STUDY TO IDENTIFY IMPORTANT PARAMETERS FOR CHARACTERIZING PESTICIDE RESIDUE TRANSFER EFFICIENCIES

EPA Science Inventory

To reduce the uncertainty associated with current estimates of children's exposure to pesticides by dermal contact and non-dietary ingestion, residue transfer data are required. Prior to conducting exhaustive studies, a screening study to identify the important parameters for...

Uncertainty importance analysis using parametric moment ratio functions.

PubMed

Wei, Pengfei; Lu, Zhenzhou; Song, Jingwen

2014-02-01

This article presents a new importance analysis framework, called parametric moment ratio function, for measuring the reduction of model output uncertainty when the distribution parameters of inputs are changed, and the emphasis is put on the mean and variance ratio functions with respect to the variances of model inputs. The proposed concepts efficiently guide the analyst to achieve a targeted reduction on the model output mean and variance by operating on the variances of model inputs. The unbiased and progressive unbiased Monte Carlo estimators are also derived for the parametric mean and variance ratio functions, respectively. Only a set of samples is needed for implementing the proposed importance analysis by the proposed estimators, thus the computational cost is free of input dimensionality. An analytical test example with highly nonlinear behavior is introduced for illustrating the engineering significance of the proposed importance analysis technique and verifying the efficiency and convergence of the derived Monte Carlo estimators. Finally, the moment ratio function is applied to a planar 10-bar structure for achieving a targeted 50% reduction of the model output variance. © 2013 Society for Risk Analysis.

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

PubMed

Davies, Gail; Lam, Max; Harris, Sarah E; Trampush, Joey W; Luciano, Michelle; Hill, W David; Hagenaars, Saskia P; Ritchie, Stuart J; Marioni, Riccardo E; Fawns-Ritchie, Chloe; Liewald, David C M; Okely, Judith A; Ahola-Olli, Ari V; Barnes, Catriona L K; Bertram, Lars; Bis, Joshua C; Burdick, Katherine E; Christoforou, Andrea; DeRosse, Pamela; Djurovic, Srdjan; Espeseth, Thomas; Giakoumaki, Stella; Giddaluru, Sudheer; Gustavson, Daniel E; Hayward, Caroline; Hofer, Edith; Ikram, M Arfan; Karlsson, Robert; Knowles, Emma; Lahti, Jari; Leber, Markus; Li, Shuo; Mather, Karen A; Melle, Ingrid; Morris, Derek; Oldmeadow, Christopher; Palviainen, Teemu; Payton, Antony; Pazoki, Raha; Petrovic, Katja; Reynolds, Chandra A; Sargurupremraj, Muralidharan; Scholz, Markus; Smith, Jennifer A; Smith, Albert V; Terzikhan, Natalie; Thalamuthu, Anbupalam; Trompet, Stella; van der Lee, Sven J; Ware, Erin B; Windham, B Gwen; Wright, Margaret J; Yang, Jingyun; Yu, Jin; Ames, David; Amin, Najaf; Amouyel, Philippe; Andreassen, Ole A; Armstrong, Nicola J; Assareh, Amelia A; Attia, John R; Attix, Deborah; Avramopoulos, Dimitrios; Bennett, David A; Böhmer, Anne C; Boyle, Patricia A; Brodaty, Henry; Campbell, Harry; Cannon, Tyrone D; Cirulli, Elizabeth T; Congdon, Eliza; Conley, Emily Drabant; Corley, Janie; Cox, Simon R; Dale, Anders M; Dehghan, Abbas; Dick, Danielle; Dickinson, Dwight; Eriksson, Johan G; Evangelou, Evangelos; Faul, Jessica D; Ford, Ian; Freimer, Nelson A; Gao, He; Giegling, Ina; Gillespie, Nathan A; Gordon, Scott D; Gottesman, Rebecca F; Griswold, Michael E; Gudnason, Vilmundur; Harris, Tamara B; Hartmann, Annette M; Hatzimanolis, Alex; Heiss, Gerardo; Holliday, Elizabeth G; Joshi, Peter K; Kähönen, Mika; Kardia, Sharon L R; Karlsson, Ida; Kleineidam, Luca; Knopman, David S; Kochan, Nicole A; Konte, Bettina; Kwok, John B; Le Hellard, Stephanie; Lee, Teresa; Lehtimäki, Terho; Li, Shu-Chen; Liu, Tian; Koini, Marisa; London, Edythe; Longstreth, Will T; Lopez, Oscar L; Loukola, Anu; Luck, Tobias; Lundervold, Astri J; Lundquist, Anders; Lyytikäinen, Leo-Pekka; Martin, Nicholas G; Montgomery, Grant W; Murray, Alison D; Need, Anna C; Noordam, Raymond; Nyberg, Lars; Ollier, William; Papenberg, Goran; Pattie, Alison; Polasek, Ozren; Poldrack, Russell A; Psaty, Bruce M; Reppermund, Simone; Riedel-Heller, Steffi G; Rose, Richard J; Rotter, Jerome I; Roussos, Panos; Rovio, Suvi P; Saba, Yasaman; Sabb, Fred W; Sachdev, Perminder S; Satizabal, Claudia L; Schmid, Matthias; Scott, Rodney J; Scult, Matthew A; Simino, Jeannette; Slagboom, P Eline; Smyrnis, Nikolaos; Soumaré, Aïcha; Stefanis, Nikos C; Stott, David J; Straub, Richard E; Sundet, Kjetil; Taylor, Adele M; Taylor, Kent D; Tzoulaki, Ioanna; Tzourio, Christophe; Uitterlinden, André; Vitart, Veronique; Voineskos, Aristotle N; Kaprio, Jaakko; Wagner, Michael; Wagner, Holger; Weinhold, Leonie; Wen, K Hoyan; Widen, Elisabeth; Yang, Qiong; Zhao, Wei; Adams, Hieab H H; Arking, Dan E; Bilder, Robert M; Bitsios, Panos; Boerwinkle, Eric; Chiba-Falek, Ornit; Corvin, Aiden; De Jager, Philip L; Debette, Stéphanie; Donohoe, Gary; Elliott, Paul; Fitzpatrick, Annette L; Gill, Michael; Glahn, David C; Hägg, Sara; Hansell, Narelle K; Hariri, Ahmad R; Ikram, M Kamran; Jukema, J Wouter; Vuoksimaa, Eero; Keller, Matthew C; Kremen, William S; Launer, Lenore; Lindenberger, Ulman; Palotie, Aarno; Pedersen, Nancy L; Pendleton, Neil; Porteous, David J; Räikkönen, Katri; Raitakari, Olli T; Ramirez, Alfredo; Reinvang, Ivar; Rudan, Igor; Dan Rujescu; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter W; Schofield, Peter R; Starr, John M; Steen, Vidar M; Trollor, Julian N; Turner, Steven T; Van Duijn, Cornelia M; Villringer, Arno; Weinberger, Daniel R; Weir, David R; Wilson, James F; Malhotra, Anil; McIntosh, Andrew M; Gale, Catharine R; Seshadri, Sudha; Mosley, Thomas H; Bressler, Jan; Lencz, Todd; Deary, Ian J

2018-05-29

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10 -8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

Identifying arbitrary parameter zonation using multiple level set functions

NASA Astrophysics Data System (ADS)

Lu, Zhiming; Vesselinov, Velimir V.; Lei, Hongzhuan

2018-07-01

In this paper, we extended the analytical level set method [1,2] for identifying a piece-wisely heterogeneous (zonation) binary system to the case with an arbitrary number of materials with unknown material properties. In the developed level set approach, starting from an initial guess, the material interfaces are propagated through iterations such that the residuals between the simulated and observed state variables (hydraulic head) is minimized. We derived an expression for the propagation velocity of the interface between any two materials, which is related to the permeability contrast between the materials on two sides of the interface, the sensitivity of the head to permeability, and the head residual. We also formulated an expression for updating the permeability of all materials, which is consistent with the steepest descent of the objective function. The developed approach has been demonstrated through many examples, ranging from totally synthetic cases to a case where the flow conditions are representative of a groundwater contaminant site at the Los Alamos National Laboratory. These examples indicate that the level set method can successfully identify zonation structures, even if the number of materials in the model domain is not exactly known in advance. Although the evolution of the material zonation depends on the initial guess field, inverse modeling runs starting with different initial guesses fields may converge to the similar final zonation structure. These examples also suggest that identifying interfaces of spatially distributed heterogeneities is more important than estimating their permeability values.

Newer Approaches to Identify Potential Untoward Effects in Functional Foods.

PubMed

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. © The Author(s) 2015.

Goal setting, using goal attainment scaling, as a method to identify patient selected items for measuring arm function.

PubMed

Ashford, Stephen; Jackson, Diana; Turner-Stokes, Lynne

2015-03-01

Following stroke or brain injury, goals for rehabilitation of the hemiparetic upper limb include restoring active function if there is return of motor control or, if none is possible, improving passive function, and facilitating care for the limb. To inform development of a new patient reported outcome measure (PROM) of active and passive function in the hemiparetic upper limb, the Arm Activity measure, we examined functional goals for the upper limb, identified during goal setting for spasticity intervention (physical therapy and concomitant botulinum toxin A interventions). Using secondary analysis of a prospective observational cohort study, functional goals determined between patients, their carers and the clinical team were assigned into categories by two raters. Goal category identification, followed by assignment of goals to a category, was undertaken and then confirmed by a second reviewer. Participants comprised nine males and seven females of mean (SD) age 54.5 (15.7) years and their carers. Fifteen had sustained a stroke and one a traumatic brain injury. Goals were used to identify five categories: passive function, active function, symptoms, cosmesis and impairment. Two passive function items not previously identified by a previous systematic review were identified. Analysis of goals important to patients and carers revealed items for inclusion in a new measure of arm function and provide a useful alternative method to involve patients and carers in standardised measure development. Copyright © 2014 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Identifying arbitrary parameter zonation using multiple level set functions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Zhiming; Vesselinov, Velimir Valentinov; Lei, Hongzhuan

In this paper, we extended the analytical level set method [1, 2] for identifying a piece-wisely heterogeneous (zonation) binary system to the case with an arbitrary number of materials with unknown material properties. In the developed level set approach, starting from an initial guess, the material interfaces are propagated through iterations such that the residuals between the simulated and observed state variables (hydraulic head) is minimized. We derived an expression for the propagation velocity of the interface between any two materials, which is related to the permeability contrast between the materials on two sides of the interface, the sensitivity ofmore » the head to permeability, and the head residual. We also formulated an expression for updating the permeability of all materials, which is consistent with the steepest descent of the objective function. The developed approach has been demonstrated through many examples, ranging from totally synthetic cases to a case where the flow conditions are representative of a groundwater contaminant site at the Los Alamos National Laboratory. These examples indicate that the level set method can successfully identify zonation structures, even if the number of materials in the model domain is not exactly known in advance. Although the evolution of the material zonation depends on the initial guess field, inverse modeling runs starting with different initial guesses fields may converge to the similar final zonation structure. These examples also suggest that identifying interfaces of spatially distributed heterogeneities is more important than estimating their permeability values.« less

Identifying arbitrary parameter zonation using multiple level set functions

DOE PAGES

Lu, Zhiming; Vesselinov, Velimir Valentinov; Lei, Hongzhuan

2018-03-14

In this paper, we extended the analytical level set method [1, 2] for identifying a piece-wisely heterogeneous (zonation) binary system to the case with an arbitrary number of materials with unknown material properties. In the developed level set approach, starting from an initial guess, the material interfaces are propagated through iterations such that the residuals between the simulated and observed state variables (hydraulic head) is minimized. We derived an expression for the propagation velocity of the interface between any two materials, which is related to the permeability contrast between the materials on two sides of the interface, the sensitivity ofmore » the head to permeability, and the head residual. We also formulated an expression for updating the permeability of all materials, which is consistent with the steepest descent of the objective function. The developed approach has been demonstrated through many examples, ranging from totally synthetic cases to a case where the flow conditions are representative of a groundwater contaminant site at the Los Alamos National Laboratory. These examples indicate that the level set method can successfully identify zonation structures, even if the number of materials in the model domain is not exactly known in advance. Although the evolution of the material zonation depends on the initial guess field, inverse modeling runs starting with different initial guesses fields may converge to the similar final zonation structure. These examples also suggest that identifying interfaces of spatially distributed heterogeneities is more important than estimating their permeability values.« less

The Importance of Social Cognition in Improving Functional Outcomes in Schizophrenia

PubMed Central

Javed, Afzal; Charles, Asha

2018-01-01

Social cognition has become recognized as an important driver of functional outcomes and overall recovery in patients with schizophrenia, mediating the relationship between neurocognition and social functioning. Since antipsychotic therapy targeting remission of clinical symptoms has been shown to have a limited impact on social cognition, there has been an increasing drive to develop therapeutic strategies to specifically improve social cognition in schizophrenia. We sought to review current evidence relating to social cognition in schizophrenia and its clinical implications, including interventions designed to target the core domains of social cognition (emotion processing, theory of mind, attributional bias, and social perception) as a means of improving functional outcomes and thereby increasing the likelihood of recovery. Relevant articles were identified by conducting a literature search in PubMed using the search terms “schizophrenia” AND “cognition” AND “social functioning,” limited to Title/Abstract, over a time period of the past 10 years. Current evidence demonstrates that schizophrenia is associated with impairments in all four core domains of social cognition, during the pre-first-episode, first-episode, early, and chronic phases of the disease, and that such impairments are important determinants of functional outcome. Interventions targeting the four core domains of social cognition comprise psychosocial approaches (social cognition training programs) and pharmacological therapies. Social cognition training programs targeting multiple and specific core domains of social cognition have shown promise in improving social cognition skills, which, in some cases, has translated into improvements in functional outcomes. Use of some psychosocial interventions has additionally resulted in improvements in clinical symptoms and/or quality of life. Pharmacological therapies, including oxytocin and certain antipsychotics, have yielded more mixed

Utility and Limitations of Using Gene Expression Data to Identify Functional Associations

PubMed Central

Peng, Cheng; Shiu, Shin-Han

2016-01-01

Gene co-expression has been widely used to hypothesize gene function through guilt-by association. However, it is not clear to what degree co-expression is informative, whether it can be applied to genes involved in different biological processes, and how the type of dataset impacts inferences about gene functions. Here our goal is to assess the utility and limitations of using co-expression as a criterion to recover functional associations between genes. By determining the percentage of gene pairs in a metabolic pathway with significant expression correlation, we found that many genes in the same pathway do not have similar transcript profiles and the choice of dataset, annotation quality, gene function, expression similarity measure, and clustering approach significantly impacts the ability to recover functional associations between genes using Arabidopsis thaliana as an example. Some datasets are more informative in capturing coordinated expression profiles and larger data sets are not always better. In addition, to recover the maximum number of known pathways and identify candidate genes with similar functions, it is important to explore rather exhaustively multiple dataset combinations, similarity measures, clustering algorithms and parameters. Finally, we validated the biological relevance of co-expression cluster memberships with an independent phenomics dataset and found that genes that consistently cluster with leucine degradation genes tend to have similar leucine levels in mutants. This study provides a framework for obtaining gene functional associations by maximizing the information that can be obtained from gene expression datasets. PMID:27935950

Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

PubMed Central

Gala, Manish; Abecasis, Goncalo; Bezieau, Stephane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Casey, Graham; Chang-Claude, Jenny; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jenkins, Mark A.; Küry, Sébastien; Le Marchand, Loic; Leal, Suzanne M.; Newcomb, Polly A.; Nickerson, Deborah A.; Potter, John D.; Schoen, Robert E.; Schumacher, Fredrick R.; Seminara, Daniela; Slattery, Martha L.; Hsu, Li; Chan, Andrew T.; White, Emily; Berndt, Sonja I.; Peters, Ulrike

2016-01-01

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). PMID:27379672

Functional Proteomics to Identify Moderators of CD8+ T Cell Function in Melanoma

DTIC Science & Technology

2015-05-01

identified 17 phage that selectively bind TIL rather than effector cells. However, none of these phage influenced CD8+ TIL expansion or function in vitro...Using a novel NextGeneration sequencing approach, we have further defined another 1,000,000 phage that selectively bind TIL , of which 100,000 are unique...Using the original approach outlined in the application, we identified a total of 17 unique phage that selectively bind CD8+ TIL but not effector or

The Functionality of Facial Appearance and Its Importance to a Korean Population

PubMed Central

Kim, Young Jun; Park, Jang Wan; Kim, Jeong Min; Park, Sun Hyung; Hwang, Jae Ha; Lee, Sam Yong; Shin, Jun Ho

2013-01-01

Background Many people have an interest in the correction of facial scars or deformities caused by trauma. The increasing ability to correct such flaws has been one of the reasons for the increase in the popularity of facial plastic surgery. In addition to its roles in communication, breathing, eating, olfaction and vision, the appearance of the face also plays an important role in human interactions, including during social activities. However, studies on the importance of the functional role of facial appearance. As a function of the face are scare. Therefore, in the present study, we evaluated the importance of the functions of the face in Korea. Methods We conducted an online panel survey of 300 participants (age range, 20-70 years). Each respondent was administered the demographic data form, Facial Function Assessment Scale, Rosenberg Self-Esteem Scale, and standard gamble questionnaires. Results In the evaluation on the importance of facial functions, a normal appearance was considered as important as communication, breathing, speech, and vision. Of the 300 participants, 85% stated that a normal appearance is important in social activities. Conclusions The results of this survey involving a cross-section of the Korean population indicated that a normal appearance was considered one of the principal facial functions. A normal appearance was considered more important than the functions of olfaction and expression. Moreover, a normal appearance was determined to be an important facial function for leading a normal life in Korea. PMID:24286044

Replacement Behaviors for Identified Functions of Challenging Behaviors

ERIC Educational Resources Information Center

Matson, Johnny L.; Shoemaker, Mary E.; Sipes, Megan; Horovitz, Max; Worley, Julie A.; Kozlowski, Alison M.

2011-01-01

Functional assessment has become a major feature of learning-based research. A critical element of the majority of these studies includes not only methods and procedures to identify the cause of the challenging behavior, but to establish replacement treatment methods. By far the most common intervention in the 176 studies we reviewed was…

Identifying taxonomic and functional surrogates for spring biodiversity conservation.

PubMed

Jyväsjärvi, Jussi; Virtanen, Risto; Ilmonen, Jari; Paasivirta, Lauri; Muotka, Timo

2018-02-27

Surrogate approaches are widely used to estimate overall taxonomic diversity for conservation planning. Surrogate taxa are frequently selected based on rarity or charisma, whereas selection through statistical modeling has been applied rarely. We used boosted-regression-tree models (BRT) fitted to biological data from 165 springs to identify bryophyte and invertebrate surrogates for taxonomic and functional diversity of boreal springs. We focused on these 2 groups because they are well known and abundant in most boreal springs. The best indicators of taxonomic versus functional diversity differed. The bryophyte Bryum weigelii and the chironomid larva Paratrichocladius skirwithensis best indicated taxonomic diversity, whereas the isopod Asellus aquaticus and the chironomid Macropelopia spp. were the best surrogates of functional diversity. In a scoring algorithm for priority-site selection, taxonomic surrogates performed only slightly better than random selection for all spring-dwelling taxa, but they were very effective in representing spring specialists, providing a distinct improvement over random solutions. However, the surrogates for taxonomic diversity represented functional diversity poorly and vice versa. When combined with cross-taxon complementarity analyses, surrogate selection based on statistical modeling provides a promising approach for identifying groundwater-dependent ecosystems of special conservation value, a key requirement of the EU Water Framework Directive. © 2018 Society for Conservation Biology.

A functional genomics screen identifies an Importin-α homolog as a regulator of stem cell function and tissue patterning during planarian regeneration.

PubMed

Hubert, Amy; Henderson, Jordana M; Cowles, Martis W; Ross, Kelly G; Hagen, Matthew; Anderson, Christa; Szeterlak, Claudia J; Zayas, Ricardo M

2015-10-12

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. We used microarrays to detect changes in gene expression in regenerating and non-regenerating tissues in planarians regenerating one side of the head and followed this with high-throughput screening by in situ hybridization and RNAi to characterize the expression patterns and function of the differentially expressed genes. Along with five previously characterized genes (Smed-cycD, Smed-morf41/mrg-1, Smed-pdss2/dlp1, Smed-slbp, and Smed-tph), we identified 20 additional genes necessary for stem cell maintenance (Smed-sart3, Smed-smarcc-1, Smed-espl1, Smed-rrm2b-1, Smed-rrm2b-2, Smed-dkc1, Smed-emg1, Smed-lig1, Smed-prim2, Smed-mcm7, and a novel sequence) or general regenerative capability (Smed-rbap46/48-2, Smed-mcm2, Smed-ptbp1, and Smed-fen-1) or that caused tissue-specific defects upon knockdown (Smed-ddc, Smed-gas8, Smed-pgbd4, and Smed-b9d2). We also found that a homolog of the nuclear transport factor Importin-α plays a role in stem cell function and tissue patterning, suggesting that controlled nuclear import of proteins is important for regeneration. Through this work, we described the roles of several previously uncharacterized genes in planarian regeneration and implicated nuclear import in this process. We have additionally created an online database to house our in situ and RNAi data to make it accessible to the planarian research community.

Resampling procedures to identify important SNPs using a consensus approach.

PubMed

Pardy, Christopher; Motyer, Allan; Wilson, Susan

2011-11-29

Our goal is to identify common single-nucleotide polymorphisms (SNPs) (minor allele frequency > 1%) that add predictive accuracy above that gained by knowledge of easily measured clinical variables. We take an algorithmic approach to predict each phenotypic variable using a combination of phenotypic and genotypic predictors. We perform our procedure on the first simulated replicate and then validate against the others. Our procedure performs well when predicting Q1 but is less successful for the other outcomes. We use resampling procedures where possible to guard against false positives and to improve generalizability. The approach is based on finding a consensus regarding important SNPs by applying random forests and the least absolute shrinkage and selection operator (LASSO) on multiple subsamples. Random forests are used first to discard unimportant predictors, narrowing our focus to roughly 100 important SNPs. A cross-validation LASSO is then used to further select variables. We combine these procedures to guarantee that cross-validation can be used to choose a shrinkage parameter for the LASSO. If the clinical variables were unavailable, this prefiltering step would be essential. We perform the SNP-based analyses simultaneously rather than one at a time to estimate SNP effects in the presence of other causal variants. We analyzed the first simulated replicate of Genetic Analysis Workshop 17 without knowledge of the true model. Post-conference knowledge of the simulation parameters allowed us to investigate the limitations of our approach. We found that many of the false positives we identified were substantially correlated with genuine causal SNPs.

Pair correlation functions for identifying spatial correlation in discrete domains

NASA Astrophysics Data System (ADS)

Gavagnin, Enrico; Owen, Jennifer P.; Yates, Christian A.

2018-06-01

Identifying and quantifying spatial correlation are important aspects of studying the collective behavior of multiagent systems. Pair correlation functions (PCFs) are powerful statistical tools that can provide qualitative and quantitative information about correlation between pairs of agents. Despite the numerous PCFs defined for off-lattice domains, only a few recent studies have considered a PCF for discrete domains. Our work extends the study of spatial correlation in discrete domains by defining a new set of PCFs using two natural and intuitive definitions of distance for a square lattice: the taxicab and uniform metric. We show how these PCFs improve upon previous attempts and compare between the quantitative data acquired. We also extend our definitions of the PCF to other types of regular tessellation that have not been studied before, including hexagonal, triangular, and cuboidal. Finally, we provide a comprehensive PCF for any tessellation and metric, allowing investigation of spatial correlation in irregular lattices for which recognizing correlation is less intuitive.

27 CFR 478.92 - How must licensed manufacturers and licensed importers identify firearms, armor piercing...

Code of Federal Regulations, 2010 CFR

2010-04-01

... Conduct of Business § 478.92 How must licensed manufacturers and licensed importers identify firearms... business; and (E) In the case of an imported firearm, the name of the country in which it was manufactured... place of business. For additional requirements relating to imported firearms, see Customs regulations at...

Indicators of ecosystem function identify alternate states in the sagebrush steppe.

PubMed

Kachergis, Emily; Rocca, Monique E; Fernandez-Gimenez, Maria E

2011-10-01

Models of ecosystem change that incorporate nonlinear dynamics and thresholds, such as state-and-transition models (STMs), are increasingly popular tools for land management decision-making. However, few models are based on systematic collection and documentation of ecological data, and of these, most rely solely on structural indicators (species composition) to identify states and transitions. As STMs are adopted as an assessment framework throughout the United States, finding effective and efficient ways to create data-driven models that integrate ecosystem function and structure is vital. This study aims to (1) evaluate the utility of functional indicators (indicators of rangeland health, IRH) as proxies for more difficult ecosystem function measurements and (2) create a data-driven STM for the sagebrush steppe of Colorado, USA, that incorporates both ecosystem structure and function. We sampled soils, plant communities, and IRH at 41 plots with similar clayey soils but different site histories to identify potential states and infer the effects of management practices and disturbances on transitions. We found that many IRH were correlated with quantitative measures of functional indicators, suggesting that the IRH can be used to approximate ecosystem function. In addition to a reference state that functions as expected for this soil type, we identified four biotically and functionally distinct potential states, consistent with the theoretical concept of alternate states. Three potential states were related to management practices (chemical and mechanical shrub treatments and seeding history) while one was related only to ecosystem processes (erosion). IRH and potential states were also related to environmental variation (slope, soil texture), suggesting that there are environmental factors within areas with similar soils that affect ecosystem dynamics and should be noted within STMs. Our approach generated an objective, data-driven model of ecosystem dynamics

Assessment Tools for Identifying Functional Limitations Associated With Functional Ankle Instability

PubMed Central

Ross, Scott E; Guskiewicz, Kevin M; Gross, Michael T; Yu, Bing

2008-01-01

Context: Assessment tools should identify functional limitations associated with functional ankle instability (FAI) by discriminating unstable from stable ankles. Objective: To identify assessment tools that discriminated FAI from stable ankles and determine the most accurate assessment tool for discriminating between FAI and stable ankles. Design: Case-control study. Setting: Research laboratory. Patients or Other Participants: Fifteen individuals with FAI and 15 healthy individuals; participants with unilateral FAI reported “giving-way” sensations and ankle sprains, whereas healthy participants did not. Intervention(s): Participants answered 12 questions on the Ankle Joint Functional Assessment Tool (AJFAT). They also performed a single-leg jump landing, which required them to jump to half their maximum jump height, land on a single leg, and stabilize quickly on a force plate. Main Outcome Measure(s): Receiver operating characteristic curves determined cutoff scores for discriminating between ankle groups for AJFAT total score and resultant vector (RV) time to stabilization. Accuracy values for discriminating between groups were determined by calculating the area under the receiver operating characteristic curves. Results: The cutoff score for discriminating between FAI and stable ankles was ≥26 (sensitivity  =  1, specificity  =  1) and ≥1.58 seconds (sensitivity  =  0.67, specificity  =  0.73) for the AJFAT total score and RV time to stabilization, respectively. The area under the curve for the AJFAT was 1.0 (asymptotic significance <.05), whereas the RV time to stabilization had an area under the curve of 0.72 (asymptotic significance <.05). Conclusions: The AJFAT was an excellent assessment tool for discriminating between ankle groups, whereas RV time to stabilization was a fair assessment tool. Although both assessments discriminated between ankle groups, the AJFAT more accurately discriminated between groups than the RV time to

Identifying functional groups for response to disturbance in an abandoned pasture

NASA Astrophysics Data System (ADS)

Lavorel, Sandra; Touzard, Blaise; Lebreton, Jean-Dominique; Clément, Bernard

1998-06-01

In an abandoned pasture in Brittany, we compared artificial small-scale disturbances to natural disturbances by wild boar and undisturbed vegetation. We developed a multivariate statistical approach which analyses how species biological attributes explain the response of community composition to disturbances. This technique, which reconciles the inductive and deductive approaches for functional classifications, identifies groups of species with similar responses to disturbance and characterizes their biological profiles. After 5 months of recolonization, artificial disturbances had a greater species richness than undisturbed vegetation as a result of recruitment of new species without the exclusion of pre-existing matrix species. Species morphology, described by canopy structure, canopy height and lateral spread, explained a large part (16 %) of community response to disturbance. Regeneration strategies, described by life history, seed mass, dispersal agent, dormancy and the existence of vegetative multiplication, explained a smaller part of community response to disturbance (8 %). Artificial disturbances were characterized by therophyte and compact rosettes with moderately dormant seeds, including a number of Asteraceae and other early successional species. Natural disturbances were colonized by leafy guerrilla species without seed dormancy. Few species were tightly related to undisturbed vegetation and were essentially grasses with a phalanx rosette morphology. The functional classification obtained is consistent with the classification of the community into fugitives, regenerators and persistors. These groups are structured according to Grubb's model for temperate grasslands, with regenerators and persistors in the matrix and fugitives taking advantage of gaps open by small-scale disturbances. The conjunction of functional diversity and species diversity within functional groups is the key to resilience to disturbance, an important ecosystem function.

Integrative analyses of transcriptome sequencing identify novel functional lncRNAs in esophageal squamous cell carcinoma.

PubMed

Li, C-Q; Huang, G-W; Wu, Z-Y; Xu, Y-J; Li, X-C; Xue, Y-J; Zhu, Y; Zhao, J-M; Li, M; Zhang, J; Wu, J-Y; Lei, F; Wang, Q-Y; Li, S; Zheng, C-P; Ai, B; Tang, Z-D; Feng, C-C; Liao, L-D; Wang, S-H; Shen, J-H; Liu, Y-J; Bai, X-F; He, J-Z; Cao, H-H; Wu, B-L; Wang, M-R; Lin, D-C; Koeffler, H P; Wang, L-D; Li, X; Li, E-M; Xu, L-Y

2017-02-13

Long non-coding RNAs (lncRNAs) have a critical role in cancer initiation and progression, and thus may mediate oncogenic or tumor suppressing effects, as well as be a new class of cancer therapeutic targets. We performed high-throughput sequencing of RNA (RNA-seq) to investigate the expression level of lncRNAs and protein-coding genes in 30 esophageal samples, comprised of 15 esophageal squamous cell carcinoma (ESCC) samples and their 15 paired non-tumor tissues. We further developed an integrative bioinformatics method, denoted URW-LPE, to identify key functional lncRNAs that regulate expression of downstream protein-coding genes in ESCC. A number of known onco-lncRNA and many putative novel ones were effectively identified by URW-LPE. Importantly, we identified lncRNA625 as a novel regulator of ESCC cell proliferation, invasion and migration. ESCC patients with high lncRNA625 expression had significantly shorter survival time than those with low expression. LncRNA625 also showed specific prognostic value for patients with metastatic ESCC. Finally, we identified E1A-binding protein p300 (EP300) as a downstream executor of lncRNA625-induced transcriptional responses. These findings establish a catalog of novel cancer-associated functional lncRNAs, which will promote our understanding of lncRNA-mediated regulation in this malignancy.

Semantic integration to identify overlapping functional modules in protein interaction networks

PubMed Central

Cho, Young-Rae; Hwang, Woochang; Ramanathan, Murali; Zhang, Aidong

2007-01-01

Background The systematic analysis of protein-protein interactions can enable a better understanding of cellular organization, processes and functions. Functional modules can be identified from the protein interaction networks derived from experimental data sets. However, these analyses are challenging because of the presence of unreliable interactions and the complex connectivity of the network. The integration of protein-protein interactions with the data from other sources can be leveraged for improving the effectiveness of functional module detection algorithms. Results We have developed novel metrics, called semantic similarity and semantic interactivity, which use Gene Ontology (GO) annotations to measure the reliability of protein-protein interactions. The protein interaction networks can be converted into a weighted graph representation by assigning the reliability values to each interaction as a weight. We presented a flow-based modularization algorithm to efficiently identify overlapping modules in the weighted interaction networks. The experimental results show that the semantic similarity and semantic interactivity of interacting pairs were positively correlated with functional co-occurrence. The effectiveness of the algorithm for identifying modules was evaluated using functional categories from the MIPS database. We demonstrated that our algorithm had higher accuracy compared to other competing approaches. Conclusion The integration of protein interaction networks with GO annotation data and the capability of detecting overlapping modules substantially improve the accuracy of module identification. PMID:17650343

Identifying hub stations and important lines of bus networks: A case study in Xiamen, China

NASA Astrophysics Data System (ADS)

Zhang, Hui; Zhuge, Chengxiang; Yu, Xiaohua

2018-07-01

Hub stations and important lines play key roles in transfers between stations. In this paper, a node failure model is proposed to identify hub stations. In the model, we introduce two new indicators called neighborhood degree ratio and transfer index to evaluate the importance of stations, which consider neighborhood stations' degree of station and the initial transfer times between stations. Moreover, line accessibility is developed to measure the importance of lines in the bus network. Xiamen bus network in 2016 is utilized to test the model. The results show that the two introduced indicators are more effective to identify hub stations compared with traditional complex network indicators such as degree, clustering coefficient and betweenness.

ORF phage display to identify cellular proteins with different functions.

PubMed

Li, Wei

2012-09-01

Open reading frame (ORF) phage display is a new branch of phage display aimed at improving its efficiency to identify cellular proteins with specific binding or functional activities. Despite the success of phage display with antibody libraries and random peptide libraries, phage display with cDNA libraries of cellular proteins identifies a high percentage of non-ORF clones encoding unnatural short peptides with minimal biological implications. This is mainly because of the uncontrollable reading frames of cellular proteins in conventional cDNA libraries. ORF phage display solves this problem by eliminating non-ORF clones to generate ORF cDNA libraries. Here I summarize the procedures of ORF phage display, discuss the factors influencing its efficiency, present examples of its versatile applications, and highlight evidence of its capability of identifying biologically relevant cellular proteins. ORF phage display coupled with different selection strategies is capable of delineating diverse functions of cellular proteins with unique advantages. Copyright © 2012 Elsevier Inc. All rights reserved.

Important caves to be identified

NASA Astrophysics Data System (ADS)

Criteria to identify significant caves on federal land are being developed by the Interior Department's Bureau of Land Management and the Agriculture Department's Forest Service under requirements of the Federal Cave Resources Protection Act of 1988. The departments gave advance notice of proposed rulemaking March 3 and invited suggestions and comments from the public for 30 days.The law requires protection, to the extent practical, of significant caves on lands administered by the Secretaries of Agriculture and Interior and includes authority to issue and revoke permits for collection and removal of cave resources and special provisions for regulation of cave resources on Indian lands. Final regulations must be published by August 18, 1989.

Intensive cardiovascular risk reduction induces sustainable changes in expression of genes and pathways important to vascular function.

PubMed

Ellsworth, Darrell L; Croft, Daniel T; Weyandt, Jamie; Sturtz, Lori A; Blackburn, Heather L; Burke, Amy; Haberkorn, Mary Jane; McDyer, Fionnuala A; Jellema, Gera L; van Laar, Ryan; Mamula, Kimberly A; Chen, Yaqin; Vernalis, Marina N

2014-04-01

Healthy lifestyle changes are thought to mediate cardiovascular disease risk through pathways affecting endothelial function and progression of atherosclerosis; however, the extent, persistence, and clinical significance of molecular change during lifestyle modification are not well known. We examined the effect of a rigorous cardiovascular disease risk reduction program on peripheral blood gene expression profiles in 63 participants and 63 matched controls to characterize molecular responses and identify regulatory pathways important to cardiovascular health. Dramatic changes in dietary fat intake (-61%; P<0.001 versus controls) and physical fitness (+34%; P<0.001) led to significant improvements in cardiovascular disease risk factors. Analysis of variance with false discovery rate correction for multiple testing (P<0.05) identified 26 genes after 12 weeks and 143 genes after 52 weeks that were differentially expressed from baseline in participants. Controls showed little change in cardiovascular disease risk factors or gene expression. Quantitative reverse transcription polymerase chain reaction validated differential expression for selected transcripts. Lifestyle modification effectively reduced expression of proinflammatory genes associated with neutrophil activation and molecular pathways important to vascular function, including cytokine production, carbohydrate metabolism, and steroid hormones. Prescription medications did not significantly affect changes in gene expression. Successful and sustained modulation of gene expression through lifestyle changes may have beneficial effects on the vascular system not apparent from traditional risk factors. Healthy lifestyles may restore homeostasis to the leukocyte transcriptome by downregulating lactoferrin and other genes important in the pathogenesis of atherosclerosis. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT01805492.

Identifying selectively important amino acid positions associated with alternative habitat environments in fish mitochondrial genomes.

PubMed

Xia, Jun Hong; Li, Hong Lian; Zhang, Yong; Meng, Zi Ning; Lin, Hao Ran

2018-05-01

Fish species inhabitating seawater (SW) or freshwater (FW) habitats have to develop genetic adaptations to alternative environment factors, especially salinity. Functional consequences of the protein variations associated with habitat environments in fish mitochondrial genomes have not yet received much attention. We analyzed 829 complete fish mitochondrial genomes and compared the amino acid differences of 13 mitochondrial protein families between FW and SW fish groups. We identified 47 specificity determining sites (SDS) that associated with FW or SW environments from 12 mitochondrial protein families. Thirty-two (68%) of the SDS sites are hydrophobic, 13 (28%) are neutral, and the remaining sites are acidic or basic. Seven of those SDS from ND1, ND2 and ND5 were scored as probably damaging to the protein structures. Furthermore, phylogenetic tree based Bayes Empirical Bayes analysis also detected 63 positive sites associated with alternative habitat environments across ten mtDNA proteins. These signatures could be important for studying mitochondrial genetic variation relevant to fish physiology and ecology.

Functional Conservation of the Transportin Nuclear Import Pathway in Divergent Organisms

PubMed Central

Siomi, Mikiko C.; Fromont, Micheline; Rain, Jean-Christophe; Wan, Lili; Wang, Fan; Legrain, Pierre; Dreyfuss, Gideon

1998-01-01

Human transportin1 (hTRN1) is the nuclear import receptor for a group of pre-mRNA/mRNA-binding proteins (heterogeneous nuclear ribonucleoproteins [hnRNP]) represented by hnRNP A1, which shuttle continuously between the nucleus and the cytoplasm. hTRN1 interacts with the M9 region of hnRNP A1, a 38-amino-acid domain rich in Gly, Ser, and Asn, and mediates the nuclear import of M9-bearing proteins in vitro. Saccharomyces cerevisiae transportin (yTRN; also known as YBR017c or Kap104p) has been identified and cloned. To understanding the nuclear import mediated by yTRN, we searched with a yeast two-hybrid system for proteins that interact with it. In an exhaustive screen of the S. cerevisiae genome, the most frequently selected open reading frame was the nuclear mRNA-binding protein, Nab2p. We delineated a ca.-50-amino-acid region in Nab2p, termed NAB35, which specifically binds yTRN and is similar to the M9 motif. NAB35 also interacts with hTRN1 and functions as a nuclear localization signal in mammalian cells. Interestingly, yTRN can also mediate the import of NAB35-bearing proteins into mammalian nuclei in vitro. We also report on additional substrates for TRN as well as sequences of Drosophila melanogaster, Xenopus laevis, and Schizosaccharomyces pombe TRNs. Together, these findings demonstrate that both the M9 signal and the nuclear import machinery utilized by the transportin pathway are conserved in evolution. PMID:9632798

Functional Comparison of Bacteria from the Human Gut and Closely Related Non-Gut Bacteria Reveals the Importance of Conjugation and a Paucity of Motility and Chemotaxis Functions in the Gut Environment.

PubMed

Dobrijevic, Dragana; Abraham, Anne-Laure; Jamet, Alexandre; Maguin, Emmanuelle; van de Guchte, Maarten

2016-01-01

The human GI tract is a complex and still poorly understood environment, inhabited by one of the densest microbial communities on earth. The gut microbiota is shaped by millennia of evolution to co-exist with the host in commensal or symbiotic relationships. Members of the gut microbiota perform specific molecular functions important in the human gut environment. This can be illustrated by the presence of a highly expanded repertoire of proteins involved in carbohydrate metabolism, in phase with the large diversity of polysaccharides originating from the diet or from the host itself that can be encountered in this environment. In order to identify other bacterial functions that are important in the human gut environment, we investigated the distribution of functional groups of proteins in a group of human gut bacteria and their close non-gut relatives. Complementary to earlier global comparisons between different ecosystems, this approach should allow a closer focus on a group of functions directly related to the gut environment while avoiding functions related to taxonomically divergent microbiota composition, which may or may not be relevant for gut homeostasis. We identified several functions that are overrepresented in the human gut bacteria which had not been recognized in a global approach. The observed under-representation of certain other functions may be equally important for gut homeostasis. Together, these analyses provide us with new information about this environment so critical to our health and well-being.

Functional Comparison of Bacteria from the Human Gut and Closely Related Non-Gut Bacteria Reveals the Importance of Conjugation and a Paucity of Motility and Chemotaxis Functions in the Gut Environment

PubMed Central

Dobrijevic, Dragana; Abraham, Anne-Laure; Jamet, Alexandre; Maguin, Emmanuelle; van de Guchte, Maarten

2016-01-01

The human GI tract is a complex and still poorly understood environment, inhabited by one of the densest microbial communities on earth. The gut microbiota is shaped by millennia of evolution to co-exist with the host in commensal or symbiotic relationships. Members of the gut microbiota perform specific molecular functions important in the human gut environment. This can be illustrated by the presence of a highly expanded repertoire of proteins involved in carbohydrate metabolism, in phase with the large diversity of polysaccharides originating from the diet or from the host itself that can be encountered in this environment. In order to identify other bacterial functions that are important in the human gut environment, we investigated the distribution of functional groups of proteins in a group of human gut bacteria and their close non-gut relatives. Complementary to earlier global comparisons between different ecosystems, this approach should allow a closer focus on a group of functions directly related to the gut environment while avoiding functions related to taxonomically divergent microbiota composition, which may or may not be relevant for gut homeostasis. We identified several functions that are overrepresented in the human gut bacteria which had not been recognized in a global approach. The observed under-representation of certain other functions may be equally important for gut homeostasis. Together, these analyses provide us with new information about this environment so critical to our health and well-being. PMID:27416027

Statistical Analyses of Scatterplots to Identify Important Factors in Large-Scale Simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kleijnen, J.P.C.; Helton, J.C.

1999-04-01

The robustness of procedures for identifying patterns in scatterplots generated in Monte Carlo sensitivity analyses is investigated. These procedures are based on attempts to detect increasingly complex patterns in the scatterplots under consideration and involve the identification of (1) linear relationships with correlation coefficients, (2) monotonic relationships with rank correlation coefficients, (3) trends in central tendency as defined by means, medians and the Kruskal-Wallis statistic, (4) trends in variability as defined by variances and interquartile ranges, and (5) deviations from randomness as defined by the chi-square statistic. The following two topics related to the robustness of these procedures are consideredmore » for a sequence of example analyses with a large model for two-phase fluid flow: the presence of Type I and Type II errors, and the stability of results obtained with independent Latin hypercube samples. Observations from analysis include: (1) Type I errors are unavoidable, (2) Type II errors can occur when inappropriate analysis procedures are used, (3) physical explanations should always be sought for why statistical procedures identify variables as being important, and (4) the identification of important variables tends to be stable for independent Latin hypercube samples.« less

Different approaches for identifying important concepts in probabilistic biomedical text summarization.

PubMed

Moradi, Milad; Ghadiri, Nasser

2018-01-01

Automatic text summarization tools help users in the biomedical domain to acquire their intended information from various textual resources more efficiently. Some of biomedical text summarization systems put the basis of their sentence selection approach on the frequency of concepts extracted from the input text. However, it seems that exploring other measures rather than the raw frequency for identifying valuable contents within an input document, or considering correlations existing between concepts, may be more useful for this type of summarization. In this paper, we describe a Bayesian summarization method for biomedical text documents. The Bayesian summarizer initially maps the input text to the Unified Medical Language System (UMLS) concepts; then it selects the important ones to be used as classification features. We introduce six different feature selection approaches to identify the most important concepts of the text and select the most informative contents according to the distribution of these concepts. We show that with the use of an appropriate feature selection approach, the Bayesian summarizer can improve the performance of biomedical summarization. Using the Recall-Oriented Understudy for Gisting Evaluation (ROUGE) toolkit, we perform extensive evaluations on a corpus of scientific papers in the biomedical domain. The results show that when the Bayesian summarizer utilizes the feature selection methods that do not use the raw frequency, it can outperform the biomedical summarizers that rely on the frequency of concepts, domain-independent and baseline methods. Copyright © 2017 Elsevier B.V. All rights reserved.

Use of multilevel logistic regression to identify the causes of differential item functioning.

PubMed

Balluerka, Nekane; Gorostiaga, Arantxa; Gómez-Benito, Juana; Hidalgo, María Dolores

2010-11-01

Given that a key function of tests is to serve as evaluation instruments and for decision making in the fields of psychology and education, the possibility that some of their items may show differential behaviour is a major concern for psychometricians. In recent decades, important progress has been made as regards the efficacy of techniques designed to detect this differential item functioning (DIF). However, the findings are scant when it comes to explaining its causes. The present study addresses this problem from the perspective of multilevel analysis. Starting from a case study in the area of transcultural comparisons, multilevel logistic regression is used: 1) to identify the item characteristics associated with the presence of DIF; 2) to estimate the proportion of variation in the DIF coefficients that is explained by these characteristics; and 3) to evaluate alternative explanations of the DIF by comparing the explanatory power or fit of different sequential models. The comparison of these models confirmed one of the two alternatives (familiarity with the stimulus) and rejected the other (the topic area) as being a cause of differential functioning with respect to the compared groups.

Identifying important motivational factors for professionals in Greek hospitals

PubMed Central

Kontodimopoulos, Nick; Paleologou, Victoria; Niakas, Dimitris

2009-01-01

Background The purpose of this study was to identify important motivational factors according to the views of health-care professionals in Greek hospitals and particularly to determine if these might differ in the public and private sectors. Methods A previously developed -and validated- instrument addressing four work-related motivators (job attributes, remuneration, co-workers and achievements) was used. Three categories of health care professionals, doctors (N = 354), nurses (N = 581) and office workers (N = 418), working in public and private hospitals, participated and motivation was compared across socio-demographic and occupational variables. Results The range of reported motivational factors was mixed and Maslow's conclusions that lower level motivational factors must be met before ascending to the next level were not confirmed. The highest ranked motivator for the entire sample, and by professional subgroup, was achievements (P < 0.001). Within subgroups, motivators were similar, and only one significant difference was observed, namely between doctors and nurses in respect to co-workers (P < 0.05). Remuneration (and salary in particular) was reported as a significant incentive only for professionals in managerial positions. Health professionals in private hospitals were motivated by all factors significantly more than their public-hospital counterparts. Conclusion The results are in agreement with the literature which focuses attention to management approaches employing both monetary and non-monetary incentives to motivate health care workers. This study showed that intrinsic factors are particularly important and should become a target for effective employee motivation. PMID:19754968

Selection on plant male function genes identifies candidates for reproductive isolation of yellow monkeyflowers.

