for seven target components. Consequently, HS sampling could be used as a complementary extraction technique for rapid screening in quality assessment of sage EOs.

  6. From screen to target: insights and approaches into the development of anti-virulence compounds

    Directory of Open Access Journals (Sweden)

    Katherine SH Beckham

    2014-09-01

    Full Text Available The detailed understanding of host-pathogen interactions provides exciting opportunities to interfere with the infection process. Anti-virulence compounds aim to modulate or pacify pathogenesis by reducing expression of critical virulence determinants. In particular, prevention of attachment by inhibiting adhesion mechanisms has been the subject of intense research. Whilst it has proven relatively straightforward to develop robust screens for potential antivirulence compounds, understanding their precise mode of action has proven much more challenging. In this review we illustrate this challenge from our own experiences working with the salicylidene acylhydrazide group of compounds. We aim to provide a useful perspective to guide researchers interested in this field and to avoid some of the obvious pitfalls.

  7. Drug search for leishmaniasis: a virtual screening approach by grid computing

    Science.gov (United States)

    Ochoa, Rodrigo; Watowich, Stanley J.; Flórez, Andrés; Mesa, Carol V.; Robledo, Sara M.; Muskus, Carlos

    2016-07-01

    The trypanosomatid protozoa Leishmania is endemic in 100 countries, with infections causing 2 million new cases of leishmaniasis annually. Disease symptoms can include severe skin and mucosal ulcers, fever, anemia, splenomegaly, and death. Unfortunately, therapeutics approved to treat leishmaniasis are associated with potentially severe side effects, including death. Furthermore, drug-resistant Leishmania parasites have developed in most endemic countries. To address an urgent need for new, safe and inexpensive anti-leishmanial drugs, we utilized the IBM World Community Grid to complete computer-based drug discovery screens (Drug Search for Leishmaniasis) using unique leishmanial proteins and a database of 600,000 drug-like small molecules. Protein structures from different Leishmania species were selected for molecular dynamics (MD) simulations, and a series of conformational "snapshots" were chosen from each MD trajectory to simulate the protein's flexibility. A Relaxed Complex Scheme methodology was used to screen 2000 MD conformations against the small molecule database, producing >1 billion protein-ligand structures. For each protein target, a binding spectrum was calculated to identify compounds predicted to bind with highest average affinity to all protein conformations. Significantly, four different Leishmania protein targets were predicted to strongly bind small molecules, with the strongest binding interactions predicted to occur for dihydroorotate dehydrogenase (LmDHODH; PDB:3MJY). A number of predicted tight-binding LmDHODH inhibitors were tested in vitro and potent selective inhibitors of Leishmania panamensis were identified. These promising small molecules are suitable for further development using iterative structure-based optimization and in vitro/in vivo validation assays.

  8. A genome-wide immunodetection screen in S. cerevisiae uncovers novel genes involved in lysosomal vacuole function and morphology.

    Directory of Open Access Journals (Sweden)

    Florante Ricarte

    Full Text Available Vacuoles of yeast Saccharomyces cerevisiae are functionally analogous to mammalian lysosomes. Both are cellular organelles responsible for macromolecular degradation, ion/pH homeostasis, and stress survival. We hypothesized that undefined gene functions remain at post-endosomal stage of vacuolar events and performed a genome-wide screen directed at such functions at the late endosome and vacuole interface - ENV genes. The immunodetection screen was designed to identify mutants that internally accumulate precursor form of the vacuolar hydrolase carboxypeptidase Y (CPY. Here, we report the uncovering and initial characterizations of twelve ENV genes. The small size of the collection and the lack of genes previously identified with vacuolar events are suggestive of the intended exclusive functional interface of the screen. Most notably, the collection includes four novel genes ENV7, ENV9, ENV10, and ENV11, and three genes previously linked to mitochondrial processes - MAM3, PCP1, PPE1. In all env mutants, vesicular trafficking stages were undisturbed in live cells as assessed by invertase and active α-factor secretion, as well as by localization of the endocytic fluorescent marker FM4-64 to the vacuole. Several mutants exhibit defects in stress survival functions associated with vacuoles. Confocal fluorescence microscopy revealed the collection to be significantly enriched in vacuolar morphologies suggestive of fusion and fission defects. These include the unique phenotype of lumenal vesicles within vacuoles in the novel env9Δ mutant and severely fragmented vacuoles upon deletion of GET4, a gene recently implicated in tail anchored membrane protein insertion. Thus, our results establish new gene functions in vacuolar function and morphology, and suggest a link between vacuolar and mitochondrial events.

  9. Coupled high-throughput functional screening and next generation sequencing for identification of plant polymer decomposing enzymes in metagenomic libraries.

    Science.gov (United States)

    Nyyssönen, Mari; Tran, Huu M; Karaoz, Ulas; Weihe, Claudia; Hadi, Masood Z; Martiny, Jennifer B H; Martiny, Adam C; Brodie, Eoin L

    2013-01-01

    Recent advances in sequencing technologies generate new predictions and hypotheses about the functional roles of environmental microorganisms. Yet, until we can test these predictions at a scale that matches our ability to generate them, most of them will remain as hypotheses. Function-based mining of metagenomic libraries can provide direct linkages between genes, metabolic traits and microbial taxa and thus bridge this gap between sequence data generation and functional predictions. Here we developed high-throughput screening assays for function-based characterization of activities involved in plant polymer decomposition from environmental metagenomic libraries. The multiplexed assays use fluorogenic and chromogenic substrates, combine automated liquid handling and use a genetically modified expression host to enable simultaneous screening of 12,160 clones for 14 activities in a total of 170,240 reactions. Using this platform we identified 374 (0.26%) cellulose, hemicellulose, chitin, starch, phosphate and protein hydrolyzing clones from fosmid libraries prepared from decomposing leaf litter. Sequencing on the Illumina MiSeq platform, followed by assembly and gene prediction of a subset of 95 fosmid clones, identified a broad range of bacterial phyla, including Actinobacteria, Bacteroidetes, multiple Proteobacteria sub-phyla in addition to some Fungi. Carbohydrate-active enzyme genes from 20 different glycoside hydrolase (GH) families were detected. Using tetranucleotide frequency (TNF) binning of fosmid sequences, multiple enzyme activities from distinct fosmids were linked, demonstrating how biochemically-confirmed functional traits in environmental metagenomes may be attributed to groups of specific organisms. Overall, our results demonstrate how functional screening of metagenomic libraries can be used to connect microbial functionality to community composition and, as a result, complement large-scale metagenomic sequencing efforts.

  10. Coupled high-throughput functional screening and next generation sequencing for identification of plant polymer decomposing enzymes in metagenomic libraries

    Directory of Open Access Journals (Sweden)

    Mari eNyyssönen

    2013-09-01

    Full Text Available Recent advances in sequencing technologies generate new predictions and hypotheses about the functional roles of environmental microorganisms. Yet, until we can test these predictions at a scale that matches our ability to generate them, most of them will remain as hypotheses. Function-based mining of metagenomic libraries can provide direct linkages between genes, metabolic traits and microbial taxa and thus bridge this gap between sequence data generation and functional predictions. Here we developed high-throughput screening assays for function-based characterization of activities involved in plant polymer decomposition from environmental metagenomic libraries. The multiplexed assays use fluorogenic and chromogenic substrates, combine automated liquid handling and use a genetically modified expression host to enable simultaneous screening of 12,160 clones for 14 activities in a total of 170,240 reactions. Using this platform we identified 374 (0.26 % cellulose, hemicellulose, chitin, starch, phosphate and protein hydrolyzing clones from fosmid libraries prepared from decomposing leaf litter. Sequencing on the Illumina MiSeq platform, followed by assembly and gene prediction of a subset of 95 fosmid clones, identified a broad range of bacterial phyla, including Actinobacteria, Bacteroidetes, multiple Proteobacteria sub-phyla in addition to some Fungi. Carbohydrate-active enzyme genes from 20 different glycoside hydrolase families were detected. Using tetranucleotide frequency binning of fosmid sequences, multiple enzyme activities from distinct fosmids were linked, demonstrating how biochemically-confirmed functional traits in environmental metagenomes may be attributed to groups of specific organisms. Overall, our results demonstrate how functional screening of metagenomic libraries can be used to connect microbial functionality to community composition and, as a result, complement large-scale metagenomic sequencing efforts.

  11. A Sleeping Beauty DNA transposon-based genetic sensor for functional screening of vitamin D3 analogues

    DEFF Research Database (Denmark)

    Staunstrup, Nicklas Heine; Sharma, Nynne; Bak, Rasmus Otkjær;

    2011-01-01

    Analogues of vitamin D3 are extensively used in the treatment of various illnesses, such as osteoporosis, inflammatory skin diseases, and cancer. Functional testing of new vitamin D3 analogues and formulations for improved systemic and topical administration is supported by sensitive screening me...... analogues. The tri-cistronic genetic sensor encodes a drug-sensoring protein, a reporter protein expressed from an activated sensor-responsive promoter, and a resistance marker....

  12. Multi-Functional Micro Projection Device as Screen Substitute for Low Power Consumption Computing

    Directory of Open Access Journals (Sweden)

    Zeev Zalevsky

    2012-03-01

    Full Text Available One of the major power consuming components in a computer is its display unit. On average the screen consumes ten times more power than the DSP processor itself. Thus, reducing the power consumption should be one of the most important tasks in the development of low power consumption computing systems. In this paper we present one possible solution involving micro projection device based upon lasers and a digital light processing (DLP matrix which is a matrix of electrically controllable mirrors capable of translating electrical signal to a time varying projected image. It can serve to substitute a screen and consume ten times less power than a conventional screen. The described device is a multifunctional highly efficient customized DLP light engine being capable of serving as an image projector and simultaneously to support range and topography estimation measurements.

  13. Optical Approach for the Thermal Partition Function of Photons

    CERN Document Server

    Moretti, V; Moretti, Valter; Iellici, Devis

    1997-01-01

    The optical manifold method to compute the one-loop effective action in a static space-time is extended from the massless scalar field to the Maxwell field in any Feynman-like covariant gauge. The method applied in the case of the Rindler space obtaining the same results as the point-splitting procedure. The result is free from Kabat's surface terms which instead affect the manifold containing conical singularities. The relation between the optical method and the direct $\\zeta$-function approach on the Euclidean Rindler manifold is discussed both in the scalar and the photon case. Problems with the thermodynamic consistency of the results obtained from the point-splitting thermal stress tensor in the case of the Rindler space are pointed out.

  14. PROCESS OF IDENTIFYING COMPETENCIES BASED ON A FUNCTIONAL APPROACH

    Directory of Open Access Journals (Sweden)

    NAOUFAL SEFIANI

    2012-01-01

    Full Text Available To cope with fast change of the technological and organizational context, managers need tools to help them to improve competence management. Our contribution aims at supporting the task of competence identification that is considered as the first step of the management process. The proposed identification involves tree stages.The first stage concerns the research of competences based on a functional approach. The second stage is to define a typology of the component of competence (characterization and the third stage to define the core competencies of competence (prioritization. The application of the method in an industrial case in the logisticsfield confirms the possibility of using the “principle of solution” to provide a dynamic process for the identification of requisite competencies.