PubMed

Aagaard, Jan E; George, Renee D; Fishman, Lila; Maccoss, Michael J; Swanson, Willie J

2013-01-01

Understanding the genetic basis of reproductive isolation promises insight into speciation and the origins of biological diversity. While progress has been made in identifying genes underlying barriers to reproduction that function after fertilization (post-zygotic isolation), we know much less about earlier acting pre-zygotic barriers. Of particular interest are barriers involved in mating and fertilization that can evolve extremely rapidly under sexual selection, suggesting they may play a prominent role in the initial stages of reproductive isolation. A significant challenge to the field of speciation genetics is developing new approaches for identification of candidate genes underlying these barriers, particularly among non-traditional model systems. We employ powerful proteomic and genomic strategies to study the genetic basis of conspecific pollen precedence, an important component of pre-zygotic reproductive isolation among yellow monkeyflowers (Mimulus spp.) resulting from male pollen competition. We use isotopic labeling in combination with shotgun proteomics to identify more than 2,000 male function (pollen tube) proteins within maternal reproductive structures (styles) of M. guttatus flowers where pollen competition occurs. We then sequence array-captured pollen tube exomes from a large outcrossing population of M. guttatus, and identify those genes with evidence of selective sweeps or balancing selection consistent with their role in pollen competition. We also test for evidence of positive selection on these genes more broadly across yellow monkeyflowers, because a signal of adaptive divergence is a common feature of genes causing reproductive isolation. Together the molecular evolution studies identify 159 pollen tube proteins that are candidate genes for conspecific pollen precedence. Our work demonstrates how powerful proteomic and genomic tools can be readily adapted to non-traditional model systems, allowing for genome-wide screens towards the

High-Throughput Genetic Identification of Functionally Important Regions of the Yeast DEAD-Box Protein Mss116p

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohr, Georg; Del Campo, Mark; Turner, Kathryn G.

The Saccharomyces cerevisiae DEAD-box protein Mss116p is a general RNA chaperone that functions in splicing mitochondrial group I and group II introns. Recent X-ray crystal structures of Mss116p in complex with ATP analogs and single-stranded RNA show that the helicase core induces a bend in the bound RNA, as in other DEAD-box proteins, while a C-terminal extension (CTE) induces a second bend, resulting in RNA crimping. Here, we illuminate these structures by using high-throughput genetic selections, unigenic evolution, and analyses of in vivo splicing activity to comprehensively identify functionally important regions and permissible amino acid substitutions throughout Mss116p. The functionallymore » important regions include those containing conserved sequence motifs involved in ATP and RNA binding or interdomain interactions, as well as previously unidentified regions, including surface loops that may function in protein-protein interactions. The genetic selections recapitulate major features of the conserved helicase motifs seen in other DEAD-box proteins but also show surprising variations, including multiple novel variants of motif III (SAT). Patterns of amino acid substitutions indicate that the RNA bend induced by the helicase core depends on ionic and hydrogen-bonding interactions with the bound RNA; identify a subset of critically interacting residues; and indicate that the bend induced by the CTE results primarily from a steric block. Finally, we identified two conserved regions - one the previously noted post II region in the helicase core and the other in the CTE - that may help displace or sequester the opposite RNA strand during RNA unwinding.« less

The importance of functional form in optimal control solutions of problems in population dynamics

USGS Publications Warehouse

Runge, M.C.; Johnson, F.A.

2002-01-01

Optimal control theory is finding increased application in both theoretical and applied ecology, and it is a central element of adaptive resource management. One of the steps in an adaptive management process is to develop alternative models of system dynamics, models that are all reasonable in light of available data, but that differ substantially in their implications for optimal control of the resource. We explored how the form of the recruitment and survival functions in a general population model for ducks affected the patterns in the optimal harvest strategy, using a combination of analytical, numerical, and simulation techniques. We compared three relationships between recruitment and population density (linear, exponential, and hyperbolic) and three relationships between survival during the nonharvest season and population density (constant, logistic, and one related to the compensatory harvest mortality hypothesis). We found that the form of the component functions had a dramatic influence on the optimal harvest strategy and the ultimate equilibrium state of the system. For instance, while it is commonly assumed that a compensatory hypothesis leads to higher optimal harvest rates than an additive hypothesis, we found this to depend on the form of the recruitment function, in part because of differences in the optimal steady-state population density. This work has strong direct consequences for those developing alternative models to describe harvested systems, but it is relevant to a larger class of problems applying optimal control at the population level. Often, different functional forms will not be statistically distinguishable in the range of the data. Nevertheless, differences between the functions outside the range of the data can have an important impact on the optimal harvest strategy. Thus, development of alternative models by identifying a single functional form, then choosing different parameter combinations from extremes on the likelihood

Word Frequency As a Cue For Identifying Function Words In Infancy

ERIC Educational Resources Information Center

Hochmann, Jean-Remy; Endress, Ansgar D.; Mehler, Jacques

2010-01-01

While content words (e.g., 'dog') tend to carry meaning, function words (e.g., 'the') mainly serve syntactic purposes. Here, we ask whether 17-month old infants can use one language-universal cue to identify function word candidates: their high frequency of occurrence. In Experiment 1, infants listened to a series of short, naturally recorded…

Experimental assessment of the importance of amino acid positions identified by an entropy-based correlation analysis of multiple-sequence alignments.

PubMed

Dietrich, Susanne; Borst, Nadine; Schlee, Sandra; Schneider, Daniel; Janda, Jan-Oliver; Sterner, Reinhard; Merkl, Rainer

2012-07-17

The analysis of a multiple-sequence alignment (MSA) with correlation methods identifies pairs of residue positions whose occupation with amino acids changes in a concerted manner. It is plausible to assume that positions that are part of many such correlation pairs are important for protein function or stability. We have used the algorithm H2r to identify positions k in the MSAs of the enzymes anthranilate phosphoribosyl transferase (AnPRT) and indole-3-glycerol phosphate synthase (IGPS) that show a high conn(k) value, i.e., a large number of significant correlations in which k is involved. The importance of the identified residues was experimentally validated by performing mutagenesis studies with sAnPRT and sIGPS from the archaeon Sulfolobus solfataricus. For sAnPRT, five H2r mutant proteins were generated by replacing nonconserved residues with alanine or the prevalent residue of the MSA. As a control, five residues with conn(k) values of zero were chosen randomly and replaced with alanine. The catalytic activities and conformational stabilities of the H2r and control mutant proteins were analyzed by steady-state enzyme kinetics and thermal unfolding studies. Compared to wild-type sAnPRT, the catalytic efficiencies (k(cat)/K(M)) were largely unaltered. In contrast, the apparent thermal unfolding temperature (T(M)(app)) was lowered in most proteins. Remarkably, the strongest observed destabilization (ΔT(M)(app) = 14 °C) was caused by the V284A exchange, which pertains to the position with the highest correlation signal [conn(k) = 11]. For sIGPS, six H2r mutant and four control proteins with alanine exchanges were generated and characterized. The k(cat)/K(M) values of four H2r mutant proteins were reduced between 13- and 120-fold, and their T(M)(app) values were decreased by up to 5 °C. For the sIGPS control proteins, the observed activity and stability decreases were much less severe. Our findings demonstrate that positions with high conn(k) values have an

PTEN IDENTIFIED AS IMPORTANT RISK FACTOR OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

PubMed Central

Hosgood, H Dean; Menashe, Idan; He, Xingzhou; Chanock, Stephen; Lan, Qing

2009-01-01

Common genetic variation may play an important role in altering chronic obstructive pulmonary disease (COPD) risk. In Xuanwei, China, the COPD rate is more than twice the Chinese national average, and COPD is strongly associated with in-home coal use. To identify genetic variation that may be associated with COPD in a population with substantial in-home coal smoke exposures, we evaluated 1,261 single nucleotide polymorphisms (SNPs) in 380 candidate genes potentially relevant for cancer and other human diseases in a population-based case-control study in Xuanwei (53 cases; 107 controls). PTEN was the most significantly associated gene with COPD in a minP analysis using 20,000 permutations (P = 0.00005). SNP-based analyses found that homozygote variant carriers of PTEN rs701848 (ORTT = 0.12, 95%CI = 0.03 - 0.47) had a significant decreased risk of COPD. PTEN, or phosphatase and tensin homolog, is an important regulator of cell cycle progression and cellular survival via the AKT signaling pathway. Our exploratory analysis suggests that genetic variation in PTEN may be an important risk factor of COPD in Xuanwei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuanwei and other populations with coal smoke exposures. PMID:19625176

Information sensitivity functions to assess parameter information gain and identifiability of dynamical systems.

PubMed

Pant, Sanjay

2018-05-01

A new class of functions, called the 'information sensitivity functions' (ISFs), which quantify the information gain about the parameters through the measurements/observables of a dynamical system are presented. These functions can be easily computed through classical sensitivity functions alone and are based on Bayesian and information-theoretic approaches. While marginal information gain is quantified by decrease in differential entropy, correlations between arbitrary sets of parameters are assessed through mutual information. For individual parameters, these information gains are also presented as marginal posterior variances, and, to assess the effect of correlations, as conditional variances when other parameters are given. The easy to interpret ISFs can be used to (a) identify time intervals or regions in dynamical system behaviour where information about the parameters is concentrated; (b) assess the effect of measurement noise on the information gain for the parameters; (c) assess whether sufficient information in an experimental protocol (input, measurements and their frequency) is available to identify the parameters; (d) assess correlation in the posterior distribution of the parameters to identify the sets of parameters that are likely to be indistinguishable; and (e) assess identifiability problems for particular sets of parameters. © 2018 The Authors.

Identifying and exploiting trait-relevant tissues with multiple functional annotations in genome-wide association studies

PubMed Central

Zhang, Shujun

2018-01-01

Genome-wide association studies (GWASs) have identified many disease associated loci, the majority of which have unknown biological functions. Understanding the mechanism underlying trait associations requires identifying trait-relevant tissues and investigating associations in a trait-specific fashion. Here, we extend the widely used linear mixed model to incorporate multiple SNP functional annotations from omics studies with GWAS summary statistics to facilitate the identification of trait-relevant tissues, with which to further construct powerful association tests. Specifically, we rely on a generalized estimating equation based algorithm for parameter inference, a mixture modeling framework for trait-tissue relevance classification, and a weighted sequence kernel association test constructed based on the identified trait-relevant tissues for powerful association analysis. We refer to our analytic procedure as the Scalable Multiple Annotation integration for trait-Relevant Tissue identification and usage (SMART). With extensive simulations, we show how our method can make use of multiple complementary annotations to improve the accuracy for identifying trait-relevant tissues. In addition, our procedure allows us to make use of the inferred trait-relevant tissues, for the first time, to construct more powerful SNP set tests. We apply our method for an in-depth analysis of 43 traits from 28 GWASs using tissue-specific annotations in 105 tissues derived from ENCODE and Roadmap. Our results reveal new trait-tissue relevance, pinpoint important annotations that are informative of trait-tissue relationship, and illustrate how we can use the inferred trait-relevant tissues to construct more powerful association tests in the Wellcome trust case control consortium study. PMID:29377896

Warming Alters Expressions of Microbial Functional Genes Important to Ecosystem Functioning

DOE PAGES

Xue, Kai; Xie, Jianping; Zhou, Aifen; ...

2016-05-06

Soil microbial communities play critical roles in ecosystem functioning and are likely altered by climate warming. However, so far, little is known about effects of warming on microbial functional gene expressions. Here, we applied functional gene array (GeoChip 3.0) to analyze cDNA reversely transcribed from total RNA to assess expressed functional genes in active soil microbial communities after nine years of experimental warming in a tallgrass prairie. Our results showed that warming significantly altered the community wide gene expressions. Specifically, expressed genes for degrading more recalcitrant carbon were stimulated by warming, likely linked to the plant community shift toward moremore » C 4 species under warming and to decrease the long-term soil carbon stability. In addition, warming changed expressed genes in labile C degradation and N cycling in different directions (increase and decrease), possibly reflecting the dynamics of labile C and available N pools during sampling. However, the average abundances of expressed genes in phosphorus and sulfur cycling were all increased by warming, implying a stable trend of accelerated P and S processes which might be a mechanism to sustain higher plant growth. Furthermore, the expressed gene composition was closely related to both dynamic (e.g., soil moisture) and stable environmental attributes (e.g., C 4 leaf C or N content), indicating that RNA analyses could also capture certain stable trends in the long-term treatment. Overall, this study revealed the importance of elucidating functional gene expressions of soil microbial community in enhancing our understanding of ecosystem responses to warming.« less

Warming Alters Expressions of Microbial Functional Genes Important to Ecosystem Functioning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xue, Kai; Xie, Jianping; Zhou, Aifen

Soil microbial communities play critical roles in ecosystem functioning and are likely altered by climate warming. However, so far, little is known about effects of warming on microbial functional gene expressions. Here, we applied functional gene array (GeoChip 3.0) to analyze cDNA reversely transcribed from total RNA to assess expressed functional genes in active soil microbial communities after nine years of experimental warming in a tallgrass prairie. Our results showed that warming significantly altered the community wide gene expressions. Specifically, expressed genes for degrading more recalcitrant carbon were stimulated by warming, likely linked to the plant community shift toward moremore » C 4 species under warming and to decrease the long-term soil carbon stability. In addition, warming changed expressed genes in labile C degradation and N cycling in different directions (increase and decrease), possibly reflecting the dynamics of labile C and available N pools during sampling. However, the average abundances of expressed genes in phosphorus and sulfur cycling were all increased by warming, implying a stable trend of accelerated P and S processes which might be a mechanism to sustain higher plant growth. Furthermore, the expressed gene composition was closely related to both dynamic (e.g., soil moisture) and stable environmental attributes (e.g., C 4 leaf C or N content), indicating that RNA analyses could also capture certain stable trends in the long-term treatment. Overall, this study revealed the importance of elucidating functional gene expressions of soil microbial community in enhancing our understanding of ecosystem responses to warming.« less

Warming Alters Expressions of Microbial Functional Genes Important to Ecosystem Functioning

PubMed Central

Xue, Kai; Xie, Jianping; Zhou, Aifen; Liu, Feifei; Li, Dejun; Wu, Liyou; Deng, Ye; He, Zhili; Van Nostrand, Joy D.; Luo, Yiqi; Zhou, Jizhong

2016-01-01

Soil microbial communities play critical roles in ecosystem functioning and are likely altered by climate warming. However, so far, little is known about effects of warming on microbial functional gene expressions. Here, we applied functional gene array (GeoChip 3.0) to analyze cDNA reversely transcribed from total RNA to assess expressed functional genes in active soil microbial communities after nine years of experimental warming in a tallgrass prairie. Our results showed that warming significantly altered the community wide gene expressions. Specifically, expressed genes for degrading more recalcitrant carbon were stimulated by warming, likely linked to the plant community shift toward more C4 species under warming and to decrease the long-term soil carbon stability. In addition, warming changed expressed genes in labile C degradation and N cycling in different directions (increase and decrease), possibly reflecting the dynamics of labile C and available N pools during sampling. However, the average abundances of expressed genes in phosphorus and sulfur cycling were all increased by warming, implying a stable trend of accelerated P and S processes which might be a mechanism to sustain higher plant growth. Furthermore, the expressed gene composition was closely related to both dynamic (e.g., soil moisture) and stable environmental attributes (e.g., C4 leaf C or N content), indicating that RNA analyses could also capture certain stable trends in the long-term treatment. Overall, this study revealed the importance of elucidating functional gene expressions of soil microbial community in enhancing our understanding of ecosystem responses to warming. PMID:27199978

Using the International Classification of Functioning, Disability, and Health to identify outcome domains for a core outcome set for aphasia: a comparison of stakeholder perspectives.

PubMed

Wallace, Sarah J; Worrall, Linda; Rose, Tanya; Le Dorze, Guylaine

2017-11-12

This study synthesised the findings of three separate consensus processes exploring the perspectives of key stakeholder groups about important aphasia treatment outcomes. This process was conducted to generate recommendations for outcome domains to be included in a core outcome set for aphasia treatment trials. International Classification of Functioning, Disability, and Health codes were examined to identify where the groups of: (1) people with aphasia, (2) family members, (3) aphasia researchers, and (4) aphasia clinicians/managers, demonstrated congruence in their perspectives regarding important treatment outcomes. Codes were contextualized using qualitative data. Congruence across three or more stakeholder groups was evident for ICF chapters: Mental functions; Communication; and Services, systems, and policies. Quality of life was explicitly identified by clinicians/managers and researchers, while people with aphasia and their families identified outcomes known to be determinants of quality of life. Core aphasia outcomes include: language, emotional wellbeing, communication, patient-reported satisfaction with treatment and impact of treatment, and quality of life. International Classification of Functioning, Disability, and Health coding can be used to compare stakeholder perspectives and identify domains for core outcome sets. Pairing coding with qualitative data may ensure important nuances of meaning are retained. Implications for rehabilitation The outcomes measured in treatment research should be relevant to stakeholders and support health care decision making. Core outcome sets (agreed, minimum set of outcomes, and outcome measures) are increasingly being used to ensure the relevancy and consistency of the outcomes measured in treatment studies. Important aphasia treatment outcomes span all components of the International Classification of Functioning, Disability, and Health. Stakeholders demonstrated congruence in the identification of important

Functional Proteomics to Identify Moderators of CD8+ T-Cell Function in Melanoma

DTIC Science & Technology

2013-09-01

could then be used to develop imaging agents that are targeted to the TILs. We used an M13 phage vector, which displays a pentavalent peptide as...of the identified transcript. To directly indentify inhibitory molecules, we have proposed to use phage - display expression libraries to perform...of TCD8. 3. To determine the ligands for molecules that can modulate the TCD8 functional state. Body: A. Phage Screen Summary Phage display

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

PubMed

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

2016-10-01

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 surveys were conducted. Of the 97 study participants, 30.9 % were diagnosed with FC, 62.9 % with FC with FI, and 6.2 % with FNRFI. ASD surveys were positive for 27 children (27.8 %). New DSM diagnoses were made in 10 out of the 15 children that completed further evaluation. Two (2.1 %) met criteria for ASD, and 12 (12.4 %) met criteria for other behavioral disorders. Average SRS and SCQ-L scores were higher in subjects with FC with FI as compared to FC alone and in those who reported no improvement versus those who reported improvement 1 year later. While positive ASD screening surveys did not correctly identify ASD in the majority, it did help to identify other unrecognized behavioral disorders in children with FDD. High screening scores were more common in children with FC with FI and in children with poorer responses to current medical treatments. •A prior study found that 29 % of children with FDD scored positive on ASD screening questionnaires. •Whether positive screens correctly identify ASD in children with FDD is unknown. What is New: •This study shows that positive ASD screens do not correctly identify ASD in children with FDD. However, the use of ASD screening questionnaires can identify previously unrecognized and untreated behavioral/developmental disorders in children with FDD. •High screening scores are more common in children with FC with FI and in children with poorer responses to current medical treatments.

Identifying Support Functions in Developmental Relationships: A Self-Determination Perspective

ERIC Educational Resources Information Center

Janssen, Suzanne; van Vuuren, Mark; de Jong, Menno D. T.

2013-01-01

This study examines the content of developmental networks from the perspective of self-determination theory. We qualitatively examine 18 proteges' constellations of developmental relationships to identify specific types of developmental support functions. Our study shows that the adoption of self-determination theory leads to a theory-based…

Hazardous drinking and military community functioning: identifying mediating risk factors.

PubMed

Foran, Heather M; Heyman, Richard E; Slep, Amy M Smith

2011-08-01

Hazardous drinking is a serious societal concern in military populations. Efforts to reduce hazardous drinking among military personnel have been limited in effectiveness. There is a need for a deeper understanding of how community-based prevention models apply to hazardous drinking in the military. Community-wide prevention efforts may be most effective in targeting community functioning (e.g., support from formal agencies, community cohesion) that impacts hazardous drinking via other proximal risk factors. The goal of the current study is to inform community-wide prevention efforts by testing a model of community functioning and mediating risk factors of hazardous drinking among active duty U.S. Air Force personnel. A large, representative survey sample of U.S. Air Force active duty members (N = 52,780) was collected at 82 bases worldwide. Hazardous drinking was assessed with the widely used Alcohol Use Disorders Identification Test (Saunders, Aasland, Babor, de la Fuente, & Grant, 1993). A variety of individual, family, and community measures were also assessed. Structural equation modeling was used to test a hypothesized model of community functioning, mediating risk factors and hazardous drinking. Depressive symptoms, perceived financial stress, and satisfaction with the U.S. Air Force were identified as significant mediators of the link between community functioning and hazardous drinking for men and women. Relationship satisfaction was also identified as a mediator for men. These results provide a framework for further community prevention research and suggest that prevention efforts geared at increasing aspects of community functioning (e.g., the U.S. Air Force Community Capacity model) may indirectly lead to reductions in hazardous drinking through other proximal risk factors.

Logging cuts the functional importance of invertebrates in tropical rainforest

PubMed Central

Ewers, Robert M.; Boyle, Michael J. W.; Gleave, Rosalind A.; Plowman, Nichola S.; Benedick, Suzan; Bernard, Henry; Bishop, Tom R.; Bakhtiar, Effendi Y.; Chey, Vun Khen; Chung, Arthur Y. C.; Davies, Richard G.; Edwards, David P.; Eggleton, Paul; Fayle, Tom M.; Hardwick, Stephen R.; Homathevi, Rahman; Kitching, Roger L.; Khoo, Min Sheng; Luke, Sarah H.; March, Joshua J.; Nilus, Reuben; Pfeifer, Marion; Rao, Sri V.; Sharp, Adam C.; Snaddon, Jake L.; Stork, Nigel E.; Struebig, Matthew J.; Wearn, Oliver R.; Yusah, Kalsum M.; Turner, Edgar C.

2015-01-01

Invertebrates are dominant species in primary tropical rainforests, where their abundance and diversity contributes to the functioning and resilience of these globally important ecosystems. However, more than one-third of tropical forests have been logged, with dramatic impacts on rainforest biodiversity that may disrupt key ecosystem processes. We find that the contribution of invertebrates to three ecosystem processes operating at three trophic levels (litter decomposition, seed predation and removal, and invertebrate predation) is reduced by up to one-half following logging. These changes are associated with decreased abundance of key functional groups of termites, ants, beetles and earthworms, and an increase in the abundance of small mammals, amphibians and insectivorous birds in logged relative to primary forest. Our results suggest that ecosystem processes themselves have considerable resilience to logging, but the consistent decline of invertebrate functional importance is indicative of a human-induced shift in how these ecological processes operate in tropical rainforests. PMID:25865801

Logging cuts the functional importance of invertebrates in tropical rainforest.

PubMed

Ewers, Robert M; Boyle, Michael J W; Gleave, Rosalind A; Plowman, Nichola S; Benedick, Suzan; Bernard, Henry; Bishop, Tom R; Bakhtiar, Effendi Y; Chey, Vun Khen; Chung, Arthur Y C; Davies, Richard G; Edwards, David P; Eggleton, Paul; Fayle, Tom M; Hardwick, Stephen R; Homathevi, Rahman; Kitching, Roger L; Khoo, Min Sheng; Luke, Sarah H; March, Joshua J; Nilus, Reuben; Pfeifer, Marion; Rao, Sri V; Sharp, Adam C; Snaddon, Jake L; Stork, Nigel E; Struebig, Matthew J; Wearn, Oliver R; Yusah, Kalsum M; Turner, Edgar C

2015-04-13

Invertebrates are dominant species in primary tropical rainforests, where their abundance and diversity contributes to the functioning and resilience of these globally important ecosystems. However, more than one-third of tropical forests have been logged, with dramatic impacts on rainforest biodiversity that may disrupt key ecosystem processes. We find that the contribution of invertebrates to three ecosystem processes operating at three trophic levels (litter decomposition, seed predation and removal, and invertebrate predation) is reduced by up to one-half following logging. These changes are associated with decreased abundance of key functional groups of termites, ants, beetles and earthworms, and an increase in the abundance of small mammals, amphibians and insectivorous birds in logged relative to primary forest. Our results suggest that ecosystem processes themselves have considerable resilience to logging, but the consistent decline of invertebrate functional importance is indicative of a human-induced shift in how these ecological processes operate in tropical rainforests.

High-throughput screening identifies microRNAs that target Nox2 and improve function after acute myocardial infarction.

PubMed

Yang, Junyu; Brown, Milton E; Zhang, Hanshuo; Martinez, Mario; Zhao, Zhihua; Bhutani, Srishti; Yin, Shenyi; Trac, David; Xi, Jianzhong Jeff; Davis, Michael E

2017-05-01

Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of ROS plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with NADPH oxidase (Nox)2 as the catalytic subunit is a major source of superoxide production, and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. With the use of the miRNA-target screening system composed of a self-assembled cell microarray (SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products in both human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed that PK3-miRNAs particles could inhibit Nox2 expression and activity and significantly improve infarct size and acute cardiac function after MI. In conclusion, our results show that miR-106b, miR-148b, and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implications for miRNA-mediated therapeutics for cardiovascular and other diseases. NEW & NOTEWORTHY NADPH oxidase (Nox)2 is a promising target for treating cardiovascular disease, but there are no specific inhibitors. Finding endogenous signals that can target Nox2 and other inflammatory molecules is of great interest. In this study, we used high-throughput screening

Estimate variable importance for recurrent event outcomes with an application to identify hypoglycemia risk factors.

PubMed

Duan, Ran; Fu, Haoda

2015-08-30

Recurrent event data are an important data type for medical research. In particular, many safety endpoints are recurrent outcomes, such as hypoglycemic events. For such a situation, it is important to identify the factors causing these events and rank these factors by their importance. Traditional model selection methods are not able to provide variable importance in this context. Methods that are able to evaluate the variable importance, such as gradient boosting and random forest algorithms, cannot directly be applied to recurrent events data. In this paper, we propose a two-step method that enables us to evaluate the variable importance for recurrent events data. We evaluated the performance of our proposed method by simulations and applied it to a data set from a diabetes study. Copyright © 2015 John Wiley & Sons, Ltd.

Identification of functionally important residues in the silkmoth pheromone biosynthesis-activating neuropeptide receptor, an insect ortholog of the vertebrate Neuromedin U Receptor

USDA-ARS?s Scientific Manuscript database

The biosynthesis of sex pheromone components in many lepidopteran insects is regulated by interactions between pheromone biosynthesis-activating neuropeptide (PBAN) and the PBAN receptor (PBANR), a class-A G-protein-coupled receptor (GPCR). To identify functionally important amino acid residues in t...

An extended set of yeast-based functional assays accurately identifies human disease mutations

PubMed Central

Sun, Song; Yang, Fan; Tan, Guihong; Costanzo, Michael; Oughtred, Rose; Hirschman, Jodi; Theesfeld, Chandra L.; Bansal, Pritpal; Sahni, Nidhi; Yi, Song; Yu, Analyn; Tyagi, Tanya; Tie, Cathy; Hill, David E.; Vidal, Marc; Andrews, Brenda J.; Boone, Charles; Dolinski, Kara; Roth, Frederick P.

2016-01-01

We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease- and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods. PMID:26975778

Functional connectome fingerprinting: identifying individuals using patterns of brain connectivity.

PubMed

Finn, Emily S; Shen, Xilin; Scheinost, Dustin; Rosenberg, Monica D; Huang, Jessica; Chun, Marvin M; Papademetris, Xenophon; Constable, R Todd

2015-11-01

Functional magnetic resonance imaging (fMRI) studies typically collapse data from many subjects, but brain functional organization varies between individuals. Here we establish that this individual variability is both robust and reliable, using data from the Human Connectome Project to demonstrate that functional connectivity profiles act as a 'fingerprint' that can accurately identify subjects from a large group. Identification was successful across scan sessions and even between task and rest conditions, indicating that an individual's connectivity profile is intrinsic, and can be used to distinguish that individual regardless of how the brain is engaged during imaging. Characteristic connectivity patterns were distributed throughout the brain, but the frontoparietal network emerged as most distinctive. Furthermore, we show that connectivity profiles predict levels of fluid intelligence: the same networks that were most discriminating of individuals were also most predictive of cognitive behavior. Results indicate the potential to draw inferences about single subjects on the basis of functional connectivity fMRI.

Phylogenomic detection and functional prediction of genes potentially important for plant meiosis.

PubMed

Zhang, Luoyan; Kong, Hongzhi; Ma, Hong; Yang, Ji

2018-02-15

Meiosis is a specialized type of cell division necessary for sexual reproduction in eukaryotes. A better understanding of the cytological procedures of meiosis has been achieved by comprehensive cytogenetic studies in plants, while the genetic mechanisms regulating meiotic progression remain incompletely understood. The increasing accumulation of complete genome sequences and large-scale gene expression datasets has provided a powerful resource for phylogenomic inference and unsupervised identification of genes involved in plant meiosis. By integrating sequence homology and expression data, 164, 131, 124 and 162 genes potentially important for meiosis were identified in the genomes of Arabidopsis thaliana, Oryza sativa, Selaginella moellendorffii and Pogonatum aloides, respectively. The predicted genes were assigned to 45 meiotic GO terms, and their functions were related to different processes occurring during meiosis in various organisms. Most of the predicted meiotic genes underwent lineage-specific duplication events during plant evolution, with about 30% of the predicted genes retaining only a single copy in higher plant genomes. The results of this study provided clues to design experiments for better functional characterization of meiotic genes in plants, promoting the phylogenomic approach to the evolutionary dynamics of the plant meiotic machineries. Copyright © 2017 Elsevier B.V. All rights reserved.

Using a Functional Architecture to Identify Human-Automation Trust Needs and Design Requirements

DTIC Science & Technology

2016-12-01

FUNCTIONAL ARCHITECTURE TO IDENTIFY HUMAN-AUTOMATION TRUST NEEDS AND DESIGN REQUIREMENTS by Bradley A. Johnson December 2016 Thesis Advisor...maximum 200 words) This thesis develops and analyzes the functional architecture for an “autonomous” unmanned aerial system performing an...INTENTIONALLY LEFT BLANK v ABSTRACT This thesis develops and analyzes the functional architecture for an “autonomous” unmanned aerial system

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

PubMed

Floyd, Brendan J; Wilkerson, Emily M; Veling, Mike T; Minogue, Catie E; Xia, Chuanwu; Beebe, Emily T; Wrobel, Russell L; Cho, Holly; Kremer, Laura S; Alston, Charlotte L; Gromek, Katarzyna A; Dolan, Brendan K; Ulbrich, Arne; Stefely, Jonathan A; Bohl, Sarah L; Werner, Kelly M; Jochem, Adam; Westphall, Michael S; Rensvold, Jarred W; Taylor, Robert W; Prokisch, Holger; Kim, Jung-Ja P; Coon, Joshua J; Pagliarini, David J

2016-08-18

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function. Copyright © 2016 Elsevier Inc. All rights reserved.

A Comparison of Functional and Structural Measures for Identifying Progression of Glaucoma

PubMed Central

Xin, Daiyan; Greenstein, Vivienne C.; Ritch, Robert; Liebmann, Jeffrey M.; De Moraes, Carlos Gustavo

2011-01-01

Purpose. To compare glaucoma progression by functional and structural tests. Methods. The authors prospectively studied 33 glaucoma patients (55 eyes); 20 eyes (15 patients) had disc hemorrhage, and 35 eyes (18 patients) had exfoliation glaucoma. The following tests were performed at two baseline and three follow-up examinations: frequency doubling perimetry (FDT), 24-2 Humphrey visual fields (HVF), multifocal visual evoked potentials (mfVEP), and optical coherence tomography (OCT). To identify progression, the baseline measurements were averaged and compared to those obtained at the final examination. Stereophotographs of the optic disc were obtained at baseline and compared with those at the final examination. Results. Patients were followed up for 21.1 ± 1.8 months. For HVF there were significant changes in mean deviation (MD) in eight (14.5%) eyes but in pattern standard deviation (P/SD) in only two (3.6%) eyes. For FDT, there were significant changes in MD in 13 (23.6%) eyes. Five eyes showed changes in MD for HVF and FDT. For mfVEP, there was an increase in abnormal points in nine (16.4%) eyes. Six of these eyes did not show significant HVF or FDT changes. For OCT, RNFL average thickness values were significantly decreased in nine (16.4%) eyes. Nine (16.4%) eyes showed progression on stereophotography; four of these eyes did not show significant changes on OCT and functional tests. Conclusions. Each test showed evidence of progression in some eyes. However, agreement among tests and stereophotography regarding which eyes showed progression was poor, illustrating the importance of following up patients with a combination of functional and structural tests. PMID:20847115

Radiative lifetimes and cooling functions for astrophysically important molecules

NASA Astrophysics Data System (ADS)

Tennyson, Jonathan; Hulme, Kelsey; Naim, Omree K.; Yurchenko, Sergei N.

2016-02-01

Extensive line lists generated as part of the ExoMol project are used to compute lifetimes for individual rotational, rovibrational and rovibronic excited states, and temperature-dependent cooling functions by summing over all dipole-allowed transitions for the states concerned. Results are presented for SiO, CaH, AlO, ScH, H2O and methane. The results for CH4 are particularly unusual with four excited states with no dipole-allowed decay route and several others, where these decays lead to exceptionally long lifetimes. These lifetime data should be useful in models of masers and estimates of critical densities, and can provide a link with laboratory measurements. Cooling functions are important in stellar and planet formation.

Regulatory network analysis of Epstein-Barr virus identifies functional modules and hub genes involved in infectious mononucleosis.

PubMed

Poorebrahim, Mansour; Salarian, Ali; Najafi, Saeideh; Abazari, Mohammad Foad; Aleagha, Maryam Nouri; Dadras, Mohammad Nasr; Jazayeri, Seyed Mohammad; Ataei, Atousa; Poortahmasebi, Vahdat

2017-05-01

Epstein-Barr virus (EBV) is the most common cause of infectious mononucleosis (IM) and establishes lifetime infection associated with a variety of cancers and autoimmune diseases. The aim of this study was to develop an integrative gene regulatory network (GRN) approach and overlying gene expression data to identify the representative subnetworks for IM and EBV latent infection (LI). After identifying differentially expressed genes (DEGs) in both IM and LI gene expression profiles, functional annotations were applied using gene ontology (GO) and BiNGO tools, and construction of GRNs, topological analysis and identification of modules were carried out using several plugins of Cytoscape. In parallel, a human-EBV GRN was generated using the Hu-Vir database for further analyses. Our analysis revealed that the majority of DEGs in both IM and LI were involved in cell-cycle and DNA repair processes. However, these genes showed a significant negative correlation in the IM and LI states. Furthermore, cyclin-dependent kinase 2 (CDK2) - a hub gene with the highest centrality score - appeared to be the key player in cell cycle regulation in IM disease. The most significant functional modules in the IM and LI states were involved in the regulation of the cell cycle and apoptosis, respectively. Human-EBV network analysis revealed several direct targets of EBV proteins during IM disease. Our study provides an important first report on the response to IM/LI EBV infection in humans. An important aspect of our data was the upregulation of genes associated with cell cycle progression and proliferation.

Machine Learning Analysis Identifies Drosophila Grunge/Atrophin as an Important Learning and Memory Gene Required for Memory Retention and Social Learning.

PubMed

Kacsoh, Balint Z; Greene, Casey S; Bosco, Giovanni

2017-11-06

High-throughput experiments are becoming increasingly common, and scientists must balance hypothesis-driven experiments with genome-wide data acquisition. We sought to predict novel genes involved in Drosophila learning and long-term memory from existing public high-throughput data. We performed an analysis using PILGRM, which analyzes public gene expression compendia using machine learning. We evaluated the top prediction alongside genes involved in learning and memory in IMP, an interface for functional relationship networks. We identified Grunge/Atrophin ( Gug/Atro ), a transcriptional repressor, histone deacetylase, as our top candidate. We find, through multiple, distinct assays, that Gug has an active role as a modulator of memory retention in the fly and its function is required in the adult mushroom body. Depletion of Gug specifically in neurons of the adult mushroom body, after cell division and neuronal development is complete, suggests that Gug function is important for memory retention through regulation of neuronal activity, and not by altering neurodevelopment. Our study provides a previously uncharacterized role for Gug as a possible regulator of neuronal plasticity at the interface of memory retention and memory extinction. Copyright © 2017 Kacsoh et al.

Identifying Elements of ICU Care That Families Report as Important But Unsatisfactory

PubMed Central

Osborn, Tristan R.; Curtis, J. Randall; Nielsen, Elizabeth L.; Back, Anthony L.; Shannon, Sarah E.

2012-01-01

Background: One in five deaths in the United States occurs in the ICU, and many of these deaths are experienced as less than optimal by families of dying people. The current study investigated the relationship between family satisfaction with ICU care and overall ratings of the quality of dying as a means of identifying targets for improving end-of-life experiences for patients and families. Methods: This multisite cross-sectional study surveyed families of patients who died in the ICU in one of 15 hospitals in western Washington State. Measures included the Family Satisfaction in the ICU (FS-ICU) and the Single-Item Quality of Dying (QOD-1) questionnaires. Associations between FS-ICU items and the QOD-1 were examined using multivariate linear regression controlling for patient and family demographics and hospital site. Results: Questionnaires were returned for 1,290 of 2,850 decedents (45%). Higher QOD-1 scores were significantly associated (all P < .05) with (1) perceived nursing skill and competence (β = 0.15), (2) support for family as decision-makers (β = 0.10), (3) family control over the patient’s care (β = 0.18), and (4) ICU atmosphere (β = 0.12). FS-ICU items that received low ratings and correlated with higher QOD-1 scores (ie, important items with room for improvement) were (1) support of family as decision-maker, (2) family control over patient’s care, and (3) ICU atmosphere. Conclusions: Increased support for families as decision-makers and for their desired level of control over patient care along with improvements in the ICU atmosphere were identified as aspects of the ICU experience that may be important targets for quality improvement. Trial registry: ClinicalTrials.gov; No.: NCT00685893; URL: www.clinicaltrials.gov. PMID:22661455

The importance of physical function to people with osteoporosis.

PubMed

Kerr, C; Bottomley, C; Shingler, S; Giangregorio, L; de Freitas, H M; Patel, C; Randall, S; Gold, D T

2017-05-01

There is increasing need to understand patient outcomes in osteoporosis. This article discusses that fracture in osteoporosis can lead to a cycle of impairment, driven by complex psychosocial factors, having a profound impact on physical function/activity which accumulates over time. More information is required on how treatments impact physical function. There is increasing need to understand patient-centred outcomes in osteoporosis (OP) clinical research and management. This multi-method paper provides insight on the effect of OP on patients' physical function and everyday activity. Data were collected from three sources: (1) targeted literature review on OP and physical function, conducted in MEDLINE, Embase and PsycINFO; (2) secondary thematic analysis of transcripts from patient interviews, conducted to develop a patient-reported outcome instrument. Transcripts were re-coded to focus on OP impact on daily activities and physical function for those with and without fracture history; and (3) discussions of the literature review and secondary qualitative analysis results with three clinical experts to review and interpret the importance and implications of the findings. Results suggest that OP, particularly with fracture, can have profound impacts on physical function/activity. These impacts accumulate over time through a cycle of impairment, as fracture leads to longer term detriments in physical function, including loss of muscle, activity avoidance and reduced physical capacity, which in turn leads to greater risk of fracture and potential for further physical restrictions. The cycle of impairment is complex, as other physical, psychosocial and treatment-related factors, such as comorbidities, fears and beliefs about physical activity and fracture risk influence physical function and everyday activity. More information on how treatments impact physical function would benefit healthcare professionals and persons with OP in making treatment decisions and

Dissecting protein function: an efficient protocol for identifying separation-of-function mutations that encode structurally stable proteins.

PubMed

Lubin, Johnathan W; Rao, Timsi; Mandell, Edward K; Wuttke, Deborah S; Lundblad, Victoria

2013-03-01

Mutations that confer the loss of a single biochemical property (separation-of-function mutations) can often uncover a previously unknown role for a protein in a particular biological process. However, most mutations are identified based on loss-of-function phenotypes, which cannot differentiate between separation-of-function alleles vs. mutations that encode unstable/unfolded proteins. An alternative approach is to use overexpression dominant-negative (ODN) phenotypes to identify mutant proteins that disrupt function in an otherwise wild-type strain when overexpressed. This is based on the assumption that such mutant proteins retain an overall structure that is comparable to that of the wild-type protein and are able to compete with the endogenous protein (Herskowitz 1987). To test this, the in vivo phenotypes of mutations in the Est3 telomerase subunit from Saccharomyces cerevisiae were compared with the in vitro secondary structure of these mutant proteins as analyzed by circular-dichroism spectroscopy, which demonstrates that ODN is a more sensitive assessment of protein stability than the commonly used method of monitoring protein levels from extracts. Reverse mutagenesis of EST3, which targeted different categories of amino acids, also showed that mutating highly conserved charged residues to the oppositely charged amino acid had an increased likelihood of generating a severely defective est3(-) mutation, which nevertheless encoded a structurally stable protein. These results suggest that charge-swap mutagenesis directed at a limited subset of highly conserved charged residues, combined with ODN screening to eliminate partially unfolded proteins, may provide a widely applicable and efficient strategy for generating separation-of-function mutations.

Functional Brain Activation Differences in Stuttering Identified with a Rapid fMRI Sequence

ERIC Educational Resources Information Center

Loucks, Torrey; Kraft, Shelly Jo; Choo, Ai Leen; Sharma, Harish; Ambrose, Nicoline G.

2011-01-01

The purpose of this study was to investigate whether brain activity related to the presence of stuttering can be identified with rapid functional MRI (fMRI) sequences that involved overt and covert speech processing tasks. The long-term goal is to develop sensitive fMRI approaches with developmentally appropriate tasks to identify deviant speech…

A systematic analysis of the PARP protein family identifies new functions critical for cell physiology

PubMed Central

Vyas, Sejal; Chesarone-Cataldo, Melissa; Todorova, Tanya; Huang, Yun-Han; Chang, Paul

2013-01-01

The poly(ADP-ribose) polymerase (PARP) family of proteins use NAD+ as their substrate to modify acceptor proteins with adenosine diphosphate-ribose (ADPr) modifications. The function of most PARPs under physiological conditions is unknown. Here, to better understand this protein family, we systematically analyze the cell cycle localization of each PARP and of poly(ADP-ribose), a product of PARP activity, then identify the knock-down phenotype of each protein and perform secondary assays to elucidate function. We show that most PARPs are cytoplasmic, identify cell cycle differences in the ratio of nuclear to cytoplasmic poly(ADP-ribose), and identify four phenotypic classes of PARP function. These include the regulation of membrane structures, cell viability, cell division, and the actin cytoskeleton. Further analysis of PARP14 shows that it is a component of focal adhesion complexes required for proper cell motility and focal adhesion function. In total, we show that PARP proteins are critical regulators of eukaryotic physiology. PMID:23917125

The functional importance of sequence versus expression variability of MHC alleles in parasite resistance.

PubMed

Axtner, Jan; Sommer, Simone

2012-12-01

Understanding selection processes driving the pronounced allelic polymorphism of the major histocompatibility complex (MHC) genes and its functional associations to parasite load have been the focus of many recent wildlife studies. Two main selection scenarios are currently debated which explain the susceptibility or resistance to parasite infections either by the effects of (1) specific MHC alleles which are selected frequency-dependent in space and time or (2) a heterozygote or divergent allele advantage. So far, most studies have focused only on structural variance in co-evolutionary processes although this might not be the only trait subject to natural selection. In the present study, we analysed structural variance stretching from exon1 through exon3 of MHC class II DRB genes as well as genotypic expression variance in relation to the gastrointestinal helminth prevalence and infection intensity in wild yellow-necked mice (Apodemus flavicollis). We found support for the functional importance of specific alleles both on the sequence and expression level. By resampling a previously investigated study population we identified specific MHC alleles affected by temporal shifts in parasite pressure and recorded associated changes in allele frequencies. The allele Apfl-DRB*23 was associated with resistance to infections by the oxyurid nematode Syphacia stroma and at the same time with susceptibility to cestode infection intensity. In line with our expectation, MHC mRNA transcript levels tended to be higher in cestode-infected animals carrying the allele Apfl-DRB*23. However, no support for a heterozygote or divergent allele advantage on the sequence or expression level was detected. The individual amino acid distance of genotypes did not explain individual differences in parasite loads and the genetic distance had no effect on MHC genotype expression. For ongoing studies on the functional importance of expression variance in parasite resistance, allele

A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast

DTIC Science & Technology

2004-05-01

AD Award Number: DAMD17-03-1-0232 TITLE: A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast PRINCIPAL INVESTIGATOR...Approach to Identify Novel Breast DAMD17-03-1-0232 Cancer Gene Targets in Yeast 6. A UTHOR(S) Craig Bennett, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S...Unlimited 13. ABSTRACT (Maximum 200 Words) We are using the yeast Saccharomyces cerevisiae to identify new cancer gene targets that interact with the

Synaptic transmission at functionally identified synapses in the enteric nervous system: roles for both ionotropic and metabotropic receptors.

PubMed

Gwynne, R M; Bornstein, J C

2007-03-01

Digestion and absorption of nutrients and the secretion and reabsorption of fluid in the gastrointestinal tract are regulated by neurons of the enteric nervous system (ENS), the extensive peripheral nerve network contained within the intestinal wall. The ENS is an important physiological model for the study of neural networks since it is both complex and accessible. At least 20 different neurochemically and functionally distinct classes of enteric neurons have been identified in the guinea pig ileum. These neurons express a wide range of ionotropic and metabotropic receptors. Synaptic potentials mediated by ionotropic receptors such as the nicotinic acetylcholine receptor, P2X purinoceptors and 5-HT(3) receptors are seen in many enteric neurons. However, prominent synaptic potentials mediated by metabotropic receptors, like the P2Y(1) receptor and the NK(1) receptor, are also seen in these neurons. Studies of synaptic transmission between the different neuron classes within the enteric neural pathways have shown that both ionotropic and metabotropic synaptic potentials play major roles at distinct synapses within simple reflex pathways. However, there are still functional synapses at which no known transmitter or receptor has been identified. This review describes the identified roles for both ionotropic and metabotropic neurotransmission at functionally defined synapses within the guinea pig ileum ENS. It is concluded that metabotropic synaptic potentials act as primary transmitters at some synapses. It is suggested identification of the interactions between different synaptic potentials in the production of complex behaviours will require the use of well validated computer models of the enteric neural circuitry.

Identifying the distinct features of geometric structures for hole trapping to generate radicals on rutile TiO₂(110) in photooxidation using density functional theory calculations with hybrid functional.

PubMed

Wang, Dong; Wang, Haifeng; Hu, P

2015-01-21

Using density functional theory calculations with HSE 06 functional, we obtained the structures of spin-polarized radicals on rutile TiO2(110), which is crucial to understand the photooxidation at the atomic level, and further calculate the thermodynamic stabilities of these radicals. By analyzing the results, we identify the structural features for hole trapping in the system, and reveal the mutual effects among the geometric structures, the energy levels of trapped hole states and their hole trapping capacities. Furthermore, the results from HSE 06 functional are compared to those from DFT + U and the stability trend of radicals against the number of slabs is tested. The effect of trapped holes on two important steps of the oxygen evolution reaction, i.e. water dissociation and the oxygen removal, is investigated and discussed.

Identifying pneumonia outbreaks of public health importance: can emergency department data assist in earlier identification?

PubMed

Hope, Kirsty; Durrheim, David N; Muscatello, David; Merritt, Tony; Zheng, Wei; Massey, Peter; Cashman, Patrick; Eastwood, Keith

2008-08-01

To retrospectively review the performance of a near real-time Emergency Department (ED) Syndromic Surveillance System operating in New South Wales for identifying pneumonia outbreaks of public health importance. Retrospective data was obtained from the NSW Emergency Department data collection for a rural hospital that has experienced a cluster of pneumonia diagnoses among teenage males in August 2006. ED standard reports were examined for signals in the overall count for each respiratory syndrome, and for elevated counts in individual subgroups including; age, sex and admission to hospital status. Using the current thresholds, the ED syndromic surveillance system would have trigged a signal for pneumonia syndrome in children aged 5-16 years four days earlier than the notification by a paediatrician and this signal was maintained for 14 days. If the ED syndromic surveillance system had been operating it could have identified the outbreak earlier than the paediatrician's notification. This may have permitted an earlier public health response. By understanding the behaviour of syndromes during outbreaks of public health importance, response protocols could be developed to facilitate earlier implementation of control measures.

A novel method for identifying disease associated protein complexes based on functional similarity protein complex networks.

PubMed

Le, Duc-Hau

2015-01-01

Protein complexes formed by non-covalent interaction among proteins play important roles in cellular functions. Computational and purification methods have been used to identify many protein complexes and their cellular functions. However, their roles in terms of causing disease have not been well discovered yet. There exist only a few studies for the identification of disease-associated protein complexes. However, they mostly utilize complicated heterogeneous networks which are constructed based on an out-of-date database of phenotype similarity network collected from literature. In addition, they only apply for diseases for which tissue-specific data exist. In this study, we propose a method to identify novel disease-protein complex associations. First, we introduce a framework to construct functional similarity protein complex networks where two protein complexes are functionally connected by either shared protein elements, shared annotating GO terms or based on protein interactions between elements in each protein complex. Second, we propose a simple but effective neighborhood-based algorithm, which yields a local similarity measure, to rank disease candidate protein complexes. Comparing the predictive performance of our proposed algorithm with that of two state-of-the-art network propagation algorithms including one we used in our previous study, we found that it performed statistically significantly better than that of these two algorithms for all the constructed functional similarity protein complex networks. In addition, it ran about 32 times faster than these two algorithms. Moreover, our proposed method always achieved high performance in terms of AUC values irrespective of the ways to construct the functional similarity protein complex networks and the used algorithms. The performance of our method was also higher than that reported in some existing methods which were based on complicated heterogeneous networks. Finally, we also tested our method with

On the importance of identifying, characterizing, and predicting fundamental phenomena towards microbial electrochemistry applications.

PubMed

Torres, César Iván

2014-06-01

The development of microbial electrochemistry research toward technological applications has increased significantly in the past years, leading to many process configurations. This short review focuses on the need to identify and characterize the fundamental phenomena that control the performance of microbial electrochemical cells (MXCs). Specifically, it discusses the importance of recent efforts to discover and characterize novel microorganisms for MXC applications, as well as recent developments to understand transport limitations in MXCs. As we increase our understanding of how MXCs operate, it is imperative to continue modeling efforts in order to effectively predict their performance, design efficient MXC technologies, and implement them commercially. Thus, the success of MXC technologies largely depends on the path of identifying, understanding, and predicting fundamental phenomena that determine MXC performance. Copyright © 2013 Elsevier Ltd. All rights reserved.

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

PubMed Central

Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Chen, Ming-Huei; Leening, Maarten J.G.; Völker, Uwe; Großmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Dörthe; Lyytikäinen, Leo-Pekka; Tiller, Daniel; Smith, J. Gustav; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco M, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kähönen, Mika; investigators, KNHI; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Lindgren, Cecilia M.; Loley, Christina; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Müller, Christian; Müller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L.; Samdarshi, Tandaw E.; Sharp, Andrew S.P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Töglhofer, Anna M.; Uitterlinden, André G.; Völzke, Henry; Ziegler, Andreas; Münzel, Thomas; März, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W.V.; Melander, Olle; Lehtimäki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Dörr, Marcus

2017-01-01

BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING. For detailed information per study, see Acknowledgments. PMID:28394258

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

PubMed Central

Gorski, Mathias; van der Most, Peter J.; Teumer, Alexander; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Nolte, Ilja M.; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F.; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P.; Chen, Ming-Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C.; Curhan, Gary C.; d’Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H.; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J.; Harris, Tamara B.; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G.; Homuth, Georg; Hu, Frank B.; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Imboden, Medea; Johansson, Åsa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K.; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean-Charles; Launer, Lenore J.; Lehtimäki, Terho; de Borst, Martin; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J. F.; Lu, Yingchang; Lyytikäinen, Leo-Pekka; McEvoy, Mark A.; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J.; Olden, Matthias; WJH Penninx, Brenda; Pistis, Giorgio; Pramstaller, Peter P.; Probst-Hensch, Nicole; Raitakari, Olli T.; Rettig, Rainer; Ridker, Paul M.; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E.; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J.; Sedaghat, Sanaz; Smith, Albert V.; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G.; Ulivi, Sheila; Viikari, Jorma S.; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Jin Wang, Jie; Yang, Qiong; Chasman, Daniel I.; Tromp, Gerard; Snieder, Harold; Heid, Iris M.; Fox, Caroline S.; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A.; Fuchsberger, Christian

2017-01-01

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples. PMID:28452372

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

PubMed

Gorski, Mathias; van der Most, Peter J; Teumer, Alexander; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Nolte, Ilja M; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P; Chen, Ming-Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C; Curhan, Gary C; d'Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J; Harris, Tamara B; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G; Homuth, Georg; Hu, Frank B; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Imboden, Medea; Johansson, Åsa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean-Charles; Launer, Lenore J; Lehtimäki, Terho; de Borst, Martin; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J F; Lu, Yingchang; Lyytikäinen, Leo-Pekka; McEvoy, Mark A; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J; Olden, Matthias; Wjh Penninx, Brenda; Pistis, Giorgio; Pramstaller, Peter P; Probst-Hensch, Nicole; Raitakari, Olli T; Rettig, Rainer; Ridker, Paul M; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J; Sedaghat, Sanaz; Smith, Albert V; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G; Ulivi, Sheila; Viikari, Jorma S; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Jin Wang, Jie; Yang, Qiong; Chasman, Daniel I; Tromp, Gerard; Snieder, Harold; Heid, Iris M; Fox, Caroline S; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A; Fuchsberger, Christian

2017-04-28

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 -8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

Time-dependent importance sampling in semiclassical initial value representation calculations for time correlation functions.

PubMed

Tao, Guohua; Miller, William H

2011-07-14

An efficient time-dependent importance sampling method is developed for the Monte Carlo calculation of time correlation functions via the initial value representation (IVR) of semiclassical (SC) theory. A prefactor-free time-dependent sampling function weights the importance of a trajectory based on the magnitude of its contribution to the time correlation function, and global trial moves are used to facilitate the efficient sampling the phase space of initial conditions. The method can be generally applied to sampling rare events efficiently while avoiding being trapped in a local region of the phase space. Results presented in the paper for two system-bath models demonstrate the efficiency of this new importance sampling method for full SC-IVR calculations.

Functional screening identifies miRNAs inducing cardiac regeneration.

PubMed

Eulalio, Ana; Mano, Miguel; Dal Ferro, Matteo; Zentilin, Lorena; Sinagra, Gianfranco; Zacchigna, Serena; Giacca, Mauro

2012-12-20

In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.

Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis.

PubMed

Senthivel, Vivek Raj; Sturrock, Marc; Piedrafita, Gabriel; Isalan, Mark

2016-12-16

Nonlinear responses to signals are widespread natural phenomena that affect various cellular processes. Nonlinearity can be a desirable characteristic for engineering living organisms because it can lead to more switch-like responses, similar to those underlying the wiring in electronics. Steeper functions are described as ultrasensitive, and can be applied in synthetic biology by using various techniques including receptor decoys, multiple co-operative binding sites, and sequential positive feedbacks. Here, we explore the inherent non-linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering. For this, we performed genome-wide transcription profiling to identify genes with ultrasensitive response functions to Hepatocyte Growth Factor (HGF). We identified 3,527 genes that react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells, grown as cysts in 3D collagen cell culture. By fitting a generic Hill function to the dose-responses of these genes we obtained a measure of the ultrasensitivity of HGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1, SNORD75, SNORD86 and ERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling.

Aspartic acid 413 is important for the normal allosteric functioning of ADP-glucose pyrophosphorylase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greene, T.W.; Woodbury, R.L.; Okita, T.W.

1996-11-01

As part of a structure-function analysis of the higher-plant ADP-glucose pyrophosphorylase (AGP), we used a random mutagenesis approach in combination with a novel bacterial complementation system to isolate over 100 mutants that were defective in glycogen production. One mutant of the large subunit M27 was identified by its capacity to only partially complement a mutation in the structural gene for the bacterial AGP (glg C), as determined by its light-staining phenotype when cells were exposed to I{sub 2} vapors. Enzyme-linked immunosorbent assay and enzymatic pyrophosphorylysis assays of M27 cell extracts showed that the level of expression and AGP activity wasmore » comparable to those of cells that expressed the wildtype recombinant enzyme. Kinetic analysis indicated that the M27 AGP displays normal Michaelis constant values for the substrates glucose-1-phosphate and ATP but requires 6- to 10-fold greater levels of 3-phosphoglycerate (3-PGA) than the wild-type recombinant enzyme for maximum activation. DNA sequence analysis showed that M27 contains a single point mutation that resulted in the replacement of aspartic acid 413 to alanine. Substitution of a lysine residue at this site almost completely abolished activation by 3-PGA. Aspartic acid 413 is adjacent to a lysine residue that was previously identified by chemical modification studies to be important in the binding of 3-PGA. The kinetic properties of M27 corroborate the importance of this region in the allosteric regulation of a higher-plant AGP. 28 refs., 3 figs., 1 tab.« less

Linking the salt transcriptome with physiological responses of a salt-resistant Populus species as a strategy to identify genes important for stress acclimation.

PubMed

Brinker, Monika; Brosché, Mikael; Vinocur, Basia; Abo-Ogiala, Atef; Fayyaz, Payam; Janz, Dennis; Ottow, Eric A; Cullmann, Andreas D; Saborowski, Joachim; Kangasjärvi, Jaakko; Altman, Arie; Polle, Andrea

2010-12-01

To investigate early salt acclimation mechanisms in a salt-tolerant poplar species (Populus euphratica), the kinetics of molecular, metabolic, and physiological changes during a 24-h salt exposure were measured. Three distinct phases of salt stress were identified by analyses of the osmotic pressure and the shoot water potential: dehydration, salt accumulation, and osmotic restoration associated with ionic stress. The duration and intensity of these phases differed between leaves and roots. Transcriptome analysis using P. euphratica-specific microarrays revealed clusters of coexpressed genes in these phases, with only 3% overlapping salt-responsive genes in leaves and roots. Acclimation of cellular metabolism to high salt concentrations involved remodeling of amino acid and protein biosynthesis and increased expression of molecular chaperones (dehydrins, osmotin). Leaves suffered initially from dehydration, which resulted in changes in transcript levels of mitochondrial and photosynthetic genes, indicating adjustment of energy metabolism. Initially, decreases in stress-related genes were found, whereas increases occurred only when leaves had restored the osmotic balance by salt accumulation. Comparative in silico analysis of the poplar stress regulon with Arabidopsis (Arabidopsis thaliana) orthologs was used as a strategy to reduce the number of candidate genes for functional analysis. Analysis of Arabidopsis knockout lines identified a lipocalin-like gene (AtTIL) and a gene encoding a protein with previously unknown functions (AtSIS) to play roles in salt tolerance. In conclusion, by dissecting the stress transcriptome of tolerant species, novel genes important for salt endurance can be identified.

Proteomics and transcriptomics analyses of Arabidopsis floral buds uncover important functions of ARABIDOPSIS SKP1-LIKE1

DOE PAGES

Lu, Dihong; Ni, Weimin; Stanley, Bruce A.; ...

2016-03-03

The ARABIDOPSIS SKP1-LIKE1 (ASK1) protein functions as a subunit of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases. Previous genetic studies showed that ASK1 plays important roles in Arabidopsis flower development and male meiosis. However, the molecular impact of ASK1-containing SCF E3 ubiquitin ligases (ASK1-E3s) on the floral proteome and transcriptome is unknown. Here we identified proteins that are potentially regulated by ASK1-E3s by comparing floral bud proteomes of wild-type and the ask1 mutant plants. More than 200 proteins were detected in the ask1 mutant but not in wild-type and >300 were detected at higher levels in the ask1 mutant than in wild-type,more » but their RNA levels were not significantly different between wild-type and ask1 floral buds as shown by transcriptomics analysis, suggesting that they are likely regulated at the protein level by ASK1-E3s. Integrated analyses of floral proteomics and transcriptomics of ask1 and wild-type uncovered several potential aspects of ASK1-E3 functions, including regulation of transcription regulators, kinases, peptidases, and ribosomal proteins, with implications on possible mechanisms of ASK1-E3 functions in floral development. In conclusion, our results suggested that ASK1-E3s play important roles in Arabidopsis protein degradation during flower development. This study opens up new possibilities for further functional studies of these candidate E3 substrates.« less

Proteomics and transcriptomics analyses of Arabidopsis floral buds uncover important functions of ARABIDOPSIS SKP1-LIKE1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Dihong; Ni, Weimin; Stanley, Bruce A.

The ARABIDOPSIS SKP1-LIKE1 (ASK1) protein functions as a subunit of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases. Previous genetic studies showed that ASK1 plays important roles in Arabidopsis flower development and male meiosis. However, the molecular impact of ASK1-containing SCF E3 ubiquitin ligases (ASK1-E3s) on the floral proteome and transcriptome is unknown. Here we identified proteins that are potentially regulated by ASK1-E3s by comparing floral bud proteomes of wild-type and the ask1 mutant plants. More than 200 proteins were detected in the ask1 mutant but not in wild-type and >300 were detected at higher levels in the ask1 mutant than in wild-type,more » but their RNA levels were not significantly different between wild-type and ask1 floral buds as shown by transcriptomics analysis, suggesting that they are likely regulated at the protein level by ASK1-E3s. Integrated analyses of floral proteomics and transcriptomics of ask1 and wild-type uncovered several potential aspects of ASK1-E3 functions, including regulation of transcription regulators, kinases, peptidases, and ribosomal proteins, with implications on possible mechanisms of ASK1-E3 functions in floral development. In conclusion, our results suggested that ASK1-E3s play important roles in Arabidopsis protein degradation during flower development. This study opens up new possibilities for further functional studies of these candidate E3 substrates.« less

Importance of cholesterol in dopamine transporter function

PubMed Central

Jones, Kymry T.; Zhen, Juan; Reith, Maarten E.A.

2012-01-01

The conformation and function of the dopamine transporter (DAT) can be affected by manipulating membrane cholesterol, yet there is no agreement as to the impact of cholesterol on the activity of lipid-raft localized DATs compared to non-raft DATs. Given the paucity of information regarding the impact of cholesterol on substrate efflux by the DAT, this study explores its influence on the kinetics of DAT-mediated DA efflux induced by dextroamphetamine, as measured by rotating disk electrode voltammetry (RDEV). Treatment with methyl-β-cyclodextrin (mβCD), which effectively depletes total membrane cholesterol- uniformly affecting cholesterol-DAT interactions in both raft and non-raft membrane domains- reduced both DA uptake and efflux rate. In contrast, disruption of raft localized DAT by cholesterol chelation with nystatin had no effect, arguing against a vital role for raft-localized DAT in substrate uptake or efflux. Supra-normal repletion of cholesterol depleted cells with the analogue desmosterol, a non-raft promoting sterol, was as effective as cholesterol itself in restoring transport rates. Further studies with Zn2+ and the conformationally-biased W84L DAT mutant supported the idea that cholesterol is important for maintaining the outward-facing DAT with normal rates of conformational interconversions. Collectively, these results point to a role for direct cholesterol-DAT interactions in regulating DAT function. PMID:22957537

Identifying aMCI with Functional Connectivity Network Characteristics based on Subtle AAL Atlas.

PubMed

Zhuo, Zhizheng; Mo, Xiao; Ma, Xiangyu; Han, Ying; Li, Haiyun

2018-05-02

To investigate the subtle functional connectivity alterations of aMCI based on AAL atlas with 1024 regions (AAL_1024 atlas). Functional MRI images of 32 aMCI patients (Male/Female:15/17, Ages:66.8±8.36y) and 35 normal controls (Male/Female:13/22, Ages: 62.4±8.14y) were obtained in this study. Firstly, functional connectivity networks were constructed by Pearson's Correlation based on the subtle AAL_1024 atlas. Then, local and global network parameters were calculated from the thresholding functional connectivity matrices. Finally, multiple-comparison analysis was performed on these parameters to find the functional network alterations of aMCI. And furtherly, a couple of classifiers were adopted to identify the aMCI by using the network parameters. More subtle local brain functional alterations were detected by using AAL_1024 atlas. And the predominate nodes including hippocampus, inferior temporal gyrus, inferior parietal gyrus were identified which was not detected by AAL_90 atlas. The identification of aMCI from normal controls were significantly improved with the highest accuracy (98.51%), sensitivity (100%) and specificity (97.14%) compared to those (88.06%, 84.38% and 91.43% for the highest accuracy, sensitivity and specificity respectively) obtained by using AAL_90 atlas. More subtle functional connectivity alterations of aMCI could be found based on AAL_1024 atlas than those based on AAL_90 atlas. Besides, the identification of aMCI could also be improved. Copyright © 2018. Published by Elsevier B.V.

[Identification of ecological corridors and its importance by integrating circuit theory].

PubMed

Song, Li Li; Qin, Ming Zhou

2016-10-01

Landscape connectivity is considered as an extraordinarily important factor affecting various ecological processes. The least cost path (LCP) on the basis of minimum cumulative resis-tance model (MCRM) may provide a more efficient approach to identify functional connectivity in heterogeneous landscapes, and is already adopted by the research of landscape functional connecti-vity assessment and ecological corridor simulation. Connectivity model on circuit theory (CMCT) replaced the edges in the graph theory with resistors, cost distance with resistance distance to measure the functional connectivity in heterogeneous landscapes. By means of Linkage Mapper tool and Circuitscape software, the simulated landscape generated from SIMMAP 2.0 software was viewed as the study object in this article, aimed at exploring how to integrate MCRM with CMCT to identify ecological corridors and relative importance of landscape factors. The results showed that two models had their individual advantages and mutual complement. MCRM could effectively identify least cost corridors among habitats. CMCT could effectively identify important landscape factor and pinch point, which had important influence on landscape connectivity. We also found that the position of pinch point was not affected by corridor width, which had obvious advantage in the research of identifying the importance of corridors. The integrated method could provide certain scientific basis for regional ecological protection planning and ecological corridor design.

Translational informatics approach for identifying the functional molecular communicators linking coronary artery disease, infection and inflammation

PubMed Central

SHARMA, ANKIT; GHATGE, MADANKUMAR; MUNDKUR, LAKSHMI; VANGALA, RAJANI KANTH

2016-01-01

Translational informatics approaches are required for the integration of diverse and accumulating data to enable the administration of effective translational medicine specifically in complex diseases such as coronary artery disease (CAD). In the current study, a novel approach for elucidating the association between infection, inflammation and CAD was used. Genes for CAD were collected from the CAD-gene database and those for infection and inflammation were collected from the UniProt database. The cytomegalovirus (CMV)-induced genes were identified from the literature and the CAD-associated clinical phenotypes were obtained from the Unified Medical Language System. A total of 55 gene ontologies (GO) termed functional communicator ontologies were identifed in the gene sets linking clinical phenotypes in the diseasome network. The network topology analysis suggested that important functions including viral entry, cell adhesion, apoptosis, inflammatory and immune responses networked with clinical phenotypes. Microarray data was extracted from the Gene Expression Omnibus (dataset: GSE48060) for highly networked disease myocardial infarction. Further analysis of differentially expressed genes and their GO terms suggested that CMV infection may trigger a xenobiotic response, oxidative stress, inflammation and immune modulation. Notably, the current study identified γ-glutamyl transferase (GGT)-5 as a potential biomarker with an odds ratio of 1.947, which increased to 2.561 following the addition of CMV and CMV-neutralizing antibody (CMV-NA) titers. The C-statistics increased from 0.530 for conventional risk factors (CRFs) to 0.711 for GGT in combination with the above mentioned infections and CRFs. Therefore, the translational informatics approach used in the current study identified a potential molecular mechanism for CMV infection in CAD, and a potential biomarker for risk prediction. PMID:27035874

Functional, communicative and critical health literacy of chronic disease patients and their importance for self-management.

PubMed

Heijmans, Monique; Waverijn, Geeke; Rademakers, Jany; van der Vaart, Rosalie; Rijken, Mieke

2015-01-01

To provide insight into the level of health literacy among chronic disease patients in the Netherlands, to identify subgroups with low literacy and to examine the associations between health literacy and self-management. Self-report questionnaires were sent to a nationwide sample of 1.341 chronic disease patients. The Dutch Functional Communicative and Critical Health Literacy scale (FCCHL), the Partners in Health scale (PIH) and Perceived Efficacy in Patient-Doctor Interactions (PEPPI-5) were used to assess health literacy and aspects of self-management. In general, health literacy skills were good. A higher age, lower education, lower income, multi-morbidity and/or functional limitations were associated with lower levels of health literacy. Communicative and critical health literacy were related to some aspects of self-management but not to all. Functional health literacy was less important. Communicative and critical health literacy play a role in successful self-management of chronic disease but the impact differs by context. Health literacy levels vary according to socio-demographic and disease characteristics of patients. Health care professionals should tailor their information and support to the health literacy skills and personal context of their patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Barcode Identifiers as a Practical Tool for Reliable Species Assignment of Medically Important Black Yeast Species

PubMed Central

Heinrichs, Guido; de Hoog, G. Sybren

2012-01-01

Herpotrichiellaceous black yeasts and relatives comprise severe pathogens flanked by nonpathogenic environmental siblings. Reliable identification by conventional methods is notoriously difficult. Molecular identification is hampered by the sequence variability in the internal transcribed spacer (ITS) domain caused by difficult-to-sequence homopolymeric regions and by poor taxonomic attribution of sequences deposited in GenBank. Here, we present a potential solution using short barcode identifiers (27 to 50 bp) based on ITS2 ribosomal DNA (rDNA), which allows unambiguous definition of species-specific fragments. Starting from proven sequences of ex-type and authentic strains, we were able to describe 103 identifiers. Multiple BLAST searches of these proposed barcode identifiers in GenBank revealed uniqueness for 100 taxonomic entities, whereas the three remaining identifiers each matched with two entities, but the species of these identifiers could easily be discriminated by differences in the remaining ITS regions. Using the proposed barcode identifiers, a 4.1-fold increase of 100% matches in GenBank was achieved in comparison to the classical approach using the complete ITS sequences. The proposed barcode identifiers will be made accessible for the diagnostic laboratory in a permanently updated online database, thereby providing a highly practical, reliable, and cost-effective tool for identification of clinically important black yeasts and relatives. PMID:22785187

Identifying 1st instar larvae for three forensically important blowfly species using "fingerprint" cuticular hydrocarbon analysis.

PubMed

Moore, Hannah E; Adam, Craig D; Drijfhout, Falko P

2014-07-01

Calliphoridae are known to be the most forensically important insects when it comes to establishing the minimum post mortem interval (PMImin) in criminal investigations. The first step in calculating the PMImin is to identify the larvae present to species level. Accurate identification which is conventionally carried out by morphological analysis is crucial because different insects have different life stage timings. Rapid identification in the immature larvae stages would drastically cut time in criminal investigations as it would eliminate the need to rear larvae to adult flies to determine the species. Cuticular hydrocarbon analysis on 1st instar larvae has been applied to three forensically important blowflies; Lucilia sericata, Calliphora vicina and Calliphora vomitoria, using gas chromatography-mass spectrometry (GC-MS) and principal component analysis (PCA). The results show that each species holds a distinct "fingerprint" hydrocarbon profile, allowing for accurate identification to be established in 1-day old larvae, when it can be challenging to apply morphological criteria. Consequently, this GC-MS based technique could accelerate and strengthen the identification process, not only for forensically important species, but also for other entomological samples which are hard to identify using morphological features. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Importance and functions of European grasslands.

PubMed

Carlier, L; De Vliegher, A; Van Cleemput, O; Boeckx, P

2005-01-01

The European agricultural policy is not simple and needs to accommodate also social and environmental requirements. Grassland will continue to be an important form of land use in Europe, but with increased diversity in management objectives and systems used. Besides its role as basic nutrient for herbivores and ruminants grasslands have opportunities for adding value by exploiting positive health characteristics in animal products from grassland and through the delivery of environmental benefits. In fact grasslands contribute to a high degree to the struggle against erosion and to the regularizing of water regimes, to the purification of fertilizers and pesticides and to biodiversity. Finally they have aesthetic role and recreational function as far as they provide public access that other agricultural uses do not allow. But even for grassland it is very difficult to create a good frame for its different tasks (1) the provision of forage for livestock, (2) protection and conservation of soil and water resources, (3) furnishing a habitat for wildlife, both flora and fauna and (4) contribution to the attractiveness of the landscape. Nevertheless it is the only crop, able to fulfil so many tasks and to fit so many requirements.

Using Multiple-Variable Matching to Identify Cultural Sources of Differential Item Functioning

ERIC Educational Resources Information Center

Wu, Amery D.; Ercikan, Kadriye

2006-01-01

Identifying the sources of differential item functioning (DIF) in international assessments is very challenging, because such sources are often nebulous and intertwined. Even though researchers frequently focus on test translation and content area, few actually go beyond these factors to investigate other cultural sources of DIF. This article…

The mid-fusiform sulcus: A landmark identifying both cytoarchitectonic and functional divisions of human ventral temporal cortex

PubMed Central

Weiner, Kevin S.; Golarai, Golijeh; Caspers, Julian; Chuapoco, Miguel R.; Mohlberg, Hartmut; Zilles, Karl; Amunts, Katrin; Grill-Spector, Kalanit

2014-01-01

Human ventral temporal cortex (VTC) plays a pivotal role in high-level vision. An under-studied macroanatomical feature of VTC is the mid-fusiform sulcus (MFS), a shallow longitudinal sulcus separating the lateral and medial fusiform gyrus (FG). Here, we quantified the morphological features of the MFS in 69 subjects (ages 7–40), and investigated its relationship to both cytoarchitectonic and functional divisions of VTC with four main findings. First, despite being a minor sulcus, we found that the MFS is a stable macroanatomical structure present in all 138 hemispheres with morphological characteristics developed by age 7. Second, the MFS is the locus of a lateral-medial cytoarchitechtonic transition within the posterior FG serving as the boundary between cytoarchitectonic regions FG1 and FG2. Third, the MFS predicts a lateral-medial functional transition in eccentricity bias representations in children, adolescents, and adults. Fourth, the anterior tip of the MFS predicts the location of a face-selective region, mFus-faces/FFA-2. These findings are the first to illustrate that a macroanatomical landmark identifies both cytoarchitectonic and functional divisions of high-level sensory cortex in humans and have important implications for understanding functional and structural organization in the human brain. PMID:24021838

Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions.

PubMed

Jiang, Tingting; Raviram, Ramya; Snetkova, Valentina; Rocha, Pedro P; Proudhon, Charlotte; Badri, Sana; Bonneau, Richard; Skok, Jane A; Kluger, Yuval

2016-10-14

Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiEκ, 3'Eκ and Edκ, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions

PubMed Central

Jiang, Tingting; Raviram, Ramya; Snetkova, Valentina; Rocha, Pedro P.; Proudhon, Charlotte; Badri, Sana; Bonneau, Richard; Skok, Jane A.; Kluger, Yuval

2016-01-01

Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiEκ, 3′Eκ and Edκ, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings. PMID:27439714

Report: EPA Can Better Reduce Risks From Illegal Pesticides by Effectively Identifying Imports for Inspection and Sampling

EPA Pesticide Factsheets

Report #17-P-0412, September 28, 2017. Low rates of inspections and sampling can create a risk that the EPA may not be identifying and deterring the import of pesticides harmful to people or the environment.

From DCPD to NTCP: The long journey towards identifying a functional hepatitis B virus receptor

PubMed Central

2015-01-01

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection. PMID:26523264

From DCPD to NTCP: the long journey towards identifying a functional hepatitis B virus receptor.

PubMed

Li, Jisu; Tong, Shuping

2015-09-01

Hepatitis B virus (HBV) is the prototype of hepatotropic DNA viruses (hepadnaviruses) infecting a wide range of human and non-human hosts. Previous studies with duck hepatitis B virus (DHBV) identified duck carboxypeptidase D (dCPD) as a host specific binding partner for full-length large envelope protein, and p120 as a binding partner for several truncated versions of the large envelope protein. p120 is the P protein of duck glycine decarboxylase (dGLDC) with restricted expression in DHBV infectible tissues. Several lines of evidence suggest the importance of dCPD, and especially p120, in productive DHBV infection, although neither dCPD nor p120 cDNA could confer susceptibility to DHBV infection in any cell line. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a binding partner for the N-terminus of HBV large envelope protein. Importantly, knock down and reconstitution experiments unequivocally demonstrated that NTCP is both necessary and sufficient for in vitro infection by HBV and hepatitis delta virus (HDV), an RNA virus using HBV envelope proteins for its transmission. What remains unclear is whether NTCP is the major HBV receptor in vivo. The fact that some HBV patients are homozygous with an NTCP mutation known to abolish its receptor function suggests the existence of NTCP-independent pathways of HBV entry. Also, NTCP very likely mediates just one step of the HBV entry process, with additional co-factors for productive HBV infection still to be discovered. NTCP offers a novel therapeutic target for the control of chronic HBV infection.

Probing Molecular Mechanisms of the Hsp90 Chaperone: Biophysical Modeling Identifies Key Regulators of Functional Dynamics

PubMed Central

Dixit, Anshuman; Verkhivker, Gennady M.

2012-01-01

Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based “conformational selection” of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters

Functionally conserved cis-regulatory elements of COL18A1 identified through zebrafish transgenesis.

PubMed

Kague, Erika; Bessling, Seneca L; Lee, Josephine; Hu, Gui; Passos-Bueno, Maria Rita; Fisher, Shannon

2010-01-15

Type XVIII collagen is a component of basement membranes, and expressed prominently in the eye, blood vessels, liver, and the central nervous system. Homozygous mutations in COL18A1 lead to Knobloch Syndrome, characterized by ocular defects and occipital encephalocele. However, relatively little has been described on the role of type XVIII collagen in development, and nothing is known about the regulation of its tissue-specific expression pattern. We have used zebrafish transgenesis to identify and characterize cis-regulatory sequences controlling expression of the human gene. Candidate enhancers were selected from non-coding sequence associated with COL18A1 based on sequence conservation among mammals. Although these displayed no overt conservation with orthologous zebrafish sequences, four regions nonetheless acted as tissue-specific transcriptional enhancers in the zebrafish embryo, and together recapitulated the major aspects of col18a1 expression. Additional post-hoc computational analysis on positive enhancer sequences revealed alignments between mammalian and teleost sequences, which we hypothesize predict the corresponding zebrafish enhancers; for one of these, we demonstrate functional overlap with the orthologous human enhancer sequence. Our results provide important insight into the biological function and regulation of COL18A1, and point to additional sequences that may contribute to complex diseases involving COL18A1. More generally, we show that combining functional data with targeted analyses for phylogenetic conservation can reveal conserved cis-regulatory elements in the large number of cases where computational alignment alone falls short. Copyright 2009 Elsevier Inc. All rights reserved.

The importance of biodiversity and dominance for multiple ecosystem functions in a human-modified tropical landscape.

PubMed

Lohbeck, Madelon; Bongers, Frans; Martinez-Ramos, Miguel; Poorter, Lourens

2016-10-01

Many studies suggest that biodiversity may be particularly important for ecosystem multifunctionality, because different species with different traits can contribute to different functions. Support, however, comes mostly from experimental studies conducted at small spatial scales in low-diversity systems. Here, we test whether different species contribute to different ecosystem functions that are important for carbon cycling in a high-diversity human-modified tropical forest landscape in Southern Mexico. We quantified aboveground standing biomass, primary productivity, litter production, and wood decomposition at the landscape level, and evaluated the extent to which tree species contribute to these ecosystem functions. We used simulations to tease apart the effects of species richness, species dominance and species functional traits on ecosystem functions. We found that dominance was more important than species traits in determining a species' contribution to ecosystem functions. As a consequence of the high dominance in human-modified landscapes, the same small subset of species mattered across different functions. In human-modified landscapes in the tropics, biodiversity may play a limited role for ecosystem multifunctionality due to the potentially large effect of species dominance on biogeochemical functions. However, given the spatial and temporal turnover in species dominance, biodiversity may be critically important for the maintenance and resilience of ecosystem functions. © 2016 The Authors. Ecology, published by Wiley Periodicals, Inc., on behalf of the Ecological Society of America.

Using the Developmental Gene Bicoid to Identify Species of Forensically Important Blowflies (Diptera: Calliphoridae)

PubMed Central

Park, Seong Hwan; Park, Chung Hyun; Zhang, Yong; Piao, Huguo; Chung, Ukhee; Kim, Seong Yoon; Ko, Kwang Soo; Yi, Cheong-Ho; Jo, Tae-Ho; Hwang, Juck-Joon

2013-01-01

Identifying species of insects used to estimate postmortem interval (PMI) is a major subject in forensic entomology. Because forensic insect specimens are morphologically uniform and are obtained at various developmental stages, DNA markers are greatly needed. To develop new autosomal DNA markers to identify species, partial genomic sequences of the bicoid (bcd) genes, containing the homeobox and its flanking sequences, from 12 blowfly species (Aldrichina grahami, Calliphora vicina, Calliphora lata, Triceratopyga calliphoroides, Chrysomya megacephala, Chrysomya pinguis, Phormia regina, Lucilia ampullacea, Lucilia caesar, Lucilia illustris, Hemipyrellia ligurriens and Lucilia sericata; Calliphoridae: Diptera) were determined and analyzed. This study first sequenced the ten blowfly species other than C. vicina and L. sericata. Based on the bcd sequences of these 12 blowfly species, a phylogenetic tree was constructed that discriminates the subfamilies of Calliphoridae (Luciliinae, Chrysomyinae, and Calliphorinae) and most blowfly species. Even partial genomic sequences of about 500 bp can distinguish most blowfly species. The short intron 2 and coding sequences downstream of the bcd homeobox in exon 3 could be utilized to develop DNA markers for forensic applications. These gene sequences are important in the evolution of insect developmental biology and are potentially useful for identifying insect species in forensic science. PMID:23586044

The importance of surface functional groups in the adsorption of copper onto walnut shell derived activated carbon.

PubMed

Xie, Ruzhen; Jin, Yan; Chen, Yao; Jiang, Wenju

2017-12-01

In this study, activated carbon (AC) was prepared from walnut shell using chemical activation. The surface chemistry of the prepared AC was modified by introducing or blocking certain functional groups, and the role of the different functional groups involved in the copper uptake was investigated. The structural and chemical heterogeneity of the produced carbons are characterized by Fourier transform infrared spectrometry, X-ray photoelectron spectroscopy, Boehm titration method and N 2 /77 K adsorption isotherm analysis. The equilibrium and the kinetics of copper adsorption onto AC were studied. The results demonstrated that the functional groups on AC played an important role in copper uptake. Among various surface functional groups, the oxygen-containing group was found to play a critical role in the copper uptake, and oxidation is the most effective way to improve Cu (II) adsorption onto AC. Ion-exchange was identified to be the dominant mechanism in the copper uptake by AC. Some other types of interactions, like complexation, were also proven to be involved in the adsorption process, while physical force was found to play a small role in the copper uptake. The regeneration of copper-loaded AC and the recovery of copper were also studied to evaluate the reusability of the oxidized AC.

Robust Selection Algorithm (RSA) for Multi-Omic Biomarker Discovery; Integration with Functional Network Analysis to Identify miRNA Regulated Pathways in Multiple Cancers.

PubMed

Sehgal, Vasudha; Seviour, Elena G; Moss, Tyler J; Mills, Gordon B; Azencott, Robert; Ram, Prahlad T

2015-01-01

MicroRNAs (miRNAs) play a crucial role in the maintenance of cellular homeostasis by regulating the expression of their target genes. As such, the dysregulation of miRNA expression has been frequently linked to cancer. With rapidly accumulating molecular data linked to patient outcome, the need for identification of robust multi-omic molecular markers is critical in order to provide clinical impact. While previous bioinformatic tools have been developed to identify potential biomarkers in cancer, these methods do not allow for rapid classification of oncogenes versus tumor suppressors taking into account robust differential expression, cutoffs, p-values and non-normality of the data. Here, we propose a methodology, Robust Selection Algorithm (RSA) that addresses these important problems in big data omics analysis. The robustness of the survival analysis is ensured by identification of optimal cutoff values of omics expression, strengthened by p-value computed through intensive random resampling taking into account any non-normality in the data and integration into multi-omic functional networks. Here we have analyzed pan-cancer miRNA patient data to identify functional pathways involved in cancer progression that are associated with selected miRNA identified by RSA. Our approach demonstrates the way in which existing survival analysis techniques can be integrated with a functional network analysis framework to efficiently identify promising biomarkers and novel therapeutic candidates across diseases.

American Bird conservancy's approach to the U.S. Important Bird Area Program - identifying the top 500 global sites

Treesearch

Robert M. Chipley

2005-01-01

The idea for the Important Bird Area Program originated in a series of studies in the early 1980s conducted by BirdLife International. Recognizing that these studies could become a powerful tool for conservation, BirdLife International began an effort to identify and gather data regarding the most important areas for birds in Europe and to make this information...

Validating the UNICEF/Washington Group Child Functioning Module for Fijian schools to identify seeing, hearing and walking difficulties.

PubMed

Sprunt, Beth; Hoq, Monsurul; Sharma, Umesh; Marella, Manjula

2017-09-20

This study investigated the seeing, hearing and walking questions of the UNICEF/Washington Group Child Functioning Module and the inter-rater reliability between teachers and parents as proxy respondents. Cross-sectional diagnostic accuracy study, two-gate design with representative sampling, comparing Module responses to reference standard assessments for 472 primary aged students in Fiji. Receiver operating characteristic curves were constructed to determine the area under the curve and optimal cut-off points. Areas under the curves ranged from 0.823 to 0.889 indicating "good" diagnostic accuracy. Inter-rater reliability between parent and teacher responses was "good" to "excellent". The optimal cut-off determined by the Youden Index was "some difficulty" however a wide spread of impairment levels were found in this category with most children either having none or substantial impairments. The diagnostic accuracy of the Module seeing, hearing and walking questions appears acceptable with either parents or teachers as proxy respondents. For education systems, use of the cut-off "some difficulty" with accompanying clinical assessment may be important to capture children who require services and learning supports and avoid potentially misleading categorization. Given the high proportion of the sample from special schools research is required to further test the Module in mainstream schools. Implications for rehabilitation Identification of children who are at risk of disability in Fiji is important to enable planning, monitoring and evaluating access to quality inclusive education. The UNICEF/Washington Group Child Functioning Module appears to be a practical and effective tool that can be used by teachers to identify children at risk of disability. Children identified on the UNICEF/Washington Group Child Functioning Module as having "some difficulty" or higher levels of difficulty in relation to vision, hearing or walking should be referred for further assessment

Identifying functional reorganization of spelling networks: an individual peak probability comparison approach

PubMed Central

Purcell, Jeremy J.; Rapp, Brenda

2013-01-01

Previous research has shown that damage to the neural substrates of orthographic processing can lead to functional reorganization during reading (Tsapkini et al., 2011); in this research we ask if the same is true for spelling. To examine the functional reorganization of spelling networks we present a novel three-stage Individual Peak Probability Comparison (IPPC) analysis approach for comparing the activation patterns obtained during fMRI of spelling in a single brain-damaged individual with dysgraphia to those obtained in a set of non-impaired control participants. The first analysis stage characterizes the convergence in activations across non-impaired control participants by applying a technique typically used for characterizing activations across studies: Activation Likelihood Estimate (ALE) (Turkeltaub et al., 2002). This method was used to identify locations that have a high likelihood of yielding activation peaks in the non-impaired participants. The second stage provides a characterization of the degree to which the brain-damaged individual's activations correspond to the group pattern identified in Stage 1. This involves performing a Mahalanobis distance statistics analysis (Tsapkini et al., 2011) that compares each of a control group's peak activation locations to the nearest peak generated by the brain-damaged individual. The third stage evaluates the extent to which the brain-damaged individual's peaks are atypical relative to the range of individual variation among the control participants. This IPPC analysis allows for a quantifiable, statistically sound method for comparing an individual's activation pattern to the patterns observed in a control group and, thus, provides a valuable tool for identifying functional reorganization in a brain-damaged individual with impaired spelling. Furthermore, this approach can be applied more generally to compare any individual's activation pattern with that of a set of other individuals. PMID:24399981

Clinically important improvement in function is common in people with or at high risk of knee OA: the MOST study

PubMed Central

White, Daniel K.; Keysor, Julie J.; LaValley, Michael P.; Lewis, Cora E.; Torner, James C.; Nevitt, Michael C.; Felson, David T.

2010-01-01

To calculate the frequency of clinically important improvement in function over 30 months and identify risk factors in people who have or are at risk of knee OA. Subjects were from MOST, a longitudinal study of persons with or at high risk of knee OA. We defined Minimal Clinically Important Improvement (MCII) with WOMAC physical function using three different methods. Baseline risk factors tested for improvement included age, gender, educational attainment, presence of radiographic knee OA (ROA), the number of comorbidities, Body Mass Index (BMI), knee pain, walking speed, isokinetic knee extensor strength, depressive symptoms, physical activity, and medication usage. We used logistic regression to evaluate the association of baseline risk factors with MCII. Of the 1801 subjects (age= 63, BMI= 31, 63% female), most had mild limitations in baseline function (WOMAC = 19 +/− 11). Regardless how defined, a substantial percentage of subjects (24%–39%) reached MCII at 30 months. Compared to their counterparts, people with MCII were less likely to have ROA and to use medications, and were more likely to have a lower BMI, less knee pain, a faster walking speed, more knee strength, and fewer depressive symptoms. After adjustment, MCII was 40% to 50% less likely in those with ROA, and 1.9 to 2.0 times more likely in those walking 1.0 m/s faster than counterparts. Clinically important improvement is frequent in people with or at high risk of knee OA. The absence of ROA and a faster walking speed appear to be associated with clinically important improvements. PMID:20395640

Understanding the Importance of the Teres Minor for Shoulder Function: Functional Anatomy and Pathology.

PubMed

Williams, Matthew D; Edwards, Thomas Bradley; Walch, Gilles

2018-03-01

Although the teres minor is often overlooked in a normal shoulder, it becomes a key component in maintaining shoulder function when other rotator cuff tendons fail. The teres minor maintains a balanced glenohumeral joint and changes from an insignificant to the most significant external rotator in the presence of major rotator cuff pathology. The presence or absence of the teres minor provides prognostic information on the outcomes of reverse total shoulder arthroplasty and tendon transfers. Clinical tests include the Patte test, the Neer dropping sign, the external rotation lag sign, and the Hertel drop sign. Advanced imaging of the teres minor can be used for classification using the Walch system. Understanding the function and pathology surrounding the teres minor is paramount in comprehensive management of the patient with shoulder pathology. Appropriate clinical examination and imaging of the teres minor are important for preoperative stratification and postoperative expectations.

The importance of hydrology in restoration of bottomland hardwood wetland functions

USGS Publications Warehouse

Hunter, R.G.; Faulkner, S.P.; Gibson, K.A.

2008-01-01

Bottomland hardwood (BLH) forests have important biogeochemical functions and it is well known that certain structural components, including pulsed hydrology, hydric soils, and hydrophytic vegetation, enhance these functions. It is unclear, however, how functions of restored BLH wetlands compare to mature, undisturbed wetlands. We measured a suite of structural and functional attributes in replicated natural BLH wetlands (NAT), restored BLH wetlands with hydrology re-established (RWH), and restored BLH wetlands without hydrology re-established (RWOH) in this study. Trees were replanted in all restored wetlands at least four years prior to the study and those wetlands with hydrology re-established had flashboard risers placed in drainage ditches to allow seasonal surface flooding. Vegetation, soils, and selected biogeochemical functions were characterized at each site. There was a marked difference in woody vegetation among the wetlands that was due primarily to site age. There was also a difference in herbaceous vegetation among the restored sites that may have been related to differences in age or hydrology. Water table fluctuations of the RWH wetlands were comparable to those of the NAT wetlands. Thus, placing flashboard risers in existing drainage ditches, along with proper management, can produce a hydroperiod that is similar to that of a relatively undisturbed BLH. Average length of saturation within the upper 15 cm of soils was 37, 104, and 97 days for RWOH, RWH, and NAT, respectively. Soil moisture, denitrification potential, and soluble organic carbon concentrations differed among wetland sites, but soil carbon and nitrogen concentrations, heterotrophic microbial activity, and readily mineralizable carbon concentrations did not. Significant linear relationships were also found between soil moisture and heterotrophic microbial activity, readily mineralizable carbon, and soluble organic carbon. In addition, sedimentation rates were higher in NAT and RWH

Functional kinomics identifies candidate therapeutic targets in head and neck cancer

PubMed Central

Moser, Russell; Xu, Chang; Kao, Michael; Annis, James; Lerma, Luisa Angelica; Schaupp, Christopher M.; Gurley, Kay E.; Jang, In Sock; Biktasova, Asel; Yarbrough, Wendell G.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.; Méndez, Eduardo

2014-01-01

Purpose To identify novel therapeutic drug targets for p53 mutant head and neck squamous cell carcinoma (HNSCC). Experimental Design RNAi kinome viability screens were performed on HNSCC cells including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19Arf. Cross-species analysis of cell lines stratified by p53 mutational status and metastatic phenotype was utilized to select 38 kinase targets. Both primary and secondary RNAi validation assays were performed on additional HNSCC cell lines to credential these kinase targets utilizing multiple phenotypic endpoints. Kinase targets were also examined via chemical inhibition utilizing a panel of kinase inhibitors. A preclinical study was conducted on the WEE1 kinase inhibitor, MK-1775. Results Our functional kinomics approach identified novel survival kinases in HNSCC involved in G2/M cell cycle checkpoint, SFK, PI3K and FAK pathways. RNAi mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis. Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry. MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53 mutant HNSCC xenograft model. Conclusions WEE1 kinase is a potential therapeutic drug target for HNSCC. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer. PMID:25125259

Functional kinomics identifies candidate therapeutic targets in head and neck cancer.