  15. CLARM: An integrative approach for functional modules discovery

    KAUST Repository

    Salem, Saeed M.

    2011-01-01

    Functional module discovery aims to find well-connected subnetworks which can serve as candidate protein complexes. Advances in High-throughput proteomic technologies have enabled the collection of large amount of interaction data as well as gene expression data. We propose, CLARM, a clustering algorithm that integrates gene expression profiles and protein protein interaction network for biological modules discovery. The main premise is that by enriching the interaction network by adding interactions between genes which are highly co-expressed over a wide range of biological and environmental conditions, we can improve the quality of the discovered modules. Protein protein interactions, known protein complexes, and gene expression profiles for diverse environmental conditions from the yeast Saccharomyces cerevisiae were used for evaluate the biological significance of the reported modules. Our experiments show that the CLARM approach is competitive to wellestablished module discovery methods. Copyright © 2011 ACM.

  16. Equation of State in a Generalized Relativistic Density Functional Approach

    CERN Document Server

    Typel, Stefan

    2015-01-01

    The basic concepts of a generalized relativistic density functional approach to the equation of state of dense matter are presented. The model is an extension of relativistic mean-field models with density-dependent couplings. It includes explicit cluster degrees of freedom. The formation and dissolution of nuclei is described with the help of mass shifts. The model can be adapted to the description of finite nuclei in order to study the effect of $\\alpha$-particle correlations at the nuclear surface on the neutron skin thickness of heavy nuclei. Further extensions of the model to include quark degrees of freedom or an energy dependence of the nucleon self-energies are outlined.

  17. Robotic approaches for rehabilitation of hand function after stroke.

    Science.gov (United States)

    Lum, Peter S; Godfrey, Sasha B; Brokaw, Elizabeth B; Holley, Rahsaan J; Nichols, Diane

    2012-11-01

    The goal of this review was to discuss the impairments in hand function after stroke and present previous work on robot-assisted approaches to movement neurorehabilitation. Robotic devices offer a unique training environment that may enhance outcomes beyond what is possible with conventional means. Robots apply forces to the hand, allowing completion of movements while preventing inappropriate movement patterns. Evidence from the literature is emerging that certain characteristics of the human-robot interaction are preferable. In light of this evidence, the robotic hand devices that have undergone clinical testing are reviewed, highlighting the authors' work in this area. Finally, suggestions for future work are offered. The ability to deliver therapy doses far higher than what has been previously tested is a potentially key advantage of robotic devices that needs further exploration. In particular, more efforts are needed to develop highly motivating home-based devices, which can increase access to high doses of assisted movement therapy.

  18. A Goal-Function Approach to Analysis of Control Situations

    DEFF Research Database (Denmark)

    Lind, Morten

    2010-01-01

    The concept of situations plays a central role in all theories of meaning and context. and serve to frame or group events and other occurrences into coherent meaningful wholes. Situations are typed, may be interconnected and organized into higher level structures. In operation of industrial...... processes situations should identify operational aspects relevant for control agent’s decision making in plant supervision and control. Control situations can be understood as recurrent and interconnected patterns of control with important implications for control and HMI design. Goal-Function approaches...... to systems modeling like Multilevel Flow Modeling can be used to represent control situations. The paper will describe an action theoretical foundation for MFM and its use for the development of a theory of control situations....

  19. Executive function and food approach behavior in middle childhood.

    Science.gov (United States)

    Groppe, Karoline; Elsner, Birgit

    2014-01-01

    Executive function (EF) has long been considered to be a unitary, domain-general cognitive ability. However, recent research suggests differentiating "hot" affective and "cool" cognitive aspects of EF. Yet, findings regarding this two-factor construct are still inconsistent. In particular, the development of this factor structure remains unclear and data on school-aged children is lacking. Furthermore, studies linking EF and overweight or obesity suggest that EF contributes to the regulation of eating behavior. So far, however, the links between EF and eating behavior have rarely been investigated in children and non-clinical populations. First, we examined whether EF can be divided into hot and cool factors or whether they actually correspond to a unitary construct in middle childhood. Second, we examined how hot and cool EF are associated with different eating styles that put children at risk of becoming overweight during development. Hot and cool EF were assessed experimentally in a non-clinical population of 1657 elementary-school children (aged 6-11 years). The "food approach" behavior was rated mainly via parent questionnaires. Findings indicate that hot EF is distinguishable from cool EF. However, only cool EF seems to represent a coherent functional entity, whereas hot EF does not seem to be a homogenous construct. This was true for a younger and an older subgroup of children. Furthermore, different EF components were correlated with eating styles, such as responsiveness to food, desire to drink, and restrained eating in girls but not in boys. This shows that lower levels of EF are not only seen in clinical populations of obese patients but are already associated with food approach styles in a normal population of elementary school-aged girls. Although the direction of effect still has to be clarified, results point to the possibility that EF constitutes a risk factor for eating styles contributing to the development of overweight in the long-term.

  20. A transfer function approach to measuring cell inheritance

    Directory of Open Access Journals (Sweden)

    Errington Rachel J

    2011-02-01

    Full Text Available Abstract Background The inheritance of cellular material between parent and daughter cells during mitosis is highly influential in defining the properties of the cell and therefore the population lineage. This is of particular relevance when studying cell population evolution to assess the impact of a disease or the perturbation due to a drug treatment. The usual technique to investigate inheritance is to use time-lapse microscopy with an appropriate biological marker, however, this is time consuming and the number of inheritance events captured are too low to be statistically meaningful. Results Here we demonstrate the use of a high throughput fluorescence measurement technique e.g. flow cytometry, to measure the fluorescence from quantum dot markers which can be used to target particular cellular sites. By relating, the fluorescence intensity measured between two time intervals to a transfer function we are able to deconvolve the inheritance of cellular material during mitosis. To demonstrate our methodology we use CdTe/ZnS quantum dots to measure the ratio of endosomes inherited by the two daughter cells during mitosis in the U2-OS, human osteoscarcoma cell line. The ratio determined is in excellent agreement with results obtained previously using a more complex and computational intensive bespoke stochastic model. Conclusions The use of a transfer function approach allows us to utilise high throughput measurement of large cell populations to derive statistically relevant measurements of the inheritance of cellular material. This approach can be used to measure the inheritance of organelles, proteins etc. and also particles introduced to cells for drug delivery.

  1. High-Throughput Behavioral Screens: the First Step towards Finding Genes Involved in Vertebrate Brain Function Using Zebrafish

    Directory of Open Access Journals (Sweden)

    Robert Gerlai

    2010-04-01

    Full Text Available The zebrafish has been in the forefront of developmental biology for three decades and has become a favorite of geneticists. Due to the accumulated genetic knowledge and tools developed for the zebrafish it is gaining popularity in other disciplines, including neuroscience. The zebrafish offers a compromise between system complexity (it is a vertebrate similar in many ways to our own species and practical simplicity (it is small, easy to keep, and prolific. Such features make zebrafish an excellent choice for high throughput mutation and drug screening. For the identification of mutation or drug induced alteration of brain function arguably the best methods are behavioral test paradigms. This review does not present experimental examples for the identification of particular genes or drugs. Instead it describes how behavioral screening methods may enable one to find functional alterations in the vertebrate brain. Furthermore, the review is not comprehensive. The behavioral test examples presented are biased according to the personal interests of the author. They will cover research areas including learning and memory, fear and anxiety, and social behavior. Nevertheless, the general principles will apply to other functional domains and should represent a snapshot of the rapidly evolving behavioral screening field with zebrafish.

  2. Distribution function approach to irreversible adsorption of interacting colloidal particles

    Science.gov (United States)

    Faraudo, Jordi; Bafaluy, Javier

    2000-01-01

    A statistical-mechanical description of the irreversible adsorption of interacting colloidal particles is developed. Our approach describes in a consistent way the interaction of particles from the bulk with adsorbed particles during the transport process towards the adsorbing surface. The macroscopic physical quantities corresponding to the actual process are expressed as averages over simpler auxiliary processes which proceed in the presence of a fixed number n of adsorbed particles. The adsorption rate verifies a generalized Langmuir equation, in which the kinetic resistance (the inverse of the kinetic coefficient) is expressed as the sum of a diffusional resistance and a resistance due to interaction with adsorbed particles during the transport process (blocking effect). Contrary to previous approaches, the blocking effect is not due to geometrical exclusion, instead it measures how the transport from the bulk is affected by the adsorbed particles. From the general expressions obtained, we have derived coverage expansions for the adsorption rate and the surface correlation function. The theory is applied to the case of colloidal particles interacting through DLVO potentials. This form of the kinetic coefficient is shown to be in agreement with recent experimental results, in which RSA fails.

  3. New scoring functions for virtual screening from molecular dynamics simulations with a quantum-refined force-field (QRFF-MD). Application to cyclin-dependent kinase 2.

    Science.gov (United States)

    Ferrara, Ph; Curioni, A; Vangrevelinghe, E; Meyer, T; Mordasini, T; Andreoni, W; Acklin, P; Jacoby, E

    2006-01-01

    A recently introduced new methodology based on ultrashort (50-100 ps) molecular dynamics simulations with a quantum-refined force-field (QRFF-MD) is here evaluated in its ability both to predict protein-ligand binding affinities and to discriminate active compounds from inactive ones. Physically based scoring functions are derived from this approach, and their performance is compared to that of several standard knowledge-based scoring functions. About 40 inhibitors of cyclin-dependent kinase 2 (CDK2) representing a broad chemical diversity were considered. The QRFF-MD method achieves a correlation coefficient, R(2), of 0.55, which is significantly better than that obtained by a number of traditional approaches in virtual screening but only slightly better than that obtained by consensus scoring (R(2) = 0.50). Compounds from the Available Chemical Directory, along with the known active compounds, were docked into the ATP binding site of CDK2 using the program Glide, and the 650 ligands from the top scored poses were considered for a QRFF-MD analysis. Combined with structural information extracted from the simulations, the QRFF-MD methodology results in similar enrichment of known actives compared to consensus scoring. Moreover, a new scoring function is introduced that combines a QRFF-MD based scoring function with consensus scoring, which results in substantial improvement on the enrichment profile.

  4. A bio-inspired approach for the design of a multifunctional robotic end-effector customized for automated maintenance of a reconfigurable vibrating screen.