PubMed

Moser, Russell; Xu, Chang; Kao, Michael; Annis, James; Lerma, Luisa Angelica; Schaupp, Christopher M; Gurley, Kay E; Jang, In Sock; Biktasova, Asel; Yarbrough, Wendell G; Margolin, Adam A; Grandori, Carla; Kemp, Christopher J; Méndez, Eduardo

2014-08-15

To identify novel therapeutic drug targets for p53-mutant head and neck squamous cell carcinoma (HNSCC). RNAi kinome viability screens were performed on HNSCC cells, including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19(Arf). Cross-species analysis of cell lines stratified by p53 mutational status and metastatic phenotype was used to select 38 kinase targets. Both primary and secondary RNAi validation assays were performed on additional HNSCC cell lines to credential these kinase targets using multiple phenotypic endpoints. Kinase targets were also examined via chemical inhibition using a panel of kinase inhibitors. A preclinical study was conducted on the WEE1 kinase inhibitor, MK-1775. Our functional kinomics approach identified novel survival kinases in HNSCC involved in G2-M cell-cycle checkpoint, SFK, PI3K, and FAK pathways. RNAi-mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis. Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry. MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53-mutant HNSCC xenograft model. WEE1 kinase is a potential therapeutic drug target for HNSCC. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer. ©2014 American Association for Cancer Research.

Import routes and nuclear functions of Argonaute and other small RNA-silencing proteins.

PubMed

Schraivogel, Daniel; Meister, Gunter

2014-09-01

Small RNAs are important regulators of gene expression in many different organisms. Nuclear and cytoplasmic biogenesis enzymes generate functional small RNAs from double-stranded (ds) or single-stranded (ss) RNA precursors, and mature small RNAs are loaded into Argonaute proteins. In the cytoplasm, small RNAs guide Argonaute proteins to complementary RNAs leading to cleavage of these targets, translational silencing, or mRNA decay. In the nucleus Argonaute proteins engage in transcriptional silencing processes such as epigenetic silencing of repetitive elements at the chromatin level. During the past few years many novel functions of small RNA-guided gene silencing proteins in the nucleus have been reported. However, their specific import routes are largely unknown. In this review we summarize the current knowledge on nuclear transport routes that Argonaute and other RNA-silencing proteins take to carry out their various functions in the nucleus. Copyright © 2014 Elsevier Ltd. All rights reserved.

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

PubMed Central

Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

2015-01-01

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

PubMed

Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

2015-08-01

Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

iAMP-2L: a two-level multi-label classifier for identifying antimicrobial peptides and their functional types.

PubMed

Xiao, Xuan; Wang, Pu; Lin, Wei-Zhong; Jia, Jian-Hua; Chou, Kuo-Chen

2013-05-15

Antimicrobial peptides (AMPs), also called host defense peptides, are an evolutionarily conserved component of the innate immune response and are found among all classes of life. According to their special functions, AMPs are generally classified into ten categories: Antibacterial Peptides, Anticancer/tumor Peptides, Antifungal Peptides, Anti-HIV Peptides, Antiviral Peptides, Antiparasital Peptides, Anti-protist Peptides, AMPs with Chemotactic Activity, Insecticidal Peptides, and Spermicidal Peptides. Given a query peptide, how can we identify whether it is an AMP or non-AMP? If it is, can we identify which functional type or types it belong to? Particularly, how can we deal with the multi-type problem since an AMP may belong to two or more functional types? To address these problems, which are obviously very important to both basic research and drug development, a multi-label classifier was developed based on the pseudo amino acid composition (PseAAC) and fuzzy K-nearest neighbor (FKNN) algorithm, where the components of PseAAC were featured by incorporating five physicochemical properties. The novel classifier is called iAMP-2L, where "2L" means that it is a 2-level predictor. The 1st-level is to answer the 1st question above, while the 2nd-level is to answer the 2nd and 3rd questions that are beyond the reach of any existing methods in this area. For the conveniences of users, a user-friendly web-server for iAMP-2L was established at http://www.jci-bioinfo.cn/iAMP-2L. Copyright © 2013 Elsevier Inc. All rights reserved.

Identifying Functional Requirements for Flexible Airspace Management Concept Using Human-In-The-Loop Simulations

NASA Technical Reports Server (NTRS)

Lee, Paul U.; Bender, Kim; Pagan, Danielle

2011-01-01

Flexible Airspace Management (FAM) is a mid- term Next Generation Air Transportation System (NextGen) concept that allows dynamic changes to airspace configurations to meet the changes in the traffic demand. A series of human-in-the-loop (HITL) studies have identified procedures and decision support requirements needed to implement FAM. This paper outlines a suggested FAM procedure and associated decision support functionality based on these HITL studies. A description of both the tools used to support the HITLs and the planned NextGen technologies available in the mid-term are presented and compared. The mid-term implementation of several NextGen capabilities, specifically, upgrades to the Traffic Management Unit (TMU), the initial release of an en route automation system, the deployment of a digital data communication system, a more flexible voice communications network, and the introduction of a tool envisioned to manage and coordinate networked ground systems can support the implementation of the FAM concept. Because of the variability in the overall deployment schedule of the mid-term NextGen capabilities, the dependency of the individual NextGen capabilities are examined to determine their impact on a mid-term implementation of FAM. A cursory review of the different technologies suggests that new functionality slated for the new en route automation system is a critical enabling technology for FAM, as well as the functionality to manage and coordinate networked ground systems. Upgrades to the TMU are less critical but important nonetheless for FAM to be fully realized. Flexible voice communications network and digital data communication system could allow more flexible FAM operations but they are not as essential.

A conserved domain in the NH2 terminus important for assembly and functional expression of pacemaker channels.

PubMed

Tran, Neil; Proenza, Catherine; Macri, Vincenzo; Petigara, Fiona; Sloan, Erin; Samler, Shannon; Accili, Eric A

2002-11-15

Pacemaker channels are formed by co-assembly of hyperpolarization-activated cyclic nucleotide-gated (HCN) subunits. Previously, we suggested that the NH(2) termini of the mouse HCN2 isoform were important for subunit co-assembly and functional channel expression. Using an alignment strategy together with yeast two-hybrid assays, patch clamp electrophysiology, and confocal imaging, we have now identified a domain within the NH(2) terminus of the HCN2 subunit that is responsible for interactions between NH(2) termini and promoting the trafficking of functional channels to the plasma membrane. This domain is composed of 52 amino acids, is located adjacent to the putative first transmembrane segment, and is highly conserved among the mammalian HCN isoforms. This conserved domain, but not the remaining unconserved NH(2)-terminal regions of HCN2, specifically interacted with itself in yeast two-hybrid assays. Moreover, the conserved domain was important for expression of currents. Whereas relatively normal whole cell HCN2 currents were produced by channels containing only the conserved domain, further deletion of this region, leaving only a more polar and putative coiled-coil segment, eliminated HCN2 currents and resulted in proteins that localized predominantly in perinuclear compartments. Thus, we suggest that this conserved domain is the critical NH(2)-terminal determinant of subunit co-assembly and trafficking of pacemaker channels.

Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function

PubMed Central

Manesia, Javed K.; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M.

2018-01-01

During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term “transcription.” By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function. PMID:27958775

Multi-tissue analysis of co-expression networks by higher-order generalized singular value decomposition identifies functionally coherent transcriptional modules.

PubMed

Xiao, Xiaolin; Moreno-Moral, Aida; Rotival, Maxime; Bottolo, Leonardo; Petretto, Enrico

2014-01-01

Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks) that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted) networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based) and humans (mRNA-sequencing-based) and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi-tissue subnetwork of co

Virus decomposition provides an important contribution to benthic deep-sea ecosystem functioning.

PubMed

Dell'Anno, Antonio; Corinaldesi, Cinzia; Danovaro, Roberto

2015-04-21

Viruses are key biological agents of prokaryotic mortality in the world oceans, particularly in deep-sea ecosystems where nearly all of the prokaryotic C production is transformed into organic detritus. However, the extent to which the decomposition of viral particles (i.e., organic material of viral origin) influences the functioning of benthic deep-sea ecosystems remains completely unknown. Here, using various independent approaches, we show that in deep-sea sediments an important fraction of viruses, once they are released by cell lysis, undergo fast decomposition. Virus decomposition rates in deep-sea sediments are high even at abyssal depths and are controlled primarily by the extracellular enzymatic activities that hydrolyze the proteins of the viral capsids. We estimate that on a global scale the decomposition of benthic viruses releases ∼37-50 megatons of C per year and thus represents an important source of labile organic compounds in deep-sea ecosystems. Organic material released from decomposed viruses is equivalent to 3 ± 1%, 6 ± 2%, and 12 ± 3% of the input of photosynthetically produced C, N, and P supplied through particles sinking to bathyal/abyssal sediments. Our data indicate that the decomposition of viruses provides an important, previously ignored contribution to deep-sea ecosystem functioning and has an important role in nutrient cycling within the largest ecosystem of the biosphere.

Virus decomposition provides an important contribution to benthic deep-sea ecosystem functioning

PubMed Central

Dell’Anno, Antonio; Corinaldesi, Cinzia

2015-01-01

Viruses are key biological agents of prokaryotic mortality in the world oceans, particularly in deep-sea ecosystems where nearly all of the prokaryotic C production is transformed into organic detritus. However, the extent to which the decomposition of viral particles (i.e., organic material of viral origin) influences the functioning of benthic deep-sea ecosystems remains completely unknown. Here, using various independent approaches, we show that in deep-sea sediments an important fraction of viruses, once they are released by cell lysis, undergo fast decomposition. Virus decomposition rates in deep-sea sediments are high even at abyssal depths and are controlled primarily by the extracellular enzymatic activities that hydrolyze the proteins of the viral capsids. We estimate that on a global scale the decomposition of benthic viruses releases ∼37–50 megatons of C per year and thus represents an important source of labile organic compounds in deep-sea ecosystems. Organic material released from decomposed viruses is equivalent to 3 ± 1%, 6 ± 2%, and 12 ± 3% of the input of photosynthetically produced C, N, and P supplied through particles sinking to bathyal/abyssal sediments. Our data indicate that the decomposition of viruses provides an important, previously ignored contribution to deep-sea ecosystem functioning and has an important role in nutrient cycling within the largest ecosystem of the biosphere. PMID:25848024

Conceptual framework for patient-important treatment outcomes for pelvic organ prolapse.

PubMed

Sung, Vivian W; Rogers, Rebecca G; Barber, Matthew D; Clark, Melissa A

2014-04-01

To develop a comprehensive conceptual framework representing the most important outcomes for women seeking treatment for pelvic organ prolapse (POP). Twenty-five women with POP were recruited and participated in four semi-structured focus groups to refine and assess the content validity of a conceptual framework representing patient-important outcomes for POP. Specifically, the focus groups addressed the following three aims: (1) to evaluate the content and appropriateness of domains in our framework; (2) to identify gaps in the framework; and (3) to determine the relative importance of our framework domains from the patient perspective. Sessions were transcribed, coded, and qualitatively and quantitatively analyzed using analytic induction and deductive analysis to identify themes and domains relevant to women with POP. Our focus groups confirmed the importance of vaginal bulge symptoms (discomfort, bother, and adaptation), and the overarching domains and subdomains of physical (physical function and participation), social (social function, relationships, and sexual function), and mental health (emotional distress, preoccupation, and body image). Patients ranked outcomes in the following order of importance: (1) the resolution of vaginal bulge symptoms, (2) improvement in physical function; (3) improvement in sexual function; (4) improvement in body image perception; and (5) improvement in social function. We developed a conceptual framework for patient important outcomes of women seeking treatment for POP. This framework can improve the transparency and interpretation of POP study findings from the patient perspective. Vaginal bulge and its associated discomfort are most important for the definition of POP treatment success from the patient perspective. © 2013 Wiley Periodicals, Inc.

Editor's Highlight: High-Throughput Functional Genomics Identifies Modulators of TCE Metabolite Genotoxicity and Candidate Susceptibility Genes.

PubMed

De La Rosa, Vanessa Y; Asfaha, Jonathan; Fasullo, Michael; Loguinov, Alex; Li, Peng; Moore, Lee E; Rothman, Nathaniel; Nakamura, Jun; Swenberg, James A; Scelo, Ghislaine; Zhang, Luoping; Smith, Martyn T; Vulpe, Chris D

2017-11-01

Trichloroethylene (TCE), an industrial chemical and environmental contaminant, is a human carcinogen. Reactive metabolites are implicated in renal carcinogenesis associated with TCE exposure, yet the toxicity mechanisms of these metabolites and their contribution to cancer and other adverse effects remain unclear. We employed an integrated functional genomics approach that combined functional profiling studies in yeast and avian DT40 cell models to provide new insights into the specific mechanisms contributing to toxicity associated with TCE metabolites. Genome-wide profiling studies in yeast identified the error-prone translesion synthesis (TLS) pathway as an import mechanism in response to TCE metabolites. The role of TLS DNA repair was further confirmed by functional profiling in DT40 avian cell lines, but also revealed that TLS and homologous recombination DNA repair likely play competing roles in cellular susceptibility to TCE metabolites in higher eukaryotes. These DNA repair pathways are highly conserved between yeast, DT40, and humans. We propose that in humans, mutagenic TLS is favored over homologous recombination repair in response to TCE metabolites. The results of these studies contribute to the body of evidence supporting a mutagenic mode of action for TCE-induced renal carcinogenesis mediated by reactive metabolites in humans. Our approach illustrates the potential for high-throughput in vitro functional profiling in yeast to elucidate toxicity pathways (molecular initiating events, key events) and candidate susceptibility genes for focused study. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

LUMINOSITY FUNCTIONS OF SPITZER-IDENTIFIED PROTOSTARS IN NINE NEARBY MOLECULAR CLOUDS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kryukova, E.; Megeath, S. T.; Allen, T. S.

2012-08-15

We identify protostars in Spitzer surveys of nine star-forming (SF) molecular clouds within 1 kpc: Serpens, Perseus, Ophiuchus, Chamaeleon, Lupus, Taurus, Orion, Cep OB3, and Mon R2, which combined host over 700 protostar candidates. These clouds encompass a variety of SF environments, including both low-mass and high-mass SF regions, as well as dense clusters and regions of sparsely distributed star formation. Our diverse cloud sample allows us to compare protostar luminosity functions in these varied environments. We combine near- and mid-infrared photometry from the Two Micron All Sky Survey and Spitzer to create 1-24 {mu}m spectral energy distributions (SEDs). Usingmore » protostars from the c2d survey with well-determined bolometric luminosities, we derive a relationship between bolometric luminosity, mid-IR luminosity (integrated from 1-24 {mu}m), and SED slope. Estimations of the bolometric luminosities for protostar candidates are combined to create luminosity functions for each cloud. Contamination due to edge-on disks, reddened Class II sources, and galaxies is estimated and removed from the luminosity functions. We find that luminosity functions for high-mass SF clouds (Orion, Mon R2, and Cep OB3) peak near 1 L{sub Sun} and show a tail extending toward luminosities above 100 L{sub Sun }. The luminosity functions of the low-mass SF clouds (Serpens, Perseus, Ophiuchus, Taurus, Lupus, and Chamaeleon) do not exhibit a common peak, however the combined luminosity function of these regions peaks below 1 L{sub Sun }. Finally, we examine the luminosity functions as a function of the local surface density of young stellar objects. In the Orion molecular clouds, we find a significant difference between the luminosity functions of protostars in regions of high and low stellar density, the former of which is biased toward more luminous sources. This may be the result of primordial mass segregation, although this interpretation is not unique. We compare our

Scanning genomic areas under selection sweep and association mapping as tools to identify horticultural important genes in watermelon

USDA-ARS?s Scientific Manuscript database

Watermelon (Citrullus lanatus var. lanatus) contains 88% water, sugars, and several important health-related compounds, including lycopene, citrulline, arginine, and glutathione. The current genetic diversity study uses microsatellites with known map positions to identify genomic regions that under...

H-1 Nuclear Magnetic Resonance Metabolomics Analysis Identifies Novel Urinary Biomarkers for Lung Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

MCClay, Joseph L.; Adkins, Daniel E.; Isern, Nancy G.

2010-06-04

Chronic obstructive pulmonary disease (COPD), characterized by chronic airflow limitation, is a serious and growing public health concern. The major environmental risk factor for COPD is tobacco smoking, but the biological mechanisms underlying COPD are not well understood. In this study, we used proton nuclear magnetic resonance (1H-NMR) spectroscopy to identify and quantify metabolites associated with lung function in COPD. Plasma and urine were collected from 197 adults with COPD and from 195 adults without COPD. Samples were assayed using a 600 MHz NMR spectrometer, and the resulting spectra were analyzed against quantitative spirometric measures of lung function. After correctingmore » for false discoveries and adjusting for covariates (sex, age, smoking) several spectral regions in urine were found to be significantly associated with baseline lung function. These regions correspond to the metabolites trigonelline, hippurate and formate. Concentrations of each metabolite, standardized to urinary creatinine, were associated with baseline lung function (minimum p-value = 0.0002 for trigonelline). No significant associations were found with plasma metabolites. Two of the three urinary metabolites positively associated with baseline lung function, i.e. hippurate and formate, are often related to gut microflora. This suggests that the microbiome composition is variable between individuals with different lung function. Alternatively, the nature and origins of all three associated metabolites may reflect lifestyle differences affecting overall health. Our results will require replication and validation, but demonstrate the utility of NMR metabolomics as a screening tool for identifying novel biomarkers of lung disease or disease risk.« less

A complex network-based importance measure for mechatronics systems

NASA Astrophysics Data System (ADS)

Wang, Yanhui; Bi, Lifeng; Lin, Shuai; Li, Man; Shi, Hao

2017-01-01

In view of the negative impact of functional dependency, this paper attempts to provide an alternative importance measure called Improved-PageRank (IPR) for measuring the importance of components in mechatronics systems. IPR is a meaningful extension of the centrality measures in complex network, which considers usage reliability of components and functional dependency between components to increase importance measures usefulness. Our work makes two important contributions. First, this paper integrates the literature of mechatronic architecture and complex networks theory to define component network. Second, based on the notion of component network, a meaningful IPR is brought into the identifying of important components. In addition, the IPR component importance measures, and an algorithm to perform stochastic ordering of components due to the time-varying nature of usage reliability of components and functional dependency between components, are illustrated with a component network of bogie system that consists of 27 components.

Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling.

PubMed

Scharin Täng, M; Redfors, B; Lindbom, M; Svensson, J; Ramunddal, T; Ohlsson, C; Shao, Y; Omerovic, E

2012-12-01

IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF-1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. Copyright © 2012 Elsevier Ltd. All rights reserved.

Comprehensive evaluation of disease- and trait-specific enrichment for eight functional elements among GWAS-identified variants.

PubMed

Markunas, Christina A; Johnson, Eric O; Hancock, Dana B

2017-07-01

Genome-wide association study (GWAS)-identified variants are enriched for functional elements. However, we have limited knowledge of how functional enrichment may differ by disease/trait and tissue type. We tested a broad set of eight functional elements for enrichment among GWAS-identified SNPs (p < 5×10 -8 ) from the NHGRI-EBI Catalog across seven disease/trait categories: cancer, cardiovascular disease, diabetes, autoimmune disease, psychiatric disease, neurological disease, and anthropometric traits. SNPs were annotated using HaploReg for the eight functional elements across any tissue: DNase sites, expression quantitative trait loci (eQTL), sequence conservation, enhancers, promoters, missense variants, sequence motifs, and protein binding sites. In addition, tissue-specific annotations were considered for brain vs. blood. Disease/trait SNPs were compared to a control set of 4809 SNPs matched to the GWAS SNPs (N = 1639) on allele frequency, gene density, distance to nearest gene, and linkage disequilibrium at ~3:1 ratio. Enrichment analyses were conducted using logistic regression, with Bonferroni correction. Overall, a significant enrichment was observed for all functional elements, except sequence motifs. Missense SNPs showed the strongest magnitude of enrichment. eQTLs were the only functional element significantly enriched across all diseases/traits. Magnitudes of enrichment were generally similar across diseases/traits, where enrichment was statistically significant. Blood vs. brain tissue effects on enrichment were dependent on disease/trait and functional element (e.g., cardiovascular disease: eQTLs P TissueDifference  = 1.28 × 10 -6 vs. enhancers P TissueDifference  = 0.94). Identifying disease/trait-relevant functional elements and tissue types could provide new insight into the underlying biology, by guiding a priori GWAS analyses (e.g., brain enhancer elements for psychiatric disease) or facilitating post hoc interpretation.

Functional connectivity decreases in autism in emotion, self, and face circuits identified by Knowledge-based Enrichment Analysis.

PubMed

Cheng, Wei; Rolls, Edmund T; Zhang, Jie; Sheng, Wenbo; Ma, Liang; Wan, Lin; Luo, Qiang; Feng, Jianfeng

2017-03-01

A powerful new method is described called Knowledge based functional connectivity Enrichment Analysis (KEA) for interpreting resting state functional connectivity, using circuits that are functionally identified using search terms with the Neurosynth database. The method derives its power by focusing on neural circuits, sets of brain regions that share a common biological function, instead of trying to interpret single functional connectivity links. This provides a novel way of investigating how task- or function-related networks have resting state functional connectivity differences in different psychiatric states, provides a new way to bridge the gap between task and resting-state functional networks, and potentially helps to identify brain networks that might be treated. The method was applied to interpreting functional connectivity differences in autism. Functional connectivity decreases at the network circuit level in 394 patients with autism compared with 473 controls were found in networks involving the orbitofrontal cortex, anterior cingulate cortex, middle temporal gyrus cortex, and the precuneus, in networks that are implicated in the sense of self, face processing, and theory of mind. The decreases were correlated with symptom severity. Copyright © 2017. Published by Elsevier Inc.

Functional Analysis of Problem Behavior: A Systematic Approach for Identifying Idiosyncratic Variables

PubMed Central

Roscoe, Eileen M.; Schlichenmeyer, Kevin J.; Dube, William V.

2015-01-01

When inconclusive functional analysis (FA) outcomes occur, a number of modifications have been made to enhance the putative establishing operation or consequence associated with behavioral maintenance. However, a systematic method for identifying relevant events to test during modified FAs has not been evaluated. The purpose of this study was to develop and evaluate a technology for systematically identifying events to test in a modified FA after an initial FA led to inconclusive outcomes. Six individuals whose initial FA showed little or no responding or high levels only in the control condition participated. An indirect assessment (IA) questionnaire developed for identifying idiosyncratic variables was administered, and a descriptive analysis (DA) was conducted. Results from the IA only or a combination of the IA and DA were used to inform modified FA test and control conditions. Conclusive FA outcomes were obtained with five of the six participants during the modified FA phase. PMID:25930176

Identifying thematic roles from neural representations measured by functional magnetic resonance imaging.

PubMed

Wang, Jing; Cherkassky, Vladimir L; Yang, Ying; Chang, Kai-Min Kevin; Vargas, Robert; Diana, Nicholas; Just, Marcel Adam

2016-01-01

The generativity and complexity of human thought stem in large part from the ability to represent relations among concepts and form propositions. The current study reveals how a given object such as rabbit is neurally encoded differently and identifiably depending on whether it is an agent ("the rabbit punches the monkey") or a patient ("the monkey punches the rabbit"). Machine-learning classifiers were trained on functional magnetic resonance imaging (fMRI) data evoked by a set of short videos that conveyed agent-verb-patient propositions. When tested on a held-out video, the classifiers were able to reliably identify the thematic role of an object from its associated fMRI activation pattern. Moreover, when trained on one subset of the study participants, classifiers reliably identified the thematic roles in the data of a left-out participant (mean accuracy = .66), indicating that the neural representations of thematic roles were common across individuals.

Extensions of PDZ domains as important structural and functional elements.

PubMed

Wang, Conan K; Pan, Lifeng; Chen, Jia; Zhang, Mingjie

2010-08-01

'Divide and conquer' has been the guiding strategy for the study of protein structure and function. Proteins are divided into domains with each domain having a canonical structural definition depending on its type. In this review, we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function; we call these regions 'extensions'. We focus on the highly abundant PDZ (PSD-95, DLG1 and ZO-1) domain. Using bioinformatics, we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results ( http://bcz102.ust.hk/pdzex/ ). We propose, using well-studied PDZ domains as illustrative examples, that the roles of PDZ extensions can be classified into at least four categories: 1) protein dynamics-based modulation of target binding affinity, 2) provision of binding sites for macro-molecular assembly, 3) structural integration of multi-domain modules, and 4) expansion of the target ligand-binding pocket. Our review highlights the potential structural and functional importance of domain extensions, highlighting the significance of looking beyond the canonical boundaries of protein domains in general.

Identifying the domains of context important to implementation science: a study protocol.

PubMed

Squires, Janet E; Graham, Ian D; Hutchinson, Alison M; Michie, Susan; Francis, Jill J; Sales, Anne; Brehaut, Jamie; Curran, Janet; Ivers, Noah; Lavis, John; Linklater, Stefanie; Fenton, Shannon; Noseworthy, Thomas; Vine, Jocelyn; Grimshaw, Jeremy M

2015-09-28

There is growing recognition that "context" can and does modify the effects of implementation interventions aimed at increasing healthcare professionals' use of research evidence in clinical practice. However, conceptual clarity about what exactly comprises "context" is lacking. The purpose of this research program is to develop, refine, and validate a framework that identifies the key domains of context (and their features) that can facilitate or hinder (1) healthcare professionals' use of evidence in clinical practice and (2) the effectiveness of implementation interventions. A multi-phased investigation of context using mixed methods will be conducted. The first phase is a concept analysis of context using the Walker and Avant method to distinguish between the defining and irrelevant attributes of context. This phase will result in a preliminary framework for context that identifies its important domains and their features according to the published literature. The second phase is a secondary analysis of qualitative data from 13 studies of interviews with 312 healthcare professionals on the perceived barriers and enablers to their application of research evidence in clinical practice. These data will be analyzed inductively using constant comparative analysis. For the third phase, we will conduct semi-structured interviews with key health system stakeholders and change agents to elicit their knowledge and beliefs about the contextual features that influence the effectiveness of implementation interventions and healthcare professionals' use of evidence in clinical practice. Results from all three phases will be synthesized using a triangulation protocol to refine the context framework drawn from the concept analysis. The framework will then be assessed for content validity using an iterative Delphi approach with international experts (researchers and health system stakeholders/change agents). This research program will result in a framework that identifies the

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer.

PubMed

Lu, Hengyu; Villafane, Nicole; Dogruluk, Turgut; Grzeskowiak, Caitlin L; Kong, Kathleen; Tsang, Yiu Huen; Zagorodna, Oksana; Pantazi, Angeliki; Yang, Lixing; Neill, Nicholas J; Kim, Young Won; Creighton, Chad J; Verhaak, Roel G; Mills, Gordon B; Park, Peter J; Kucherlapati, Raju; Scott, Kenneth L

2017-07-01

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK , and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2 , and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR . ©2017 American Association for Cancer Research.

Systematic Determination of Human Cyclin Dependent Kinase (CDK)-9 Interactome Identifies Novel Functions in RNA Splicing Mediated by the DEAD Box (DDX)-5/17 RNA Helicases.

PubMed

Yang, Jun; Zhao, Yingxin; Kalita, Mridul; Li, Xueling; Jamaluddin, Mohammad; Tian, Bing; Edeh, Chukwudi B; Wiktorowicz, John E; Kudlicki, Andrzej; Brasier, Allan R

2015-10-01

Inducible transcriptional elongation is a rapid, stereotypic mechanism for activating immediate early immune defense genes by the epithelium in response to viral pathogens. Here, the recruitment of a multifunctional complex containing the cyclin dependent kinase 9 (CDK9) triggers the process of transcriptional elongation activating resting RNA polymerase engaged with innate immune response (IIR) genes. To identify additional functional activity of the CDK9 complex, we conducted immunoprecipitation (IP) enrichment-stable isotope labeling LC-MS/MS of the CDK9 complex in unstimulated cells and from cells activated by a synthetic dsRNA, polyinosinic/polycytidylic acid [poly (I:C)]. 245 CDK9 interacting proteins were identified with high confidence in the basal state and 20 proteins in four functional classes were validated by IP-SRM-MS. These data identified that CDK9 interacts with DDX 5/17, a family of ATP-dependent RNA helicases, important in alternative RNA splicing of NFAT5, and mH2A1 mRNA two proteins controlling redox signaling. A direct comparison of the basal versus activated state was performed using stable isotope labeling and validated by IP-SRM-MS. Recruited into the CDK9 interactome in response to poly(I:C) stimulation are HSPB1, DNA dependent kinases, and cytoskeletal myosin proteins that exchange with 60S ribosomal structural proteins. An integrated human CDK9 interactome map was developed containing all known human CDK9- interacting proteins. These data were used to develop a probabilistic global map of CDK9-dependent target genes that predicted two functional states controlling distinct cellular functions, one important in immune and stress responses. The CDK9-DDX5/17 complex was shown to be functionally important by shRNA-mediated knockdown, where differential accumulation of alternatively spliced NFAT5 and mH2A1 transcripts and alterations in downstream redox signaling were seen. The requirement of CDK9 for DDX5 recruitment to NFAT5 and mH2A1

Linking the Salt Transcriptome with Physiological Responses of a Salt-Resistant Populus Species as a Strategy to Identify Genes Important for Stress Acclimation1[W][OA

PubMed Central

Brinker, Monika; Brosché, Mikael; Vinocur, Basia; Abo-Ogiala, Atef; Fayyaz, Payam; Janz, Dennis; Ottow, Eric A.; Cullmann, Andreas D.; Saborowski, Joachim; Kangasjärvi, Jaakko; Altman, Arie; Polle, Andrea

2010-01-01

To investigate early salt acclimation mechanisms in a salt-tolerant poplar species (Populus euphratica), the kinetics of molecular, metabolic, and physiological changes during a 24-h salt exposure were measured. Three distinct phases of salt stress were identified by analyses of the osmotic pressure and the shoot water potential: dehydration, salt accumulation, and osmotic restoration associated with ionic stress. The duration and intensity of these phases differed between leaves and roots. Transcriptome analysis using P. euphratica-specific microarrays revealed clusters of coexpressed genes in these phases, with only 3% overlapping salt-responsive genes in leaves and roots. Acclimation of cellular metabolism to high salt concentrations involved remodeling of amino acid and protein biosynthesis and increased expression of molecular chaperones (dehydrins, osmotin). Leaves suffered initially from dehydration, which resulted in changes in transcript levels of mitochondrial and photosynthetic genes, indicating adjustment of energy metabolism. Initially, decreases in stress-related genes were found, whereas increases occurred only when leaves had restored the osmotic balance by salt accumulation. Comparative in silico analysis of the poplar stress regulon with Arabidopsis (Arabidopsis thaliana) orthologs was used as a strategy to reduce the number of candidate genes for functional analysis. Analysis of Arabidopsis knockout lines identified a lipocalin-like gene (AtTIL) and a gene encoding a protein with previously unknown functions (AtSIS) to play roles in salt tolerance. In conclusion, by dissecting the stress transcriptome of tolerant species, novel genes important for salt endurance can be identified. PMID:20959419

Quantum coupled mutation finder: predicting functionally or structurally important sites in proteins using quantum Jensen-Shannon divergence and CUDA programming.

PubMed

Gültas, Mehmet; Düzgün, Güncel; Herzog, Sebastian; Jäger, Sven Joachim; Meckbach, Cornelia; Wingender, Edgar; Waack, Stephan

2014-04-03

The identification of functionally or structurally important non-conserved residue sites in protein MSAs is an important challenge for understanding the structural basis and molecular mechanism of protein functions. Despite the rich literature on compensatory mutations as well as sequence conservation analysis for the detection of those important residues, previous methods often rely on classical information-theoretic measures. However, these measures usually do not take into account dis/similarities of amino acids which are likely to be crucial for those residues. In this study, we present a new method, the Quantum Coupled Mutation Finder (QCMF) that incorporates significant dis/similar amino acid pair signals in the prediction of functionally or structurally important sites. The result of this study is twofold. First, using the essential sites of two human proteins, namely epidermal growth factor receptor (EGFR) and glucokinase (GCK), we tested the QCMF-method. The QCMF includes two metrics based on quantum Jensen-Shannon divergence to measure both sequence conservation and compensatory mutations. We found that the QCMF reaches an improved performance in identifying essential sites from MSAs of both proteins with a significantly higher Matthews correlation coefficient (MCC) value in comparison to previous methods. Second, using a data set of 153 proteins, we made a pairwise comparison between QCMF and three conventional methods. This comparison study strongly suggests that QCMF complements the conventional methods for the identification of correlated mutations in MSAs. QCMF utilizes the notion of entanglement, which is a major resource of quantum information, to model significant dissimilar and similar amino acid pair signals in the detection of functionally or structurally important sites. Our results suggest that on the one hand QCMF significantly outperforms the previous method, which mainly focuses on dissimilar amino acid signals, to detect essential sites

Liver Function Indicators Performed Better to Eliminate Cardioembolic Stroke than to Identify It from Stroke Subtypes.

PubMed

Tan, Ge; Yuan, Ruozhen; Hao, Zilong; Lei, Chunyan; Xiong, Yao; Xu, Mangmang; Liu, Ming

2017-01-01

Identifying the etiology of ischemic stroke is essential to acute management and secondary prevention. The value of liver function indicators in differentiating stroke subtypes remains to be evaluated. A total of 1333 acute ischemic stroke patients were included. Liver function indicators collected within 24 hours from stroke onset, including alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and bilirubin (BILI), were collapsed into quartiles (Q) and also dichotomized by Q1. Multivariate regression analysis was conducted to identify the independent association between liver function indicators and cardioembolic stroke (SCE). Area under the curve (AUC) of receiver operating characteristic analysis was conducted, and sensitivity (Sen), specificity (Spe), positive prospective value (PPV), and negative prospective value (NPV) were determined to evaluate the predictive value of liver function indicators for SCE. AST, GGT, and BILI were associated with SCE. After adjustment, only AST was related to SCE independently. The incidence of SCE in the Q1 of AST, GGT, and BILI, particularly in the Q1 of AST, was quite low. The ability of AST, GGT, and BILI to identify SCE was poor, with low AUC, Sen, and PPV. The value of AST, GGT, and BILI in eliminating SCE from stroke subtypes was good, with high Spe and moderate NPV, and was enhanced after combining each liver function indicator. Results of present study demonstrated that AST, GGT, and BILI, particularly AST, had a potential to eliminate SCE from stroke subtypes, and the ability of eliminating SCE would be strengthened after combining each liver function indicator together. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Functional measures developed for clinical populations identified impairment among active workers with upper extremity disorders

PubMed Central

Gardner, Bethany T.; Dale, Ann Marie; Buckner-Petty, Skye; Rachford, Robert; Strickland, Jaime; Kaskutas, Vicki; Evanoff, Bradley

2017-01-01

Purpose Few studies have explored measures of function across a range of health outcomes in a general working population. Using four upper extremity (UE) case definitions from the scientific literature, we described the performance of functional measures of work, activities of daily living, and overall health. Methods A sample of 573 workers completed several functional measures: modified recall versions of the QuickDASH, Levine Functional Status Scale (FSS), DASH Work module (DASH-W), and standard SF-8 physical component score. We determined case status based on four UE case definitions: 1) UE symptoms, 2) UE musculoskeletal disorders (MSD), 3) carpal tunnel syndrome (CTS), and 4) work limitations due to UE symptoms. We calculated effect sizes for each case definition to show the magnitude of the differences that were detected between cases and non-cases for each case definition on each functional measure. Sensitivity and specificity analyses showed how well each measure identified functional impairments across the UE case definitions. Results All measures discriminated between cases and non-cases for each case definition with the largest effect sizes for CTS and work limitations, particularly for the modified FSS and DASH-W measures. Specificity was high and sensitivity was low for outcomes of UE symptoms and UE MSD in all measures. Sensitivity was high for CTS and work limitations. Conclusions Functional measures developed specifically for use in clinical, treatment-seeking populations may identify mild levels of impairment in relatively healthy, active working populations, but measures performed better among workers with CTS or those reporting limitations at work. PMID:26091980

Triangulating Principal Effectiveness: How Perspectives of Parents, Teachers, and Assistant Principals Identify the Central Importance of Managerial Skills

ERIC Educational Resources Information Center

Grissom, Jason A.; Loeb, Susanna

2011-01-01

While the importance of effective principals is undisputed, few studies have identified specific skills that principals need to promote school success. This study draws on unique data combining survey responses from principals, assistant principals, teachers, and parents with rich administrative data to determine which principal skills correlate…

Identifying functionally informative evolutionary sequence profiles.

PubMed

Gil, Nelson; Fiser, Andras

2018-04-15

Multiple sequence alignments (MSAs) can provide essential input to many bioinformatics applications, including protein structure prediction and functional annotation. However, the optimal selection of sequences to obtain biologically informative MSAs for such purposes is poorly explored, and has traditionally been performed manually. We present Selection of Alignment by Maximal Mutual Information (SAMMI), an automated, sequence-based approach to objectively select an optimal MSA from a large set of alternatives sampled from a general sequence database search. The hypothesis of this approach is that the mutual information among MSA columns will be maximal for those MSAs that contain the most diverse set possible of the most structurally and functionally homogeneous protein sequences. SAMMI was tested to select MSAs for functional site residue prediction by analysis of conservation patterns on a set of 435 proteins obtained from protein-ligand (peptides, nucleic acids and small substrates) and protein-protein interaction databases. Availability and implementation: A freely accessible program, including source code, implementing SAMMI is available at https://github.com/nelsongil92/SAMMI.git. andras.fiser@einstein.yu.edu. Supplementary data are available at Bioinformatics online.

Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

PubMed Central

O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

2014-01-01

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy

PubMed Central

Hershberger, Ray E.; Pinto, Jose Renato; Parks, Sharie B.; Kushner, Jessica D.; Li, Duanxiang; Ludwigsen, Susan; Cowan, Jason; Morales, Ana; Parvatiyar, Michelle S.; Potter, James D.

2009-01-01

Background A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. Methods and Results We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified six TNNT2 protein-altering variants in nine probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the nine probands had DCM without a family history, and five had familial DCM. Only one mutation (Lys210del) could be attributed as definitively causative from prior reports. Four of the five missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree and molecular genetic data these five mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca2+ sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease-causing. Conclusions We conclude that the combination of clinical, pedigree, molecular genetic and functional data strengthen the interpretation of TNNT2 mutations in DCM. PMID:20031601

Proteomic analysis identifies a novel function for galectin-3 in the cell entry of parvovirus.

PubMed

Garcin, Pierre; Cohen, Sarah; Terpstra, Sanne; Kelly, Isabelle; Foster, Leonard J; Panté, Nelly

2013-02-21

Cellular factors associated with the parvovirus minute virus of mice (MVM) during infection are thought to play important roles in the MVM life cycle but only a few of these have been identified. Here we used a proteomic-based approach in order to identify host-binding partners of MVM. Using purified MVM as bait for immunoprecipitation assays, a total of 150 proteins were identified in MVM immunoprecipitates by quantitative liquid chromatography-tandem mass spectrometry. Galectin-3 was one of six proteins showing a statistically significant enrichment across replicates. Small interfering RNA depletion studies revealed an important role for galectin-3 in MVM endocytosis and infectivity in LA9 mouse fibroblast cells. Galectin-3-depleted cells were less susceptible to MVM infection than control cells and showed a significant reduction of MVM cellular uptake, but not of MVM binding to the cell surface. Our results indicate an important role for galectin-3 in the cellular uptake of MVM. We propose that galectin-3 facilitates the access of MVM to its receptor(s) at the plasma membrane and in this way promotes MVM endocytosis. Copyright © 2012 Elsevier B.V. All rights reserved.

Functionally distinct amygdala subregions identified using DTI and high-resolution fMRI

PubMed Central

Balderston, Nicholas L.; Schultz, Douglas H.; Hopkins, Lauren

2015-01-01

Although the amygdala is often directly linked with fear and emotion, amygdala neurons are activated by a wide variety of emotional and non-emotional stimuli. Different subregions within the amygdala may be engaged preferentially by different aspects of emotional and non-emotional tasks. To test this hypothesis, we measured and compared the effects of novelty and fear on amygdala activity. We used high-resolution blood oxygenation level-dependent (BOLD) imaging and streamline tractography to subdivide the amygdala into three distinct functional subunits. We identified a laterobasal subregion connected with the visual cortex that responds generally to visual stimuli, a non-projecting region that responds to salient visual stimuli, and a centromedial subregion connected with the diencephalon that responds only when a visual stimulus predicts an aversive outcome. We provide anatomical and functional support for a model of amygdala function where information enters through the laterobasal subregion, is processed by intrinsic circuits in the interspersed tissue, and is then passed to the centromedial subregion, where activation leads to behavioral output. PMID:25969533

Functional sub-division of the Drosophila genome via chromatin looping: the emerging importance of CP190.

PubMed

Ahanger, Sajad H; Shouche, Yogesh S; Mishra, Rakesh K

2013-01-01

Insulators help in organizing the eukaryotic genomes into physically and functionally autonomous regions through the formation of chromatin loops. Recent findings in Drosophila and vertebrates suggest that insulators anchor multiple loci through long-distance interactions which may be mechanistically linked to insulator function. Important to such processes in Drosophila is CP190, a common co-factor of insulator complexes. CP190 is also known to associate with the nuclear matrix, components of the RNAi machinery, active promoters and borders of the repressive chromatin domains. Although CP190 plays a pivotal role in insulator function in Drosophila, vertebrates lack a probable functional equivalent of CP190 and employ CTCF as the major factor to carry out insulator function/chromatin looping. In this review, we discuss the emerging role of CP190 in tethering genome, specifically in the perspective of insulator function in Drosophila. Future studies aiming genome-wide role of CP190 in chromatin looping is likely to give important insights into the mechanism of genome organization.

Proteins related to the functions of fibroblast-like synoviocytes identified by proteomic analysis.

PubMed

Zhang, Hui; Fan, Lie Ying; Zong, Ming; Sun, Li Shan; Lu, Liu

2012-01-01

It is well known that the fibroblast-like synoviocytes (FLS) play a key role in pathogenesis of rheumatoid arthritis (RA). This study was performed to separate the differentially expressed proteins of FLS from the patients with RA or osteoarthritis (OA) by two-dimensional electrophoresis (2-DE), and found proteins associated with the functions of FLS by mass spectrometry (MS). Total proteins were extracted and quantified from the primary cultured FLS from patients of RA (n=8) or OA (n=6). Proteins were separated by high-resolution 2-DE, and identified the differentially expressed proteins by MS. Western blot analyses was used to validated the expression of candidate proteins. The mRNA of these proteins was detected by semi-quantitative fluorescent PCR. There are 1147 protein spots from RA and 1324 protein spots from OA showed on 2-DE graphs, respectively. We have selected 84 protein spots for MS analysis, and 27 protein spots were successfully identified. We have found that protein isoaspartyl methyltransferase (PIMT) and pirin (iron-binding nuclear protein, PIR) with lower expression in RA, and thioredoxin 1(Trx-1) only expressed in RA may be associated with functions of FLS. Western Blot confirmed the expression of PIMT and pirin lower in RA, and Trx-1 expressed only in RA. The results of semi-quantitative fluorescent PCR are also consistent with 2-DE graphs. PIMT, pirin and Trx-1 affect the functions of FLS in some style and can be the drug targets of RA.

Combined distribution functions: A powerful tool to identify cation coordination geometries in liquid systems

NASA Astrophysics Data System (ADS)

Sessa, Francesco; D'Angelo, Paola; Migliorati, Valentina

2018-01-01

In this work we have developed an analytical procedure to identify metal ion coordination geometries in liquid media based on the calculation of Combined Distribution Functions (CDFs) starting from Molecular Dynamics (MD) simulations. CDFs provide a fingerprint which can be easily and unambiguously assigned to a reference polyhedron. The CDF analysis has been tested on five systems and has proven to reliably identify the correct geometries of several ion coordination complexes. This tool is simple and general and can be efficiently applied to different MD simulations of liquid systems.

Use of a latency-based demand assessment to identify potential demands for functional analyses.

PubMed

Call, Nathan A; Miller, Sarah J; Mintz, Joslyn Cynkus; Mevers, Joanna Lomas; Scheithauer, Mindy C; Eshelman, Julie E; Beavers, Gracie A

2016-12-01

Unlike potential tangible positive reinforcers, which are typically identified for inclusion in functional analyses empirically using preference assessments, demands are most often selected arbitrarily or based on caregiver report. The present study evaluated the use of a demand assessment with 12 participants who exhibited escape-maintained problem behavior. Participants were exposed to 10 demands, with aversiveness measured by average latency to the first instance of problem behavior. In subsequent functional analyses, results of a demand condition that included the demand with the shortest latency to problem behavior resulted in identification of an escape function for 11 of the participants. In contrast, a demand condition that included the demand with the longest latency resulted in identification of an escape function for only 5 participants. The implication of these findings is that for the remaining 7 participants, selection of the demand for the functional analysis without using the results of the demand assessment could have produced a false-negative finding. © 2016 Society for the Experimental Analysis of Behavior.

Moral Complexity: The Fatal Attraction of Truthiness and the Importance of Mature Moral Functioning.

PubMed

Narvaez, Darcia

2010-03-01

Recently, intuitionist theories have been effective in capturing the academic discourse about morality. Intuitionist theories, like rationalist theories, offer important but only partial understanding of moral functioning. Both can be fallacious and succumb to truthiness: the attachment to one's opinions because they "feel right," potentially leading to harmful action or inaction. Both intuition and reasoning are involved in deliberation and expertise. Both are malleable from environmental and educational influence, making questions of normativity-which intuitions and reasoning skills to foster-of utmost importance. Good intuition and reasoning inform mature moral functioning, which needs to include capacities that promote sustainable human well-being. Individual capacities for habituated empathic concern and moral metacognition-moral locus of control, moral self-regulation, and moral self-reflection-comprise mature moral functioning, which also requires collective capacities for moral dialogue and moral institutions. These capacities underlie moral innovation and are necessary for solving the complex challenges humanity faces. © The Author(s) 2010.

Identifying functional cancer-specific miRNA-mRNA interactions in testicular germ cell tumor.

PubMed

Sedaghat, Nafiseh; Fathy, Mahmood; Modarressi, Mohammad Hossein; Shojaie, Ali

2016-09-07

Testicular cancer is the most common cancer in men aged between 15 and 35 and more than 90% of testicular neoplasms are originated at germ cells. Recent research has shown the impact of microRNAs (miRNAs) in different types of cancer, including testicular germ cell tumor (TGCT). MicroRNAs are small non-coding RNAs which affect the development and progression of cancer cells by binding to mRNAs and regulating their expressions. The identification of functional miRNA-mRNA interactions in cancers, i.e. those that alter the expression of genes in cancer cells, can help delineate post-regulatory mechanisms and may lead to new treatments to control the progression of cancer. A number of sequence-based methods have been developed to predict miRNA-mRNA interactions based on the complementarity of sequences. While necessary, sequence complementarity is, however, not sufficient for presence of functional interactions. Alternative methods have thus been developed to refine the sequence-based interactions using concurrent expression profiles of miRNAs and mRNAs. This study aims to find functional cancer-specific miRNA-mRNA interactions in TGCT. To this end, the sequence-based predicted interactions are first refined using an ensemble learning method, based on two well-known methods of learning miRNA-mRNA interactions, namely, TaLasso and GenMiR++. Additional functional analyses were then used to identify a subset of interactions to be most likely functional and specific to TGCT. The final list of 13 miRNA-mRNA interactions can be potential targets for identifying TGCT-specific interactions and future laboratory experiments to develop new therapies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genome-Wide Association Study Identifying Candidate Genes Influencing Important Agronomic Traits of Flax (Linum usitatissimum L.) Using SLAF-seq

PubMed Central

Xie, Dongwei; Dai, Zhigang; Yang, Zemao; Sun, Jian; Zhao, Debao; Yang, Xue; Zhang, Liguo; Tang, Qing; Su, Jianguang

2018-01-01

Flax (Linum usitatissimum L.) is an important cash crop, and its agronomic traits directly affect yield and quality. Molecular studies on flax remain inadequate because relatively few flax genes have been associated with agronomic traits or have been identified as having potential applications. To identify markers and candidate genes that can potentially be used for genetic improvement of crucial agronomic traits, we examined 224 specimens of core flax germplasm; specifically, phenotypic data for key traits, including plant height, technical length, number of branches, number of fruits, and 1000-grain weight were investigated under three environmental conditions before specific-locus amplified fragment sequencing (SLAF-seq) was employed to perform a genome-wide association study (GWAS) for these five agronomic traits. Subsequently, the results were used to screen single nucleotide polymorphism (SNP) loci and candidate genes that exhibited a significant correlation with the important agronomic traits. Our analyses identified a total of 42 SNP loci that showed significant correlations with the five important agronomic flax traits. Next, candidate genes were screened in the 10 kb zone of each of the 42 SNP loci. These SNP loci were then analyzed by a more stringent screening via co-identification using both a general linear model (GLM) and a mixed linear model (MLM) as well as co-occurrences in at least two of the three environments, whereby 15 final candidate genes were obtained. Based on these results, we determined that UGT and PL are candidate genes for plant height, GRAS and XTH are candidate genes for the number of branches, Contig1437 and LU0019C12 are candidate genes for the number of fruits, and PHO1 is a candidate gene for the 1000-seed weight. We propose that the identified SNP loci and corresponding candidate genes might serve as a biological basis for improving crucial agronomic flax traits. PMID:29375606

Genome-Wide Association Study Identifying Candidate Genes Influencing Important Agronomic Traits of Flax (Linum usitatissimum L.) Using SLAF-seq.

PubMed

Xie, Dongwei; Dai, Zhigang; Yang, Zemao; Sun, Jian; Zhao, Debao; Yang, Xue; Zhang, Liguo; Tang, Qing; Su, Jianguang

2017-01-01

Flax ( Linum usitatissimum L.) is an important cash crop, and its agronomic traits directly affect yield and quality. Molecular studies on flax remain inadequate because relatively few flax genes have been associated with agronomic traits or have been identified as having potential applications. To identify markers and candidate genes that can potentially be used for genetic improvement of crucial agronomic traits, we examined 224 specimens of core flax germplasm; specifically, phenotypic data for key traits, including plant height, technical length, number of branches, number of fruits, and 1000-grain weight were investigated under three environmental conditions before specific-locus amplified fragment sequencing (SLAF-seq) was employed to perform a genome-wide association study (GWAS) for these five agronomic traits. Subsequently, the results were used to screen single nucleotide polymorphism (SNP) loci and candidate genes that exhibited a significant correlation with the important agronomic traits. Our analyses identified a total of 42 SNP loci that showed significant correlations with the five important agronomic flax traits. Next, candidate genes were screened in the 10 kb zone of each of the 42 SNP loci. These SNP loci were then analyzed by a more stringent screening via co-identification using both a general linear model (GLM) and a mixed linear model (MLM) as well as co-occurrences in at least two of the three environments, whereby 15 final candidate genes were obtained. Based on these results, we determined that UGT and PL are candidate genes for plant height, GRAS and XTH are candidate genes for the number of branches, Contig1437 and LU0019C12 are candidate genes for the number of fruits, and PHO1 is a candidate gene for the 1000-seed weight. We propose that the identified SNP loci and corresponding candidate genes might serve as a biological basis for improving crucial agronomic flax traits.

Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles | Office of Cancer Genomics

Cancer.gov

Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic.

Crowd-sourced Ontology for Photoleukocoria: Identifying Common Internet Search Terms for a Potentially Important Pediatric Ophthalmic Sign.

PubMed

Staffieri, Sandra E; Kearns, Lisa S; Sanfilippo, Paul G; Craig, Jamie E; Mackey, David A; Hewitt, Alex W

2018-02-01

Leukocoria is the most common presenting sign for pediatric eye disease including retinoblastoma and cataract, with worse outcomes if diagnosis is delayed. We investigated whether individuals could identify leukocoria in photographs (photoleukocoria) and examined their subsequent Internet search behavior. Using a web-based questionnaire, in this cross-sectional study we invited adults aged over 18 years to view two photographs of a child with photoleukocoria, and then search the Internet to determine a possible diagnosis and action plan. The most commonly used search terms and websites accessed were recorded. The questionnaire was completed by 1639 individuals. Facebook advertisement was the most effective recruitment strategy. The mean age of all respondents was 38.95 ± 14.59 years (range, 18-83), 94% were female, and 59.3% had children. An abnormality in the images presented was identified by 1613 (98.4%) participants. The most commonly used search terms were: "white," "pupil," "photo," and "eye" reaching a variety of appropriate websites or links to print or social media articles. Different words or phrases were used to describe the same observation of photoleukocoria leading to a range of websites. Variations in the description of observed signs and search words influenced the sites reached, information obtained, and subsequent help-seeking intentions. Identifying the most commonly used search terms for photoleukocoria is an important step for search engine optimization. Being directed to the most appropriate websites informing of the significance of photoleukocoria and the appropriate actions to take could improve delays in diagnosis of important pediatric eye disease such as retinoblastoma or cataract.

Chronnectome fingerprinting: Identifying individuals and predicting higher cognitive functions using dynamic brain connectivity patterns.

PubMed

Liu, Jin; Liao, Xuhong; Xia, Mingrui; He, Yong

2018-02-01

The human brain is a large, interacting dynamic network, and its architecture of coupling among brain regions varies across time (termed the "chronnectome"). However, very little is known about whether and how the dynamic properties of the chronnectome can characterize individual uniqueness, such as identifying individuals as a "fingerprint" of the brain. Here, we employed multiband resting-state functional magnetic resonance imaging data from the Human Connectome Project (N = 105) and a sliding time-window dynamic network analysis approach to systematically examine individual time-varying properties of the chronnectome. We revealed stable and remarkable individual variability in three dynamic characteristics of brain connectivity (i.e., strength, stability, and variability), which was mainly distributed in three higher order cognitive systems (i.e., default mode, dorsal attention, and fronto-parietal) and in two primary systems (i.e., visual and sensorimotor). Intriguingly, the spatial patterns of these dynamic characteristics of brain connectivity could successfully identify individuals with high accuracy and could further significantly predict individual higher cognitive performance (e.g., fluid intelligence and executive function), which was primarily contributed by the higher order cognitive systems. Together, our findings highlight that the chronnectome captures inherent functional dynamics of individual brain networks and provides implications for individualized characterization of health and disease. © 2017 Wiley Periodicals, Inc.

Remote Sensing of plant functional types: Relative importance of biochemical and structural plant traits

NASA Astrophysics Data System (ADS)

Kattenborn, Teja; Schmidtlein, Sebastian

2017-04-01

Monitoring ecosystems is a key priority in order to understand vegetation patterns, underlying resource cycles and changes their off. Driven by biotic and abiotic factors, plant species within an ecosystem are likely to share similar structural, physiological or phenological traits and can therefore be grouped into plant functional types (PFT). It can be assumed that plants which share similar traits also share similar optical characteristics. Therefore optical remote sensing was identified as a valuable tool for differentiating PFT. Although several authors list structural and biochemical plant traits which are important for differentiating PFT using hyperspectral remote sensing, there is no quantitative or qualitative information on the relative importance of these traits. Thus, little is known about the explicit role of plant traits for an optical discrimination of PFT. One of the main reasons for this is that various optical traits affect the same wavelength regions and it is therefore difficult to isolate the discriminative power of a single trait. A way to determine the effect of single plant traits on the optical reflectance of plant canopies is given by radiative transfer models. The most established radiative transfer model is PROSAIL, which incorporates biochemical and structural plant traits, such as pigment contents or leaf area index. In the present study 25 grassland species of different PFT were cultivated and traits relevant for PROSAIL were measured for the entire vegetation season of 2016. The information content of each trait for differentiating PFTs was determined by applying a Multi-response Permutation Procedure on the actual traits, as well as on simulated canopy spectra derived from PROSAIL. According to our results some traits, especially biochemical traits, show a weaker separability of PFT on a spectral level than compared to the actual trait measurements. Overall structural traits (leaf angle and leaf area index) are more important for

Using Model Point Spread Functions to Identifying Binary Brown Dwarf Systems

NASA Astrophysics Data System (ADS)

Matt, Kyle; Stephens, Denise C.; Lunsford, Leanne T.

2017-01-01

A Brown Dwarf (BD) is a celestial object that is not massive enough to undergo hydrogen fusion in its core. BDs can form in pairs called binaries. Due to the great distances between Earth and these BDs, they act as point sources of light and the angular separation between binary BDs can be small enough to appear as a single, unresolved object in images, according to Rayleigh Criterion. It is not currently possible to resolve some of these objects into separate light sources. Stephens and Noll (2006) developed a method that used model point spread functions (PSFs) to identify binary Trans-Neptunian Objects, we will use this method to identify binary BD systems in the Hubble Space Telescope archive. This method works by comparing model PSFs of single and binary sources to the observed PSFs. We also use a method to compare model spectral data for single and binary fits to determine the best parameter values for each component of the system. We describe these methods, its challenges and other possible uses in this poster.

Analysis of functional importance of binding sites in the Drosophila gap gene network model.

PubMed

Kozlov, Konstantin; Gursky, Vitaly V; Kulakovskiy, Ivan V; Dymova, Arina; Samsonova, Maria

2015-01-01

The statistical thermodynamics based approach provides a promising framework for construction of the genotype-phenotype map in many biological systems. Among important aspects of a good model connecting the DNA sequence information with that of a molecular phenotype (gene expression) is the selection of regulatory interactions and relevant transcription factor bindings sites. As the model may predict different levels of the functional importance of specific binding sites in different genomic and regulatory contexts, it is essential to formulate and study such models under different modeling assumptions. We elaborate a two-layer model for the Drosophila gap gene network and include in the model a combined set of transcription factor binding sites and concentration dependent regulatory interaction between gap genes hunchback and Kruppel. We show that the new variants of the model are more consistent in terms of gene expression predictions for various genetic constructs in comparison to previous work. We quantify the functional importance of binding sites by calculating their impact on gene expression in the model and calculate how these impacts correlate across all sites under different modeling assumptions. The assumption about the dual interaction between hb and Kr leads to the most consistent modeling results, but, on the other hand, may obscure existence of indirect interactions between binding sites in regulatory regions of distinct genes. The analysis confirms the previously formulated regulation concept of many weak binding sites working in concert. The model predicts a more or less uniform distribution of functionally important binding sites over the sets of experimentally characterized regulatory modules and other open chromatin domains.

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

PubMed

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. Copyright © 2016 Agrawal and Hardin.

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

PubMed Central

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

2016-01-01

Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents. PMID:27177310

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

PubMed

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

2016-05-12

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

Functional Transcranial Doppler Sonography and a Spatial Orientation Paradigm Identify the Non-Dominant Hemisphere

ERIC Educational Resources Information Center

Dorst, J.; Haag, A.; Knake, S.; Oertel, W. H.; Hamer, H. M.; Rosenow, F.

2008-01-01

Rationale: Functional transcranial Doppler sonography (fTCD) during word generation is well established for language lateralization. In this study, we evaluated a fTCD paradigm to reliably identify the non-dominant hemisphere. Methods: Twenty-nine right-handed healthy subjects (27.1 [plus or minus] 7.6 years) performed the "cube perspective test"…

Chemical screening identifies ROCK as a target for recovering mitochondrial function in Hutchinson-Gilford progeria syndrome.

PubMed

Kang, Hyun Tae; Park, Joon Tae; Choi, Kobong; Choi, Hyo Jei Claudia; Jung, Chul Won; Kim, Gyu Ree; Lee, Young-Sam; Park, Sang Chul

2017-06-01

Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent. To elucidate the underlying mechanism of ROCK in regulating ROS levels, we performed a yeast two-hybrid screen and discovered that ROCK1 interacts with Rac1b. ROCK activation phosphorylated Rac1b at Ser71 and increased ROS levels by facilitating the interaction between Rac1b and cytochrome c. Conversely, ROCK inactivation with Y-27632 abolished their interaction, concomitant with ROS reduction. Additionally, ROCK activation resulted in mitochondrial dysfunction, whereas ROCK inactivation with Y-27632 induced the recovery of mitochondrial function. Furthermore, a reduction in the frequency of abnormal nuclear morphology and DNA double-strand breaks was observed along with decreased ROS levels. Thus, our study reveals a novel mechanism through which alleviation of the HGPS phenotype is mediated by the recovery of mitochondrial function upon ROCK inactivation. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Walking the interactome to identify human miRNA-disease associations through the functional link between miRNA targets and disease genes

PubMed Central

2013-01-01

Background MicroRNAs (miRNAs) are important post-transcriptional regulators that have been demonstrated to play an important role in human diseases. Elucidating the associations between miRNAs and diseases at the systematic level will deepen our understanding of the molecular mechanisms of diseases. However, miRNA-disease associations identified by previous computational methods are far from completeness and more effort is needed. Results We developed a computational framework to identify miRNA-disease associations by performing random walk analysis, and focused on the functional link between miRNA targets and disease genes in protein-protein interaction (PPI) networks. Furthermore, a bipartite miRNA-disease network was constructed, from which several miRNA-disease co-regulated modules were identified by hierarchical clustering analysis. Our approach achieved satisfactory performance in identifying known cancer-related miRNAs for nine human cancers with an area under the ROC curve (AUC) ranging from 71.3% to 91.3%. By systematically analyzing the global properties of the miRNA-disease network, we found that only a small number of miRNAs regulated genes involved in various diseases, genes associated with neurological diseases were preferentially regulated by miRNAs and some immunological diseases were associated with several specific miRNAs. We also observed that most diseases in the same co-regulated module tended to belong to the same disease category, indicating that these diseases might share similar miRNA regulatory mechanisms. Conclusions In this study, we present a computational framework to identify miRNA-disease associations, and further construct a bipartite miRNA-disease network for systematically analyzing the global properties of miRNA regulation of disease genes. Our findings provide a broad perspective on the relationships between miRNAs and diseases and could potentially aid future research efforts concerning miRNA involvement in disease pathogenesis

Efficacy of identifying neural components in the face and emotion processing system in schizophrenia using a dynamic functional localizer.

PubMed

Arnold, Aiden E G F; Iaria, Giuseppe; Goghari, Vina M

2016-02-28

Schizophrenia is associated with deficits in face perception and emotion recognition. Despite consistent behavioural results, the neural mechanisms underlying these cognitive abilities have been difficult to isolate, in part due to differences in neuroimaging methods used between studies for identifying regions in the face processing system. Given this problem, we aimed to validate a recently developed fMRI-based dynamic functional localizer task for use in studies of psychiatric populations and specifically schizophrenia. Previously, this functional localizer successfully identified each of the core face processing regions (i.e. fusiform face area, occipital face area, superior temporal sulcus), and regions within an extended system (e.g. amygdala) in healthy individuals. In this study, we tested the functional localizer success rate in 27 schizophrenia patients and in 24 community controls. Overall, the core face processing regions were localized equally between both the schizophrenia and control group. Additionally, the amygdala, a candidate brain region from the extended system, was identified in nearly half the participants from both groups. These results indicate the effectiveness of a dynamic functional localizer at identifying regions of interest associated with face perception and emotion recognition in schizophrenia. The use of dynamic functional localizers may help standardize the investigation of the facial and emotion processing system in this and other clinical populations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Functional importance of blood flow dynamics and partial oxygen pressure in the anterior pituitary.

PubMed

Schaeffer, Marie; Hodson, David J; Lafont, Chrystel; Mollard, Patrice

2010-12-01

The pulsatile release of hormone is obligatory for the control of a range of important body homeostatic functions. To generate these pulses, endocrine organs have developed finely regulated mechanisms to modulate blood flow both to meet the metabolic demand associated with intense endocrine cell activity and to ensure the temporally precise uptake of secreted hormone into the bloodstream. With a particular focus on the pituitary gland as a model system, we review here the importance of the interplay between blood flow regulation and oxygen tensions in the functioning of endocrine systems, and the known regulatory signals involved in the modification of flow patterns under both normal physiological and pathological conditions. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

In silico identification of functional regions in proteins.

PubMed

Nimrod, Guy; Glaser, Fabian; Steinberg, David; Ben-Tal, Nir; Pupko, Tal

2005-06-01

In silico prediction of functional regions on protein surfaces, i.e. sites of interaction with DNA, ligands, substrates and other proteins, is of utmost importance in various applications in the emerging fields of proteomics and structural genomics. When a sufficient number of homologs is found, powerful prediction schemes can be based on the observation that evolutionarily conserved regions are often functionally important, typically, only the principal functionally important region of the protein is detected, while secondary functional regions with weaker conservation signals are overlooked. Moreover, it is challenging to unambiguously identify the boundaries of the functional regions. We present a new methodology, called PatchFinder, that automatically identifies patches of conserved residues that are located in close proximity to each other on the protein surface. PatchFinder is based on the following steps: (1) Assignment of conservation scores to each amino acid position on the protein surface. (2) Assignment of a score to each putative patch, based on its likelihood to be functionally important. The patch of maximum likelihood is considered to be the main functionally important region, and the search is continued for non-overlapping patches of secondary importance. We examined the accuracy of the method using the IGPS enzyme, the SH2 domain and a benchmark set of 112 proteins. These examples demonstrated that PatchFinder is capable of identifying both the main and secondary functional patches. The PatchFinder program is available at: http://ashtoret.tau.ac.il/~nimrodg/

Critical role of the pore domain in the cold response of TRPM8 channels identified by ortholog functional comparison.

PubMed

Pertusa, María; Rivera, Bastián; González, Alejandro; Ugarte, Gonzalo; Madrid, Rodolfo

2018-06-07

In mammals, the main molecular entity involved in innocuous cold transduction is TRPM8.  This polymodal ion channel is activated by cold, cooling compounds such as menthol and voltage.  Despite its relevance, the molecular determinants involved in its activation by cold remain elusive.  In this study we explored the use of TRPM8 orthologs with different cold responses, as a strategy to identify new molecular determinants related with its thermosensitivity.  We focused on mouse TRPM8 (mTRPM8) and chicken TRPM8 (cTRPM8), which present complementary thermo- and chemo-sensitive phenotypes.  While mTRPM8 displays larger responses to cold than cTRPM8, the avian ortholog shows a higher sensitivity to menthol compared to the mouse channel, in both HEK293 cells and primary somatosensory neurons.  We took advantage of these differences to build multiple functional chimeras between these orthologs, in order to identify the regions that account for these discrepancies.  Using a combination of calcium imaging and patch clamping, we identified a region encompassing positions 526-556 in the N-terminus, whose replacement by the cTRPM8 homolog sequence potentiated its response to agonists.  More importantly, we found that the characteristic cold response of these orthologs is due to non-conserved residues located within the pore loop, suggesting that TRPM8 has evolved by increasing the magnitude of its cold response through changes in this region.  Our results reveal that these structural domains are critically involved in cold-sensitivity and functional modulation of TRPM8, and support the idea that the pore domain is a key molecular determinant in temperature responses of this thermo-TRP channel. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

The importance of hippocampal dynamic connectivity in explaining memory function in multiple sclerosis.

PubMed

van Geest, Quinten; Hulst, Hanneke E; Meijer, Kim A; Hoyng, Lieke; Geurts, Jeroen J G; Douw, Linda

2018-05-01

Brain dynamics (i.e., variable strength of communication between areas), even at the scale of seconds, are thought to underlie complex human behavior, such as learning and memory. In multiple sclerosis (MS), memory problems occur often and have so far only been related to "stationary" brain measures (e.g., atrophy, lesions, activation and stationary (s) functional connectivity (FC) over an entire functional scanning session). However, dynamics in FC (dFC) between the hippocampus and the (neo)cortex may be another important neurobiological substrate of memory impairment in MS that has not yet been explored. Therefore, we investigated hippocampal dFC during a functional (f) magnetic resonance imaging (MRI) episodic memory task and its relationship with verbal and visuospatial memory performance outside the MR scanner. Thirty-eight MS patients and 29 healthy controls underwent neuropsychological tests to assess memory function. Imaging (1.5T) was obtained during performance of a memory task. We assessed hippocampal volume, functional activation, and sFC (i.e., FC of the hippocampus with the rest of the brain averaged over the entire scan, using an atlas-based approach). Dynamic FC of the hippocampus was calculated using a sliding window approach. No group differences were found in hippocampal activation, sFC, and dFC. However, stepwise forward regression analyses in patients revealed that lower dFC of the left hippocampus (standardized β = -0.30; p  =   .021) could explain an additional 7% of variance (53% in total) in verbal memory, in addition to female sex and larger left hippocampal volume. For visuospatial memory, lower dFC of the right hippocampus (standardized β = -0.38; p  =   .013) could explain an additional 13% of variance (24% in total) in addition to higher sFC of the right hippocampus. Low hippocampal dFC is an important indicator for maintained memory performance in MS, in addition to other hippocampal imaging measures. Hence, brain dynamics

Using Functional Signatures to Identify Repositioned Drugs for Breast, Myelogenous Leukemia and Prostate Cancer

PubMed Central

Shigemizu, Daichi; Hu, Zhenjun; Hung, Jui-Hung; Huang, Chia-Ling; Wang, Yajie; DeLisi, Charles

2012-01-01

The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine. PMID:22346740

Lignin, mitochondrial family, and photorespiratory transporter classification as case studies in using co-expression, co-response, and protein locations to aid in identifying transport functions

PubMed Central

Tohge, Takayuki; Fernie, Alisdair R.

2014-01-01

Whole genome sequencing and the relative ease of transcript profiling have facilitated the collection and data warehousing of immense quantities of expression data. However, a substantial proportion of genes are not yet functionally annotated a problem which is particularly acute for transport proteins. In Arabidopsis, for example, only a minor fraction of the estimated 700 intracellular transporters have been identified at the molecular genetic level. Furthermore it is only within the last couple of years that critical genes such as those encoding the final transport step required for the long distance transport of sucrose and the first transporter of the core photorespiratory pathway have been identified. Here we will describe how transcriptional coordination between genes of known function and non-annotated genes allows the identification of putative transporters on the premise that such co-expressed genes tend to be functionally related. We will additionally extend this to include the expansion of this approach to include phenotypic information from other levels of cellular organization such as proteomic and metabolomic data and provide case studies wherein this approach has successfully been used to fill knowledge gaps in important metabolic pathways and physiological processes. PMID:24672529

A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation

PubMed Central

Zhao, Zhenze; Ma, Xiuye; Hsiao, Tzu-Hung; Lin, Gregory; Kosti, Adam; Yu, Xiaojie; Suresh, Uthra; Chen, Yidong; Tomlinson, Gail E.; Pertsemlidis, Alexander; Du, Liqin

2014-01-01

Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation-inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy. PMID:24811707

Determining Epigenetic Targets: A Beginner's Guide to Identifying Genome Functionality Through Database Analysis.

PubMed

Hay, Elizabeth A; Cowie, Philip; MacKenzie, Alasdair

2017-01-01

There can now be little doubt that the cis-regulatory genome represents the largest information source within the human genome essential for health. In addition to containing up to five times more information than the coding genome, the cis-regulatory genome also acts as a major reservoir of disease-associated polymorphic variation. The cis-regulatory genome, which is comprised of enhancers, silencers, promoters, and insulators, also acts as a major functional target for epigenetic modification including DNA methylation and chromatin modifications. These epigenetic modifications impact the ability of cis-regulatory sequences to maintain tissue-specific and inducible expression of genes that preserve health. There has been limited ability to identify and characterize the functional components of this huge and largely misunderstood part of the human genome that, for decades, was ignored as "Junk" DNA. In an attempt to address this deficit, the current chapter will first describe methods of identifying and characterizing functional elements of the cis-regulatory genome at a genome-wide level using databases such as ENCODE, the UCSC browser, and NCBI. We will then explore the databases on the UCSC genome browser, which provides access to DNA methylation and chromatin modification datasets. Finally, we will describe how we can superimpose the huge volume of study data contained in the NCBI archives onto that contained within the UCSC browser in order to glean relevant in vivo study data for any locus within the genome. An ability to access and utilize these information sources will become essential to informing the future design of experiments and subsequent determination of the role of epigenetics in health and disease and will form a critical step in our development of personalized medicine.

A functional screen for copper homeostasis genes identifies a pharmacologically tractable cellular system

PubMed Central

2014-01-01

Background 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. Results 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. Conclusions 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. PMID:24708151

From functional architecture to functional connectomics.

PubMed

Reid, R Clay

2012-07-26

"Receptive Fields, Binocular Interaction and Functional Architecture in the Cat's Visual Cortex" by Hubel and Wiesel (1962) reported several important discoveries: orientation columns, the distinct structures of simple and complex receptive fields, and binocular integration. But perhaps the paper's greatest influence came from the concept of functional architecture (the complex relationship between in vivo physiology and the spatial arrangement of neurons) and several models of functionally specific connectivity. They thus identified two distinct concepts, topographic specificity and functional specificity, which together with cell-type specificity constitute the major determinants of nonrandom cortical connectivity. Orientation columns are iconic examples of topographic specificity, whereby axons within a column connect with cells of a single orientation preference. Hubel and Wiesel also saw the need for functional specificity at a finer scale in their model of thalamic inputs to simple cells, verified in the 1990s. The difficult but potentially more important question of functional specificity between cortical neurons is only now becoming tractable with new experimental techniques. Copyright © 2012 Elsevier Inc. All rights reserved.

Do patient-reported outcome measures cover personal factors important to people with rheumatoid arthritis? A mixed methods design using the International Classification of Functioning, Disability and Health as frame of reference.

PubMed

Dür, Mona; Coenen, Michaela; Stoffer, Michaela Alexandra; Fialka-Moser, Veronika; Kautzky-Willer, Alexandra; Kjeken, Ingvild; Drăgoi, Răzvan Gabriel; Mattsson, Malin; Boström, Carina; Smolen, Josef; Stamm, Tanja Alexandra

2015-02-25

Personal factors (PFs) are internal factors that determine functioning and the individuals' experience of disability. Their coverage by patient-reported outcome measures (PROMs) has not been examined in rheumatoid arthritis (RA) so far. The aims of this study were to identify PFs important in the life stories of people with RA and to determine their coverage by PROMs used in RA. The qualitative data of people with RA was explored to identify PFs. Additionally a systematic literature search was conducted to find PROMs used in RA. PROMs items were linked to the components, domains and categories of the International Classification of Functioning, Disability and Health (ICF) to determine the coverage of important PFs by PROMs. Twelve PFs were found to be important in the life stories of people with RA. The PFs coping and reflecting about one's life in an optimistic way were covered most frequently, each by 14 of the 42 explored PROMs, while job satisfaction was not covered at all. The London Coping with Rheumatoid Arthritis Questionnaire, General Self-Efficacy Scale, Arthritis Self-Efficacy Scale, Rheumatoid Arthritis Self-Efficacy Questionnaire and Revised Ways of Coping Inventory covered most PFs. Nineteen PROMs did not cover any of the PFs. Several PFs were identified as important in the life stories of people with RA, but only 55% of the PROMS covered some of these PFs. When evaluating PFs important to people with RA, health professionals should be alert on which PROMs can be used to assess which PFs.

Is testosterone important in LUT function in men and women? ICI-RS 2015.

PubMed

Badawi, Jasmin Katrin; Bosch, Ruud; Djurhuus, Jens Christian; Hanna-Mitchell, Ann T

2017-04-01

This review article is a collaborative report based upon the Authors' presentations and Group discussion on the role of testosterone (T) in the male and female lower urinary tract (LUT) which took place at the 6th International Consultation on Incontinence Research Society's (ICI-RS) annual meeting, in Bristol, UK (September 8-10, 2015). It comprises overviews and opinions on both the current state of knowledge of the role of T in LUT function and dysfunction in both sexes. Results from animal studies suggest that T treatment may be beneficial for disorders of the LUT in women including urinary incontinence and pelvic organ prolapse. The need for clinical studies to evaluate the effect of T treatment in peri- and post-menopausal women, taking into account the type of applied androgen, the application form, timing and dosage, is especially emphasized. In males, findings on the impact of T on the male external urethral sphincter underscores that there is still much to learn about its role in male LUT physiology. The important topic of the use of T therapy in the treatment of enuresis in the young, both sexes, is also discussed. The importance of understanding the steroidogenic pathways linking T with estradiol is discussed as being of paramount importance in researching the unique actions of T in the LUT. The overall conclusion is that further research into the role of T in LUT function and dysfunction across genders and age groups (young to old) is extremely important. Neurourol. Urodynam. 36:859-862, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Identifying the needs of elderly, hearing-impaired persons: the importance and utility of hearing aid attributes.

PubMed

Meister, Hartmut; Lausberg, Isabel; Kiessling, Juergen; von Wedel, Hasso; Walger, Martin

2002-11-01

Older patients represent the majority of hearing-aid users. The needs of elderly, hearing-impaired subjects are not entirely identified. The present study aims to determine the importance of fundamental hearing-aid attributes and to elicit the utility of associated hypothetical hearing aids for older patients. This was achieved using a questionnaire-based conjoint analysis--a decompositional approach to preference measurement offering a realistic study design. A random sample of 200 experienced hearing-aid users participated in the study. Though three out of the six examined attributes revealed age-related dependencies, the only significant effect was found for the attribute "handling", which was considerably more important for older than younger hearing-aid users. A trend of decreasing importance of speech intelligibility in noise and increasing significance of speech in quiet was observed for subjects older than 70 years. In general, the utility of various hypothetical hearing aids was similar for older and younger subjects. Apart from the attribute "handling", older and younger subjects have comparable needs regarding hearing-aid features. On the basis of the examined attributes, there is no requirement for hearing aids designed specifically for elderly hearing-aid users, provided that ergonomic features are considered and the benefits of modern technology are made fully available for older patients.

A genetic screen for terminator function in yeast identifies a role for a new functional domain in termination factor Nab3

PubMed Central

Loya, Travis J.; O’Rourke, Thomas W.; Reines, Daniel

2012-01-01

The yeast IMD2 gene encodes an enzyme involved in GTP synthesis. Its expression is controlled by guanine nucleotides through a set of alternate start sites and an intervening transcriptional terminator. In the off state, transcription results in a short non-coding RNA that starts upstream of the gene. Transcription terminates via the Nrd1-Nab3-Sen1 complex and is degraded by the nuclear exosome. Using a sensitive terminator read-through assay, we identified trans-acting Terminator Override (TOV) genes that operate this terminator. Four genes were identified: the RNA polymerase II phosphatase SSU72, the RNA polymerase II binding protein PCF11, the TRAMP subunit TRF4 and the hnRNP-like, NAB3. The TOV phenotype can be explained by the loss of function of these gene products as described in models in which termination and RNA degradation are coupled to the phosphorylation state of RNA polymerase II's repeat domain. The most interesting mutations were those found in NAB3, which led to the finding that the removal of merely three carboxy-terminal amino acids compromised Nab3's function. This region of previously unknown function is distant from the protein's well-known RNA binding and Nrd1 binding domains. Structural homology modeling suggests this Nab3 ‘tail’ forms an α-helical multimerization domain that helps assemble it onto an RNA substrate. PMID:22564898

A genetic screen for terminator function in yeast identifies a role for a new functional domain in termination factor Nab3.

PubMed

Loya, Travis J; O'Rourke, Thomas W; Reines, Daniel

2012-08-01

The yeast IMD2 gene encodes an enzyme involved in GTP synthesis. Its expression is controlled by guanine nucleotides through a set of alternate start sites and an intervening transcriptional terminator. In the off state, transcription results in a short non-coding RNA that starts upstream of the gene. Transcription terminates via the Nrd1-Nab3-Sen1 complex and is degraded by the nuclear exosome. Using a sensitive terminator read-through assay, we identified trans-acting Terminator Override (TOV) genes that operate this terminator. Four genes were identified: the RNA polymerase II phosphatase SSU72, the RNA polymerase II binding protein PCF11, the TRAMP subunit TRF4 and the hnRNP-like, NAB3. The TOV phenotype can be explained by the loss of function of these gene products as described in models in which termination and RNA degradation are coupled to the phosphorylation state of RNA polymerase II's repeat domain. The most interesting mutations were those found in NAB3, which led to the finding that the removal of merely three carboxy-terminal amino acids compromised Nab3's function. This region of previously unknown function is distant from the protein's well-known RNA binding and Nrd1 binding domains. Structural homology modeling suggests this Nab3 'tail' forms an α-helical multimerization domain that helps assemble it onto an RNA substrate.

Use of a Drosophila Genome-Wide Conserved Sequence Database to Identify Functionally Related cis-Regulatory Enhancers

PubMed Central

Brody, Thomas; Yavatkar, Amarendra S; Kuzin, Alexander; Kundu, Mukta; Tyson, Leonard J; Ross, Jermaine; Lin, Tzu-Yang; Lee, Chi-Hon; Awasaki, Takeshi; Lee, Tzumin; Odenwald, Ward F

2012-01-01

Background: Phylogenetic footprinting has revealed that cis-regulatory enhancers consist of conserved DNA sequence clusters (CSCs). Currently, there is no systematic approach for enhancer discovery and analysis that takes full-advantage of the sequence information within enhancer CSCs. Results: We have generated a Drosophila genome-wide database of conserved DNA consisting of >100,000 CSCs derived from EvoPrints spanning over 90% of the genome. cis-Decoder database search and alignment algorithms enable the discovery of functionally related enhancers. The program first identifies conserved repeat elements within an input enhancer and then searches the database for CSCs that score highly against the input CSC. Scoring is based on shared repeats as well as uniquely shared matches, and includes measures of the balance of shared elements, a diagnostic that has proven to be useful in predicting cis-regulatory function. To demonstrate the utility of these tools, a temporally-restricted CNS neuroblast enhancer was used to identify other functionally related enhancers and analyze their structural organization. Conclusions: cis-Decoder reveals that co-regulating enhancers consist of combinations of overlapping shared sequence elements, providing insights into the mode of integration of multiple regulating transcription factors. The database and accompanying algorithms should prove useful in the discovery and analysis of enhancers involved in any developmental process. Developmental Dynamics 241:169–189, 2012. © 2011 Wiley Periodicals, Inc. Key findings A genome-wide catalog of Drosophila conserved DNA sequence clusters. cis-Decoder discovers functionally related enhancers. Functionally related enhancers share balanced sequence element copy numbers. Many enhancers function during multiple phases of development. PMID:22174086

Molecular and functional analyses of a maize autoactive NB-LRR protein identify precise structural requirements for activity.

PubMed

Wang, Guan-Feng; Ji, Jiabing; El-Kasmi, Farid; Dangl, Jeffery L; Johal, Guri; Balint-Kurti, Peter J

2015-02-01

Plant disease resistance is often mediated by nucleotide binding-leucine rich repeat (NLR) proteins which remain auto-inhibited until recognition of specific pathogen-derived molecules causes their activation, triggering a rapid, localized cell death called a hypersensitive response (HR). Three domains are recognized in one of the major classes of NLR proteins: a coiled-coil (CC), a nucleotide binding (NB-ARC) and a leucine rich repeat (LRR) domains. The maize NLR gene Rp1-D21 derives from an intergenic recombination event between two NLR genes, Rp1-D and Rp1-dp2 and confers an autoactive HR. We report systematic structural and functional analyses of Rp1 proteins in maize and N. benthamiana to characterize the molecular mechanism of NLR activation/auto-inhibition. We derive a model comprising the following three main features: Rp1 proteins appear to self-associate to become competent for activity. The CC domain is signaling-competent and is sufficient to induce HR. This can be suppressed by the NB-ARC domain through direct interaction. In autoactive proteins, the interaction of the LRR domain with the NB-ARC domain causes de-repression and thus disrupts the inhibition of HR. Further, we identify specific amino acids and combinations thereof that are important for the auto-inhibition/activity of Rp1 proteins. We also provide evidence for the function of MHD2, a previously uncharacterized, though widely conserved NLR motif. This work reports several novel insights into the precise structural requirement for NLR function and informs efforts towards utilizing these proteins for engineering disease resistance.

Functional Genomics Analysis of Big Data Identifies Novel Peroxisome Proliferator-Activated Receptor γ Target Single Nucleotide Polymorphisms Showing Association With Cardiometabolic Outcomes.

PubMed

Richardson, Kris; Schnitzler, Gavin R; Lai, Chao-Qiang; Ordovas, Jose M

2015-12-01

Cardiovascular disease and type 2 diabetes mellitus represent overlapping diseases where a large portion of the variation attributable to genetics remains unexplained. An important player in their pathogenesis is peroxisome proliferator-activated receptor γ (PPARγ) that is involved in lipid and glucose metabolism and maintenance of metabolic homeostasis. We used a functional genomics methodology to interrogate human chromatin immunoprecipitation-sequencing, genome-wide association studies, and expression quantitative trait locus data to inform selection of candidate functional single nucleotide polymorphisms (SNPs) falling in PPARγ motifs. We derived 27 328 chromatin immunoprecipitation-sequencing peaks for PPARγ in human adipocytes through meta-analysis of 3 data sets. The PPARγ consensus motif showed greatest enrichment and mapped to 8637 peaks. We identified 146 SNPs in these motifs. This number was significantly less than would be expected by chance, and Inference of Natural Selection from Interspersed Genomically coHerent elemenTs analysis indicated that these motifs are under weak negative selection. A screen of these SNPs against genome-wide association studies for cardiometabolic traits revealed significant enrichment with 16 SNPs. A screen against the MuTHER expression quantitative trait locus data revealed 8 of these were significantly associated with altered gene expression in human adipose, more than would be expected by chance. Several SNPs fall close, or are linked by expression quantitative trait locus to lipid-metabolism loci including CYP26A1. We demonstrated the use of functional genomics to identify SNPs of potential function. Specifically, that SNPs within PPARγ motifs that bind PPARγ in adipocytes are significantly associated with cardiometabolic disease and with the regulation of transcription in adipose. This method may be used to uncover functional SNPs that do not reach significance thresholds in the agnostic approach of genome

Systematic reviews identify important methodological flaws in stroke rehabilitation therapy primary studies: review of reviews.

PubMed

Santaguida, Pasqualina; Oremus, Mark; Walker, Kathryn; Wishart, Laurie R; Siegel, Karen Lohmann; Raina, Parminder

2012-04-01

A "review of reviews" was undertaken to assess methodological issues in studies evaluating nondrug rehabilitation interventions in stroke patients. MEDLINE, CINAHL, PsycINFO, and the Cochrane Database of Systematic Reviews were searched from January 2000 to January 2008 within the stroke rehabilitation setting. Electronic searches were supplemented by reviews of reference lists and citations identified by experts. Eligible studies were systematic reviews; excluded citations were narrative reviews or reviews of reviews. Review characteristics and criteria for assessing methodological quality of primary studies within them were extracted. The search yielded 949 English-language citations. We included a final set of 38 systematic reviews. Cochrane reviews, which have a standardized methodology, were generally of higher methodological quality than non-Cochrane reviews. Most systematic reviews used standardized quality assessment criteria for primary studies, but not all were comprehensive. Reviews showed that primary studies had problems with randomization, allocation concealment, and blinding. Baseline comparability, adverse events, and co-intervention or contamination were not consistently assessed. Blinding of patients and providers was often not feasible and was not evaluated as a source of bias. The eligible systematic reviews identified important methodological flaws in the evaluated primary studies, suggesting the need for improvement of research methods and reporting. Copyright © 2012 Elsevier Inc. All rights reserved.

Ensemble gene function prediction database reveals genes important for complex I formation in Arabidopsis thaliana.

PubMed

Hansen, Bjoern Oest; Meyer, Etienne H; Ferrari, Camilla; Vaid, Neha; Movahedi, Sara; Vandepoele, Klaas; Nikoloski, Zoran; Mutwil, Marek

2018-03-01

Recent advances in gene function prediction rely on ensemble approaches that integrate results from multiple inference methods to produce superior predictions. Yet, these developments remain largely unexplored in plants. We have explored and compared two methods to integrate 10 gene co-function networks for Arabidopsis thaliana and demonstrate how the integration of these networks produces more accurate gene function predictions for a larger fraction of genes with unknown function. These predictions were used to identify genes involved in mitochondrial complex I formation, and for five of them, we confirmed the predictions experimentally. The ensemble predictions are provided as a user-friendly online database, EnsembleNet. The methods presented here demonstrate that ensemble gene function prediction is a powerful method to boost prediction performance, whereas the EnsembleNet database provides a cutting-edge community tool to guide experimentalists. © 2017 The Authors. New Phytologist © 2017 New Phytologist Trust.

A Loss-of-Function Screen for Phosphatases that Regulate Neurite Outgrowth Identifies PTPN12 as a Negative Regulator of TrkB Tyrosine Phosphorylation

PubMed Central

Ambjørn, Malene; Dubreuil, Véronique; Miozzo, Federico; Nigon, Fabienne; Møller, Bente; Issazadeh-Navikas, Shohreh; Berg, Jacob; Lees, Michael; Sap, Jan

2013-01-01

Alterations in function of the neurotrophin BDNF are associated with neurodegeneration, cognitive decline, and psychiatric disorders. BDNF promotes axonal outgrowth and branching, regulates dendritic tree morphology and is important for axonal regeneration after injury, responses that largely result from activation of its tyrosine kinase receptor TrkB. Although intracellular neurotrophin (NT) signaling presumably reflects the combined action of kinases and phosphatases, little is known about the contributions of the latter to TrkB regulation. The issue is complicated by the fact that phosphatases belong to multiple independently evolved families, which are rarely studied together. We undertook a loss-of-function RNA-interference-based screen of virtually all known (254) human phosphatases to understand their function in BDNF/TrkB-mediated neurite outgrowth in differentiated SH-SY5Y cells. This approach identified phosphatases from diverse families, which either positively or negatively modulate BDNF-TrkB-mediated neurite outgrowth, and most of which have little or no previously established function related to NT signaling. “Classical” protein tyrosine phosphatases (PTPs) accounted for 13% of the candidate regulatory phosphatases. The top classical PTP identified as a negative regulator of BDNF-TrkB-mediated neurite outgrowth was PTPN12 (also called PTP-PEST). Validation and follow-up studies showed that endogenous PTPN12 antagonizes tyrosine phosphorylation of TrkB itself, and the downstream activation of ERK1/2. We also found PTPN12 to negatively regulate phosphorylation of p130cas and FAK, proteins with previously described functions related to cell motility and growth cone behavior. Our data provide the first comprehensive survey of phosphatase function in NT signaling and neurite outgrowth. They reveal the complexity of phosphatase control, with several evolutionarily unrelated phosphatase families cooperating to affect this biological response, and hence

Functional SNP associated with birth weight in independent populations identified with a permutation step added to GBLUP-GWAS

USDA-ARS?s Scientific Manuscript database

This study was conducted as an initial assessment of a newly available genotyping assay containing about 34,000 common SNP included on previous SNP chips, and 199,000 sequence variants predicted to affect gene function. Objectives were to identify functional variants associated with birth weight in...

Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes.

PubMed

Wong, John K L; Campbell, Desmond; Ngo, Ngoc Diem; Yeung, Fanny; Cheng, Guo; Tang, Clara S M; Chung, Patrick H Y; Tran, Ngoc Son; So, Man-Ting; Cherny, Stacey S; Sham, Pak C; Tam, Paul K; Garcia-Barcelo, Maria-Mercè

2016-12-12

Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted. We aim to identify genetic risk factors by a "trio-based" exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients. Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients. Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD.

Affinity resins as new tools for identifying target proteins of ascorbic acid.

PubMed

Iwaoka, Yuji; Nishino, Kohei; Ishikawa, Takahiro; Ito, Hideyuki; Sawa, Yoshihiro; Tai, Akihiro

2018-02-12

l-Ascorbic acid (AA) has diverse physiological functions, but little is known about the functional mechanisms of AA. In this study, we synthesized two types of affinity resin on which AA is immobilized in a stable form to identify new AA-targeted proteins, which can provide important clues for elucidating unknown functional mechanisms of AA. To our knowledge, an affinity resin on which AA as a ligand is immobilized has not been prepared, because AA is very unstable and rapidly degraded in an aqueous solution. By using the affinity resins, cytochrome c (cyt c) was identified as an AA-targeted protein, and we showed that oxidized cyt c exhibits specific affinity for AA. These results suggest that two kinds of AA-affinity resin can be powerful tools to identify new target proteins of AA.