    Science.gov (United States)

    Makinde, O A; Mpofu, K; Vrabic, R; Ramatsetse, B I

    2017-01-01

    The development of a robotic-driven maintenance solution capable of automatically maintaining reconfigurable vibrating screen (RVS) machine when utilized in dangerous and hazardous underground mining environment has called for the design of a multifunctional robotic end-effector capable of carrying out all the maintenance tasks on the RVS machine. In view of this, the paper presents a bio-inspired approach which unfolds the design of a novel multifunctional robotic end-effector embedded with mechanical and control mechanisms capable of automatically maintaining the RVS machine. To achieve this, therblig and morphological methodologies (which classifies the motions as well as the actions required by the robotic end-effector in carrying out RVS machine maintenance tasks), obtained from a detailed analogy of how human being (i.e. a machine maintenance manager) will carry out different maintenance tasks on the RVS machine, were used to obtain the maintenance objective functions or goals of the multifunctional robotic end-effector as well as the maintenance activity constraints of the RVS machine that must be adhered to by the multifunctional robotic end-effector during the machine maintenance. The results of the therblig and morphological analyses of five (5) different maintenance tasks capture and classify one hundred and thirty-four (134) repetitive motions and fifty-four (54) functions required in automating the maintenance tasks of the RVS machine. Based on these findings, a worm-gear mechanism embedded with fingers extruded with a hexagonal shaped heads capable of carrying out the "gripping and ungrasping" and "loosening and bolting" functions of the robotic end-effector and an electric cylinder actuator module capable of carrying out "unpinning and hammering" functions of the robotic end-effector were integrated together to produce the customized multifunctional robotic end-effector capable of automatically maintaining the RVS machine. The axial forces ([Formula

  5. A Screening-Level Approach for Comparing Risks Affecting Aquatic Ecosystem Services over Socio-Environmental Gradients

    Science.gov (United States)

    Harmon, T. C.; Conde, D.; Villamizar, S. R.; Reid, B.; Escobar, J.; Rusak, J.; Hoyos, N.; Scordo, F.; Perillo, G. M.; Piccolo, M. C.; Zilio, M.; Velez, M.

    2015-12-01

    Assessing risks to aquatic ecosystems services (ES) is challenging and time-consuming, and effective strategies for prioritizing more detailed assessment efforts are needed. We propose a screening-level risk analysis (SRA) approach that scales ES risk using socioeconomic and environmental indices to capture anthropic and climatic pressures, as well as the capacity for institutional responses to those pressures. The method considers ES within a watershed context, and uses expert input to prioritize key services and the associated pressures that threaten them. The SRA approach focuses on estimating ES risk affect factors, which are the sum of the intensity factors for all hazards or pressures affecting the ES. We estimate the pressure intensity factors in a novel manner, basing them on the nation's (i) human development (proxied by Inequality-adjusted Human Development Index, IHDI), (ii) environmental regulatory and monitoring state (Environmental Performance Index, EPI) and (iii) the current level of water stress in the watershed (baseline water stress, BWS). Anthropic intensity factors for future conditions are derived from the baseline values based on the nation's 10-year trend in IHDI and EPI; ES risks in nations with stronger records of change are rewarded more/penalized less in estimates for good/poor future management scenarios. Future climatic intensity factors are tied to water stress estimates based on two general circulation model (GCM) outcomes. We demonstrate the method for an international array of six sites representing a wide range of socio-environmental settings. The outcomes illustrate novel consequences of the scaling scheme. Risk affect factors may be greater in a highly developed region under intense climatic pressure, or in less well-developed regions due to human factors (e.g., poor environmental records). As a screening-level tool, the SRA approach offers considerable promise for ES risk comparisons among watersheds and regions so that

  6. A Model-Based Approach to Constructing Music Similarity Functions

    Directory of Open Access Journals (Sweden)

    Lamere Paul

    2007-01-01

    Full Text Available Several authors have presented systems that estimate the audio similarity of two pieces of music through the calculation of a distance metric, such as the Euclidean distance, between spectral features calculated from the audio, related to the timbre or pitch of the signal. These features can be augmented with other, temporally or rhythmically based features such as zero-crossing rates, beat histograms, or fluctuation patterns to form a more well-rounded music similarity function. It is our contention that perceptual or cultural labels, such as the genre, style, or emotion of the music, are also very important features in the perception of music. These labels help to define complex regions of similarity within the available feature spaces. We demonstrate a machine-learning-based approach to the construction of a similarity metric, which uses this contextual information to project the calculated features into an intermediate space where a music similarity function that incorporates some of the cultural information may be calculated.

  7. Altering Cardiac Function via Transgenesis A Nuts and Bolts Approach.

    Science.gov (United States)

    Robbins, J

    1997-08-01

    Transgenesis provides a means to modify the mammalian genome. By directing expression of a engineered protein to the heart, one now is able to remodel effectively the cardiac protein profile and study the consequences of a single genetic manipulation at the molecular, biochemical, cytological, and physiologic levels. Often, a particular pathology or even a global remodeling process such as hypertrophy is accompanied by the upregulation or downregulation of a gene or set(s) of genes. What is not known is whether these changes represent a beneficial compensatory response or contribute to the continued degeneration of normal heart function. The ability to perform genetic manipulations on cardiac gene expression via transgenesis offers one a rapid and effective means of extending the correlations noted to the mechanistic level. Now, one can, in theory, express a candidate protein at a particular developmental time and determine the direct consequences of its appearance. Similarly, one can explore structure-function relationships, both between different forms of a protein family and in terms of active domains within a protein, by expressing a transgene that encodes a suitable mutation or ectopic protein isoform. This review explores the practical considerations of the transgenic approach in terms of what is important for a successful experiment from the necessary animal husbandry to designing constructs that will express at appropriate levels in the heart. (Trends Cardiovasc Med 1997;7:185-191). © 1997, Elsevier Science Inc.

  8. Molecular Approaches to Functionalization of Dental Implant Surfaces

    Directory of Open Access Journals (Sweden)

    Angelina O. Zekiy

    2015-12-01

    Full Text Available The present review examines several approaches to improve properties of dental implants by modifying their bioactive surfaces (functionalization using the techniques of molecular transplantation. The first group of functional ligands is designed to enhance osseointegration of implants, it includes growth factors, promoting the formation and bone remodeling: bone morphogenetic proteins (BMPs, platelet-derived growth factor (PDGF, fibroblast growth factor (FGF and their combinations with each other, and several other ones. The second group of bioactive molecules does not directly stimulate bone formation, but it promotes osteoblast seeding on the implant surface due to the adhesive properties, thus accelerating osseointegration. Finally, the third group of substances used to increase the antibacterial properties of coatings, thereby reducing the formation of bacterial film on the implant surface and the risk of inflammatory rejection of the implant. Key issues of using biofunctional coatings, despite their obvious promise today still are relatively high cost, difficulties of controlling properties and its storage between the fabrication and installation of implants in the bone of the recipient.

  9. ABOUT COMPLEX APPROACH TO MODELLING OF TECHNOLOGICAL MACHINES FUNCTIONING

    Directory of Open Access Journals (Sweden)

    A. A. Honcharov

    2015-01-01

    Full Text Available Problems arise in the process of designing, production and investigation of a complicated technological machine. These problems concern not only properties of some types of equipment but they have respect to regularities of control object functioning as a whole. A technological machine is thought of as such technological complex where it is possible to lay emphasis on a control system (or controlling device and a controlled object. The paper analyzes a number of existing approaches to construction of models for controlling devices and their functioning. A complex model for a technological machine operation has been proposed in the paper; in other words it means functioning of a controlling device and a controlled object of the technological machine. In this case models of the controlling device and the controlled object of the technological machine can be represented as aggregate combination (elements of these models. The paper describes a conception on realization of a complex model for a technological machine as a model for interaction of units (elements in the controlling device and the controlled object. When a control activation is given to the controlling device of the technological machine its modelling is executed at an algorithmic or logic level and the obtained output signals are interpreted as events and information about them is transferred to executive mechanisms.The proposed scheme of aggregate integration considers element models as object classes and the integration scheme is presented as a combination of object property values (combination of a great many input and output contacts and combination of object interactions (in the form of an integration operator. Spawn of parent object descendants of the technological machine model and creation of their copies in various project parts is one of the most important means of the distributed technological machine modelling that makes it possible to develop complicated models of

  10. [Consequences of the daily rhythm of organ functions and of metabolic processes for screening].

    Science.gov (United States)

    Stolze, G; Schäfer, C; Müller, K; Schmidt, L; Lestin, H

    1975-08-01

    The effects of the influencing factors such as age, sex, exposition to pharmaca, physical activity, alimentary load and endogenic daily rhythm on sensitivity and specifity of the parameters of screening are briefly described. It is reported on the results of examinations of one of these influencing factors and on the endogenic daily rhythm with the help of selected instances.

  11. A mutagenesis screen in the mouse: Identification of novel gene functions in embryonic development

    NARCIS (Netherlands)

    Wansleeben, C.

    2010-01-01

    Developmental genetics has been a field of interest for over a hundred years. We have set out to perform an ENU mutagenesis screen in the mouse at E10.5. In the first chapter the pathways and developmental processes described in this thesis are introduced. In the second chapter we describe the ENU-m

  12. 49 CFR 1546.407 - Training, testing, and knowledge of individuals who perform screening functions.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Training, testing, and knowledge of individuals... Carrier Conducts Screening § 1546.407 Training, testing, and knowledge of individuals who perform... test prescribed by TSA. (f) Knowledge requirements. Each foreign air carrier must ensure...

  13. 49 CFR 1544.407 - Training, testing, and knowledge of individuals who perform screening functions.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Training, testing, and knowledge of individuals... Qualifications When the Aircraft Operator Performs Screening § 1544.407 Training, testing, and knowledge of... on-the-job training test prescribed by TSA. (f) Knowledge requirements. Each aircraft operator...

  14. A functional genomics screen identifies an Importin-α homolog as a regulator of stem cell function and tissue patterning during planarian regeneration

    OpenAIRE

    2015-01-01

    Background Planarians are renowned for their regenerative capacity and are an attractive model for the study of adult stem cells and tissue regeneration. In an effort to better understand the molecular mechanisms underlying planarian regeneration, we performed a functional genomics screen aimed at identifying genes involved in this process in Schmidtea mediterranea. Methods We used microarrays to detect changes in gene expression in regenerating and non-regenerating tissues in planarians rege...

  15. A novel decision tree approach based on transcranial Doppler sonography to screen for blunt cervical vascular injuries.