Identifying important comorbidity among cancer populations using administrative data: Prevalence and impact on survival.

PubMed

Sarfati, Diana; Gurney, Jason; Lim, Bee Teng; Bagheri, Nasser; Simpson, Andrew; Koea, Jonathan; Dennett, Elizabeth

2016-03-01

Our study sought to optimize the identification and investigate the impact of comorbidity in cancer patients using routinely collected hospitalization data. We undertook an iterative process of classification of important clinical conditions involving evaluation of relevant literature and consultation with clinicians. Patients diagnosed with colon, rectal, breast, ovarian, uterine, stomach, liver, renal or bladder cancers (n = 14,096) between 2006 and 2008 were identified from the New Zealand Cancer Registry. Conditions were identified using data on diagnoses from hospital admissions for 5 years prior to cancer diagnosis. Patients were followed up until end of 2009 using routine mortality data. Prevalence estimates for each condition by site were calculated. All-cause mortality impact of common conditions was investigated using Cox regression models adjusted for age and stage at diagnosis. Patients with liver and stomach cancers tended to have higher comorbidity and those with breast cancer, lower comorbidity than other cancer patients. Of the 50 conditions, the most common were hypertension (prevalence 8.0-20.9%), cardiac conditions (2.1-13.5%) and diabetes with (2.3-13.3%) and without (2.9-12.9%) complications. Comorbidity was associated with higher all-cause mortality but the impact varied by condition and across cancer site, with impact less for cancers with poor prognoses. Conditions most consistently associated with adverse outcomes across all cancer sites were renal disease, coagulopathies and congestive heart failure. Comorbidity is highly prevalent in cancer populations, but prevalence and impact of conditions differ markedly by cancer type. © 2013 Wiley Publishing Asia Pty Ltd.

Finding a Needle in the Haystack: Identification of Functionally Important Minority Phases in an Operating Battery.

PubMed

Zhang, Kai; Ren, Fang; Wang, Xuelong; Hu, Enyuan; Xu, Yahong; Yang, Xiao-Qing; Li, Hong; Chen, Liquan; Pianetta, Piero; Mehta, Apurva; Yu, Xiqian; Liu, Yijin

2017-12-13

The in-depth understanding of the minority phases' roles in functional materials, e.g., batteries, is critical for optimizing the system performance and the operational efficiency. Although the visualization of battery electrode under operating conditions has been demonstrated, the development of advanced data-mining approaches is still needed in order to identify minority phases and to understand their functionalities. The present study uses nanoscale X-ray spectromicroscopy to study a functional LiCoO 2 /Li battery pouch cell. The data-mining approaches developed herein were used to search through over 10 million X-ray absorption spectra that cover more than 100 active cathode particles. Two particles with unanticipated chemical fingerprints were identified and further analyzed, providing direct evidence and valuable insight into the undesired side reactions involving the cation dissolution and precipitation as well as the local overlithiation-caused subparticle domain deactivation. The data-mining approach described in this work is widely applicable to many other structurally complex and chemically heterogeneous systems, in which the secondary/minority phases could critically affect the overall performance of the system, well beyond battery research.

Microbial functional diversity plays an important role in the degradation of polyhydroxybutyrate (PHB) in soil.

PubMed

Dey, Samrat; Tribedi, Prosun

2018-03-01

Towards bioremediation of recalcitrant materials like synthetic polymer, soil has been recognized as a traditional site for disposal and subsequent degradation as some microorganisms in soil can degrade the polymer in a non-toxic, cost-effective, and environment friendly way. Microbial functional diversity is a constituent of biodiversity that includes wide range of metabolic activities that can influence numerous aspects of ecosystem functioning like ecosystem stability, nutrient availability, ecosystem dynamics, etc. Thus, in the current study, we assumed that microbial functional diversity could play an important role in polymer degradation in soil. To verify this hypothesis, we isolated soil from five different sites of landfill and examined several microbiological parameters wherein we observed a significant variation in heterotrophic microbial count as well as microbial activities among the soil microcosms tested. Multivariate analysis (principle component analysis) based on the carbon sources utilization pattern revealed that soil microcosms showed different metabolic patterns suggesting the variable distribution of microorganisms among the soil microcosms tested. Since microbial functional diversity depends on both microbial richness and evenness, Shannon diversity index was determined to measure microbial richness and Gini coefficient was determined to measure microbial evenness. The tested soil microcosms exhibited variation in both microbial richness and evenness suggesting the considerable difference in microbial functional diversity among the tested microcosms. We then measured polyhydroxybutyrate (PHB) degradation in soil microcosms after desired period of incubation of PHB in soil wherein we found that soil microcosms having higher functional diversity showed enhanced PHB degradation and soil microcosms having lower functional diversity showed reduced PHB degradation. We also noticed that all the tested soil microcosms showed similar pattern in both

Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

PubMed

Zhang, Shuxiao; Ross, Kevin D; Seidner, Glen A; Gorman, Michael R; Poon, Tiffany H; Wang, Xiaobo; Keithley, Elizabeth M; Lee, Patricia N; Martindale, Mark Q; Joiner, William J; Hamilton, Bruce A

2015-07-01

Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei. Homologous genes from unicellular organisms and invertebrate animals predict interactions with small GTPases, but the corresponding domains are absent in mammalian Nmf9. Intriguingly, homozygotes for null mutations in the Drosophila homolog, CG45058, show profound locomotor defects and premature death, while heterozygotes show striking effects on sleep and activity phenotypes. These results link a novel gene orthology group to discrete neurological functions, and show conserved requirement across wide phylogenetic distance and domain level structural changes.

In vivo Labeling of Constellations of Functionally Identified Neurons for Targeted in vitro Recordings

PubMed Central

Lien, Anthony D.; Scanziani, Massimo

2011-01-01

Relating the functional properties of neurons in an intact organism with their cellular and synaptic characteristics is necessary for a mechanistic understanding of brain function. However, while the functional properties of cortical neurons (e.g., tuning to sensory stimuli) are necessarily determined in vivo, detailed cellular and synaptic analysis relies on in vitro techniques. Here we describe an approach that combines in vivo calcium imaging (for functional characterization) with photo-activation of fluorescent proteins (for neuron labeling), thereby allowing targeted in vitro recording of multiple neurons with known functional properties. We expressed photo-activatable GFP rendered non-diffusible through fusion with a histone protein (H2B–PAGFP) in the mouse visual cortex to rapidly photo-label constellations of neurons in vivo at cellular and sub-cellular resolution using two-photon excitation. This photo-labeling method was compatible with two-photon calcium imaging of neuronal responses to visual stimuli, allowing us to label constellations of neurons with specific functional properties. Photo-labeled neurons were easily identified in vitro in acute brain slices and could be targeted for whole-cell recording. We also demonstrate that in vitro and in vivo image stacks of the same photo-labeled neurons could be registered to one another, allowing the exact in vivo response properties of individual neurons recorded in vitro to be known. The ability to perform in vitro recordings from neurons with known functional properties opens up exciting new possibilities for dissecting the cellular, synaptic, and circuit mechanisms that underlie neuronal function in vivo. PMID:22144948

UET: a database of evolutionarily-predicted functional determinants of protein sequences that cluster as functional sites in protein structures.

PubMed

Lua, Rhonald C; Wilson, Stephen J; Konecki, Daniel M; Wilkins, Angela D; Venner, Eric; Morgan, Daniel H; Lichtarge, Olivier

2016-01-04

The structure and function of proteins underlie most aspects of biology and their mutational perturbations often cause disease. To identify the molecular determinants of function as well as targets for drugs, it is central to characterize the important residues and how they cluster to form functional sites. The Evolutionary Trace (ET) achieves this by ranking the functional and structural importance of the protein sequence positions. ET uses evolutionary distances to estimate functional distances and correlates genotype variations with those in the fitness phenotype. Thus, ET ranks are worse for sequence positions that vary among evolutionarily closer homologs but better for positions that vary mostly among distant homologs. This approach identifies functional determinants, predicts function, guides the mutational redesign of functional and allosteric specificity, and interprets the action of coding sequence variations in proteins, people and populations. Now, the UET database offers pre-computed ET analyses for the protein structure databank, and on-the-fly analysis of any protein sequence. A web interface retrieves ET rankings of sequence positions and maps results to a structure to identify functionally important regions. This UET database integrates several ways of viewing the results on the protein sequence or structure and can be found at http://mammoth.bcm.tmc.edu/uet/. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

A new process sensitivity index to identify important system processes under process model and parametric uncertainty

DOE PAGES

Dai, Heng; Ye, Ming; Walker, Anthony P.; ...

2017-03-28

A hydrological model consists of multiple process level submodels, and each submodel represents a process key to the operation of the simulated system. Global sensitivity analysis methods have been widely used to identify important processes for system model development and improvement. The existing methods of global sensitivity analysis only consider parametric uncertainty, and are not capable of handling model uncertainty caused by multiple process models that arise from competing hypotheses about one or more processes. To address this problem, this study develops a new method to probe model output sensitivity to competing process models by integrating model averaging methods withmore » variance-based global sensitivity analysis. A process sensitivity index is derived as a single summary measure of relative process importance, and the index includes variance in model outputs caused by uncertainty in both process models and their parameters. Here, for demonstration, the new index is used to assign importance to the processes of recharge and geology in a synthetic study of groundwater reactive transport modeling. The recharge process is simulated by two models that convert precipitation to recharge, and the geology process is simulated by two models of hydraulic conductivity. Each process model has its own random parameters. Finally, the new process sensitivity index is mathematically general, and can be applied to a wide range of problems in hydrology and beyond.« less

A new process sensitivity index to identify important system processes under process model and parametric uncertainty

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Heng; Ye, Ming; Walker, Anthony P.

A hydrological model consists of multiple process level submodels, and each submodel represents a process key to the operation of the simulated system. Global sensitivity analysis methods have been widely used to identify important processes for system model development and improvement. The existing methods of global sensitivity analysis only consider parametric uncertainty, and are not capable of handling model uncertainty caused by multiple process models that arise from competing hypotheses about one or more processes. To address this problem, this study develops a new method to probe model output sensitivity to competing process models by integrating model averaging methods withmore » variance-based global sensitivity analysis. A process sensitivity index is derived as a single summary measure of relative process importance, and the index includes variance in model outputs caused by uncertainty in both process models and their parameters. Here, for demonstration, the new index is used to assign importance to the processes of recharge and geology in a synthetic study of groundwater reactive transport modeling. The recharge process is simulated by two models that convert precipitation to recharge, and the geology process is simulated by two models of hydraulic conductivity. Each process model has its own random parameters. Finally, the new process sensitivity index is mathematically general, and can be applied to a wide range of problems in hydrology and beyond.« less

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer. | Office of Cancer Genomics

Cancer.gov

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets.

Functional mechanisms of drought tolerance in subtropical maize (Zea mays L.) identified using genome-wide association mapping.

PubMed

Thirunavukkarasu, Nepolean; Hossain, Firoz; Arora, Kanika; Sharma, Rinku; Shiriga, Kaliyugam; Mittal, Swati; Mohan, Sweta; Namratha, Pottekatt Mohanlal; Dogga, Sreelatha; Rani, Tikka Shobha; Katragadda, Sumalini; Rathore, Abhishek; Shah, Trushar; Mohapatra, Trilochan; Gupta, Hari Shankar

2014-12-24

Earlier studies were focused on the genetics of temperate and tropical maize under drought. We identified genetic loci and their association with functional mechanisms in 240 accessions of subtropical maize using a high-density marker set under water stress. Out of 61 significant SNPs (11 were false-discovery-rate-corrected associations), identified across agronomic traits, models, and locations by subjecting the accessions to water stress at flowering stage, 48% were associated with drought-tolerant genes. Maize gene models revealed that SNPs mapped for agronomic traits were in fact associated with number of functional traits as follows: stomatal closure, 28; flowering, 15; root development, 5; detoxification, 4; and reduced water potential, 2. Interactions of these SNPS through the functional traits could lead to drought tolerance. The SNPs associated with ABA-dependent signalling pathways played a major role in the plant's response to stress by regulating a series of functions including flowering, root development, auxin metabolism, guard cell functions, and scavenging reactive oxygen species (ROS). ABA signalling genes regulate flowering through epigenetic changes in stress-responsive genes. ROS generated by ABA signalling are reduced by the interplay between ethylene, ABA, and detoxification signalling transductions. Integration of ABA-signalling genes with auxin-inducible genes regulates root development which in turn, maintains the water balance by regulating electrochemical gradient in plant. Several genes are directly or indirectly involved in the functioning of agronomic traits related to water stress. Genes involved in these crucial biological functions interacted significantly in order to maintain the primary as well as exclusive functions related to coping with water stress. SNPs associated with drought-tolerant genes involved in strategic biological functions will be useful to understand the mechanisms of drought tolerance in subtropical maize.

Developing clinical practice guidelines: target audiences, identifying topics for guidelines, guideline group composition and functioning and conflicts of interest

PubMed Central

2012-01-01

Clinical practice guidelines are one of the foundations of efforts to improve health care. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearing houses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this first paper we discuss: the target audience(s) for guidelines and their use of guidelines; identifying topics for guidelines; guideline group composition (including consumer involvement) and the processes by which guideline groups function and the important procedural issue of managing conflicts of interest in guideline development. PMID:22762776

Developing clinical practice guidelines: target audiences, identifying topics for guidelines, guideline group composition and functioning and conflicts of interest.

PubMed

Eccles, Martin P; Grimshaw, Jeremy M; Shekelle, Paul; Schünemann, Holger J; Woolf, Steven

2012-07-04

Clinical practice guidelines are one of the foundations of efforts to improve health care. In 1999, we authored a paper about methods to develop guidelines. Since it was published, the methods of guideline development have progressed both in terms of methods and necessary procedures and the context for guideline development has changed with the emergence of guideline clearing houses and large scale guideline production organisations (such as the UK National Institute for Health and Clinical Excellence). It therefore seems timely to, in a series of three articles, update and extend our earlier paper. In this first paper we discuss: the target audience(s) for guidelines and their use of guidelines; identifying topics for guidelines; guideline group composition (including consumer involvement) and the processes by which guideline groups function and the important procedural issue of managing conflicts of interest in guideline development.

In Silico Functional Networks Identified in Fish Nucleated Red Blood Cells by Means of Transcriptomic and Proteomic Profiling.

PubMed

Puente-Marin, Sara; Nombela, Iván; Ciordia, Sergio; Mena, María Carmen; Chico, Verónica; Coll, Julio; Ortega-Villaizan, María Del Mar

2018-04-09

Nucleated red blood cells (RBCs) of fish have, in the last decade, been implicated in several immune-related functions, such as antiviral response, phagocytosis or cytokine-mediated signaling. RNA-sequencing (RNA-seq) and label-free shotgun proteomic analyses were carried out for in silico functional pathway profiling of rainbow trout RBCs. For RNA-seq, a de novo assembly was conducted, in order to create a transcriptome database for RBCs. For proteome profiling, we developed a proteomic method that combined: (a) fractionation into cytosolic and membrane fractions, (b) hemoglobin removal of the cytosolic fraction, (c) protein digestion, and (d) a novel step with pH reversed-phase peptide fractionation and final Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometric (LC ESI-MS/MS) analysis of each fraction. Combined transcriptome- and proteome- sequencing data identified, in silico, novel and striking immune functional networks for rainbow trout nucleated RBCs, which are mainly linked to innate and adaptive immunity. Functional pathways related to regulation of hematopoietic cell differentiation, antigen presentation via major histocompatibility complex class II (MHCII), leukocyte differentiation and regulation of leukocyte activation were identified. These preliminary findings further implicate nucleated RBCs in immune function, such as antigen presentation and leukocyte activation.

Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function

PubMed Central

Artigas, María Soler; Loth, Daan W; Wain, Louise V; Gharib, Sina A; Obeidat, Ma’en; Tang, Wenbo; Zhai, Guangju; Zhao, Jing Hua; Smith, Albert Vernon; Huffman, Jennifer E; Albrecht, Eva; Jackson, Catherine M; Evans, David M; Cadby, Gemma; Fornage, Myriam; Manichaikul, Ani; Lopez, Lorna M; Johnson, Toby; Aldrich, Melinda C; Aspelund, Thor; Barroso, Inês; Campbell, Harry; Cassano, Patricia A; Couper, David J; Eiriksdottir, Gudny; Franceschini, Nora; Garcia, Melissa; Gieger, Christian; Gislason, Gauti Kjartan; Grkovic, Ivica; Hammond, Christopher J; Hancock, Dana B; Harris, Tamara B; Ramasamy, Adaikalavan; Heckbert, Susan R; Heliövaara, Markku; Homuth, Georg; Hysi, Pirro G; James, Alan L; Jankovic, Stipan; Joubert, Bonnie R; Karrasch, Stefan; Klopp, Norman; Koch, Beate; Kritchevsky, Stephen B; Launer, Lenore J; Liu, Yongmei; Loehr, Laura R; Lohman, Kurt; Loos, Ruth JF; Lumley, Thomas; Al Balushi, Khalid A; Ang, Wei Q; Barr, R Graham; Beilby, John; Blakey, John D; Boban, Mladen; Boraska, Vesna; Brisman, Jonas; Britton, John R; Brusselle, Guy G; Cooper, Cyrus; Curjuric, Ivan; Dahgam, Santosh; Deary, Ian J; Ebrahim, Shah; Eijgelsheim, Mark; Francks, Clyde; Gaysina, Darya; Granell, Raquel; Gu, Xiangjun; Hankinson, John L; Hardy, Rebecca; Harris, Sarah E; Henderson, John; Henry, Amanda; Hingorani, Aroon D; Hofman, Albert; Holt, Patrick G; Hui, Jennie; Hunter, Michael L; Imboden, Medea; Jameson, Karen A; Kerr, Shona M; Kolcic, Ivana; Kronenberg, Florian; Liu, Jason Z; Marchini, Jonathan; McKeever, Tricia; Morris, Andrew D; Olin, Anna-Carin; Porteous, David J; Postma, Dirkje S; Rich, Stephen S; Ring, Susan M; Rivadeneira, Fernando; Rochat, Thierry; Sayer, Avan Aihie; Sayers, Ian; Sly, Peter D; Smith, George Davey; Sood, Akshay; Starr, John M; Uitterlinden, André G; Vonk, Judith M; Wannamethee, S Goya; Whincup, Peter H; Wijmenga, Cisca; Williams, O Dale; Wong, Andrew; Mangino, Massimo; Marciante, Kristin D; McArdle, Wendy L; Meibohm, Bernd; Morrison, Alanna C; North, Kari E; Omenaas, Ernst; Palmer, Lyle J; Pietiläinen, Kirsi H; Pin, Isabelle; Polašek, Ozren; Pouta, Anneli; Psaty, Bruce M; Hartikainen, Anna-Liisa; Rantanen, Taina; Ripatti, Samuli; Rotter, Jerome I; Rudan, Igor; Rudnicka, Alicja R; Schulz, Holger; Shin, So-Youn; Spector, Tim D; Surakka, Ida; Vitart, Veronique; Völzke, Henry; Wareham, Nicholas J; Warrington, Nicole M; Wichmann, H-Erich; Wild, Sarah H; Wilk, Jemma B; Wjst, Matthias; Wright, Alan F; Zgaga, Lina; Zemunik, Tatijana; Pennell, Craig E; Nyberg, Fredrik; Kuh, Diana; Holloway, John W; Boezen, H Marike; Lawlor, Debbie A; Morris, Richard W; Probst-Hensch, Nicole; Kaprio, Jaakko; Wilson, James F; Hayward, Caroline; Kähönen, Mika; Heinrich, Joachim; Musk, Arthur W; Jarvis, Deborah L; Gläser, Sven; Järvelin, Marjo-Riitta; Stricker, Bruno H Ch; Elliott, Paul; O’Connor, George T; Strachan, David P; London, Stephanie J; Hall, Ian P; Gudnason, Vilmundur; Tobin, Martin D

2011-01-01

Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. PMID:21946350

Strategies to identify natural antisense transcripts.

PubMed

Sun, Yulong; Li, Dijie; Zhang, Ru; Peng, Shang; Zhang, Ge; Yang, Tuanmin; Qian, Airong

2017-01-01

Natural antisense transcripts, originally considered as transcriptional noises arising from so-called "junk DNA″, are recently recognized as important modulators for gene regulation. They are prevalent in nearly all realms of life and have been found to modulate gene expression positively or negatively. By affecting almost all stages of gene expression range from pre-transcriptional, transcriptional and post-transcriptional to translation, NATs are fundamentally involved in various biological processes. However, compared to increasing huge data from transcriptional analysis especially high-throughput sequencing technologies (such as RNA-seq), limited functional NATs (around 70) are so far reported, which hinder our advanced comprehensive understanding for this field. Hence, efficient strategies for identifying NATs are urgently desired. In this review, we discussed the current strategies for identifying NATs, with a focus on the advantages, disadvantages, and applications of methods isolating functional NATs. Moreover, publicly available databases for NATs were also discussed. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

A bootstrap based Neyman-Pearson test for identifying variable importance.

PubMed

Ditzler, Gregory; Polikar, Robi; Rosen, Gail

2015-04-01

Selection of most informative features that leads to a small loss on future data are arguably one of the most important steps in classification, data analysis and model selection. Several feature selection (FS) algorithms are available; however, due to noise present in any data set, FS algorithms are typically accompanied by an appropriate cross-validation scheme. In this brief, we propose a statistical hypothesis test derived from the Neyman-Pearson lemma for determining if a feature is statistically relevant. The proposed approach can be applied as a wrapper to any FS algorithm, regardless of the FS criteria used by that algorithm, to determine whether a feature belongs in the relevant set. Perhaps more importantly, this procedure efficiently determines the number of relevant features given an initial starting point. We provide freely available software implementations of the proposed methodology.

Functional genomics identifies regulators of the phototransduction machinery in the Drosophila larval eye and adult ocelli.

PubMed

Mishra, Abhishek Kumar; Bargmann, Bastiaan O R; Tsachaki, Maria; Fritsch, Cornelia; Sprecher, Simon G

2016-02-15

Sensory perception of light is mediated by specialized Photoreceptor neurons (PRs) in the eye. During development all PRs are genetically determined to express a specific Rhodopsin (Rh) gene and genes mediating a functional phototransduction pathway. While the genetic and molecular mechanisms of PR development is well described in the adult compound eye, it remains unclear how the expression of Rhodopsins and the phototransduction cascade is regulated in other visual organs in Drosophila, such as the larval eye and adult ocelli. Using transcriptome analysis of larval PR-subtypes and ocellar PRs we identify and study new regulators required during PR differentiation or necessary for the expression of specific signaling molecules of the functional phototransduction pathway. We found that the transcription factor Krüppel (Kr) is enriched in the larval eye and controls PR differentiation by promoting Rh5 and Rh6 expression. We also identified Camta, Lola, Dve and Hazy as key genes acting during ocellar PR differentiation. Further we show that these transcriptional regulators control gene expression of the phototransduction cascade in both larval eye and adult ocelli. Our results show that PR cell type-specific transcriptome profiling is a powerful tool to identify key transcriptional regulators involved during several aspects of PR development and differentiation. Our findings greatly contribute to the understanding of how combinatorial action of key transcriptional regulators control PR development and the regulation of a functional phototransduction pathway in both larval eye and adult ocelli. Copyright © 2015 Elsevier Inc. All rights reserved.

A Rasch Differential Item Functioning Analysis of the Massachusetts Youth Screening Instrument: Identifying Race and Gender Differential Item Functioning among Juvenile Offenders

ERIC Educational Resources Information Center

Cauffman, Elizabeth; MacIntosh, Randall

2006-01-01

The juvenile justice system needs a tool that can identify and assess mental health problems among youths quickly with validity and reliability. The goal of this article is to evaluate the racial/ethnic and gender differential item functioning (DIF) of the Massachusetts Youth Screening Instrument-Second Version (MAYSI-2) using the Rasch Model.…

Functional screening for miRNAs targeting Smad4 identified miR-199a as a negative regulator of TGF-β signalling pathway

PubMed Central

Zhang, Yan; Fan, Kai-Ji; Sun, Qiang; Chen, Ai-Zhong; Shen, Wen-Long; Zhao, Zhi-Hu; Zheng, Xiao-Fei; Yang, Xiao

2012-01-01

The transforming growth factor-β (TGF-β) signalling pathway participates in various biological processes. Dysregulation of Smad4, a central cellular transducer of TGF-β signalling, is implicated in a wide range of human diseases and developmental disorders. However, the mechanisms underlying Smad4 dysregulation are not fully understood. Using a functional screening approach based on luciferase reporter assays, we identified 39 microRNAs (miRNAs) as potential regulators of Smad4 from an expression library of 388 human miRNAs. The screening was supported by bioinformatic analysis, as 24 of 39 identified miRNAs were also predicted to target Smad4. MiR-199a, one of the identified miRNAs, was inversely correlated with Smad4 expression in various human cancer cell lines and gastric cancer tissues, and repressed Smad4 expression and blocked canonical TGF-β transcriptional responses in cell lines. These effects were dependent on the presence of a conserved, but not perfect seed paired, miR-199a-binding site in the Smad4 3′-untranslated region (UTR). Overexpression of miR-199a significantly inhibited the ability of TGF-β to induce gastric cancer cell growth arrest and apoptosis in vitro, and promoted anchorage-independent growth in soft agar, suggesting that miR-199a plays an oncogenic role in human gastric tumourigenesis. In conclusion, our functional screening uncovers multiple miRNAs that regulate the cellular responsiveness to TGF-β signalling and reveals important roles of miR-199a in gastric cancer by directly targeting Smad4. PMID:22821565

Identifying specific beliefs to target to improve restaurant employees' intentions for performing three important food safety behaviors.

PubMed

Pilling, Valerie K; Brannon, Laura A; Shanklin, Carol W; Howells, Amber D; Roberts, Kevin R

2008-06-01

Current national food safety training programs appear ineffective at improving food safety practices in foodservice operations, given the substantial number of Americans affected by foodborne illnesses after eating in restaurants each year. The Theory of Planned Behavior (TpB) was used to identify important beliefs that may be targeted to improve foodservice employees' intentions for three food safety behaviors that have the most substantial affect on public health: hand washing, using thermometers, and proper handling of food contact surfaces. In a cross-sectional design, foodservice employees (n=190) across three midwestern states completed a survey assessing TpB components and knowledge for the three food safety behaviors. Multiple regression analyses were performed on the TpB components for each behavior. Independent-samples t tests identified TpB beliefs that discriminated between participants who absolutely intend to perform the behaviors and those with lower intention. Employees' attitudes were the one consistent predictor of intentions for performing all three behaviors. However, a unique combination of important predictors existed for each separate behavior. Interventions for improving employees' behavioral intentions for food safety should focus on TpB components that predict intentions for each behavior and should bring all employees' beliefs in line with those of the employees who already intend to perform the food safety behaviors. Registered dietitians; dietetic technicians, registered; and foodservice managers can use these results to enhance training sessions and motivational programs to improve employees' food safety behaviors. Results also assist these professionals in recognizing their responsibility for enforcing and providing adequate resources for proper food safety behaviors.

Imported Wines: Identifying and Removing Wines Contaminated with Diethylene Glycol.

DTIC Science & Technology

1986-03-01

at controlling health risks, BATF has used its labeling authority to prohibit the marketing of alcoholic beverages that are mislabeled by virtue of...or beverages contaminated with harmful substances into the U.S. market . DEG, a toxic substance, would be such a contaminant. The BATF’S authority in...representing a significant risk to health are identified and removed from k the market . BATF did not conduct a risk assessment or seek an assess- ment from

Mean Excess Function as a method of identifying sub-exponential tails: Application to extreme daily rainfall

NASA Astrophysics Data System (ADS)

Nerantzaki, Sofia; Papalexiou, Simon Michael

2017-04-01

Identifying precisely the distribution tail of a geophysical variable is tough, or, even impossible. First, the tail is the part of the distribution for which we have the less empirical information available; second, a universally accepted definition of tail does not and cannot exist; and third, a tail may change over time due to long-term changes. Unfortunately, the tail is the most important part of the distribution as it dictates the estimates of exceedance probabilities or return periods. Fortunately, based on their tail behavior, probability distributions can be generally categorized into two major families, i.e., sub-exponentials (heavy-tailed) and hyper-exponentials (light-tailed). This study aims to update the Mean Excess Function (MEF), providing a useful tool in order to asses which type of tail better describes empirical data. The MEF is based on the mean value of a variable over a threshold and results in a zero slope regression line when applied for the Exponential distribution. Here, we construct slope confidence intervals for the Exponential distribution as functions of sample size. The validation of the method using Monte Carlo techniques on four theoretical distributions covering major tail cases (Pareto type II, Log-normal, Weibull and Gamma) revealed that it performs well especially for large samples. Finally, the method is used to investigate the behavior of daily rainfall extremes; thousands of rainfall records were examined, from all over the world and with sample size over 100 years, revealing that heavy-tailed distributions can describe more accurately rainfall extremes.

THE DYNAMICS OF A NEUROMUSCULAR SYSTEM FUNCTIONAL CONDITION DURING THE PREPARATION FOR IMPORTANT CONTESTS

PubMed Central

Titov, G.

1973-01-01

The aim of this research was to determine a conjugation of the functional condition dynamics of the neuromuscular organs, visual analyser, latent period of the motorial activity and supporting kinosthetic functions at different stages of preparation of the sportsmen for important contests. The following research methods were used to achieve this aim: a functional mobility of the neuromuscular organs was determined with the help of an electrostimulation method (excitability thresholds, frequency range of optimum and maximum rhythm, data on the changes of a bioelectric potential in relation to electrical stimuli); a functional condition of the visual analyser was determined with the use of an electrostimulation method (excitability thresholds, frequency range of phosefan in the reaction to a threshold irritant); a grey matter neurodynamics was determined with the help of a chronoreflexometry using an audio irritant of a different power with the preliminary strain of motor centres or without it; supporting kinosthetic functions were determined with the help of seismotremography and stabilography (frequency and amplitude of tremor, deviations of the gravity centre of the body in different positions of the Romberg test). All the research on the systems mentioned was carried out within the preparatory, main and contest periods during the preparation for the important contests. Gymnasts, boxers and fencers were under observation. In all there were carried out 570 observations of 54 sportsmen of a high sporting qualification. The functional condition of the visual analyser at a satisfactory level of training was characterised by relatively low excitability thresholds and high frequency limits of phosefan. The functional mobility of the neuromuscular organs was reduced during this period. The supporting kinosthetic functions became apparent in the instability of frequency and amplitude tremor characteristics and general gravity centre deviations. The latent period of the

Finding a Needle in the Haystack: Identification of Functionally Important Minority Phases in an Operating Battery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Kai; Ren, Fang; Wang, Xuelong

The in-depth understanding of the minority phases’ roles in functional materials, e.g., batteries, is critical for optimizing the system performance and the operational efficiency. Although the visualization of battery electrode under operating conditions has been demonstrated, the development of advanced data-mining approaches is still needed in order to identify minority phases and to understand their functionalities. The present study uses nanoscale X-ray spectromicroscopy to study a functional LiCoO 2/Li battery pouch cell. The data-mining approaches developed herein were used to search through over 10 million X-ray absorption spectra that cover more than 100 active cathode particles. Two particles with unanticipatedmore » chemical fingerprints were identified and further analyzed, providing direct evidence and valuable insight into the undesired side reactions involving the cation dissolution and precipitation as well as the local overlithiation-caused subparticle domain deactivation. As a result, the data-mining approach described in this work is widely applicable to many other structurally complex and chemically heterogeneous systems, in which the secondary/minority phases could critically affect the overall performance of the system, well beyond battery research.« less

Finding a Needle in the Haystack: Identification of Functionally Important Minority Phases in an Operating Battery

DOE PAGES

Zhang, Kai; Ren, Fang; Wang, Xuelong; ...

2017-11-08

The in-depth understanding of the minority phases’ roles in functional materials, e.g., batteries, is critical for optimizing the system performance and the operational efficiency. Although the visualization of battery electrode under operating conditions has been demonstrated, the development of advanced data-mining approaches is still needed in order to identify minority phases and to understand their functionalities. The present study uses nanoscale X-ray spectromicroscopy to study a functional LiCoO 2/Li battery pouch cell. The data-mining approaches developed herein were used to search through over 10 million X-ray absorption spectra that cover more than 100 active cathode particles. Two particles with unanticipatedmore » chemical fingerprints were identified and further analyzed, providing direct evidence and valuable insight into the undesired side reactions involving the cation dissolution and precipitation as well as the local overlithiation-caused subparticle domain deactivation. As a result, the data-mining approach described in this work is widely applicable to many other structurally complex and chemically heterogeneous systems, in which the secondary/minority phases could critically affect the overall performance of the system, well beyond battery research.« less

SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.

PubMed

Li, Man; Li, Yong; Weeks, Olivia; Mijatovic, Vladan; Teumer, Alexander; Huffman, Jennifer E; Tromp, Gerard; Fuchsberger, Christian; Gorski, Mathias; Lyytikäinen, Leo-Pekka; Nutile, Teresa; Sedaghat, Sanaz; Sorice, Rossella; Tin, Adrienne; Yang, Qiong; Ahluwalia, Tarunveer S; Arking, Dan E; Bihlmeyer, Nathan A; Böger, Carsten A; Carroll, Robert J; Chasman, Daniel I; Cornelis, Marilyn C; Dehghan, Abbas; Faul, Jessica D; Feitosa, Mary F; Gambaro, Giovanni; Gasparini, Paolo; Giulianini, Franco; Heid, Iris; Huang, Jinyan; Imboden, Medea; Jackson, Anne U; Jeff, Janina; Jhun, Min A; Katz, Ronit; Kifley, Annette; Kilpeläinen, Tuomas O; Kumar, Ashish; Laakso, Markku; Li-Gao, Ruifang; Lohman, Kurt; Lu, Yingchang; Mägi, Reedik; Malerba, Giovanni; Mihailov, Evelin; Mohlke, Karen L; Mook-Kanamori, Dennis O; Robino, Antonietta; Ruderfer, Douglas; Salvi, Erika; Schick, Ursula M; Schulz, Christina-Alexandra; Smith, Albert V; Smith, Jennifer A; Traglia, Michela; Yerges-Armstrong, Laura M; Zhao, Wei; Goodarzi, Mark O; Kraja, Aldi T; Liu, Chunyu; Wessel, Jennifer; Boerwinkle, Eric; Borecki, Ingrid B; Bork-Jensen, Jette; Bottinger, Erwin P; Braga, Daniele; Brandslund, Ivan; Brody, Jennifer A; Campbell, Archie; Carey, David J; Christensen, Cramer; Coresh, Josef; Crook, Errol; Curhan, Gary C; Cusi, Daniele; de Boer, Ian H; de Vries, Aiko P J; Denny, Joshua C; Devuyst, Olivier; Dreisbach, Albert W; Endlich, Karlhans; Esko, Tõnu; Franco, Oscar H; Fulop, Tibor; Gerhard, Glenn S; Glümer, Charlotte; Gottesman, Omri; Grarup, Niels; Gudnason, Vilmundur; Hansen, Torben; Harris, Tamara B; Hayward, Caroline; Hocking, Lynne; Hofman, Albert; Hu, Frank B; Husemoen, Lise Lotte N; Jackson, Rebecca D; Jørgensen, Torben; Jørgensen, Marit E; Kähönen, Mika; Kardia, Sharon L R; König, Wolfgang; Kooperberg, Charles; Kriebel, Jennifer; Launer, Lenore J; Lauritzen, Torsten; Lehtimäki, Terho; Levy, Daniel; Linksted, Pamela; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J F; Lupo, Antonio; Meisinger, Christine; Melander, Olle; Metspalu, Andres; Mitchell, Paul; Nauck, Matthias; Nürnberg, Peter; Orho-Melander, Marju; Parsa, Afshin; Pedersen, Oluf; Peters, Annette; Peters, Ulrike; Polasek, Ozren; Porteous, David; Probst-Hensch, Nicole M; Psaty, Bruce M; Qi, Lu; Raitakari, Olli T; Reiner, Alex P; Rettig, Rainer; Ridker, Paul M; Rivadeneira, Fernando; Rossouw, Jacques E; Schmidt, Frank; Siscovick, David; Soranzo, Nicole; Strauch, Konstantin; Toniolo, Daniela; Turner, Stephen T; Uitterlinden, André G; Ulivi, Sheila; Velayutham, Dinesh; Völker, Uwe; Völzke, Henry; Waldenberger, Melanie; Wang, Jie Jin; Weir, David R; Witte, Daniel; Kuivaniemi, Helena; Fox, Caroline S; Franceschini, Nora; Goessling, Wolfram; Köttgen, Anna; Chu, Audrey Y

2017-03-01

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 -7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 -8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation. Copyright © 2017 by the American Society of Nephrology.

NF-E2 p45 Is Important for Establishing Normal Function of Platelets

PubMed Central

Fujita, Rie; Takayama-Tsujimoto, Mariko; Satoh, Hironori; Gutiérrez, Laura; Aburatani, Hiroyuki; Fujii, Satoshi; Sarai, Akinori; Bresnick, Emery H.

2013-01-01

NF-E2 is a heterodimeric transcription factor consisting of p45 and small Maf subunits. Since p45−/− mice display severe thrombocytopenia, p45 is recognized as a critical regulator of platelet production from megakaryocytes. To identify direct p45 target genes in megakaryocytes, we used chromatin immunoprecipitation (ChIP) sequencing to analyze the genome-wide chromatin occupancy of p45 in primary megakaryocytes. p45 target gene candidates obtained from the analysis are implicated in the production and function of platelets. Two of these genes, Selp and Myl9, were verified as direct p45 targets through multiple approaches. Since P-selectin, encoded by Selp, plays a critical role in platelet function during thrombogenesis, we tested whether p45 determines the intrinsic reactivity and potency of platelets generated from megakaryocytes. Mice expressing a hypomorphic p45 mutant instead of wild-type p45 in megakaryocytes (p45−/−:ΔNTD-Tg mice) displayed platelet hypofunction accompanied by mild thrombocytopenia. Furthermore, lung metastasis of melanoma cells, which requires platelet activation, was repressed in p45−/−:ΔNTD-Tg mice compared to control mice, validating the impaired function of platelets produced from p45−/−:ΔNTD-Tg megakaryocytes. By activating genes in megakaryocytes that mediate platelet production and function, p45 determines the quantity and quality of platelets. PMID:23648484

Potential ligand-binding residues in rat olfactory receptors identified by correlated mutation analysis

NASA Technical Reports Server (NTRS)

Singer, M. S.; Oliveira, L.; Vriend, G.; Shepherd, G. M.

1995-01-01

A family of G-protein-coupled receptors is believed to mediate the recognition of odor molecules. In order to identify potential ligand-binding residues, we have applied correlated mutation analysis to receptor sequences from the rat. This method identifies pairs of sequence positions where residues remain conserved or mutate in tandem, thereby suggesting structural or functional importance. The analysis supported molecular modeling studies in suggesting several residues in positions that were consistent with ligand-binding function. Two of these positions, dominated by histidine residues, may play important roles in ligand binding and could confer broad specificity to mammalian odor receptors. The presence of positive (overdominant) selection at some of the identified positions provides additional evidence for roles in ligand binding. Higher-order groups of correlated residues were also observed. Each group may interact with an individual ligand determinant, and combinations of these groups may provide a multi-dimensional mechanism for receptor diversity.

A quadratically regularized functional canonical correlation analysis for identifying the global structure of pleiotropy with NGS data

PubMed Central

Zhu, Yun; Fan, Ruzong; Xiong, Momiao

2017-01-01

Investigating the pleiotropic effects of genetic variants can increase statistical power, provide important information to achieve deep understanding of the complex genetic structures of disease, and offer powerful tools for designing effective treatments with fewer side effects. However, the current multiple phenotype association analysis paradigm lacks breadth (number of phenotypes and genetic variants jointly analyzed at the same time) and depth (hierarchical structure of phenotype and genotypes). A key issue for high dimensional pleiotropic analysis is to effectively extract informative internal representation and features from high dimensional genotype and phenotype data. To explore correlation information of genetic variants, effectively reduce data dimensions, and overcome critical barriers in advancing the development of novel statistical methods and computational algorithms for genetic pleiotropic analysis, we proposed a new statistic method referred to as a quadratically regularized functional CCA (QRFCCA) for association analysis which combines three approaches: (1) quadratically regularized matrix factorization, (2) functional data analysis and (3) canonical correlation analysis (CCA). Large-scale simulations show that the QRFCCA has a much higher power than that of the ten competing statistics while retaining the appropriate type 1 errors. To further evaluate performance, the QRFCCA and ten other statistics are applied to the whole genome sequencing dataset from the TwinsUK study. We identify a total of 79 genes with rare variants and 67 genes with common variants significantly associated with the 46 traits using QRFCCA. The results show that the QRFCCA substantially outperforms the ten other statistics. PMID:29040274

In Silico Functional Networks Identified in Fish Nucleated Red Blood Cells by Means of Transcriptomic and Proteomic Profiling

PubMed Central

Puente-Marin, Sara; Ciordia, Sergio; Mena, María Carmen; Chico, Verónica; Coll, Julio

2018-01-01

Nucleated red blood cells (RBCs) of fish have, in the last decade, been implicated in several immune-related functions, such as antiviral response, phagocytosis or cytokine-mediated signaling. RNA-sequencing (RNA-seq) and label-free shotgun proteomic analyses were carried out for in silico functional pathway profiling of rainbow trout RBCs. For RNA-seq, a de novo assembly was conducted, in order to create a transcriptome database for RBCs. For proteome profiling, we developed a proteomic method that combined: (a) fractionation into cytosolic and membrane fractions, (b) hemoglobin removal of the cytosolic fraction, (c) protein digestion, and (d) a novel step with pH reversed-phase peptide fractionation and final Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometric (LC ESI-MS/MS) analysis of each fraction. Combined transcriptome- and proteome- sequencing data identified, in silico, novel and striking immune functional networks for rainbow trout nucleated RBCs, which are mainly linked to innate and adaptive immunity. Functional pathways related to regulation of hematopoietic cell differentiation, antigen presentation via major histocompatibility complex class II (MHCII), leukocyte differentiation and regulation of leukocyte activation were identified. These preliminary findings further implicate nucleated RBCs in immune function, such as antigen presentation and leukocyte activation. PMID:29642539

System analysis identifies distinct and common functional networks governed by transcription factor ASCL1, in glioma and small cell lung cancer.

PubMed

Donakonda, Sainitin; Sinha, Swati; Dighe, Shrinivas Nivrutti; Rao, Manchanahalli R Satyanarayana

2017-07-25

ASCL1 is a basic Helix-Loop-Helix transcription factor (TF), which is involved in various cellular processes like neuronal development and signaling pathways. Transcriptome profiling has shown that ASCL1 overexpression plays an important role in the development of glioma and Small Cell Lung Carcinoma (SCLC), but distinct and common molecular mechanisms regulated by ASCL1 in these cancers are unknown. In order to understand how it drives the cellular functional network in these two tumors, we generated a gene expression profile in a glioma cell line (U87MG) to identify ASCL1 gene targets by an si RNA silencing approach and then compared this with a publicly available dataset of similarly silenced SCLC (NCI-H1618 cells). We constructed TF-TF and gene-gene interactions, as well as protein interaction networks of ASCL1 regulated genes in glioma and SCLC cells. Detailed network analysis uncovered various biological processes governed by ASCL1 target genes in these two tumor cell lines. We find that novel ASCL1 functions related to mitosis and signaling pathways influencing development and tumor growth are affected in both glioma and SCLC cells. In addition, we also observed ASCL1 governed functional networks that are distinct to glioma and SCLC.

Cryptic biodiversity effects: importance of functional redundancy revealed through addition of food web complexity.

PubMed

Philpott, Stacy M; Pardee, Gabriella L; Gonthier, David J

2012-05-01

Interactions between predators and the degree of functional redundancy among multiple predator species may determine whether herbivores experience increased or decreased predation risk. Specialist parasites can modify predator behavior, yet rarely have cascading effects on multiple predator species and prey been evaluated. We examined influences of specialist phorid parasites (Pseudacteon spp.) on three predatory ant species and herbivores in a coffee agroecosystem. Specifically, we examined whether changes in ant richness affected fruit damage by the coffee berry borer (Hypothenemus hampei) and whether phorids altered multi-predator effects. Each ant species reduced borer damage, and without phorids, increasing predator richness did not further decrease borer damage. However, with phorids, activity of one ant species was reduced, indicating that the presence of multiple ant species was necessary to limit borer damage. In addition, phorid presence revealed synergistic effects of multiple ant species, not observed without the presence of this parasite. Thus, a trait-mediated cascade resulting from a parasite-induced predator behavioral change revealed the importance of functional redundancy, predator diversity, and food web complexity for control of this important pest.

Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL6 in non-small cell lung cancer in vivo

PubMed Central

Vicent, Silvestre; Sayles, Leanne C.; Vaka, Dedeepya; Khatri, Purvesh; Gevaert, Olivier; Chen, Ron; Zheng, Yanyan; Gillespie, Anna K.; Clarke, Nicole; Xu, Yue; Shrager, Joseph; Hoang, Chuong D.; Plevritis, Sylvia; Butte, Atul J.; Sweet-Cordero, E. Alejandro

2013-01-01

Cancer-associated fibroblasts (CAFs) have been reported to support tumor progression by a variety of mechanisms. However, their role in the progression of non-small cell lung cancer (NSCLC) remains poorly defined. In addition, the extent to which specific proteins secreted by CAFs contribute directly to tumor growth is unclear. To study the role of CAFs in NSCLC, a cross-species functional characterization of mouse and human lung CAFs was performed. CAFs supported the growth of lung cancer cells in vivo by secretion of soluble factors that directly stimulate the growth of tumor cells. Gene expression analysis comparing normal mouse lung fibroblasts (NFs) and mouse lung CAFs identified multiple genes that correlate with the CAF phenotype. A gene signature of secreted genes upregulated in CAFs was an independent marker of poor survival in NSCLC patients. This secreted gene signature was upregulated in NFs after long-term exposure to tumor cells, demonstrating that NFs are “educated” by tumor cells to acquire a CAF-like phenotype. Functional studies identified important roles for CLCF1-CNTFR and IL6-IL6R signaling, in promoting growth of NSCLC cells. This study identifies novel soluble factors contributing to the CAF protumorigenic phenotype in NSCLC and suggests new avenues for the development of therapeutic strategies. PMID:22962265

Genomic Analyses Yield Markers for Identifying Agronomically Important Genes in Potato

USDA-ARS?s Scientific Manuscript database

This study explores the genetic architecture underling the potato evolution through a comprehensive assessment of wild and cultivated potato species based on the re-sequencing of 201 accessions of Solanum section Petota with >12 × genome coverage. We identified 450 domesticated genes, which showed e...