    Science.gov (United States)

    Purvis, Dianna; Aldaghlas, Tayseer; Trickey, Amber W; Rizzo, Anne; Sikdar, Siddhartha

    2013-06-01

    Early detection and treatment of blunt cervical vascular injuries prevent adverse neurologic sequelae. Current screening criteria can miss up to 22% of these injuries. The study objective was to investigate bedside transcranial Doppler sonography for detecting blunt cervical vascular injuries in trauma patients using a novel decision tree approach. This prospective pilot study was conducted at a level I trauma center. Patients undergoing computed tomographic angiography for suspected blunt cervical vascular injuries were studied with transcranial Doppler sonography. Extracranial and intracranial vasculatures were examined with a portable power M-mode transcranial Doppler unit. The middle cerebral artery mean flow velocity, pulsatility index, and their asymmetries were used to quantify flow patterns and develop an injury decision tree screening protocol. Student t tests validated associations between injuries and transcranial Doppler predictive measures. We evaluated 27 trauma patients with 13 injuries. Single vertebral artery injuries were most common (38.5%), followed by single internal carotid artery injuries (30%). Compared to patients without injuries, mean flow velocity asymmetry was higher for single internal carotid artery (P = .003) and single vertebral artery (P = .004) injuries. Similarly, pulsatility index asymmetry was higher in single internal carotid artery (P = .015) and single vertebral artery (P = .042) injuries, whereas the lowest pulsatility index was elevated for bilateral vertebral artery injuries (P = .006). The decision tree yielded 92% specificity, 93% sensitivity, and 93% correct classifications. In this pilot feasibility study, transcranial Doppler measures were significantly associated with the blunt cervical vascular injury status, suggesting that transcranial Doppler sonography might be a viable bedside screening tool for trauma. Patient-specific hemodynamic information from transcranial Doppler assessment has the potential to alter

  16. A multi-assay screening approach for assessment of endocrine-active contaminants in wastewater effluent samples

    Energy Technology Data Exchange (ETDEWEB)

    Metcalfe, Chris D., E-mail: cmetcalfe@trentu.ca [Environmental and Resource Studies, Trent University, Peterborough, ON, K9J 7B8 (Canada); Kleywegt, Sonya [Standards Development Branch, Ontario Ministry of the Environment, 40 St. Clair Ave. West, Toronto, ON, M4V 1M2 (Canada); Letcher, Robert J. [Ecotoxicology and Wildlife Health Division, Science and Technology Branch, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, ON, K1A 0H3 (Canada); Topp, Edward [Agriculture and Agri-Food Canada, Southern Crop Protection and Food Research Centre, London, ON, N5V 7T3 (Canada); Wagh, Purva; Trudeau, Vance L.; Moon, Thomas W. [Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, ON, K1N 6N5 (Canada)

    2013-06-01

    Environmental agencies must monitor an ever increasing range of contaminants of emerging concern, including endocrine disrupting compounds (EDCs). An alternative to using ultra-trace chemical analysis of samples for EDCs is to test for biological activity using in vitro screening assays, then use these assay results to direct analytical chemistry approaches. In this study, we used both analytical approaches and in vitro bioassays to characterize the EDCs present in treated wastewater from four wastewater treatment plants (WWTPs) in Ontario, Canada. Estrogen-mediated activity was assessed using a yeast estrogenicity screening (YES) assay. An in vitro competitive binding assay was used to assess capacity to interfere with binding of the thyroid hormone, thyroxine (T4) to the recombinant human thyroid hormone transport protein, transthyretin (i.e. hTTR). An in vitro binding assay with a rat peroxisome proliferator responsive element transfected into a rainbow trout gill cell line was used to evaluate binding and subsequent gene expression via the peroxisome proliferator activated receptor (PPAR). Analyses of a suite of contaminants known to be EDCs in extracts from treated wastewater were conducted using either gas chromatography with mass spectrometry (GC-MS) or liquid chromatography with tandem mass spectrometry (LC-MS/MS). Estrogenic activity was detected in the YES assay only in those extracts that contained detectable amounts of estradiol (E2). There was a positive relationship between the degree of response in the T4-hTTR assay and the amounts of polybrominated diphenyl ether (PBDE) congeners 47 and 99, triclosan and the PBDE metabolite, 4-OH-BDE17. Several wastewater extracts gave a positive response in the PPAR assay, but these responses were not correlated with the amounts of any of the EDCs analyzed by LC-MS/MS. Overall, these data indicate that a step-wise approach is feasible using a combination of in vitro testing and instrumental analysis to monitor for

  17. Delivering an Automated and Integrated Approach to Combination Screening Using Acoustic-Droplet Technology.

    Science.gov (United States)

    Cross, Kevin; Craggs, Richard; Swift, Denise; Sitaram, Anesh; Daya, Sandeep; Roberts, Mark; Hawley, Shaun; Owen, Paul; Isherwood, Bev

    2016-02-01

    Drug combination testing in the pharmaceutical industry has typically been driven by late-stage opportunistic strategies rather than by early testing to identify drug combinations for clinical investigation that may deliver improved efficacy. A rationale for combinations exists across a number of diseases in which pathway redundancy or resistance to therapeutics are evident. However, early assays are complicated by the absence of both assay formats representative of disease biology and robust infrastructure to screen drug combinations in a medium-throughput capacity. When applying drug combination testing studies, it may be difficult to translate a study design into the required well contents for assay plates because of the number of compounds and concentrations involved. Dispensing these plates increases in difficulty as the number of compounds and concentration points increase and compounds are subsequently rolled onto additional labware. We describe the development of a software tool, in conjunction with the use of acoustic droplet technology, as part of a compound management platform, which allows the design of an assay incorporating combinations of compounds. These enhancements to infrastructure facilitate the design and ordering of assay-ready compound combination plates and the processing of combinations data from high-content organotypic assays.

  18. A phenotypic screening approach to identify anticancer compounds derived from marine fungi.

    Science.gov (United States)

    Ellinger, Bernhard; Silber, Johanna; Prashar, Anjali; Landskron, Johannes; Weber, Jonas; Rehermann, Sarah; Müller, Franz-Josef; Smith, Stephen; Wrigley, Stephen; Taskén, Kjetil; Gribbon, Philip; Labes, Antje; Imhoff, Johannes F

    2014-04-01

    This study covers the isolation, testing, and identification of natural products with anticancer properties. Secondary metabolites were isolated from fungal strains originating from a variety of marine habitats. Strain culture protocols were optimized with respect to growth media composition and fermentation conditions. From these producers, isolated compounds were screened for their effect on the viability and proliferation of a subset of the NCI60 panel of cancer cell lines. Active compounds of interest were identified and selected for detailed assessments and structural elucidation using nuclear magnetic resonance. This revealed the majority of fungal-derived compounds represented known anticancer chemotypes, confirming the integrity of the process and the ability to identify suitable compounds. Examination of effects of selected compounds on cancer-associated cell signaling pathways used phospho flow cytometry in combination with 3D fluorescent cell barcoding. In parallel, the study addressed the logistical aspects of maintaining multiple cancer cell lines in culture simultaneously. A potential solution involving microbead-based cell culture was investigated (BioLevitator, Hamilton). Selected cell lines were cultured in microbead and 2D methods and cell viability tests showed comparable compound inhibition in both methods (R2=0.95). In a further technology assessment, an image-based assay system was investigated for its utility as a possible complement to ATP-based detection for quantifying cell growth and viability in a label-free manner.

  19. Accelerometry-based gait analysis, an additional objective approach to screen subjects at risk for falling.

    Science.gov (United States)

    Senden, R; Savelberg, H H C M; Grimm, B; Heyligers, I C; Meijer, K

    2012-06-01

    This study investigated whether the Tinetti scale, as a subjective measure for fall risk, is associated with objectively measured gait characteristics. It is studied whether gait parameters are different for groups that are stratified for fall risk using the Tinetti scale. Moreover, the discriminative power of gait parameters to classify elderly according to the Tinetti scale is investigated. Gait of 50 elderly with a Tinneti>24 and 50 elderly with a Tinetti≤24 was analyzed using acceleration-based gait analysis. Validated algorithms were used to derive spatio-temporal gait parameters, harmonic ratio, inter-stride amplitude variability and root mean square (RMS) from the accelerometer data. Clear differences in gait were found between the groups. All gait parameters correlated with the Tinetti scale (r-range: 0.20-0.73). Only walking speed, step length and RMS showed moderate to strong correlations and high discriminative power to classify elderly according to the Tinetti scale. It is concluded that subtle gait changes that have previously been related to fall risk are not captured by the subjective assessment. It is therefore worthwhile to include objective gait assessment in fall risk screening.

  20. Identification of Important Chemical Features of 11β-Hydroxysteroid Dehydrogenase Type1 Inhibitors: Application of Ligand Based Virtual Screening and Density Functional Theory

    Directory of Open Access Journals (Sweden)

    Keun Woo Lee

    2012-04-01

    Full Text Available 11ß-Hydroxysteroid dehydrogenase type1 (11ßHSD1 regulates the conversion from inactive cortisone to active cortisol. Increased cortisol results in diabetes, hence quelling the activity of 11ßHSD1 has been thought of as an effective approach for the treatment of diabetes. Quantitative hypotheses were developed and validated to identify the critical chemical features with reliable geometric constraints that contribute to the inhibition of 11ßHSD1 function. The best hypothesis, Hypo1, which contains one-HBA; one-Hy-Ali, and two-RA features, was validated using Fischer’s randomization method, a test and a decoy set. The well validated, Hypo1, was used as 3D query to perform a virtual screening of three different chemical databases. Compounds selected by Hypo1 in the virtual screening were filtered by applying Lipinski’s rule of five, ADMET, and molecular docking. Finally, five hit compounds were selected as virtual novel hit molecules for 11ßHSD1 based on their electronic properties calculated by Density functional theory.

  1. Functionalized graphene quantum dots loaded with free radicals combined with liquid chromatography and tandem mass spectrometry to screen radical scavenging natural antioxidants from Licorice and Scutellariae.

    Science.gov (United States)

    Wang, Guoying; Niu, XiuLi; Shi, Gaofeng; Chen, Xuefu; Yao, Ruixing; Chen, Fuwen

    2014-12-01

    A novel screening method was developed for the detection and identification of radical scavenging natural antioxidants based on a free radical reaction combined with liquid chromatography with tandem mass spectrometry. Functionalized graphene quantum dots were prepared for loading free radicals in the complex screening system. The detection was performed with and without a preliminary exposure of the samples to specific free radicals on the functionalized graphene quantum dots, which can facilitate charge transfer between free radicals and antioxidants. The difference in chromatographic peak areas was used to identify potential antioxidants. This is a novel approach to simultaneously evaluate the antioxidant power of a component versus a free radical, and to identify it in a vegetal matrix. The structures of the antioxidants in the samples were identified using tandem mass spectrometry and comparison with standards. Fourteen compounds were found to possess potential antioxidant activity, and their free radical scavenging capacities were investigated. The order of scavenging capacity of 14 compounds was compared according to their free radical scavenging rate. 4',5,6,7-Tetrahydroxyflavone (radical scavenging rate: 0.05253 mL mg(-1) s(-1) ) showed the strongest capability for scavenging free radicals.