Objective and subjective psychosocial functioning in bipolar disorder: an investigation of the relative importance of neurocognition, social cognition and emotion regulation.

PubMed

Van Rheenen, Tamsyn E; Rossell, Susan L

2014-06-01

People with bipolar disorder (BD) experience significant psychosocial impairment. Understandings of the nature and causes of such impairment is limited by the lack of research exploring the extent to which subjectively reported functioning should be valued as an indicator of objective dysfunction, or examining the relative influence of neurocognition, social cognition and emotion regulation on these important, but different aspects of psychosocial functioning in the context of mania and depression symptoms. This study aimed to address this paucity of research by conducting a comprehensive investigation of psychosocial functioning in a well characterised group of BD patients. Fifty-one BD patients were compared to 52 healthy controls on objectively and subjectively assessed psychosocial outcomes. Relationships between current mood symptoms, psychosocial function and neurocognitive, social cognitive and emotion regulation measures were also examined in the patient group. Patients had significantly worse scores on the global objective and subjective functioning measures relative to controls. In the patient group, although these scores were correlated, regression analyses showed that variance in each of the measures was explained by different predictors. Depressive symptomatology was the most important predictor of global subjective functioning, and neurocognition had a concurrent and important influence with depressive symptoms on objective psychosocial function. Emotion regulation also had an indirect effect on psychosocial functioning via its influence on depressive symptomatology. As this study was cross-sectional in nature, we are unable to draw precise conclusions regarding contributing pathways involved in psychosocial functioning in BD. These results suggest that patients' own evaluations of their subjective functioning represent important indicators of the extent to which their observable function is impaired. They also highlight the importance of

The domain organization of the bacterial intermediate filament-like protein crescentin is important for assembly and function

PubMed Central

Cabeen, Matthew T; Herrmann, Harald; Jacobs-Wagner, Christine

2011-01-01

Crescentin is a bacterial filament-forming protein that exhibits domain organization features found in metazoan intermediate filament (IF) proteins. Structure-function studies of eukaryotic IFs have been hindered by a lack of simple genetic systems and easily quantifiable phenotypes. Here we exploit the characteristic localization of the crescentin structure along the inner curvature of Caulobacter crescentus cells and the loss of cell curvature associated with impaired crescentin function to analyze the importance of the domain organization of crescentin. By combining biochemistry and ultrastructural analysis in vitro with cellular localization and functional studies, we show that crescentin requires its distinctive domain organization, and furthermore that different structural elements have distinct structural and functional contributions. The head domain can be functionally subdivided into two subdomains; the first (amino-terminal) is required for function but not assembly, while the second is necessary for structure assembly. The rod domain is similarly required for structure assembly, and the linker L1 appears important to prevent runaway assembly into nonfunctional aggregates. The data also suggest that the stutter and the tail domain have critical functional roles in stabilizing crescentin structures against disassembly by monovalent cations in the cytoplasm. This study suggests that the IF-like behavior of crescentin is a consequence of its domain organization, implying that the IF protein layout is an adaptable cytoskeletal motif, much like the actin and tubulin folds, that is broadly exploited for various functions throughout life from bacteria to humans. © 2011 Wiley-Liss, Inc. PMID:21360832

A large shRNA library approach identifies lncRNA Ntep as an essential regulator of cell proliferation

PubMed Central

Beermann, Julia; Kirste, Dominique; Iwanov, Katharina; Lu, Dongchao; Kleemiß, Felix; Kumarswamy, Regalla; Schimmel, Katharina; Bär, Christian; Thum, Thomas

2018-01-01

The mammalian cell cycle is a complex and tightly controlled event. Myriads of different control mechanisms are involved in its regulation. Long non-coding RNAs (lncRNA) have emerged as important regulators of many cellular processes including cellular proliferation. However, a more global and unbiased approach to identify lncRNAs with importance for cell proliferation is missing. Here, we present a lentiviral shRNA library-based approach for functional lncRNA profiling. We validated our library approach in NIH3T3 (3T3) fibroblasts by identifying lncRNAs critically involved in cell proliferation. Using stringent selection criteria we identified lncRNA NR_015491.1 out of 3842 different RNA targets represented in our library. We termed this transcript Ntep (non-coding transcript essential for proliferation), as a bona fide lncRNA essential for cell cycle progression. Inhibition of Ntep in 3T3 and primary fibroblasts prevented normal cell growth and expression of key fibroblast markers. Mechanistically, we discovered that Ntep is important to activate P53 concomitant with increased apoptosis and cell cycle blockade in late G2/M. Our findings suggest Ntep to serve as an important regulator of fibroblast proliferation and function. In summary, our study demonstrates the applicability of an innovative shRNA library approach to identify long non-coding RNA functions in a massive parallel approach. PMID:29099486

The quality of clinical maternal and neonatal healthcare - a strategy for identifying 'routine care signal functions'.

PubMed

Brenner, Stephan; De Allegri, Manuela; Gabrysch, Sabine; Chinkhumba, Jobiba; Sarker, Malabika; Muula, Adamson S

2015-01-01

A variety of clinical process indicators exists to measure the quality of care provided by maternal and neonatal health (MNH) programs. To allow comparison across MNH programs in low- and middle-income countries (LMICs), a core set of essential process indicators is needed. Although such a core set is available for emergency obstetric care (EmOC), the 'EmOC signal functions', a similar approach is currently missing for MNH routine care evaluation. We describe a strategy for identifying core process indicators for routine care and illustrate their usefulness in a field example. We first developed an indicator selection strategy by combining epidemiological and programmatic aspects relevant to MNH in LMICs. We then identified routine care process indicators meeting our selection criteria by reviewing existing quality of care assessment protocols. We grouped these indicators into three categories based on their main function in addressing risk factors of maternal or neonatal complications. We then tested this indicator set in a study assessing MNH quality of clinical care in 33 health facilities in Malawi. Our strategy identified 51 routine care processes: 23 related to initial patient risk assessment, 17 to risk monitoring, 11 to risk prevention. During the clinical performance assessment a total of 82 cases were observed. Birth attendants' adherence to clinical standards was lowest in relation to risk monitoring processes. In relation to major complications, routine care processes addressing fetal and newborn distress were performed relatively consistently, but there were major gaps in the performance of routine care processes addressing bleeding, infection, and pre-eclampsia risks. The identified set of process indicators could identify major gaps in the quality of obstetric and neonatal care provided during the intra- and immediate postpartum period. We hope our suggested indicators for essential routine care processes will contribute to streamlining MNH program

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boisvert, Annie; Jones, Steven; Issop, Leeyah

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 targetmore » 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. - Highlights: • Phthalate plasticizers exert toxic effects on male

Dynamic Biological Functioning Important for Simulating and Stabilizing Ocean Biogeochemistry

NASA Astrophysics Data System (ADS)

Buchanan, P. J.; Matear, R. J.; Chase, Z.; Phipps, S. J.; Bindoff, N. L.

2018-04-01

The biogeochemistry of the ocean exerts a strong influence on the climate by modulating atmospheric greenhouse gases. In turn, ocean biogeochemistry depends on numerous physical and biological processes that change over space and time. Accurately simulating these processes is fundamental for accurately simulating the ocean's role within the climate. However, our simulation of these processes is often simplistic, despite a growing understanding of underlying biological dynamics. Here we explore how new parameterizations of biological processes affect simulated biogeochemical properties in a global ocean model. We combine 6 different physical realizations with 6 different biogeochemical parameterizations (36 unique ocean states). The biogeochemical parameterizations, all previously published, aim to more accurately represent the response of ocean biology to changing physical conditions. We make three major findings. First, oxygen, carbon, alkalinity, and phosphate fields are more sensitive to changes in the ocean's physical state. Only nitrate is more sensitive to changes in biological processes, and we suggest that assessment protocols for ocean biogeochemical models formally include the marine nitrogen cycle to assess their performance. Second, we show that dynamic variations in the production, remineralization, and stoichiometry of organic matter in response to changing environmental conditions benefit the simulation of ocean biogeochemistry. Third, dynamic biological functioning reduces the sensitivity of biogeochemical properties to physical change. Carbon and nitrogen inventories were 50% and 20% less sensitive to physical changes, respectively, in simulations that incorporated dynamic biological functioning. These results highlight the importance of a dynamic biology for ocean properties and climate.

Gross motor function is an important predictor of daily physical activity in young people with bilateral spastic cerebral palsy.

PubMed

Bania, Theofani A; Taylor, Nicholas F; Baker, Richard J; Graham, H Kerr; Karimi, Leila; Dodd, Karen J

2014-12-01

The aim of the study was to describe daily physical activity levels of adolescents and young adults with bilateral spastic cerebral palsy (CP) and to identify factors that help predict these levels. Daily physical activity was measured using an accelerometer-based activity monitor in 45 young people with bilateral spastic CP (23 males, 22 females; mean age 18y 6mo [SD 2y 5mo] range 16y 1mo-20y 11mo); classified as Gross Motor Function Classification System (GMFCS) level II or III and with contractures of <20° at hip and knee. Predictor variables included demographic characteristics (age, sex, weight) and physical characteristics (gross motor function, lower limb muscle strength, 6min walk distance). Data were analyzed using the information-theoretic approach, using the Akaike information criterion (AIC) and linear regression. Daily activity levels were low compared with published norms. Gross Motor Function Measure Dimension-E (GMFM-E; walking, running, and jumping) was the only common predictor variable in models that best predicted energy expenditure, number of steps, and time spent sitting/lying. GMFM Dimension-D (standing) and bilateral reverse leg press strength contributed to the models that predicted daily physical activity. Adolescents and young adults with bilateral spastic CP and mild to moderate walking disabilities have low levels of daily activity. The GMFM-E was an important predictor of daily physical activity. © 2014 Mac Keith Press.

A Statistical Method of Identifying Interactions in Neuron–Glia Systems Based on Functional Multicell Ca2+ Imaging

PubMed Central

Nakae, Ken; Ikegaya, Yuji; Ishikawa, Tomoe; Oba, Shigeyuki; Urakubo, Hidetoshi; Koyama, Masanori; Ishii, Shin

2014-01-01

Crosstalk between neurons and glia may constitute a significant part of information processing in the brain. We present a novel method of statistically identifying interactions in a neuron–glia network. We attempted to identify neuron–glia interactions from neuronal and glial activities via maximum-a-posteriori (MAP)-based parameter estimation by developing a generalized linear model (GLM) of a neuron–glia network. The interactions in our interest included functional connectivity and response functions. We evaluated the cross-validated likelihood of GLMs that resulted from the addition or removal of connections to confirm the existence of specific neuron-to-glia or glia-to-neuron connections. We only accepted addition or removal when the modification improved the cross-validated likelihood. We applied the method to a high-throughput, multicellular in vitro Ca2+ imaging dataset obtained from the CA3 region of a rat hippocampus, and then evaluated the reliability of connectivity estimates using a statistical test based on a surrogate method. Our findings based on the estimated connectivity were in good agreement with currently available physiological knowledge, suggesting our method can elucidate undiscovered functions of neuron–glia systems. PMID:25393874

MADGiC: a model-based approach for identifying driver genes in cancer

PubMed Central

Korthauer, Keegan D.; Kendziorski, Christina

2015-01-01

Motivation: Identifying and prioritizing somatic mutations is an important and challenging area of cancer research that can provide new insights into gene function as well as new targets for drug development. Most methods for prioritizing mutations rely primarily on frequency-based criteria, where a gene is identified as having a driver mutation if it is altered in significantly more samples than expected according to a background model. Although useful, frequency-based methods are limited in that all mutations are treated equally. It is well known, however, that some mutations have no functional consequence, while others may have a major deleterious impact. The spatial pattern of mutations within a gene provides further insight into their functional consequence. Properly accounting for these factors improves both the power and accuracy of inference. Also important is an accurate background model. Results: Here, we develop a Model-based Approach for identifying Driver Genes in Cancer (termed MADGiC) that incorporates both frequency and functional impact criteria and accommodates a number of factors to improve the background model. Simulation studies demonstrate advantages of the approach, including a substantial increase in power over competing methods. Further advantages are illustrated in an analysis of ovarian and lung cancer data from The Cancer Genome Atlas (TCGA) project. Availability and implementation: R code to implement this method is available at http://www.biostat.wisc.edu/ kendzior/MADGiC/. Contact: kendzior@biostat.wisc.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25573922

Hydrogen exchange differences between chemoreceptor signaling complexes localize to functionally important subdomains.

PubMed

Koshy, Seena S; Li, Xuni; Eyles, Stephen J; Weis, Robert M; Thompson, Lynmarie K

2014-12-16

The goal of understanding mechanisms of transmembrane signaling, one of many key life processes mediated by membrane proteins, has motivated numerous studies of bacterial chemotaxis receptors. Ligand binding to the receptor causes a piston motion of an α helix in the periplasmic and transmembrane domains, but it is unclear how the signal is then propagated through the cytoplasmic domain to control the activity of the associated kinase CheA. Recent proposals suggest that signaling in the cytoplasmic domain involves opposing changes in dynamics in different subdomains. However, it has been difficult to measure dynamics within the functional system, consisting of extended arrays of receptor complexes with two other proteins, CheA and CheW. We have combined hydrogen exchange mass spectrometry with vesicle template assembly of functional complexes of the receptor cytoplasmic domain to reveal that there are significant signaling-associated changes in exchange, and these changes localize to key regions of the receptor involved in the excitation and adaptation responses. The methylation subdomain exhibits complex changes that include slower hydrogen exchange in complexes in a kinase-activating state, which may be partially consistent with proposals that this subdomain is stabilized in this state. The signaling subdomain exhibits significant protection from hydrogen exchange in complexes in a kinase-activating state, suggesting a tighter and/or larger interaction interface with CheA and CheW in this state. These first measurements of the stability of protein subdomains within functional signaling complexes demonstrate the promise of this approach for measuring functionally important protein dynamics within the various physiologically relevant states of multiprotein complexes.

Hydrogen Exchange Differences between Chemoreceptor Signaling Complexes Localize to Functionally Important Subdomains

PubMed Central

2015-01-01

The goal of understanding mechanisms of transmembrane signaling, one of many key life processes mediated by membrane proteins, has motivated numerous studies of bacterial chemotaxis receptors. Ligand binding to the receptor causes a piston motion of an α helix in the periplasmic and transmembrane domains, but it is unclear how the signal is then propagated through the cytoplasmic domain to control the activity of the associated kinase CheA. Recent proposals suggest that signaling in the cytoplasmic domain involves opposing changes in dynamics in different subdomains. However, it has been difficult to measure dynamics within the functional system, consisting of extended arrays of receptor complexes with two other proteins, CheA and CheW. We have combined hydrogen exchange mass spectrometry with vesicle template assembly of functional complexes of the receptor cytoplasmic domain to reveal that there are significant signaling-associated changes in exchange, and these changes localize to key regions of the receptor involved in the excitation and adaptation responses. The methylation subdomain exhibits complex changes that include slower hydrogen exchange in complexes in a kinase-activating state, which may be partially consistent with proposals that this subdomain is stabilized in this state. The signaling subdomain exhibits significant protection from hydrogen exchange in complexes in a kinase-activating state, suggesting a tighter and/or larger interaction interface with CheA and CheW in this state. These first measurements of the stability of protein subdomains within functional signaling complexes demonstrate the promise of this approach for measuring functionally important protein dynamics within the various physiologically relevant states of multiprotein complexes. PMID:25420045

Triangulating Principal Effectiveness: How Perspectives of Parents, Teachers, and Assistant Principals Identify the Central Importance of Managerial Skills. Working Paper 35

ERIC Educational Resources Information Center

Grissom, Jason A.; Loeb, Susanna

2009-01-01

While the importance of effective principals is undisputed, few studies have addressed what specific skills principals need to promote school success. This study draws on unique data combining survey responses from principals, assistant principals, teachers and parents with rich administrative data to identify which principal skills matter most…

Salmonella Persistence in Tomatoes Requires a Distinct Set of Metabolic Functions Identified by Transposon Insertion Sequencing.

PubMed

de Moraes, Marcos H; Desai, Prerak; Porwollik, Steffen; Canals, Rocio; Perez, Daniel R; Chu, Weiping; McClelland, Michael; Teplitski, Max

2017-03-01

Human enteric pathogens, such as Salmonella spp. and verotoxigenic Escherichia coli , are increasingly recognized as causes of gastroenteritis outbreaks associated with the consumption of fruits and vegetables. Persistence in plants represents an important part of the life cycle of these pathogens. The identification of the full complement of Salmonella genes involved in the colonization of the model plant (tomato) was carried out using transposon insertion sequencing analysis. With this approach, 230,000 transposon insertions were screened in tomato pericarps to identify loci with reduction in fitness, followed by validation of the screen results using competition assays of the isogenic mutants against the wild type. A comparison with studies in animals revealed a distinct plant-associated set of genes, which only partially overlaps with the genes required to elicit disease in animals. De novo biosynthesis of amino acids was critical to persistence within tomatoes, while amino acid scavenging was prevalent in animal infections. Fitness reduction of the Salmonella amino acid synthesis mutants was generally more severe in the tomato rin mutant, which hyperaccumulates certain amino acids, suggesting that these nutrients remain unavailable to Salmonella spp. within plants. Salmonella lipopolysaccharide (LPS) was required for persistence in both animals and plants, exemplifying some shared pathogenesis-related mechanisms in animal and plant hosts. Similarly to phytopathogens, Salmonella spp. required biosynthesis of amino acids, LPS, and nucleotides to colonize tomatoes. Overall, however, it appears that while Salmonella shares some strategies with phytopathogens and taps into its animal virulence-related functions, colonization of tomatoes represents a distinct strategy, highlighting this pathogen's flexible metabolism. IMPORTANCE Outbreaks of gastroenteritis caused by human pathogens have been increasingly associated with foods of plant origin, with tomatoes being

Salmonella Persistence in Tomatoes Requires a Distinct Set of Metabolic Functions Identified by Transposon Insertion Sequencing

PubMed Central

Desai, Prerak; Porwollik, Steffen; Canals, Rocio; Perez, Daniel R.; Chu, Weiping; McClelland, Michael; Teplitski, Max

2016-01-01

ABSTRACT Human enteric pathogens, such as Salmonella spp. and verotoxigenic Escherichia coli, are increasingly recognized as causes of gastroenteritis outbreaks associated with the consumption of fruits and vegetables. Persistence in plants represents an important part of the life cycle of these pathogens. The identification of the full complement of Salmonella genes involved in the colonization of the model plant (tomato) was carried out using transposon insertion sequencing analysis. With this approach, 230,000 transposon insertions were screened in tomato pericarps to identify loci with reduction in fitness, followed by validation of the screen results using competition assays of the isogenic mutants against the wild type. A comparison with studies in animals revealed a distinct plant-associated set of genes, which only partially overlaps with the genes required to elicit disease in animals. De novo biosynthesis of amino acids was critical to persistence within tomatoes, while amino acid scavenging was prevalent in animal infections. Fitness reduction of the Salmonella amino acid synthesis mutants was generally more severe in the tomato rin mutant, which hyperaccumulates certain amino acids, suggesting that these nutrients remain unavailable to Salmonella spp. within plants. Salmonella lipopolysaccharide (LPS) was required for persistence in both animals and plants, exemplifying some shared pathogenesis-related mechanisms in animal and plant hosts. Similarly to phytopathogens, Salmonella spp. required biosynthesis of amino acids, LPS, and nucleotides to colonize tomatoes. Overall, however, it appears that while Salmonella shares some strategies with phytopathogens and taps into its animal virulence-related functions, colonization of tomatoes represents a distinct strategy, highlighting this pathogen's flexible metabolism. IMPORTANCE Outbreaks of gastroenteritis caused by human pathogens have been increasingly associated with foods of plant origin, with tomatoes

HsTRPA of the Red Imported Fire Ant, Solenopsis invicta, Functions as a Nocisensor and Uncovers the Evolutionary Plasticity of HsTRPA Channels

PubMed Central

Wang, Xinyue; Li, Tianbang; Tominaga, Makoto

2018-01-01

Solenopsis invicta, the red imported fire ant, represents one of the most devastating invasive species. To understand their sensory physiology, we identified and characterized their Hymenoptera-specific (Hs) TRPA channel, SiHsTRPA. Consistent with the sensory functions of SiHsTRPA, it is activated by heat, an electrophile, and an insect repellent. Nevertheless, SiHsTRPA does not respond to most of the honey bee ortholog (AmHsTRPA)-activating compounds. The jewel wasp ortholog (NvHsTRPA) is activated by these compounds even though it outgroups both AmHsTRPA and SiHsTRPA. Characterization of AmHsTRPA/SiHsTRPA chimeric channels revealed that the amino acids in the N terminus, as well as ankyrin repeat 2 (AR2) of AmHsTRPA, are essential for the response to camphor. Furthermore, amino acids in ARs 3 and 5–7 were specifically required for the response to diallyl disulfide. Thus, amino acid substitutions in the corresponding domains of SiHsTRPA during evolution would be responsible for the loss of chemical sensitivity. SiHsTRPA-activating compounds repel red imported fire ants, suggesting that SiHsTRPA functions as a sensor for noxious compounds. SiHsTRPA represents an example of the species-specific modulation of orthologous TRPA channel properties by amino acid substitutions in multiple domains, and SiHsTRPA-activating compounds could be used to develop a method for controlling red imported fire ants. PMID:29445768

Age at Immigration and Kidney Function among Self-Identified Healthy Africans in the United States.

PubMed

Ali, Mana; Mwendwa, Denée T; Sims, Regina; Ricks, Madia; Sumner, Anne E

2016-02-01

Kidney disease disparately affects those of African descent. Age trends have generally been established for kidney function in the overall US population, but the contribution of age at the time of immigration for African immigrants is unknown. To examine the independent and joint effects of age and age at the time of immigration, and kidney function. Estimated glomerular filtration rate (eGFR) was calculated for 93 African immigrants (60 % male; mean age = 33.5). Hierarchical regression and post hoc analyses revealed a significant age × age at the time of immigration interaction after accounting for traditional risk factors among those who immigrated at age ≤21. Younger age at the time of immigration to the US may exacerbate an inverse relationship between age and kidney function in a self-identified healthy African immigrant sample. Investigation of biopsychosocial factors associated with kidney health among African immigrants is warranted.

Identifying classes of persons with mild intellectual disability or borderline intellectual functioning: a latent class analysis.

PubMed

Nouwens, Peter J G; Lucas, Rosanne; Smulders, Nienke B M; Embregts, Petri J C M; van Nieuwenhuizen, Chijs

2017-07-17

Persons with mild intellectual disability or borderline intellectual functioning are often studied as a single group with similar characteristics. However, there are indications that differences exist within this population. Therefore, the aim of this study was to identify classes of persons with mild intellectual disability or borderline intellectual functioning and to examine whether these classes are related to individual and/or environmental characteristics. Latent class analysis was performed using file data of 250 eligible participants with a mean age of 26.1 (SD 13.8, range 3-70) years. Five distinct classes of persons with mild intellectual disability or borderline intellectual functioning were found. These classes significantly differed in individual and environmental characteristics. For example, persons with a mild intellectual disability experienced fewer problems than those with borderline intellectual disability. The identification of five classes implies that a differentiated approach is required towards persons with mild intellectual disability or borderline intellectual functioning.

The Importance of Residual Kidney Function in Haemodialysis Patients.

PubMed

Kong, Jessica; Davies, Matthew; Mount, Peter

2018-06-19

In contrast to peritoneal dialysis, residual kidney function is commonly disregarded for haemodialysis patients, and not regularly monitored or taken into account in routine clinical care. This is despite evidence that higher levels of residual kidney function in haemodialysis patients associate with better outcomes including survival, total solute clearance, nutrition, inflammation, and fluid balance. This review aims to summarise the clinical effects of residual kidney function specifically in haemodialysis patients. Some level of residual kidney function is present in over 80% of patients at the time of dialysis initiation, and while this declines over time, up to 30% of patients on haemodialysis for 5 years still have a measurable level of native kidney function. There is little evidence on how best to preserve residual kidney function in haemodialysis patients, although it has been observed that intensive haemodialysis regimens in incident haemodialysis patients appear to accelerate residual kidney function decline. Residual kidney function is not commonly factored in to haemodialysis prescription and measures of adequacy, despite the fact that some guidelines such as KDOQI and European Best Practice Guidelines suggest that it is reasonable to do. This likely relates, at least in part, to perceived concerns regarding the inconvenience of timed urine collections, and to the complexity and lack of consensus regarding the methods for integrating the intermittent clearance of haemodialysis with the continuous clearance of native renal function. Further research is required into how best to maintain and maximise the benefits of residual kidney function in haemodialysis patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Identifying functional thermodynamics in autonomous Maxwellian ratchets

NASA Astrophysics Data System (ADS)

Boyd, Alexander B.; Mandal, Dibyendu; Crutchfield, James P.

2016-02-01

We introduce a family of Maxwellian Demons for which correlations among information bearing degrees of freedom can be calculated exactly and in compact analytical form. This allows one to precisely determine Demon functional thermodynamic operating regimes, when previous methods either misclassify or simply fail due to approximations they invoke. This reveals that these Demons are more functional than previous candidates. They too behave either as engines, lifting a mass against gravity by extracting energy from a single heat reservoir, or as Landauer erasers, consuming external work to remove information from a sequence of binary symbols by decreasing their individual uncertainty. Going beyond these, our Demon exhibits a new functionality that erases bits not by simply decreasing individual-symbol uncertainty, but by increasing inter-bit correlations (that is, by adding temporal order) while increasing single-symbol uncertainty. In all cases, but especially in the new erasure regime, exactly accounting for informational correlations leads to tight bounds on Demon performance, expressed as a refined Second Law of thermodynamics that relies on the Kolmogorov-Sinai entropy for dynamical processes and not on changes purely in system configurational entropy, as previously employed. We rigorously derive the refined Second Law under minimal assumptions and so it applies quite broadly—for Demons with and without memory and input sequences that are correlated or not. We note that general Maxwellian Demons readily violate previously proposed, alternative such bounds, while the current bound still holds. As such, it broadly describes the minimal energetic cost of any computation by a thermodynamic system.

Linking social anxiety and adolescent romantic relationship functioning: indirect effects and the importance of peers.

PubMed

Hebert, Karen R; Fales, Jessica; Nangle, Douglas W; Papadakis, Alison A; Grover, Rachel L

2013-11-01

Peer relationships undergo dramatic shifts in form and function during adolescence, at the same time the incidence of socially evaluative fears sharply rises. Despite well-established links between social anxiety and broader interpersonal functioning, there is a dearth of research evaluating the impact of social anxiety on functioning in close relationships during this developmental stage. The present study examines the impact of social anxiety on functioning in close friendships and romantic relationships during adolescence. From a developmental psychopathology perspective, it was expected that social anxiety would influence functioning (quality, length, satisfaction) in romantic relationships through its influence on functioning in same- and other-sex friendships. Participants included 314 adolescents (60.5% female, 14-19 years of age) with a prior or current history of romantic relationship involvement. Structural equation modeling was used to test a mediation model positing an indirect pathway from social anxiety to romantic relationship functioning through functioning in close same- and other-sex friendships. Given known gender differences in social anxiety and relationship functioning, gender also was explored as a potential moderator. Results supported the hypothesized indirect pathway whereby social anxiety was associated with impairment in same-sex friendships; functioning in same-sex friendships was associated with functioning in other-sex friendships, which was associated, in turn, with functioning in romantic relationships. While the hypothesized indirect pathway was significant among both boys and girls, there was greater continuity of functioning between same- and other-sex friendships for girls. These findings highlight the importance of examining the multiple downstream effects of social anxiety on perceived social functioning in adolescence, and suggest that continuity may exist for maladaptive patterns of socialization, particularly across

Identifying the Functional Requirements for an Arizona Astronomy Data Hub (AADH)

NASA Astrophysics Data System (ADS)

Stahlman, G.; Heidorn, P. B.

2015-12-01

Astronomy data represent a curation challenge for information managers, as well as for astronomers. Extracting knowledge from these heterogeneous and complex datasets is particularly complicated and requires both interdisciplinary and domain expertise to accomplish true curation, with an overall goal of facilitating reproducible science through discoverability and persistence. A group of researchers and professional staff at the University of Arizona held several meetings during the spring of 2015 about astronomy data and the role of the university in curation of that data. The group decided that it was critical to obtain a broader consensus on the needs of the community. With assistance from a Start for Success grant provided by the University of Arizona Office of Research and Discovery and funding from the American Astronomical Society (AAS), a workshop was held in early July 2015, with 28 participants plus 4 organizers in attendance. Representing University researchers as well as astronomical facilities and a scholarly society, the group verified that indeed there is a problem with the long-term curation of some astronomical data not associated with major facilities, and that a repository or "data hub" with the correct functionality could facilitate research and the preservation and use of astronomy data. The workshop members also identified a set of next steps, including the identification of possible data and metadata to be included in the Hub. The participants further helped to identify additional information that must be gathered before construction of the AADH could begin, including identifying significant datasets that do not currently have sufficient preservation and dissemination infrastructure, as well as some data associated with journal publications and the broader context of the data beyond that directly published in the journals. Workshop participants recommended that a set of grant proposal should be developed that ensures community buy-in and

Identifying organic aerosol sources by comparing functional group composition in chamber and atmospheric particles

PubMed Central

Russell, Lynn M.; Bahadur, Ranjit; Ziemann, Paul J.

2011-01-01

Measurements of submicron particles by Fourier transform infrared spectroscopy in 14 campaigns in North America, Asia, South America, and Europe were used to identify characteristic organic functional group compositions of fuel combustion, terrestrial vegetation, and ocean bubble bursting sources, each of which often accounts for more than a third of organic mass (OM), and some of which is secondary organic aerosol (SOA) from gas-phase precursors. The majority of the OM consists of alkane, carboxylic acid, hydroxyl, and carbonyl groups. The organic functional groups formed from combustion and vegetation emissions are similar to the secondary products identified in chamber studies. The near absence of carbonyl groups in the observed SOA associated with combustion is consistent with alkane rather than aromatic precursors, and the absence of organonitrate groups can be explained by their hydrolysis in humid ambient conditions. The remote forest observations have ratios of carboxylic acid, organic hydroxyl, and nonacid carbonyl groups similar to those observed for isoprene and monoterpene chamber studies, but in biogenic aerosols transported downwind of urban areas the formation of esters replaces the acid and hydroxyl groups and leaves only nonacid carbonyl groups. The carbonyl groups in SOA associated with vegetation emissions provides striking evidence for the mechanism of esterification as the pathway for possible oligomerization reactions in the atmosphere. Forest fires include biogenic emissions that produce SOA with organic components similar to isoprene and monoterpene chamber studies, also resulting in nonacid carbonyl groups in SOA. PMID:21317360

Functional binding interaction identified between the axonal CAM L1 and members of the ERM family

PubMed Central

Dickson, Tracey C.; Mintz, C. David; Benson, Deanna L.; Salton, Stephen R.J.

2002-01-01

Ayeast two-hybrid library was screened using the cytoplasmic domain of the axonal cell adhesion molecule L1 to identify binding partners that may be involved in the regulation of L1 function. The intracellular domain of L1 bound to ezrin, a member of the ezrin, radixin, and moesin (ERM) family of membrane–cytoskeleton linking proteins, at a site overlapping that for AP2, a clathrin adaptor. Binding of bacterial fusion proteins confirmed this interaction. To determine whether ERM proteins interact with L1 in vivo, extracellular antibodies to L1 were used to force cluster the protein on cultured hippocampal neurons and PC12 cells, which were then immunolabeled for ERM proteins. Confocal analysis revealed a precise pattern of codistribution between ERMs and L1 clusters in axons and PC12 neurites, whereas ERMs in dendrites and spectrin labeling remained evenly distributed. Transfection of hippocampal neurons grown on an L1 substrate with a dominant negative ERM construct resulted in extensive and abnormal elaboration of membrane protrusions and an increase in axon branching, highlighting the importance of the ERM–actin interaction in axon development. Together, our data indicate that L1 binds directly to members of the ERM family and suggest this association may coordinate aspects of axonal morphogenesis. PMID:12070130

Functional binding interaction identified between the axonal CAM L1 and members of the ERM family.

PubMed

Dickson, Tracey C; Mintz, C David; Benson, Deanna L; Salton, Stephen R J

2002-06-24

A yeast two-hybrid library was screened using the cytoplasmic domain of the axonal cell adhesion molecule L1 to identify binding partners that may be involved in the regulation of L1 function. The intracellular domain of L1 bound to ezrin, a member of the ezrin, radixin, and moesin (ERM) family of membrane-cytoskeleton linking proteins, at a site overlapping that for AP2, a clathrin adaptor. Binding of bacterial fusion proteins confirmed this interaction. To determine whether ERM proteins interact with L1 in vivo, extracellular antibodies to L1 were used to force cluster the protein on cultured hippocampal neurons and PC12 cells, which were then immunolabeled for ERM proteins. Confocal analysis revealed a precise pattern of codistribution between ERMs and L1 clusters in axons and PC12 neurites, whereas ERMs in dendrites and spectrin labeling remained evenly distributed. Transfection of hippocampal neurons grown on an L1 substrate with a dominant negative ERM construct resulted in extensive and abnormal elaboration of membrane protrusions and an increase in axon branching, highlighting the importance of the ERM-actin interaction in axon development. Together, our data indicate that L1 binds directly to members of the ERM family and suggest this association may coordinate aspects of axonal morphogenesis.

A P-Norm Robust Feature Extraction Method for Identifying Differentially Expressed Genes

PubMed Central

Liu, Jian; Liu, Jin-Xing; Gao, Ying-Lian; Kong, Xiang-Zhen; Wang, Xue-Song; Wang, Dong

2015-01-01

In current molecular biology, it becomes more and more important to identify differentially expressed genes closely correlated with a key biological process from gene expression data. In this paper, based on the Schatten p-norm and Lp-norm, a novel p-norm robust feature extraction method is proposed to identify the differentially expressed genes. In our method, the Schatten p-norm is used as the regularization function to obtain a low-rank matrix and the Lp-norm is taken as the error function to improve the robustness to outliers in the gene expression data. The results on simulation data show that our method can obtain higher identification accuracies than the competitive methods. Numerous experiments on real gene expression data sets demonstrate that our method can identify more differentially expressed genes than the others. Moreover, we confirmed that the identified genes are closely correlated with the corresponding gene expression data. PMID:26201006

A P-Norm Robust Feature Extraction Method for Identifying Differentially Expressed Genes.

PubMed

Liu, Jian; Liu, Jin-Xing; Gao, Ying-Lian; Kong, Xiang-Zhen; Wang, Xue-Song; Wang, Dong

2015-01-01

In current molecular biology, it becomes more and more important to identify differentially expressed genes closely correlated with a key biological process from gene expression data. In this paper, based on the Schatten p-norm and Lp-norm, a novel p-norm robust feature extraction method is proposed to identify the differentially expressed genes. In our method, the Schatten p-norm is used as the regularization function to obtain a low-rank matrix and the Lp-norm is taken as the error function to improve the robustness to outliers in the gene expression data. The results on simulation data show that our method can obtain higher identification accuracies than the competitive methods. Numerous experiments on real gene expression data sets demonstrate that our method can identify more differentially expressed genes than the others. Moreover, we confirmed that the identified genes are closely correlated with the corresponding gene expression data.

Eukaryotic genes of archaebacterial origin are more important than the more numerous eubacterial genes, irrespective of function.

PubMed

Cotton, James A; McInerney, James O

2010-10-05

The traditional tree of life shows eukaryotes as a distinct lineage of living things, but many studies have suggested that the first eukaryotic cells were chimeric, descended from both Eubacteria (through the mitochondrion) and Archaebacteria. Eukaryote nuclei thus contain genes of both eubacterial and archaebacterial origins, and these genes have different functions within eukaryotic cells. Here we report that archaebacterium-derived genes are significantly more likely to be essential to yeast viability, are more highly expressed, and are significantly more highly connected and more central in the yeast protein interaction network. These findings hold irrespective of whether the genes have an informational or operational function, so that many features of eukaryotic genes with prokaryotic homologs can be explained by their origin, rather than their function. Taken together, our results show that genes of archaebacterial origin are in some senses more important to yeast metabolism than genes of eubacterial origin. This importance reflects these genes' origin as the ancestral nuclear component of the eukaryotic genome.

Functional resilience of microbial ecosystems in soil: How important is a spatial analysis?

NASA Astrophysics Data System (ADS)

König, Sara; Banitz, Thomas; Centler, Florian; Frank, Karin; Thullner, Martin

2015-04-01

Microbial life in soil is exposed to fluctuating environmental conditions influencing the performance of microbially mediated ecosystem services such as biodegradation of contaminants. However, as this environment is typically very heterogeneous, spatial aspects can be expected to play a major role for the ability to recover from a stress event. To determine key processes for functional resilience, simple scenarios with varying stress intensities were simulated within a microbial simulation model and the biodegradation rate in the recovery phase monitored. Parameters including microbial growth and dispersal rates were varied over a typical range to consider microorganisms with varying properties. Besides an aggregated temporal monitoring, the explicit observation of the spatio-temporal dynamics proved essential to understand the recovery process. For a mechanistic understanding of the model system, scenarios were also simulated with selected processes being switched-off. Results of the mechanistic and the spatial view show that the key factors for functional recovery with respect to biodegradation after a simple stress event depend on the location of the observed habitats. The limiting factors near unstressed areas are spatial processes - the mobility of the bacteria as well as substrate diffusion - the longer the distance to the unstressed region the more important becomes the process growth. Furthermore, recovery depends on the stress intensity - after a low stress event the spatial configuration has no influence on the key factors for functional resilience. To confirm these results, we repeated the stress scenarios but this time including an additional dispersal network representing a fungal network in soil. The system benefits from an increased spatial performance due to the higher mobility of the degrading microorganisms. However, this effect appears only in scenarios where the spatial distribution of the stressed area plays a role. With these simulations we

Gain-of-function assays in the axolotl (Ambystoma mexicanum) to identify signaling pathways that induce and regulate limb regeneration.

PubMed

Lee, Jangwoo; Aguilar, Cristian; Gardiner, David

2013-01-01

The adult salamander has been studied as a model for regeneration of complex tissues for many decades. Only recently with the development of gain-of-function assays for regeneration, has it been possible to screen for and assay the function of the multitude of signaling factors that have been identified in studies of embryonic development and tumorigenesis. Given the conservation of function of these regulatory pathways controlling growth and pattern formation, it is now possible to use the functional assays in the salamander to test the ability of endogenous as well as small-molecule signaling factors to induce a regenerative response.

Specific membrane lipid composition is important for plasmodesmata function in Arabidopsis.

PubMed

Grison, Magali S; Brocard, Lysiane; Fouillen, Laetitia; Nicolas, William; Wewer, Vera; Dörmann, Peter; Nacir, Houda; Benitez-Alfonso, Yoselin; Claverol, Stéphane; Germain, Véronique; Boutté, Yohann; Mongrand, Sébastien; Bayer, Emmanuelle M

2015-04-01

Plasmodesmata (PD) are nano-sized membrane-lined channels controlling intercellular communication in plants. Although progress has been made in identifying PD proteins, the role played by major membrane constituents, such as the lipids, in defining specialized membrane domains in PD remains unknown. Through a rigorous isolation of "native" PD membrane fractions and comparative mass spectrometry-based analysis, we demonstrate that lipids are laterally segregated along the plasma membrane (PM) at the PD cell-to-cell junction in Arabidopsis thaliana. Remarkably, our results show that PD membranes display enrichment in sterols and sphingolipids with very long chain saturated fatty acids when compared with the bulk of the PM. Intriguingly, this lipid profile is reminiscent of detergent-insoluble membrane microdomains, although our approach is valuably detergent-free. Modulation of the overall sterol composition of young dividing cells reversibly impaired the PD localization of the glycosylphosphatidylinositol-anchored proteins Plasmodesmata Callose Binding 1 and the β-1,3-glucanase PdBG2 and altered callose-mediated PD permeability. Altogether, this study not only provides a comprehensive analysis of the lipid constituents of PD but also identifies a role for sterols in modulating cell-to-cell connectivity, possibly by establishing and maintaining the positional specificity of callose-modifying glycosylphosphatidylinositol proteins at PD. Our work emphasizes the importance of lipids in defining PD membranes. © 2015 American Society of Plant Biologists. All rights reserved.

Specific Membrane Lipid Composition Is Important for Plasmodesmata Function in Arabidopsis

PubMed Central

Grison, Magali S.; Brocard, Lysiane; Fouillen, Laetitia; Nicolas, William; Wewer, Vera; Dörmann, Peter; Nacir, Houda; Benitez-Alfonso, Yoselin; Claverol, Stéphane; Germain, Véronique; Boutté, Yohann; Mongrand, Sébastien; Bayer, Emmanuelle M.

2015-01-01

Plasmodesmata (PD) are nano-sized membrane-lined channels controlling intercellular communication in plants. Although progress has been made in identifying PD proteins, the role played by major membrane constituents, such as the lipids, in defining specialized membrane domains in PD remains unknown. Through a rigorous isolation of “native” PD membrane fractions and comparative mass spectrometry-based analysis, we demonstrate that lipids are laterally segregated along the plasma membrane (PM) at the PD cell-to-cell junction in Arabidopsis thaliana. Remarkably, our results show that PD membranes display enrichment in sterols and sphingolipids with very long chain saturated fatty acids when compared with the bulk of the PM. Intriguingly, this lipid profile is reminiscent of detergent-insoluble membrane microdomains, although our approach is valuably detergent-free. Modulation of the overall sterol composition of young dividing cells reversibly impaired the PD localization of the glycosylphosphatidylinositol-anchored proteins Plasmodesmata Callose Binding 1 and the β-1,3-glucanase PdBG2 and altered callose-mediated PD permeability. Altogether, this study not only provides a comprehensive analysis of the lipid constituents of PD but also identifies a role for sterols in modulating cell-to-cell connectivity, possibly by establishing and maintaining the positional specificity of callose-modifying glycosylphosphatidylinositol proteins at PD. Our work emphasizes the importance of lipids in defining PD membranes. PMID:25818623

Optimizing health system response to patient's needs: an argument for the importance of functioning information.

PubMed

Hopfe, Maren; Prodinger, Birgit; Bickenbach, Jerome E; Stucki, Gerold

2017-06-06

Current health systems are increasingly challenged to meet the needs of a growing number of patients living with chronic and often multiple health conditions. The primary outcome of care, it is argued, is not merely curing disease but also optimizing functioning over a person's life span. According to the World Health Organization, functioning can serve as foundation for a comprehensive picture of health and augment the biomedical perspective with a broader and more comprehensive picture of health as it plays out in people's lives. The crucial importance of information about patient's functioning for a well-performing health system, however, has yet to be sufficiently appreciated. This paper argues that functioning information is fundamental in all components of health systems and enhances the capacity of health systems to optimize patients' health and health-related needs. Beyond making sense of biomedical disease patterns, health systems can profit from using functioning information to improve interprofessional collaboration and achieve cross-cutting disease treatment outcomes. Implications for rehabilitation Functioning is a key health outcome for rehabilitation within health systems. Information on restoring, maintaining, and optimizing human functioning can strengthen health system response to patients' health and rehabilitative needs. Functioning information guides health systems to achieve cross-cutting health outcomes that respond to the needs of the growing number of individuals living with chronic and multiple health conditions. Accounting for individuals functioning helps to overcome fragmentation of care and to improve interprofessional collaboration across settings.

Protruding vulva mutants identify novel loci and Wnt signaling factors that function during Caenorhabditis elegans vulva development.

PubMed

Eisenmann, D M; Kim, S K

2000-11-01

The Caenorhabditis elegans vulva develops from the progeny of three vulval precursor cells (VPCs) induced to divide and differentiate by a signal from the somatic gonad. Evolutionarily conserved Ras and Notch extracellular signaling pathways are known to function during this process. To identify novel loci acting in vulval development, we carried out a genetic screen for mutants having a protruding-vulva (Pvl) mutant phenotype. Here we report the initial genetic characterization of several novel loci: bar-1, pvl-4, pvl-5, and pvl-6. In addition, on the basis of their Pvl phenotypes, we show that the previously identified genes lin-26, mom-3/mig-14, egl-18, and sem-4 also function during vulval development. Our characterization indicates that (1) pvl-4 and pvl-5 are required for generation/survival of the VPCs; (2) bar-1, mom-3/mig-14, egl-18, and sem-4 play a role in VPC fate specification; (3) lin-26 is required for proper VPC fate execution; and (4) pvl-6 acts during vulval morphogenesis. In addition, two of these genes, bar-1 and mom-3/mig-14, are known to function in processes regulated by Wnt signaling, suggesting that a Wnt signaling pathway is acting during vulval development.

Gain-of-function mutations in beet DODA2 identify key residues for betalain pigment evolution.

PubMed

Bean, Alexander; Sunnadeniya, Rasika; Akhavan, Neda; Campbell, Annabelle; Brown, Matthew; Lloyd, Alan

2018-05-13

The key enzymatic step in betalain biosynthesis involves conversion of l-3,4-dihydroxyphenylalanine (l-DOPA) to betalamic acid. One class of enzymes capable of this is 3,4-dihydroxyphenylalanine 4,5-dioxygenase (DODA). In betalain-producing species, multiple paralogs of this gene are maintained. This study demonstrates which paralogs function in the betalain pathway and determines the residue changes required to evolve a betalain-nonfunctional DODA into a betalain-functional DODA. Functionalities of two pairs of DODAs were tested by expression in beets, Arabidopsis and yeast, and gene silencing was performed by virus-induced gene silencing. Site-directed mutagenesis identified amino acid residues essential for betalamic acid production. Beta vulgaris and Mirabilis jalapa both possess a DODA1 lineage that functions in the betalain pathway and at least one other lineage, DODA2, that does not. Site-directed mutagenesis resulted in betalain biosynthesis by a previously nonfunctional DODA, revealing key residues required for evolution of the betalain pathway. Divergent functionality of DODA paralogs, one clade involved in betalain biosynthesis but others not, is present in various Caryophyllales species. A minimum of seven amino acid residue changes conferred betalain enzymatic activity to a betalain-nonfunctional DODA paralog, providing insight into the evolution of the betalain pigment pathway in plants. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Cross-linking mass spectrometry and mutagenesis confirm the functional importance of surface interactions between CYP3A4 and holo/apo cytochrome b(5).