  2. 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

  3. Improved genome-scale multi-target virtual screening via a novel collaborative filtering approach to cold-start problem

    Science.gov (United States)

    Lim, Hansaim; Gray, Paul; Xie, Lei; Poleksic, Aleksandar

    2016-12-01

    Conventional one-drug-one-gene approach has been of limited success in modern drug discovery. Polypharmacology, which focuses on searching for multi-targeted drugs to perturb disease-causing networks instead of designing selective ligands to target individual proteins, has emerged as a new drug discovery paradigm. Although many methods for single-target virtual screening have been developed to improve the efficiency of drug discovery, few of these algorithms are designed for polypharmacology. Here, we present a novel theoretical framework and a corresponding algorithm for genome-scale multi-target virtual screening based on the one-class collaborative filtering technique. Our method overcomes the sparseness of the protein-chemical interaction data by means of interaction matrix weighting and dual regularization from both chemicals and proteins. While the statistical foundation behind our method is general enough to encompass genome-wide drug off-target prediction, the program is specifically tailored to find protein targets for new chemicals with little to no available interaction data. We extensively evaluate our method using a number of the most widely accepted gene-specific and cross-gene family benchmarks and demonstrate that our method outperforms other state-of-the-art algorithms for predicting the interaction of new chemicals with multiple proteins. Thus, the proposed algorithm may provide a powerful tool for multi-target drug design.

  4. Screening currency notes for microbial pathogens and antibiotic resistance genes using a shotgun metagenomic approach.

    Directory of Open Access Journals (Sweden)

    Saakshi Jalali

    Full Text Available Fomites are a well-known source of microbial infections and previous studies have provided insights into the sojourning microbiome of fomites from various sources. Paper currency notes are one of the most commonly exchanged objects and its potential to transmit pathogenic organisms has been well recognized. Approaches to identify the microbiome associated with paper currency notes have been largely limited to culture dependent approaches. Subsequent studies portrayed the use of 16S ribosomal RNA based approaches which provided insights into the taxonomical distribution of the microbiome. However, recent techniques including shotgun sequencing provides resolution at gene level and enable estimation of their copy numbers in the metagenome. We investigated the microbiome of Indian paper currency notes using a shotgun metagenome sequencing approach. Metagenomic DNA isolated from samples of frequently circulated denominations of Indian currency notes were sequenced using Illumina Hiseq sequencer. Analysis of the data revealed presence of species belonging to both eukaryotic and prokaryotic genera. The taxonomic distribution at kingdom level revealed contigs mapping to eukaryota (70%, bacteria (9%, viruses and archae (~1%. We identified 78 pathogens including Staphylococcus aureus, Corynebacterium glutamicum, Enterococcus faecalis, and 75 cellulose degrading organisms including Acidothermus cellulolyticus, Cellulomonas flavigena and Ruminococcus albus. Additionally, 78 antibiotic resistance genes were identified and 18 of these were found in all the samples. Furthermore, six out of 78 pathogens harbored at least one of the 18 common antibiotic resistance genes. To the best of our knowledge, this is the first report of shotgun metagenome sequence dataset of paper currency notes, which can be useful for future applications including as bio-surveillance of exchangeable fomites for infectious agents.

  5. A Suggested Approach To Simplify and Improve Cervical Screening in the United States

    OpenAIRE

    Schiffman, Mark; Wentzensen, Nicolas

    2016-01-01

    Cervical cancer prevention strategies in the United States have become complicated and even controversial, despite advanced understanding of carcinogenic human papillomavirus (HPV) infection as the necessary causal agent. Twenty years ago, etiologic and methodologic studies had already yielded two powerful preventive approaches. There are excellent vaccines to prevent the most carcinogenic types of HPV infection; reduced HPV endemicity will ultimately prevent a large fraction of cervical prec...

  6. Access to Mammography Facilities and Detection of Breast Cancer by Screening Mammography: A GIS Approach.

    Science.gov (United States)

    Rahman, Selina; Price, James H; Dignan, Mark; Rahman, Saleh; Lindquist, Peter S; Jordan, Timothy R

    2009-01-01

    OBJECTIVES: The objective of the study was to examine the association between access to mammography facilities and utilization of screening mammography in an urban population. METHODS: Data on female breast cancer cases were obtained from an extensive mammography surveillance project. Distance to mammography facilities was measured by using GIS, which was followed by measuring geographical access to mammography facilities using Floating Catchment Area (FCA) method (considering all available facilities within an arbitrary radius from the woman's residence by using Arc GIS 9.0 software). RESULTS: Of 2,024 women, 91.4% were Caucasian; age ranged from 25 to 98 years; most (95%) were non-Hispanic in origin. Logistic regression found age, family history, hormone replacement therapy, physician recommendation, and breast cancer stage at diagnosis to be significant predictors of having had a previous mammogram. Women having higher access to mammography facilities were less likely to have had a previous mammogram compared to women who had low access, considering all the facilities within 10 miles (OR=0.41, CI=0.22-0.76), 30 miles (OR=0.52, CI=0.29-0.91) and 40 miles (OR=0.51, CI=0.28-0.92) radiuses. CONCLUSIONS: Physical distance to mammography facilities does not necessarily predict utilization of mammogram and greater access does not assure greater utilizations, due to constraints imposed by socio economic and cultural barriers. Future studies should focus on measuring access to mammography facilities capturing a broader dimension of access considering qualitative aspect of facilities, as well as other travel impedances.

  7. An integrative approach to ortholog prediction for disease-focused and other functional studies

    Directory of Open Access Journals (Sweden)

    Perrimon Norbert

    2011-08-01

    Full Text Available Abstract Background Mapping of orthologous genes among species serves an important role in functional genomics by allowing researchers to develop hypotheses about gene function in one species based on what is known about the functions of orthologs in other species. Several tools for predicting orthologous gene relationships are available. However, these tools can give different results and identification of predicted orthologs is not always straightforward. Results We report a simple but effective tool, the Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool (DIOPT; http://www.flyrnai.org/diopt, for rapid identification of orthologs. DIOPT integrates existing approaches, facilitating rapid identification of orthologs among human, mouse, zebrafish, C. elegans, Drosophila, and S. cerevisiae. As compared to individual tools, DIOPT shows increased sensitivity with only a modest decrease in specificity. Moreover, the flexibility built into the DIOPT graphical user interface allows researchers with different goals to appropriately 'cast a wide net' or limit results to highest confidence predictions. DIOPT also displays protein and domain alignments, including percent amino acid identity, for predicted ortholog pairs. This helps users identify the most appropriate matches among multiple possible orthologs. To facilitate using model organisms for functional analysis of human disease-associated genes, we used DIOPT to predict high-confidence orthologs of disease genes in Online Mendelian Inheritance in Man (OMIM and genes in genome-wide association study (GWAS data sets. The results are accessible through the DIOPT diseases and traits query tool (DIOPT-DIST; http://www.flyrnai.org/diopt-dist. Conclusions DIOPT and DIOPT-DIST are useful resources for researchers working with model organisms, especially those who are interested in exploiting model organisms such as Drosophila to study the functions of human disease genes.

  8. Phonon spectral functions of photo-generated hot carrier plasmas: effects of carrier screening and plasmon-phonon coupling

    Science.gov (United States)

    Yi, Kyung-Soo; Kim, Hye-Jung

    2017-02-01

    We investigate spectral behavior of phonon spectral functions in an interacting multi-component hot carrier plasma. Spectral analysis of various phonon spectral functions is performed considering carrier-phonon channels of polar and nonpolar optical phonons, acoustic deformation-potential, and piezoelectric Coulomb couplings. Effects of phonon self-energy corrections are examined at finite temperature within a random phase approximation extended to include the effects of dynamic screening, plasmon-phonon coupling, and local-field corrections of the plasma species. We provide numerical data for the case of a photo-generated electron-hole plasma formed in a wurtzite GaN. Our result shows the clear significance of the multiplicity of the plasma species in the phonon spectral functions of a multi-component plasma giving rise to a variety of spectral behaviors of carrier-phonon coupled collective modes. A useful sum rule on the plasma-species-resolved dielectric functions is also found.

  9. Polymicrobial Multi-functional Approach for Enhancement of Crop Productivity.

    Science.gov (United States)

    Reddy, Chilekampalli A; Saravanan, Ramu S

    2013-01-01

    There is an increasing global need for enhancing the food production to meet the needs of the fast-growing human population. Traditional approach to increasing agricultural productivity through high inputs of chemical nitrogen and phosphate fertilizers and pesticides is not sustainable because of high costs and concerns about global warming, environmental pollution, and safety concerns. Therefore, the use of naturally occurring soil microbes for increasing productivity of food crops is an attractive eco-friendly, cost-effective, and sustainable alternative to the use of chemical fertilizers and pesticides. There is a vast body of published literature on microbial symbiotic and nonsymbiotic nitrogen fixation, multiple beneficial mechanisms used by plant growth-promoting rhizobacteria (PGPR), the nature and significance of mycorrhiza-plant symbiosis, and the growing technology on production of efficacious microbial inoculants. These areas are briefly reviewed here. The construction of an inoculant with a consortium of microbes with multiple beneficial functions such as N(2) fixation, biocontrol, phosphate solubilization, and other plant growth-promoting properties is a positive new development in this area in that a single inoculant can be used effectively for increasing the productivity of a broad spectrum of crops including legumes, cereals, vegetables, and grasses. Such a polymicrobial inoculant containing several microorganisms for each major function involved in promoting the plant growth and productivity gives it greater stability and wider applications for a range of major crops. Intensifying research in this area leading to further advances in our understanding of biochemical/molecular mechanisms involved in plant-microbe-soil interactions coupled with rapid advances in the genomics-proteomics of beneficial microbes should lead to the design and development of inoculants with greater efficacy for increasing the productivity of a wide range of crops.

  10. Executive Function and Food Approach Behavior in Middle Childhood

    Directory of Open Access Journals (Sweden)

    Karoline eGroppe

    2014-05-01

    Full Text Available Executive function (EF has long been considered to be a unitary, domain-general cognitive ability. However, recent research suggests differentiating ‘hot’ affective and ‘cool’ cognitive aspects of EF. Yet, findings regarding this two-factor construct are still inconsistent. In particular, the development of this factor structure remains unclear and data on school-aged children is lacking. Furthermore, studies linking EF and overweight or obesity suggest that EF contributes to the regulation of eating behavior. So far, however, the links between EF and eating behavior have rarely been investigated in children and non-clinical populations.First, we examined whether EF can be divided into hot and cool factors or whether they actually correspond to a unitary construct in middle childhood. Second, we examined how hot and cool EF are associated with different eating styles that put children at risk of becoming overweight during development. Hot and cool EF were assessed experimentally in a non-clinical population of 1,657 elementary-school children (aged 6-11 years. The ‘food approach’ behavior was rated mainly via parent questionnaires.Findings indicate that hot EF is distinguishable from cool EF. However, only cool EF seems to represent a coherent functional entity, whereas hot EF does not seem to be a homogenous construct. This was true for a younger and an older subgroup of children. Furthermore, different EF components were correlated with eating styles, such as responsiveness to food, desire to drink, and restrained eating in girls but not in boys. This shows that lower levels of EF are not only seen in clinical populations of obese patients but are already associated with food approach styles in a normal population of elementary school-aged girls. Although the direction of effect still has to be clarified, results point to the possibility that EF constitutes a risk factor for eating styles contributing to the development of

  11. Chemical Reactions Using a Non-Equilibrium Wigner Function Approach

    Directory of Open Access Journals (Sweden)

    Ramón F. Álvarez-Estrada

    2016-10-01

    Full Text Available A three-dimensional model of binary chemical reactions is studied. We consider an ab initio quantum two-particle system subjected to an attractive interaction potential and to a heat bath at thermal equilibrium at absolute temperature T > 0 . Under the sole action of the attraction potential, the two particles can either be bound or unbound to each other. While at T = 0 , there is no transition between both states, such a transition is possible when T > 0 (due to the heat bath and plays a key role as k B T approaches the magnitude of the attractive potential. We focus on a quantum regime, typical of chemical reactions, such that: (a the thermal wavelength is shorter than the range of the attractive potential (lower limit on T and (b ( 3 / 2 k B T does not exceed the magnitude of the attractive potential (upper limit on T. In this regime, we extend several methods previously applied to analyze the time duration of DNA thermal denaturation. The two-particle system is then described by a non-equilibrium Wigner function. Under Assumptions (a and (b, and for sufficiently long times, defined by a characteristic time scale D that is subsequently estimated, the general dissipationless non-equilibrium equation for the Wigner function is approximated by a Smoluchowski-like equation displaying dissipation and quantum effects. A comparison with the standard chemical kinetic equations is made. The time τ required for the two particles to transition from the bound state to unbound configurations is studied by means of the mean first passage time formalism. An approximate formula for τ, in terms of D and exhibiting the Arrhenius exponential factor, is obtained. Recombination processes are also briefly studied within our framework and compared with previous well-known methods.

  12. Exponential wealth distribution : a new approach from functional iteration theory*

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    López José-Luis

    2012-08-01

    Full Text Available Different approaches are possible in order to derive the exponential regime in statistical systems. Here, a new functional equation is proposed in an economic context to explain the wealth exponential distribution. Concretely, the new iteration [1] given by egin{equation} f_{n+1}(x = int!!int_{u+v>x},{f_n(uf_n(vover u+v} ; {mathrm d}u{mathrm d}v ,. onumber label{syst1} end{equation} f n + 1 ( x = ∫ ∫ u + v > x   f n ( u f n ( v u + v d u d v   . It is found that the exponential distribution is a stable fixed point of this functional iteration equation. From this point of view, it is easily understood why the exponential wealth distribution (or by extension, other kind of distributions is asymptotically obtained in different multi-agent economic models. Différentes approches pour dériver le régime asymptotique exponentiel dans les systèmes statistiques sont possibles. Ici une nouvelle équation fonctionnelle est proposée, dans le cadre des systèmes économiques, pour expliquer la distribution exponentielle. Nous montrons que cette distribution est le seul point fixe vers lequel la dynamique de cette équation fonctionnelle évolue quand l’itération va vers l’infini. De ce point de vue, il est facile de comprendre l’ubiquité de cette distribution (ou d’autres en différents problèmes statistiques réels.

  13. Screening for otologic functional impairments in the elderly: whose job is it anyway?

    Directory of Open Access Journals (Sweden)

    B.E. Weinstein

    2011-03-01

    Full Text Available Among the most prevalent of chronic conditions affecting older adults globally, hearing loss prevalence is increasing and its impact on society growing. Untreated hearing loss diminishes ones ability to communicate and its strong association with depression and cognitive decline adds further to the burden of hearing loss. Hearing health care is rarely included in the traditional medical exam for older adults, it is typically not considered a risk factor for cognitive decline or falls, and it is not a condition for which routine screening has been recommended by the U.S. Preventive Services Task Force. Yet in older adults, disability typically results from many small risks acting together with different people having a different pattern of multifactorial risk (U.S. Preventive Services Task Force, 2010. The importance of preventive hearing health care in primary care is discussed along with a screening strategy with targeted interventions designed to target older at risk adults.

  14. The malarial drug target Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR): development of a 3-D model for identification of novel, structural and functional features and for inhibitor screening.

    Science.gov (United States)

    Goble, Jessica L; Adendorff, Matthew R; de Beer, Tjaart A P; Stephens, Linda L; Blatch, Gregory L

    2010-01-01

    A three-dimensional model of the malarial drug target protein PfDXR was generated, and validated using structure-checking programs and protein docking studies. Structural and functional features unique to PfDXR were identified using the model and comparative sequence analyses with apicomplexan and non-apicomplexan DXR proteins. Furthermore, we have used the model to develop an efficient approach to screen for potential tool compounds for use in the rational design of novel DXR inhibitors.

  15. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs

    Directory of Open Access Journals (Sweden)

    Matt Q. Clark

    2016-07-01

    Full Text Available Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons are used in all these behaviors, but the identity (or even existence of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines—chosen for sparse neuronal expression—to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°. A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program.

  16. The m/r SEBT: development of a functional screening tool for dance educators.

    Science.gov (United States)

    Wilson, Margaret; Batson, Glenna

    2014-12-01

    Dance screenings provide direct and indirect data bearing on a dancer's readiness to undertake rigorous physical training. Rarely, however, are dance teachers able to translate results from these screenings into practical technical knowledge. In this article, an example of a preseason assessment tool is presented that translates scientific findings into useful information for dance teachers conducting auditions. Designed as a baseline assessment of the dancer during auditioning, the m/r SEBT tool helps teachers stratify technical levels, identify injury risk, and consequently assist with immediate and appropriate recommendations for supplemental training and//or follow-up with a medical professional. The tool evolved out of more than 3 years of collaborative, multisite research utilizing the Star Excursion Balance Test (SEBT) as a dynamic test of balance. Modifications were made to render the test more dance-specific and to increase balance challenges. Within the 3-year period, more than 100 dancers were tested in four sites, two in the United States and two in the United Kingdom. Despite the relatively large collective sample size, neither the original SEBT nor its modifications (m/r SEBT) held robust face or content validity as balance screens. What did emerge, however, were qualitative criteria that the authors organized into a feasible assessment tool for preseason auditions. While this tool awaits further validation, its current evolution helps serve as a bridge between dance teachers' clinical and practical knowledge.

  17. Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches.

    Science.gov (United States)

    Lee, Jonathan A; Berg, Ellen L

    2013-12-01

    Innovation and new molecular entity production by the pharmaceutical industry has been below expectations. Surprisingly, more first-in-class small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 1999 and 2008 were identified by functional phenotypic lead generation strategies reminiscent of pre-genomics pharmacology than contemporary molecular targeted strategies that encompass the vast majority of lead generation efforts. This observation, in conjunction with the difficulty in validating molecular targets for drug discovery, has diminished the impact of the "genomics revolution" and has led to a growing grassroots movement and now broader trend in pharma to reconsider the use of modern physiology-based or phenotypic drug discovery (PDD) strategies. This "From the Guest Editors" column provides an introduction and overview of the two-part special issues of Journal of Biomolecular Screening on PDD. Terminology and the business case for use of PDD are defined. Key issues such as assay performance, chemical optimization, target identification, and challenges to the organization and implementation of PDD are discussed. Possible solutions for these challenges and a new neoclassic vision for PDD that combines phenotypic and functional approaches with technology innovations resulting from the genomics-driven era of target-based drug discovery (TDD) are also described. Finally, an overview of the manuscripts in this special edition is provided.

  18. Selectionist and evolutionary approaches to brain function: a critical appraisal

    Directory of Open Access Journals (Sweden)

    Chrisantha Thomas Fernando

    2012-04-01

    Full Text Available We consider approaches to brain dynamics and function that have been claimed to be Darwinian. These include Edelman’s theory of neuronal group selection, Changeux’s theory of synaptic selection and selective stabilization of pre-representations, Seung’s Darwinian synapse, Loewenstein’s synaptic melioration, Adam’s selfish synapse and Calvin’s replicating activity patterns. Except for the last two, the proposed mechanisms are selectionist but not truly Darwinian, because no replicators with information transfer to copies and hereditary variation can be identified in them. All of them fit, however, a generalized selectionist framework conforming to the picture of Price’s covariance formulation, which deliberately was not specific even to selection in biology, and therefore does not imply an algorithmic picture of biological evolution. Bayesian models and reinforcement learning are formally in agreement with selection dynamics. A classification of search algorithms is shown to include Darwinian replicators (evolutionary units with multiplication, heredity and variability as the most powerful mechanism in a sparsely occupied search space. Examples of why parallel competitive search with information transfer among the units is efficient are given. Finally, we review our recent attempts to construct and analyze simple models of true Darwinian evolutionary units in the brain in terms of connectivity and activity copying of neuronal groups. Although none of the proposed neuronal replicators include miraculous mechanisms, their identification remains a challenge but also a great promise.

  19. Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liying; Sedykh, Alexander; Tripathi, Ashutosh [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States); Zhu, Hao [The Rutgers Center for Computational and Integrative Biology, Rutgers University, Camden, NJ (United States); Department of Chemistry, Rutgers University, Camden, NJ (United States); Afantitis, Antreas; Mouchlis, Varnavas D.; Melagraki, Georgia [NovaMechanics Ltd., Nicosia (Cyprus); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC (United States); Tropsha, Alexander, E-mail: alex_tropsha@unc.edu [Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC (United States)

    2013-10-01

    Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor (ER)-mediated endocrine disruption to facilitate their prioritization for future screening. A database of relative binding affinity of a large number of ERα and/or ERβ ligands was assembled (546 for ERα and 137 for ERβ). Both single-task learning (STL) and multi-task learning (MTL) continuous quantitative structure–activity relationship (QSAR) models were developed for predicting ligand binding affinity to ERα or ERβ. High predictive accuracy was achieved for ERα binding affinity (MTL R{sup 2} = 0.71, STL R{sup 2} = 0.73). For ERβ binding affinity, MTL models were significantly more predictive (R{sup 2} = 0.53, p < 0.05) than STL models. In addition, docking studies were performed on a set of ER agonists/antagonists (67 agonists and 39 antagonists for ERα, 48 agonists and 32 antagonists for ERβ, supplemented by putative decoys/non-binders) using the following ER structures (in complexes with respective ligands) retrieved from the Protein Data Bank: ERα agonist (PDB ID: 1L2I), ERα antagonist (PDB ID: 3DT3), ERβ agonist (PDB ID: 2NV7), and ERβ antagonist (PDB ID: 1L2J). We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation. - Highlights: • This is the largest curated dataset inclusive of ERα and β (the latter is unique). • New methodology that for the first time affords acceptable ERβ models. • A combination of QSAR and docking enables prediction of affinity and function.

  20. A Functional Genomic Approach to Chlorinated Ethenes Bioremediation

    Science.gov (United States)

    Lee, P. K.; Brodie, E. L.; MacBeth, T. W.; Deeb, R. A.; Sorenson, K. S.; Andersen, G. L.; Alvarez-Cohen, L.

    2007-12-01

    With the recent advances in genomic sciences, a knowledge-based approach can now be taken to optimize the bioremediation of trichloroethene (TCE). During the bioremediation of a heterogeneous subsurface, it is vital to identify and quantify the functionally important microorganisms present, characterize the microbial community and measure their physiological activity. In our field experiments, quantitative PCR (qPCR) was coupled with reverse-transcription (RT) to analyze both copy numbers and transcripts expressed by the 16S rRNA gene and three reductive dehalogenase (RDase) genes as biomarkers of Dehalococcoides spp. in the groundwater of a TCE-DNAPL site at Ft. Lewis (WA) that was serially subjected to biostimulation and bioaugmentation. Genes in the Dehalococcoides genus were targeted as they are the only known organisms that can completely dechlorinate TCE to the innocuous product ethene. Biomarker quantification revealed an overall increase of more than three orders of magnitude in the total Dehalococcoides population and quantification of the more liable and stringently regulated mRNAs confirmed that Dehalococcoides spp. were active. Parallel with our field experiments, laboratory studies were conducted to explore the physiology of Dehalococcoides isolates in order to develop relevant biomarkers that are indicative of the metabolic state of cells. Recently, we verified the function of the nitrogenase operon in Dehalococcoides sp. strain 195 and nitrogenase-encoding genes are ideal biomarker targets to assess cellular nitrogen requirement. To characterize the microbial community, we applied a high-density phylogenetic microarray (16S PhyloChip) that simultaneous monitors over 8,700 unique taxa to track the bacterial and archaeal populations through different phases of treatment. As a measure of species richness, 1,300 to 1,520 taxa were detected in groundwater samples extracted during different stages of treatment as well as in the bioaugmentation culture. We

  1. In silico prediction and screening of modular crystal structures via a high-throughput genomic approach

    Science.gov (United States)

    Li, Yi; Li, Xu; Liu, Jiancong; Duan, Fangzheng; Yu, Jihong

    2015-09-01

    High-throughput computational methods capable of predicting, evaluating and identifying promising synthetic candidates with desired properties are highly appealing to today's scientists. Despite some successes, in silico design of crystalline materials with complex three-dimensionally extended structures remains challenging. Here we demonstrate the application of a new genomic approach to ABC-6 zeolites, a family of industrially important catalysts whose structures are built from the stacking of modular six-ring layers. The sequences of layer stacking, which we deem the genes of this family, determine the structures and the properties of ABC-6 zeolites. By enumerating these gene-like stacking sequences, we have identified 1,127 most realizable new ABC-6 structures out of 78 groups of 84,292 theoretical ones, and experimentally realized 2 of them. Our genomic approach can extract crucial structural information directly from these gene-like stacking sequences, enabling high-throughput identification of synthetic targets with desired properties among a large number of candidate structures.

  2. Filtered density function approach for reactive transport in groundwater

    Science.gov (United States)

    Suciu, Nicolae; Schüler, Lennart; Attinger, Sabine; Knabner, Peter

    2016-04-01

    Spatial filtering may be used in coarse-grained simulations (CGS) of reactive transport in groundwater, similar to the large eddy simulations (LES) in turbulence. The filtered density function (FDF), stochastically equivalent to a probability density function (PDF), provides a statistical description of the sub-grid, unresolved, variability of the concentration field. Besides closing the chemical source terms in the transport equation for the mean concentration, like in LES-FDF methods, the CGS-FDF approach aims at quantifying the uncertainty over the whole hierarchy of heterogeneity scales exhibited by natural porous media. Practically, that means estimating concentration PDFs on coarse grids, at affordable computational costs. To cope with the high dimensionality of the problem in case of multi-component reactive transport and to reduce the numerical diffusion, FDF equations are solved by particle methods. But, while trajectories of computational particles are modeled as stochastic processes indexed by time, the concentration's heterogeneity is modeled as a random field, with multi-dimensional, spatio-temporal sets of indices. To overcome this conceptual inconsistency, we consider FDFs/PDFs of random species concentrations weighted by conserved scalars and we show that their evolution equations can be formulated as Fokker-Planck equations describing stochastically equivalent processes in concentration-position spaces. Numerical solutions can then be approximated by the density in the concentration-position space of an ensemble of computational particles governed by the associated Itô equations. Instead of sequential particle methods we use a global random walk (GRW) algorithm, which is stable, free of numerical diffusion, and practically insensitive to the increase of the number of particles. We illustrate the general FDF approach and the GRW numerical solution for a reduced complexity problem consisting of the transport of a single scalar in groundwater

  3. Complete genome-wide screening and subtractive genomic approach revealed new virulence factors, potential drug targets against bio-war pathogen Brucella melitensis 16M

    Directory of Open Access Journals (Sweden)

    Pradeepkiran JA

    2015-03-01

    Full Text Available Jangampalli Adi Pradeepkiran,1* Sri Bhashyam Sainath,2,3* Konidala Kranthi Kumar,1 Matcha Bhaskar1 1Division of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati, India; 2CIMAR/CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, Porto, Portugal, 3Department of Biotechnology, Vikrama Simhapuri University, Nellore, Andhra Pradesh, India *These authors contributed equally to this work Abstract: Brucella melitensis 16M is a Gram-negative coccobacillus that infects both animals and humans. It causes a disease known as brucellosis, which is characterized by acute febrile illness in humans and causes abortions in livestock. To prevent and control brucellosis, identification of putative drug targets is crucial. The present study aimed to identify drug targets in B. melitensis 16M by using a subtractive genomic approach. We used available database repositories (Database of Essential Genes, Kyoto Encyclopedia of Genes and Genomes Automatic Annotation Server, and Kyoto Encyclopedia of Genes and Genomes to identify putative genes that are nonhomologous to humans and essential for pathogen B. melitensis 16M. The results revealed that among 3 Mb genome size of pathogen, 53 putative characterized and 13 uncharacterized hypothetical genes were identified; further, from Basic Local Alignment Search Tool protein analysis, one hypothetical protein showed a close resemblance (50% to Silicibacter pomeroyi DUF1285 family protein (2RE3. A further homology model of the target was constructed using MODELLER 9.12 and optimized through variable target function method by molecular dynamics optimization with simulating annealing. The stereochemical quality of the restrained model was evaluated by PROCHECK, VERIFY-3D, ERRAT, and WHATIF servers. Furthermore, structure-based virtual screening was carried out against the predicted active site of the respective protein using the

  4. A Participatory Approach to Develop the Power Mobility Screening Tool and the Power Mobility Clinical Driving Assessment Tool

    Directory of Open Access Journals (Sweden)

    Deepan C. Kamaraj

    2014-01-01

    Full Text Available The electric powered wheelchair (EPW is an indispensable assistive device that increases participation among individuals with disabilities. However, due to lack of standardized assessment tools, developing evidence based training protocols for EPW users to improve driving skills has been a challenge. In this study, we adopt the principles of participatory research and employ qualitative methods to develop the Power Mobility Screening Tool (PMST and Power Mobility Clinical Driving Assessment (PMCDA. Qualitative data from professional experts and expert EPW users who participated in a focus group and a discussion forum were used to establish content validity of the PMCDA and the PMST. These tools collectively could assess a user’s current level of bodily function and their current EPW driving capacity. Further multicenter studies are necessary to evaluate the psychometric properties of these tests and develop EPW driving training protocols based on these assessment tools.

  5. A less invasive approach to screening for early onset neonatal GBS.

    LENUS (Irish Health Repository)

    Glackin, S

    2015-03-01

    Recent recommendations for the management of an asymptomatic term infant with one septic risk factor for Group B Streptococcal (GBS) invasive disease have advised a clinical approach. Following a previous audit in our unit which showed that high numbers of asymptomatic infants were receiving antibiotics, a new protocol was introduced which emphasised the importance of clinical examination. This study assessed the safety and efficacy of this new protocol through chart review of 1855 eligible infants. We found a statistically significant decrease (P < 0.0001) from 444 (19%) to 121 (6.5%) in the total number of term infants who underwent septic evaluations and received antibiotics. 241 asymptomatic infants with one septic risk factor were managed conservatively. No eligible infants had GBS invasive disease during the three month study period. The new protocol is a safe and effective tool for evaluating infants at risk of GBS invasive disease.

  6. Pharmacological chaperone approaches for rescuing GPCR mutants: Current state, challenges, and screening strategies.

    Science.gov (United States)

    Beerepoot, Pieter; Nazari, Reza; Salahpour, Ali

    2017-03-01

    A substantial number of G-protein coupled receptors (GPCRs) genetic disorders are due to mutations that cause misfolding or dysfunction of the receptor product. Pharmacological chaperoning approaches can rescue such mutant receptors by stabilizing protein conformations that behave similar to the wild type protein. For example, this can be achieved by improving folding efficiency and/or interaction with chaperone proteins. Although efficacy of pharmacological chaperones has been demonstrated in vitro for a variety of GPCRs, translation to clinical use has been limited. In this paper we discuss the history of pharmacological chaperones of GPCR's and other membrane proteins, the challenges in translation to the clinic, and the use of different assays for pharmacological chaperone discovery.

  7. A culture-independent approach to unravel uncultured bacteria and functional genes in a complex microbial community.

    Directory of Open Access Journals (Sweden)

    Yun Wang

    Full Text Available Most microorganisms in nature are uncultured with unknown functionality. Sequence-based metagenomics alone answers 'who/what are there?' but not 'what are they doing and who is doing it and how?'. Function-based metagenomics reveals gene function but is usually limited by the specificity and sensitivity of screening strategies, especially the identification of clones whose functional gene expression has no distinguishable activity or phenotypes. A 'biosensor-based genetic transducer' (BGT technique, which employs a whole-cell biosensor to quantitatively detect expression of inserted genes encoding designated functions, is able to screen for functionality of unknown genes from uncultured microorganisms. In this study, BGT was integrated with Stable isotope probing (SIP-enabled Metagenomics to form a culture-independent SMB toolbox. The utility of this approach was demonstrated in the discovery of a novel functional gene cluster in naphthalene contaminated groundwater. Specifically, metagenomic sequencing of the (13C-DNA fraction obtained by SIP indicated that an uncultured Acidovorax sp. was the dominant key naphthalene degrader in-situ, although three culturable Pseudomonas sp. degraders were also present in the same groundwater. BGT verified the functionality of a new nag2 operon which co-existed with two other nag and two nah operons for naphthalene biodegradation in the same microbial community. Pyrosequencing analysis showed that the nag2 operon was the key functional operon in naphthalene degradation in-situ, and shared homology with both nag operons in Ralstonia sp. U2 and Polaromonas naphthalenivorans CJ2. The SMB toolbox will be useful in providing deep insights into uncultured microorganisms and unravelling their ecological roles in natural environments.

  8. Functional metagenomics: a high throughput screening method to decipher microbiota-driven NF-κB modulation in the human gut.

    Directory of Open Access Journals (Sweden)

    Omar Lakhdari

    Full Text Available BACKGROUND/AIM: The human intestinal microbiota plays an important role in modulation of mucosal immune responses. To study interactions between intestinal epithelial cells (IECs and commensal bacteria, a functional metagenomic approach was developed. One interest of metagenomics is to provide access to genomes of uncultured microbes. We aimed at identifying bacterial genes involved in regulation of NF-κB signaling in IECs. A high throughput cell-based screening assay allowing rapid detection of NF-κB modulation in IECs was established using the reporter-gene strategy to screen metagenomic libraries issued from the human intestinal microbiota. METHODS: A plasmid containing the secreted alkaline phosphatase (SEAP gene under the control of NF-κB binding elements was stably transfected in HT-29 cells. The reporter clone HT-29/kb-seap-25 was selected and characterized. Then, a first screening of a metagenomic library from Crohn's disease patients was performed to identify NF-κB modulating clones. Furthermore, genes potentially involved in the effect of one stimulatory metagenomic clone were determined by sequence analysis associated to mutagenesis by transposition. RESULTS: The two proinflammatory cytokines, TNF-α and IL-1β, were able to activate the reporter system, translating the activation of the NF-κB signaling pathway and NF-κB inhibitors, BAY 11-7082, caffeic acid phenethyl ester and MG132 were efficient. A screening of 2640 metagenomic clones led to the identification of 171 modulating clones. Among them, one stimulatory metagenomic clone, 52B7, was further characterized. Sequence analysis revealed that its metagenomic DNA insert might belong to a new Bacteroides strain and we identified 2 loci encoding an ABC transport system and a putative lipoprotein potentially involved in 52B7 effect on NF-κB. CONCLUSIONS: We have established a robust high throughput screening assay for metagenomic libraries derived from the human intestinal

  9. Race/Ethnicity and Adoption of a Population Health Management Approach to Colorectal Cancer Screening in a Community-Based Healthcare System.

    Science.gov (United States)

    Mehta, Shivan J; Jensen, Christopher D; Quinn, Virginia P; Schottinger, Joanne E; Zauber, Ann G; Meester, Reinier; Laiyemo, Adeyinka O; Fedewa, Stacey; Goodman, Michael; Fletcher, Robert H; Levin, Theodore R; Corley, Douglas A; Doubeni, Chyke A

    2016-11-01

    Screening outreach programs using population health management principles offer services uniformly to all eligible persons, but racial/ethnic colorectal cancer (CRC) screening patterns in such programs are not well known. To examine the association between race/ethnicity and the receipt of CRC screening and timely follow-up of positive results before and after implementation of a screening program. Retrospective cohort study of screen-eligible individuals at the Kaiser Permanente Northern California community-based integrated healthcare delivery system (2004-2013). A total of 868,934 screen-eligible individuals 51-74 years of age at cohort entry, which included 662,872 persons in the period before program implementation (2004-2006), 654,633 during the first 3 years after implementation (2007-2009), and 665,268 in the period from 4 to 7 years (2010-2013) after program implementation. A comprehensive system-wide long-term effort to increase CRC that included leadership alignment, goal-setting, and quality assurance through a PHM approach, using mailed fecal immunochemical testing (FIT) along with offering screening at office visits. Differences over time and by race/ethnicity in up-to-date CRC screening (overall and by test type) and timely follow-up of a positive screen. Race/ethnicity categories included non-Hispanic white, non-Hispanic black, Hispanic/Latino, Asian/Pacific Islander, Native American, and multiple races. From 2004 to 2013, age/sex-adjusted CRC screening rates increased in all groups, including 35.2 to 81.1 % among whites and 35.6 to 78.0 % among blacks. Screening rates among Hispanics (33.1 to 78.3 %) and Native Americans (29.4 to 74.5 %) remained lower than those for whites both before and after program implementation. Blacks, who had slightly higher rates before program implementation (adjusted rate ratio [RR] = 1.04, 99 % CI: 1.02-1.05), had lower rates after program implementation (RR for period from 4 to 7 years = 0.97, 99 % CI: 0

  10. Screen-Space Normal Distribution Function Caching for Consistent Multi-Resolution Rendering of Large Particle Data

    KAUST Repository

    Ibrahim, Mohamed

    2017-08-28

    Molecular dynamics (MD) simulations are crucial to investigating important processes in physics and thermodynamics. The simulated atoms are usually visualized as hard spheres with Phong shading, where individual particles and their local density can be perceived well in close-up views. However, for large-scale simulations with 10 million particles or more, the visualization of large fields-of-view usually suffers from strong aliasing artifacts, because the mismatch between data size and output resolution leads to severe under-sampling of the geometry. Excessive super-sampling can alleviate this problem, but is prohibitively expensive. This paper presents a novel visualization method for large-scale particle data that addresses aliasing while enabling interactive high-quality rendering. We introduce the novel concept of screen-space normal distribution functions (S-NDFs) for particle data. S-NDFs represent the distribution of surface normals that map to a given pixel in screen space, which enables high-quality re-lighting without re-rendering particles. In order to facilitate interactive zooming, we cache S-NDFs in a screen-space mipmap (S-MIP). Together, these two concepts enable interactive, scale-consistent re-lighting and shading changes, as well as zooming, without having to re-sample the particle data. We show how our method facilitates the interactive exploration of real-world large-scale MD simulation data in different scenarios.

  11. A high throughput genetic screen identifies new early meiotic recombination functions in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Arnaud De Muyt

    2009-09-01

    Full Text Available Meiotic recombination is initiated by the formation of numerous DNA double-strand breaks (DSBs catalysed by the widely conserved Spo11 protein. In Saccharomyces cerevisiae, Spo11 requires nine other proteins for meiotic DSB formation; however, unlike Spo11, few of these are conserved across kingdoms. In order to investigate this recombination step in higher eukaryotes, we took advantage of a high-throughput meiotic mutant screen carried out in the model plant Arabidopsis thaliana. A collection of 55,000 mutant lines was screened, and spo11-like mutations, characterised by a drastic decrease in chiasma formation at metaphase I associated with an absence of synapsis at prophase, were selected. This screen led to the identification of two populations of mutants classified according to their recombination defects: mutants that repair meiotic DSBs using the sister chromatid such as Atdmc1 or mutants that are unable to make DSBs like Atspo11-1. We found that in Arabidopsis thaliana at least four proteins are necessary for driving meiotic DSB repair via the homologous chromosomes. These include the previously characterised DMC1 and the Hop1-related ASY1 proteins, but also the meiotic specific cyclin SDS as well as the Hop2 Arabidopsis homologue AHP2. Analysing the mutants defective in DSB formation, we identified the previously characterised AtSPO11-1, AtSPO11-2, and AtPRD1 as well as two new genes, AtPRD2 and AtPRD3. Our data thus increase the number of proteins necessary for DSB formation in Arabidopsis thaliana to five. Unlike SPO11 and (to a minor extent PRD1, these two new proteins are poorly conserved among species, suggesting that the DSB formation mechanism, but not its regulation, is conserved among eukaryotes.

  12. High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics.

    Science.gov (United States)

    Gintjee, Thomas J J; Magh, Alvin S H; Bertoni, Carmen

    2014-11-14

    Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.

  13. High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics

    Directory of Open Access Journals (Sweden)

    Thomas J.J. Gintjee

    2014-11-01

    Full Text Available Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD, the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD.

  14. Recent progress in the identification and development of anti-malarial agents using virtual screening based approaches.

    Science.gov (United States)

    Shah, Priyanka; Tiwari, Sunita; Siddiqi, Mohammad Imran

    2015-01-01

    Malaria has continued to be one of the most perplexing diseases for biological science community around the world due to its prevalent devastating nature and quick developing resistance against the frontline drugs. Artimisinin-based combination therapy (ACT) has been so far found to be among the best therapies against Plasmodium pathogens but alarming emergence of resistance in parasites against every known chemotherapy has prompted the scientific community to step up all the efforts towards development of new and affordable anti-malarial drugs. Computer-aided approaches have received enormous attention in recent years in the field of identification and design of novel drugs. In this review, we summarize recently published research concerning the identification and development of anti-malarial compounds using virtual screening approaches. It would be admirable to discern the successful application of in silico studies for anti-malarial drug discovery hitherto and would certainly help in generating new avenues for pursuing integrated studies between the experimentalists and computational chemists in a systematic manner as a time and cost efficient alternative for future antimalarial drug discovery projects.

  15. A methodological approach to screen diverse cheese-related bacteria for their ability to produce aroma compounds.

    Science.gov (United States)

    Pogačić, Tomislav; Maillard, Marie-Bernadette; Leclerc, Aurélie; Hervé, Christophe; Chuat, Victoria; Yee, Alyson L; Valence, Florence; Thierry, Anne

    2015-04-01

    Microorganisms play an important role in the development of cheese flavor. The aim of this study was to develop an approach to facilitate screening of various cheese-related bacteria for their ability to produce aroma compounds. We combined i) curd-based slurry medium incubated under conditions mimicking cheese manufacturing and ripening, ii) powerful method of extraction of volatiles, headspace trap, coupled to gas chromatography-mass spectrometry (HS-trap-GC-MS), and iii) metabolomics-based method of data processing using the XCMS package of R software and multivariate analysis. This approach was applied to eleven species: five lactic acid bacteria (Leuconostoc lactis, Lactobacillus sakei, Lactobacillus paracasei, Lactobacillus fermentum, and Lactobacillus helveticus), four actinobacteria (Brachybacterium articum, Brachybacterium tyrofermentans, Brevibacterium aurantiacum, and Microbacterium gubbeenense), Propionibacterium freudenreichii, and Hafnia alvei. All the strains grew, with maximal populations ranging from 7.4 to 9.2 log (CFU/mL). In total, 52 volatile aroma compounds were identified, of which 49 varied significantly in abundance between bacteria. Principal component analysis of volatile profiles differentiated species by their ability to produce ethyl esters (associated with Brachybacteria), sulfur compounds and branched-chain alcohols (H. alvei), branched-chain acids (H. alvei, P. freudenreichii and L. paracasei), diacetyl and related carbonyl compounds (M. gubbeenense and L. paracasei), among others.

  16. Screening and ranking of POPs for global half-life: QSAR approaches for prioritization based on molecular structure.

    Science.gov (United States)

    Gramatica, Paola; Papa, Ester

    2007-04-15

    Persistence in the environment is an important criterion in prioritizing hazardous chemicals and in identifying new persistent organic pollutants (POPs). Degradation half-life in various compartments is among the more commonly used criteria for studying environmental persistence, but the limited availability of experimental data or reliable estimates is a serious problem. Available half-life data for degradation in air, water, sediment, and soil, for a set of 250 organic POP-type chemicals, were combined in a multivariate approach by principal component analysis to obtain a ranking of the studied organic pollutants according to their relative overall half-life. A global half-life index (GHLI) applicable for POP