PubMed

Zhao, Chunsheng; Gao, Qiuxia; Roberts, Arthur G; Shaffer, Scott A; Doneanu, Catalin E; Xue, Song; Goodlett, David R; Nelson, Sidney D; Atkins, William M

2012-11-27

Cytochrome b(5) (cyt b(5)) is one of the key components in the microsomal cytochrome P450 monooxygenase system. Consensus has not been reached about the underlying mechanism of cyt b(5) modulation of CYP catalysis. Both cyt b(5) and apo b(5) are reported to stimulate the activity of several P450 isoforms. In this study, the surface interactions of both holo and apo b(5) with CYP3A4 were investigated and compared for the first time. Chemical cross-linking coupled with mass spectrometric analysis was used to identify the potential electrostatic interactions between the protein surfaces. Subsequently, the models of interaction of holo/apo b(5) with CYP3A4 were built using the identified interacting sites as constraints. Both cyt b(5) and apo b(5) were predicted to bind to the same groove on CYP3A4 with close contacts to the B-B' loop of CYP3A4, a substrate recognition site. Mutagenesis studies further confirmed that the interacting sites on CYP3A4 (Lys96, Lys127, and Lys421) are functionally important. Mutation of these residues reduced or abolished cyt b(5) binding affinity. The critical role of Arg446 on CYP3A4 in binding to cyt b(5) and/or cytochrome P450 reductase was also discovered. The results indicated that electrostatic interactions on the interface of the two proteins are functionally important. The results indicate that apo b(5) can dock with CYP3A4 in a manner analogous to that of holo b(5), so electron transfer from cyt b(5) is not required for its effects.

Quantitative DNA Methylation Analysis Identifies a Single CpG Dinucleotide Important for ZAP-70 Expression and Predictive of Prognosis in Chronic Lymphocytic Leukemia

PubMed Central

Claus, Rainer; Lucas, David M.; Stilgenbauer, Stephan; Ruppert, Amy S.; Yu, Lianbo; Zucknick, Manuela; Mertens, Daniel; Bühler, Andreas; Oakes, Christopher C.; Larson, Richard A.; Kay, Neil E.; Jelinek, Diane F.; Kipps, Thomas J.; Rassenti, Laura Z.; Gribben, John G.; Döhner, Hartmut; Heerema, Nyla A.; Marcucci, Guido; Plass, Christoph; Byrd, John C.

2012-01-01

Purpose Increased ZAP-70 expression predicts poor prognosis in chronic lymphocytic leukemia (CLL). Current methods for accurately measuring ZAP-70 expression are problematic, preventing widespread application of these tests in clinical decision making. We therefore used comprehensive DNA methylation profiling of the ZAP-70 regulatory region to identify sites important for transcriptional control. Patients and Methods High-resolution quantitative DNA methylation analysis of the entire ZAP-70 gene regulatory regions was conducted on 247 samples from patients with CLL from four independent clinical studies. Results Through this comprehensive analysis, we identified a small area in the 5′ regulatory region of ZAP-70 that showed large variability in methylation in CLL samples but was universally methylated in normal B cells. High correlation with mRNA and protein expression, as well as activity in promoter reporter assays, revealed that within this differentially methylated region, a single CpG dinucleotide and neighboring nucleotides are particularly important in ZAP-70 transcriptional regulation. Furthermore, by using clustering approaches, we identified a prognostic role for this site in four independent data sets of patients with CLL using time to treatment, progression-free survival, and overall survival as clinical end points. Conclusion Comprehensive quantitative DNA methylation analysis of the ZAP-70 gene in CLL identified important regions responsible for transcriptional regulation. In addition, loss of methylation at a specific single CpG dinucleotide in the ZAP-70 5′ regulatory sequence is a highly predictive and reproducible biomarker of poor prognosis in this disease. This work demonstrates the feasibility of using quantitative specific ZAP-70 methylation analysis as a relevant clinically applicable prognostic test in CLL. PMID:22564988

Can structural and functional characteristics be used to identify riparian zone width in southern Appalachian headwater catchments?

Treesearch

Barton Clinton; James Vose; Jennifer Knoepp; Katherine Elliott; Barbara Reynolds; Stanley Zarnock

2010-01-01

We characterized structural and functional attributes along hillslope gradients in headwater catchments. We endeavored to identify parameters that described significant transitions along the hillslope. On each of four catchments, we installed eight 50 m transects perpendicular to the stream. Structural attributes included woody and herbaceous vegetation; woody debris...

Functional Genomic Screen Identifies Klebsiella pneumoniae Factors Implicated in Blocking Nuclear Factor κB (NF-κB) Signaling*

PubMed Central

Tomás, Anna; Lery, Leticia; Regueiro, Verónica; Pérez-Gutiérrez, Camino; Martínez, Verónica; Moranta, David; Llobet, Enrique; González-Nicolau, Mar; Insua, Jose L.; Tomas, Juan M.; Sansonetti, Philippe J.; Tournebize, Régis; Bengoechea, José A.

2015-01-01

Klebsiella pneumoniae is an etiologic agent of community-acquired and nosocomial pneumonia. It has been shown that K. pneumoniae infections are characterized by reduced early inflammatory response. Recently our group has shown that K. pneumoniae dampens the activation of inflammatory responses by antagonizing the activation of the NF-κB canonical pathway. Our results revealed that K. pneumoniae capsule polysaccharide (CPS) was necessary but not sufficient to attenuate inflammation. To identify additional Klebsiella factors required to dampen inflammation, we standardized and applied a high-throughput gain-of-function screen to examine a Klebsiella transposon mutant library. We identified 114 mutants that triggered the activation of NF-κB. Two gene ontology categories accounted for half of the loci identified in the screening: metabolism and transport genes (32% of the mutants) and envelope-related genes (17%). Characterization of the mutants revealed that the lack of the enterobactin siderophore was linked to a reduced CPS expression, which in turn underlined the NF-κB activation induced by the mutant. The lipopolysaccharide (LPS) O-polysaccharide and the pullulanase (PulA) type 2 secretion system (T2SS) are required for full effectiveness of the immune evasion. Importantly, these factors do not play a redundant role. The fact that LPS O-polysaccharide and T2SS mutant-induced responses were dependent on TLR2-TLR4-MyD88 activation suggested that LPS O-polysaccharide and PulA perturbed Toll-like receptor (TLR)-dependent recognition of K. pneumoniae. Finally, we demonstrate that LPS O-polysaccharide and pulA mutants are attenuated in the pneumonia mouse model. We propose that LPS O-polysaccharide and PulA T2SS could be new targets for the design of new antimicrobials. Increasing TLR-governed defense responses might provide also selective alternatives for the management of K. pneumoniae pneumonia. PMID:25971969

Positive selection moments identify potential functional residues in human olfactory receptors

NASA Technical Reports Server (NTRS)

Singer, M. S.; Weisinger-Lewin, Y.; Lancet, D.; Shepherd, G. M.

1996-01-01

Correlated mutation analysis and molecular models of olfactory receptors have provided evidence that residues in the transmembrane domains form a binding pocket for odor ligands. As an independent test of these results, we have calculated positive selection moments for the alpha-helical sixth transmembrane domain (TM6) of human olfactory receptors. The moments can be used to identify residues that have been preferentially affected by positive selection and are thus likely to interact with odor ligands. The results suggest that residue 622, which is commonly a serine or threonine, could form critical H-bonds. In some receptors a dual-serine subsite, formed by residues 622 and 625, could bind hydroxyl determinants on odor ligands. The potential importance of these residues is further supported by site-directed mutagenesis in the beta-adrenergic receptor. The findings should be of practical value for future physiological studies, binding assays, and site-directed mutagenesis.

A new process sensitivity index to identify important system processes under process model and parametric uncertainty

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Heng; Ye, Ming; Walker, Anthony P.

Hydrological models are always composed of multiple components that represent processes key to intended model applications. When a process can be simulated by multiple conceptual-mathematical models (process models), model uncertainty in representing the process arises. While global sensitivity analysis methods have been widely used for identifying important processes in hydrologic modeling, the existing methods consider only parametric uncertainty but ignore the model uncertainty for process representation. To address this problem, this study develops a new method to probe multimodel process sensitivity by integrating the model averaging methods into the framework of variance-based global sensitivity analysis, given that the model averagingmore » methods quantify both parametric and model uncertainty. A new process sensitivity index is derived as a metric of relative process importance, and the index includes variance in model outputs caused by uncertainty in both process models and model parameters. For demonstration, the new index is used to evaluate the processes of recharge and geology in a synthetic study of groundwater reactive transport modeling. The recharge process is simulated by two models that converting precipitation to recharge, and the geology process is also simulated by two models of different parameterizations of hydraulic conductivity; each process model has its own random parameters. The new process sensitivity index is mathematically general, and can be applied to a wide range of problems in hydrology and beyond.« less

Identifying the Most Important 21st Century Workforce Competencies: An Analysis of the Occupational Information Network (O*NET). Research Report. ETS RR-13-21

ERIC Educational Resources Information Center

Burrus, Jeremy; Jackson, Teresa; Xi, Nuo; Steinberg, Jonathan

2013-01-01

To identify the most important competencies for college graduates to succeed in the 21st century workforce, we conducted an analysis of the Occupational Information Network (O*NET) database. O*NET is a large job analysis operated and maintained by the U.S. Department of Labor. We specifically analyzed ratings of the importance of abilities (52…

Childhood executive function inventory (CHEXI): a promising measure for identifying young children with ADHD?

PubMed

Thorell, Lisa B; Eninger, Lilianne; Brocki, Karin C; Bohlin, Gunilla

2010-01-01

The present study investigated whether the Childhood Executive Function Inventory (CHEXI) can discriminate between young children fulfilling the diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) and normally developing children. Unlike other executive function rating instruments, the CHEXI focuses specifically on inhibitory control and working memory, without including items that overlap with the diagnostic criteria of ADHD. The CHEXI was found to discriminate very well between children fulfilling the criteria for ADHD and normally developing children, also when controlling for the effect of IQ and socioeconomic status (SES). Both sensitivity and specificity of the two CHEXI subscales were shown to be high using either parent or teacher ratings. The highest overall classification rate was found for parent ratings on the inhibition subscale, with sensitivity and specificity reaching 93.3. To summarize, the CHEXI should be considered a promising measure for identifying young children with ADHD, although it is for future research to determine whether the CHEXI can be successfully used to also discriminate between different psychopathological groups.

Time-dependent importance sampling in semiclassical initial value representation calculations for time correlation functions. II. A simplified implementation.

PubMed

Tao, Guohua; Miller, William H

2012-09-28

An efficient time-dependent (TD) Monte Carlo (MC) importance sampling method has recently been developed [G. Tao and W. H. Miller, J. Chem. Phys. 135, 024104 (2011)] for the evaluation of time correlation functions using the semiclassical (SC) initial value representation (IVR) methodology. In this TD-SC-IVR method, the MC sampling uses information from both time-evolved phase points as well as their initial values, and only the "important" trajectories are sampled frequently. Even though the TD-SC-IVR was shown in some benchmark examples to be much more efficient than the traditional time-independent sampling method (which uses only initial conditions), the calculation of the SC prefactor-which is computationally expensive, especially for large systems-is still required for accepted trajectories. In the present work, we present an approximate implementation of the TD-SC-IVR method that is completely prefactor-free; it gives the time correlation function as a classical-like magnitude function multiplied by a phase function. Application of this approach to flux-flux correlation functions (which yield reaction rate constants) for the benchmark H + H(2) system shows very good agreement with exact quantum results. Limitations of the approximate approach are also discussed.

Keeping the LINC: the importance of nucleocytoskeletal coupling in intracellular force transmission and cellular function.

PubMed

Lombardi, Maria L; Lammerding, Jan

2011-12-01

Providing a stable physical connection between the nucleus and the cytoskeleton is essential for a wide range of cellular functions and it could also participate in mechanosensing by transmitting intra- and extra-cellular mechanical stimuli via the cytoskeleton to the nucleus. Nesprins and SUN proteins, located at the nuclear envelope, form the LINC (linker of nucleoskeleton and cytoskeleton) complex that connects the nucleus to the cytoskeleton; underlying nuclear lamins contribute to anchoring LINC complex components at the nuclear envelope. Disruption of the LINC complex or loss of lamins can result in disturbed perinuclear actin and intermediate filament networks and causes severe functional defects, including impaired nuclear positioning, cell polarization and cell motility. Recent studies have identified the LINC complex as the major force-transmitting element at the nuclear envelope and suggest that many of the aforementioned defects can be attributed to disturbed force transmission between the nucleus and the cytoskeleton. Thus mutations in nesprins, SUN proteins or lamins, which have been linked to muscular dystrophies and cardiomyopathies, may weaken or completely eliminate LINC complex function at the nuclear envelope and result in impaired intracellular force transmission, thereby disrupting critical cellular functions.

ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements.

PubMed

Taylor, James; Tyekucheva, Svitlana; King, David C; Hardison, Ross C; Miller, Webb; Chiaromonte, Francesca

2006-12-01

Genomic sequence signals - such as base composition, presence of particular motifs, or evolutionary constraint - have been used effectively to identify functional elements. However, approaches based only on specific signals known to correlate with function can be quite limiting. When training data are available, application of computational learning algorithms to multispecies alignments has the potential to capture broader and more informative sequence and evolutionary patterns that better characterize a class of elements. However, effective exploitation of patterns in multispecies alignments is impeded by the vast number of possible alignment columns and by a limited understanding of which particular strings of columns may characterize a given class. We have developed a computational method, called ESPERR (evolutionary and sequence pattern extraction through reduced representations), which uses training examples to learn encodings of multispecies alignments into reduced forms tailored for the prediction of chosen classes of functional elements. ESPERR produces a greatly improved Regulatory Potential score, which can discriminate regulatory regions from neutral sites with excellent accuracy ( approximately 94%). This score captures strong signals (GC content and conservation), as well as subtler signals (with small contributions from many different alignment patterns) that characterize the regulatory elements in our training set. ESPERR is also effective for predicting other classes of functional elements, as we show for DNaseI hypersensitive sites and highly conserved regions with developmental enhancer activity. Our software, training data, and genome-wide predictions are available from our Web site (http://www.bx.psu.edu/projects/esperr).

Functional requirements for the man-vehicle systems research facility. [identifying and correcting human errors during flight simulation

NASA Technical Reports Server (NTRS)

Clement, W. F.; Allen, R. W.; Heffley, R. K.; Jewell, W. F.; Jex, H. R.; Mcruer, D. T.; Schulman, T. M.; Stapleford, R. L.

1980-01-01

The NASA Ames Research Center proposed a man-vehicle systems research facility to support flight simulation studies which are needed for identifying and correcting the sources of human error associated with current and future air carrier operations. The organization of research facility is reviewed and functional requirements and related priorities for the facility are recommended based on a review of potentially critical operational scenarios. Requirements are included for the experimenter's simulation control and data acquisition functions, as well as for the visual field, motion, sound, computation, crew station, and intercommunications subsystems. The related issues of functional fidelity and level of simulation are addressed, and specific criteria for quantitative assessment of various aspects of fidelity are offered. Recommendations for facility integration, checkout, and staffing are included.

A genome-wide linkage and association study of musical aptitude identifies loci containing genes related to inner ear development and neurocognitive functions

PubMed Central

Oikkonen, J.; Huang, Y.; Onkamo, P.; Ukkola-Vuoti, L.; Raijas, P.; Karma, K.; Vieland, V. J.; Järvelä, I.

2014-01-01

Humans have developed the perception, production and processing of sounds into the art of music. A genetic contribution to these skills of musical aptitude has long been suggested. We performed a genome-wide scan in 76 pedigrees (767 individuals) characterized for the ability to discriminate pitch (SP), duration (ST) and sound patterns (KMT), which are primary capacities for music perception. Using the Bayesian linkage and association approach implemented in program package KELVIN, especially designed for complex pedigrees, several SNPs near genes affecting the functions of the auditory pathway and neurocognitive processes were identified. The strongest association was found at 3q21.3 (rs9854612) with combined SP, ST and KMT test scores (COMB). This region is located a few dozen kilobases upstream of the GATA binding protein 2 (GATA2) gene. GATA2 regulates the development of cochlear hair cells and the inferior colliculus (IC), which are important in tonotopic mapping. The highest probability of linkage was obtained for phenotype SP at 4p14, located next to the region harboring the protocadherin 7 gene, PCDH7. Two SNPs rs13146789 and rs13109270 of PCDH7 showed strong association. PCDH7 has been suggested to play a role in cochlear and amygdaloid complexes. Functional class analysis showed that inner ear and schizophrenia related genes were enriched inside the linked regions. This study is the first to show the importance of auditory pathway genes in musical aptitude. PMID:24614497

A genome-wide linkage and association study of musical aptitude identifies loci containing genes related to inner ear development and neurocognitive functions.

PubMed

Oikkonen, J; Huang, Y; Onkamo, P; Ukkola-Vuoti, L; Raijas, P; Karma, K; Vieland, V J; Järvelä, I

2015-02-01

Humans have developed the perception, production and processing of sounds into the art of music. A genetic contribution to these skills of musical aptitude has long been suggested. We performed a genome-wide scan in 76 pedigrees (767 individuals) characterized for the ability to discriminate pitch (SP), duration (ST) and sound patterns (KMT), which are primary capacities for music perception. Using the Bayesian linkage and association approach implemented in program package KELVIN, especially designed for complex pedigrees, several single nucleotide polymorphisms (SNPs) near genes affecting the functions of the auditory pathway and neurocognitive processes were identified. The strongest association was found at 3q21.3 (rs9854612) with combined SP, ST and KMT test scores (COMB). This region is located a few dozen kilobases upstream of the GATA binding protein 2 (GATA2) gene. GATA2 regulates the development of cochlear hair cells and the inferior colliculus (IC), which are important in tonotopic mapping. The highest probability of linkage was obtained for phenotype SP at 4p14, located next to the region harboring the protocadherin 7 gene, PCDH7. Two SNPs rs13146789 and rs13109270 of PCDH7 showed strong association. PCDH7 has been suggested to play a role in cochlear and amygdaloid complexes. Functional class analysis showed that inner ear and schizophrenia-related genes were enriched inside the linked regions. This study is the first to show the importance of auditory pathway genes in musical aptitude.

Identifying Differential Item Functioning of Rating Scale Items with the Rasch Model: An Introduction and an Application

ERIC Educational Resources Information Center

Myers, Nicholas D.; Wolfe, Edward W.; Feltz, Deborah L.; Penfield, Randall D.

2006-01-01

This study (a) provided a conceptual introduction to differential item functioning (DIF), (b) introduced the multifaceted Rasch rating scale model (MRSM) and an associated statistical procedure for identifying DIF in rating scale items, and (c) applied this procedure to previously collected data from American coaches who responded to the coaching…

Identifying pathogenic processes by integrating microarray data with prior knowledge

PubMed Central

2014-01-01

Background It is of great importance to identify molecular processes and pathways that are involved in disease etiology. Although there has been an extensive use of various high-throughput methods for this task, pathogenic pathways are still not completely understood. Often the set of genes or proteins identified as altered in genome-wide screens show a poor overlap with canonical disease pathways. These findings are difficult to interpret, yet crucial in order to improve the understanding of the molecular processes underlying the disease progression. We present a novel method for identifying groups of connected molecules from a set of differentially expressed genes. These groups represent functional modules sharing common cellular function and involve signaling and regulatory events. Specifically, our method makes use of Bayesian statistics to identify groups of co-regulated genes based on the microarray data, where external information about molecular interactions and connections are used as priors in the group assignments. Markov chain Monte Carlo sampling is used to search for the most reliable grouping. Results Simulation results showed that the method improved the ability of identifying correct groups compared to traditional clustering, especially for small sample sizes. Applied to a microarray heart failure dataset the method found one large cluster with several genes important for the structure of the extracellular matrix and a smaller group with many genes involved in carbohydrate metabolism. The method was also applied to a microarray dataset on melanoma cancer patients with or without metastasis, where the main cluster was dominated by genes related to keratinocyte differentiation. Conclusion Our method found clusters overlapping with known pathogenic processes, but also pointed to new connections extending beyond the classical pathways. PMID:24758699

Machine Learning Classification to Identify the Stage of Brain-Computer Interface Therapy for Stroke Rehabilitation Using Functional Connectivity.

PubMed

Mohanty, Rosaleena; Sinha, Anita M; Remsik, Alexander B; Dodd, Keith C; Young, Brittany M; Jacobson, Tyler; McMillan, Matthew; Thoma, Jaclyn; Advani, Hemali; Nair, Veena A; Kang, Theresa J; Caldera, Kristin; Edwards, Dorothy F; Williams, Justin C; Prabhakaran, Vivek

2018-01-01

Interventional therapy using brain-computer interface (BCI) technology has shown promise in facilitating motor recovery in stroke survivors; however, the impact of this form of intervention on functional networks outside of the motor network specifically is not well-understood. Here, we investigated resting-state functional connectivity (rs-FC) in stroke participants undergoing BCI therapy across stages, namely pre- and post-intervention, to identify discriminative functional changes using a machine learning classifier with the goal of categorizing participants into one of the two therapy stages. Twenty chronic stroke participants with persistent upper-extremity motor impairment received neuromodulatory training using a closed-loop neurofeedback BCI device, and rs-functional MRI (rs-fMRI) scans were collected at four time points: pre-, mid-, post-, and 1 month post-therapy. To evaluate the peak effects of this intervention, rs-FC was analyzed from two specific stages, namely pre- and post-therapy. In total, 236 seeds spanning both motor and non-motor regions of the brain were computed at each stage. A univariate feature selection was applied to reduce the number of features followed by a principal component-based data transformation used by a linear binary support vector machine (SVM) classifier to classify each participant into a therapy stage. The SVM classifier achieved a cross-validation accuracy of 92.5% using a leave-one-out method. Outside of the motor network, seeds from the fronto-parietal task control, default mode, subcortical, and visual networks emerged as important contributors to the classification. Furthermore, a higher number of functional changes were observed to be strengthening from the pre- to post-therapy stage than the ones weakening, both of which involved motor and non-motor regions of the brain. These findings may provide new evidence to support the potential clinical utility of BCI therapy as a form of stroke rehabilitation that not only

The use of functional chemical-protein associations to identify multi-pathway renoprotectants.

PubMed

Xu, Jia; Meng, Kexin; Zhang, Rui; Yang, He; Liao, Chang; Zhu, Wenliang; Jiao, Jundong

2014-01-01

Typically, most nephropathies can be categorized as complex human diseases in which the cumulative effect of multiple minor genes, combined with environmental and lifestyle factors, determines the disease phenotype. Thus, multi-target drugs would be more likely to facilitate comprehensive renoprotection than single-target agents. In this study, functional chemical-protein association analysis was performed to retrieve multi-target drugs of high pathway wideness from the STITCH 3.1 database. Pathway wideness of a drug evaluated the efficiency of regulation of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in quantity. We identified nine experimentally validated renoprotectants that exerted remarkable impact on KEGG pathways by targeting a limited number of proteins. We selected curcumin as an illustrative compound to display the advantage of multi-pathway drugs on renoprotection. We compared curcumin with hemin, an agonist of heme oxygenase-1 (HO-1), which significantly affects only one KEGG pathway, porphyrin and chlorophyll metabolism (adjusted p = 1.5×10-5). At the same concentration (10 µM), both curcumin and hemin equivalently mitigated oxidative stress in H2O2-treated glomerular mesangial cells. The benefit of using hemin was derived from its agonistic effect on HO-1, providing relief from oxidative stress. Selective inhibition of HO-1 completely blocked the action of hemin but not that of curcumin, suggesting simultaneous multi-pathway intervention by curcumin. Curcumin also increased cellular autophagy levels, enhancing its protective effect; however, hemin had no effects. Based on the fact that the dysregulation of multiple pathways is implicated in the etiology of complex diseases, we proposed a feasible method for identifying multi-pathway drugs from compounds with validated targets. Our efforts will help identify multi-pathway agents capable of providing comprehensive protection against renal injuries.

Using Functional Signature Ontology (FUSION) to Identify Mechanisms of Action for Natural Products

PubMed Central

Potts, Malia B.; Kim, Hyun Seok; Fisher, Kurt W.; Hu, Youcai; Carrasco, Yazmin P.; Bulut, Gamze Betul; Ou, Yi-Hung; Herrera-Herrera, Mireya L.; Cubillos, Federico; Mendiratta, Saurabh; Xiao, Guanghua; Hofree, Matan; Ideker, Trey; Xie, Yang; Huang, Lily Jun-shen; Lewis, Robert E.; MacMillan, John B.; White, Michael A.

2014-01-01

A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by siRNA and synthetic microRNA libraries. With this strategy, we matched proteins and microRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected short-interfering RNAs, microRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets. PMID:24129700

Resequencing the susceptibility gene, ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases

PubMed Central

2014-01-01

Introduction The majority of the genetic variance of systemic lupus erythematosus (SLE) remains unexplained by the common disease-common variant hypothesis. Rare variants, which are not detectable by genome-wide association studies because of their low frequencies, are predicted to explain part of this ”missing heritability.” However, recent studies identifying rare variants within known disease-susceptibility loci have failed to show genetic associations because of their extremely low frequencies, leading to the questioning of the contribution of rare variants to disease susceptibility. A common (minor allele frequency = 17.4% in cases) nonsynonymous coding variant rs1143679 (R77H) in ITGAM (CD11b), which forms half of the heterodimeric integrin receptor, complement receptor 3 (CR3), is robustly associated with SLE and has been shown to impair CR3-mediated phagocytosis. Methods We resequenced ITGAM in 73 SLE cases and identified two previously unidentified, case-specific nonsynonymous variants, F941V and G1145S. Both variants were genotyped in 2,107 and 949 additional SLE cases, respectively, to estimate their frequencies in a disease population. An in vitro model was used to assess the impact of F941V and G1145S, together with two nonsynonymous ITGAM polymorphisms, A858V (rs1143683) and M441T (rs11861251), on CR3-mediated phagocytosis. A paired two-tailed t test was used to compare the phagocytic capabilities of each variant with that of wild-type CR3. Results Both rare variants, F941V and G1145S, significantly impair CR3-mediated phagocytosis in an in vitro model (61% reduction, P = 0.006; 26% reduction, P = 0.0232). However, neither of the common variants, M441T and A858V, had an effect on phagocytosis. Neither rare variant was observed again in the genotyping of additional SLE cases, suggesting that there frequencies are extremely low. Conclusions Our results add further evidence to the functional importance of ITGAM in SLE pathogenesis through impaired

Isolated severe tricuspid regurgitation: the importance of identifying underlying mechanism.

PubMed

Poh, Kian Keong; Solis, Jorge; Hung, Judy

2008-07-21

An 88-year-old woman presented with right heart failure, history of diarrhoea, abdominal pain, weight lost, dyspnoea over several weeks and a new pan-systolic murmur. Echocardiography showed retracted tricuspid leaflets with incomplete coaptation resulting in severe regurgitation. Subcostal view showed an adjacent hepatic cyst leading to biopsy, which revealed neoplastic neuroendocrine cells. Her 24-hour urinary 5-hydroxyindoleacetic acid level was elevated. The unifying diagnosis was carcinoid syndrome for which she was treated. Echocardiography is an important tool for diagnosis, management and prognosis of carcinoid heart disease.

Perceived cultural importance and actual self-importance of values in cultural identification.

PubMed

Wan, Ching; Chiu, Chi-yue; Tam, Kim-pong; Lee, Sau-lai; Lau, Ivy Yee-man; Peng, Siqing

2007-02-01

Cross-cultural psychologists assume that core cultural values define to a large extent what a culture is. Typically, core values are identified through an actual self-importance approach, in which core values are those that members of the culture as a group strongly endorse. In this article, the authors propose a perceived cultural importance approach to identifying core values, in which core values are values that members of the culture as a group generally believe to be important in the culture. In 5 studies, the authors examine the utility of the perceived cultural importance approach. Results consistently showed that, compared with values of high actual self-importance, values of high perceived cultural importance play a more important role in cultural identification. These findings have important implications for conceptualizing and measuring cultures. ((c) 2007 APA, all rights reserved).

Leveraging Comparative Genomics to Identify and Functionally Characterize Genes Associated with Sperm Phenotypes in Python bivittatus (Burmese Python).

PubMed

Irizarry, Kristopher J L; Rutllant, Josep

2016-01-01

Comparative genomics approaches provide a means of leveraging functional genomics information from a highly annotated model organism's genome (such as the mouse genome) in order to make physiological inferences about the role of genes and proteins in a less characterized organism's genome (such as the Burmese python). We employed a comparative genomics approach to produce the functional annotation of Python bivittatus genes encoding proteins associated with sperm phenotypes. We identify 129 gene-phenotype relationships in the python which are implicated in 10 specific sperm phenotypes. Results obtained through our systematic analysis identified subsets of python genes exhibiting associations with gene ontology annotation terms. Functional annotation data was represented in a semantic scatter plot. Together, these newly annotated Python bivittatus genome resources provide a high resolution framework from which the biology relating to reptile spermatogenesis, fertility, and reproduction can be further investigated. Applications of our research include (1) production of genetic diagnostics for assessing fertility in domestic and wild reptiles; (2) enhanced assisted reproduction technology for endangered and captive reptiles; and (3) novel molecular targets for biotechnology-based approaches aimed at reducing fertility and reproduction of invasive reptiles. Additional enhancements to reptile genomic resources will further enhance their value.

Lamina-independent lamins in the nuclear interior serve important functions.

PubMed

Dechat, T; Gesson, K; Foisner, R

2010-01-01

Nuclear lamins were originally described as the main constituents of the nuclear lamina, a filamentous meshwork closely associated with the inner nuclear membrane. However, within recent years, it has become increasingly evident that a fraction of lamins also resides throughout the nuclear interior. As intermediate-filament-type proteins, lamins have been suggested to fulfill mainly structural functions such as providing shape and mechanical stability to the nucleus. But recent findings show that both peripheral and nucleoplasmic lamins also have important roles in essential cellular processes such as transcription, DNA replication, cell cycle progression, and chromatin organization. Furthermore, more than 300 mutations in the gene encoding A-type lamins have been associated with several human diseases now generally termed laminopathies and comprising muscular dystrophies, lipodystrophies, cardiomyopathies, and premature aging diseases. This review focuses on the lamina-independent pool of lamins in the nuclear interior, which surprisingly has not been studied in much detail so far. We discuss the properties and regulation of nucleoplasmic lamins during the cell cycle, their interaction partners, and their potential involvement in cellular processes and the development of laminopathies.

Mango (Mangifera indica L.) cv. Kent fruit mesocarp de novo transcriptome assembly identifies gene families important for ripening.

PubMed

Dautt-Castro, Mitzuko; Ochoa-Leyva, Adrian; Contreras-Vergara, Carmen A; Pacheco-Sanchez, Magda A; Casas-Flores, Sergio; Sanchez-Flores, Alejandro; Kuhn, David N; Islas-Osuna, Maria A

2015-01-01

Fruit ripening is a physiological and biochemical process genetically programmed to regulate fruit quality parameters like firmness, flavor, odor and color, as well as production of ethylene in climacteric fruit. In this study, a transcriptomic analysis of mango (Mangifera indica L.) mesocarp cv. "Kent" was done to identify key genes associated with fruit ripening. Using the Illumina sequencing platform, 67,682,269 clean reads were obtained and a transcriptome of 4.8 Gb. A total of 33,142 coding sequences were predicted and after functional annotation, 25,154 protein sequences were assigned with a product according to Swiss-Prot database and 32,560 according to non-redundant database. Differential expression analysis identified 2,306 genes with significant differences in expression between mature-green and ripe mango [1,178 up-regulated and 1,128 down-regulated (FDR ≤ 0.05)]. The expression of 10 genes evaluated by both qRT-PCR and RNA-seq data was highly correlated (R = 0.97), validating the differential expression data from RNA-seq alone. Gene Ontology enrichment analysis, showed significantly represented terms associated to fruit ripening like "cell wall," "carbohydrate catabolic process" and "starch and sucrose metabolic process" among others. Mango genes were assigned to 327 metabolic pathways according to Kyoto Encyclopedia of Genes and Genomes database, among them those involved in fruit ripening such as plant hormone signal transduction, starch and sucrose metabolism, galactose metabolism, terpenoid backbone, and carotenoid biosynthesis. This study provides a mango transcriptome that will be very helpful to identify genes for expression studies in early and late flowering mangos during fruit ripening.

Overuse wrist injuries in young athletes: What do sports physicians consider important signals and functional limitations?

PubMed

Kox, Laura S; Kuijer, P Paul F M; Opperman, Jip; Kerkhoffs, Gino M M J; Maas, Mario; Frings-Dresen, Monique H W

2018-01-01

This study's objective was to collect items from experienced sports physicians, relating to the presence and severity of overuse wrist injuries in young athletes, for developing a measurement instrument for signals of overuse wrist injury. Seven Dutch elite sports physicians involved in guidance and treatment of young athletes in wrist-loading sports (gymnastics, tennis, judo, field hockey, volleyball and rowing) participated in a focus group. They discussed signals and limitations related to overuse wrist injuries in young athletes. Data were coded and categorised into signals and limitations with subcategories, using an inductive approach. Of the resulting 61 signals and limitations in nineteen (sub)categories, 20 were considered important, forming a comprehensive item set for identifying overuse wrist injury in young athletes. Signals such as pain, "click", crepitations, swelling and limited range of motion were marked useful for early identification of overuse wrist injury. Limitations in movement and performance were considered indicative of severe overuse injury but less relevant for initial injury identification. The focus group provided 17 important signals and 3 important limitations indicative of overuse wrist injury. These provide the basis for a valid measurement instrument for identifying overuse wrist injury in young athletes, with equal emphasis on pain and on other symptoms.

Inferring Gene Family Histories in Yeast Identifies Lineage Specific Expansions

PubMed Central

Ames, Ryan M.; Money, Daniel; Lovell, Simon C.

2014-01-01

The complement of genes found in the genome is a balance between gene gain and gene loss. Knowledge of the specific genes that are gained and lost over evolutionary time allows an understanding of the evolution of biological functions. Here we use new evolutionary models to infer gene family histories across complete yeast genomes; these models allow us to estimate the relative genome-wide rates of gene birth, death, innovation and extinction (loss of an entire family) for the first time. We show that the rates of gene family evolution vary both between gene families and between species. We are also able to identify those families that have experienced rapid lineage specific expansion/contraction and show that these families are enriched for specific functions. Moreover, we find that families with specific functions are repeatedly expanded in multiple species, suggesting the presence of common adaptations and that these family expansions/contractions are not random. Additionally, we identify potential specialisations, unique to specific species, in the functions of lineage specific expanded families. These results suggest that an important mechanism in the evolution of genome content is the presence of lineage-specific gene family changes. PMID:24921666

Importance of being Nernst: Synaptic activity and functional relevance in stem cell-derived neurons

PubMed Central

Bradford, Aaron B; McNutt, Patrick M

2015-01-01

Functional synaptogenesis and network emergence are signature endpoints of neurogenesis. These behaviors provide higher-order confirmation that biochemical and cellular processes necessary for neurotransmitter release, post-synaptic detection and network propagation of neuronal activity have been properly expressed and coordinated among cells. The development of synaptic neurotransmission can therefore be considered a defining property of neurons. Although dissociated primary neuron cultures readily form functioning synapses and network behaviors in vitro, continuously cultured neurogenic cell lines have historically failed to meet these criteria. Therefore, in vitro-derived neuron models that develop synaptic transmission are critically needed for a wide array of studies, including molecular neuroscience, developmental neurogenesis, disease research and neurotoxicology. Over the last decade, neurons derived from various stem cell lines have shown varying ability to develop into functionally mature neurons. In this review, we will discuss the neurogenic potential of various stem cells populations, addressing strengths and weaknesses of each, with particular attention to the emergence of functional behaviors. We will propose methods to functionally characterize new stem cell-derived neuron (SCN) platforms to improve their reliability as physiological relevant models. Finally, we will review how synaptically active SCNs can be applied to accelerate research in a variety of areas. Ultimately, emphasizing the critical importance of synaptic activity and network responses as a marker of neuronal maturation is anticipated to result in in vitro findings that better translate to efficacious clinical treatments. PMID:26240679

Identifying Important Career Indicators of Undergraduate Geoscience Students Upon Completion of Their Degree

NASA Astrophysics Data System (ADS)

Wilson, C. E.; Keane, C. M.; Houlton, H. R.

2012-12-01

The American Geosciences Institute (AGI) decided to create the National Geoscience Student Exit Survey in order to identify the initial pathways into the workforce for these graduating students, as well as assess their preparedness for entering the workforce upon graduation. The creation of this survey stemmed from a combination of experiences with the AGI/AGU Survey of Doctorates and discussions at the following Science Education Research Center (SERC) workshops: "Developing Pathways to Strong Programs for the Future", "Strengthening Your Geoscience Program", and "Assessing Geoscience Programs". These events identified distinct gaps in understanding the experiences and perspectives of geoscience students during one of their most profound professional transitions. Therefore, the idea for the survey arose as a way to evaluate how the discipline is preparing and educating students, as well as identifying the students' desired career paths. The discussions at the workshops solidified the need for this survey and created the initial framework for the first pilot of the survey. The purpose of this assessment tool is to evaluate student preparedness for entering the geosciences workforce; identify student decision points for entering geosciences fields and remaining in the geosciences workforce; identify geosciences fields that students pursue in undergraduate and graduate school; collect information on students' expected career trajectories and geosciences professions; identify geosciences career sectors that are hiring new graduates; collect information about salary projections; overall effectiveness of geosciences departments regionally and nationally; demonstrate the value of geosciences degrees to future students, the institutions, and employers; and establish a benchmark to perform longitudinal studies of geosciences graduates to understand their career pathways and impacts of their educational experiences on these decisions. AGI's Student Exit Survey went through

Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells

PubMed Central

Bodemann, Brian; Petersen, Sean; Aruri, Jayavani; Koshy, Shiney; Richardson, Zachary; Le, Lu Q.; Krasieva, Tatiana; Roth, Michael G.; Farmer, Pat; White, Michael A.

2008-01-01

Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo), neurologic disorders (Parkinson's disease), auditory disorders (Waardenburg's syndrome), and opthalmologic disorders (age related macular degeneration). Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi) provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype and operate

Resolving anatomical and functional structure in human brain organization: identifying mesoscale organization in weighted network representations.

PubMed

Lohse, Christian; Bassett, Danielle S; Lim, Kelvin O; Carlson, Jean M

2014-10-01

Human brain anatomy and function display a combination of modular and hierarchical organization, suggesting the importance of both cohesive structures and variable resolutions in the facilitation of healthy cognitive processes. However, tools to simultaneously probe these features of brain architecture require further development. We propose and apply a set of methods to extract cohesive structures in network representations of brain connectivity using multi-resolution techniques. We employ a combination of soft thresholding, windowed thresholding, and resolution in community detection, that enable us to identify and isolate structures associated with different weights. One such mesoscale structure is bipartivity, which quantifies the extent to which the brain is divided into two partitions with high connectivity between partitions and low connectivity within partitions. A second, complementary mesoscale structure is modularity, which quantifies the extent to which the brain is divided into multiple communities with strong connectivity within each community and weak connectivity between communities. Our methods lead to multi-resolution curves of these network diagnostics over a range of spatial, geometric, and structural scales. For statistical comparison, we contrast our results with those obtained for several benchmark null models. Our work demonstrates that multi-resolution diagnostic curves capture complex organizational profiles in weighted graphs. We apply these methods to the identification of resolution-specific characteristics of healthy weighted graph architecture and altered connectivity profiles in psychiatric disease.

Genetic association study identifies a functional CNV in the WWOX gene contributes to the risk of intracranial aneurysms.

PubMed

Fan, Jin; Sun, Wen; Lin, Min; Yu, Ke; Wang, Jian; Duan, Dan; Zheng, Bo; Yang, Zhenghui; Wang, Qingsong

2016-03-29

Intracranial aneurysms (IAs) accounts for 85% of hemorrhagic stroke. Genetic factors have been known to play an important role in the development of IAs. A functional CNV (CNV-67048) of human WW domain-containing oxidoreductase (WWOX), which has been identified as a tumor suppressor gene in multiple cancers, was identified to be associated with gliomas risk previously. Here, we hypothesized that the CNV-67048 could also affect susceptibility of IAs. Based on a two-stage, case- control study with a total of 976 patients of IAs and 1,200 matched healthy controls, we found the effect size for per copy deletion was 1.35 (95% CI = 1.16-1.57; Ptrend = 1.18 × 10-4). Compared with the individuals having no deletion, significantly higher risk of IAs was detected for both subjects carrying 1 copy deletion (OR = 1.24, 95% CI = 1.02-1.52) and subjects carrying 2 copy deletion (OR = 1.77, 95% CI = 1.24-2.53). Real-time PCR was used to confirm the abnormal expression of WWOX in tissues of IA patients and influence of genotypes of CNV-67048. The expression level of WWOX in IA tissues was significantly lower than that in corresponding normal tissues (P = 0.004), and the deletion genotypes of CNV-67048 have lower WWOX mRNA levels in both tumor tissues and border tissues (P < 0.01). Our data suggests that the deletion genotypes of CNV-67048 in WWOX predispose their carriers to IAs, which might be a genetic biomarker to predict risk of IAs in Chinese.

Identifying Model-Based Reconfiguration Goals through Functional Deficiencies

NASA Technical Reports Server (NTRS)

Benazera, Emmanuel; Trave-Massuyes, Louise

2004-01-01

Model-based diagnosis is now advanced to the point autonomous systems face some uncertain and faulty situations with success. The next step toward more autonomy is to have the system recovering itself after faults occur, a process known as model-based reconfiguration. After faults occur, given a prediction of the nominal behavior of the system and the result of the diagnosis operation, this paper details how to automatically determine the functional deficiencies of the system. These deficiencies are characterized in the case of uncertain state estimates. A methodology is then presented to determine the reconfiguration goals based on the deficiencies. Finally, a recovery process interleaves planning and model predictive control to restore the functionalities in prioritized order.

Mechanistic Insight into the Host Transcription Inhibition Function of Rift Valley Fever Virus NSs and Its Importance in Virulence

PubMed Central

Terasaki, Kaori; Ramirez, Sydney I.; Makino, Shinji

2016-01-01

Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear. To examine this, we generated two RVFV MP-12 strain-derived mutant viruses. Each carried mutations in NSs that specifically targeted its general transcription inhibition function without affecting its ability to degrade PKR and inhibit IFN-β promoter induction, through its interaction with Sin3-associated protein 30, a part of the repressor complex at the IFN-β promoter. Using these mutant viruses, we have dissected the transcription inhibition function of NSs and examined its importance in RVFV virulence. Both NSs mutant viruses exhibited a differentially impaired ability to inhibit host transcription when compared with MP-12. It has been reported that NSs suppresses general transcription by interfering with the formation of the transcription factor IIH complex, through the degradation of the p62 subunit and sequestration of the p44 subunit. Our study results lead us to suggest that the ability of NSs to induce p62 degradation is the major contributor to its general transcription inhibition property, whereas its interaction with p44 may not play a significant role in this function. Importantly, RVFV MP-12-NSs mutant viruses with an impaired general transcription inhibition function showed a reduced cytotoxicity in cell culture and attenuated virulence in young mice

Mechanistic Insight into the Host Transcription Inhibition Function of Rift Valley Fever Virus NSs and Its Importance in Virulence.

PubMed

Terasaki, Kaori; Ramirez, Sydney I; Makino, Shinji

2016-10-01

Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, causes periodic outbreaks in livestocks and humans in countries of the African continent and Middle East. RVFV NSs protein, a nonstructural protein, is a major virulence factor that exhibits several important biological properties. These include suppression of general transcription, inhibition of IFN-β promoter induction and degradation of double-stranded RNA-dependent protein kinase R. Although each of these biological functions of NSs are considered important for countering the antiviral response in the host, the individual contributions of these functions towards RVFV virulence remains unclear. To examine this, we generated two RVFV MP-12 strain-derived mutant viruses. Each carried mutations in NSs that specifically targeted its general transcription inhibition function without affecting its ability to degrade PKR and inhibit IFN-β promoter induction, through its interaction with Sin3-associated protein 30, a part of the repressor complex at the IFN-β promoter. Using these mutant viruses, we have dissected the transcription inhibition function of NSs and examined its importance in RVFV virulence. Both NSs mutant viruses exhibited a differentially impaired ability to inhibit host transcription when compared with MP-12. It has been reported that NSs suppresses general transcription by interfering with the formation of the transcription factor IIH complex, through the degradation of the p62 subunit and sequestration of the p44 subunit. Our study results lead us to suggest that the ability of NSs to induce p62 degradation is the major contributor to its general transcription inhibition property, whereas its interaction with p44 may not play a significant role in this function. Importantly, RVFV MP-12-NSs mutant viruses with an impaired general transcription inhibition function showed a reduced cytotoxicity in cell culture and attenuated virulence in young mice

Importance of oestrogen receptors to preserve functional β-cell mass in diabetes.

PubMed

Tiano, Joseph P; Mauvais-Jarvis, Franck

2012-02-14

Protecting the functional mass of insulin-producing β cells of the pancreas is a major therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The gonadal hormone 17β-oestradiol (E2) is involved in reproductive, bone, cardiovascular and neuronal physiology. In rodent models of T1DM and T2DM, treatment with E2 protects pancreatic β cells against oxidative stress, amyloid polypeptide toxicity, lipotoxicity and apoptosis. Three oestrogen receptors (ERs)--ERα, ERβ and the G protein-coupled ER (GPER)--have been identified in rodent and human β cells. Whereas activation of ERα enhances glucose-stimulated insulin biosynthesis, reduces islet toxic lipid accumulation and promotes β-cell survival from proapoptotic stimuli, activation of ERβ increases glucose-stimulated insulin secretion. However, activation of GPER protects β cells from apoptosis, raises glucose-stimulated insulin secretion and lipid homeostasis without affecting insulin biosynthesis. Oestrogens are also improving islet engraftment in rodent models of pancreatic islet transplantation. This Review describes developments in the role of ERs in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, we discuss why and how enhancing ER action in β cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus.

A landscape ecology approach identifies important drivers of urban biodiversity.

PubMed

Turrini, Tabea; Knop, Eva

2015-04-01

Cities are growing rapidly worldwide, yet a mechanistic understanding of the impact of urbanization on biodiversity is lacking. We assessed the impact of urbanization on arthropod diversity (species richness and evenness) and abundance in a study of six cities and nearby intensively managed agricultural areas. Within the urban ecosystem, we disentangled the relative importance of two key landscape factors affecting biodiversity, namely the amount of vegetated area and patch isolation. To do so, we a priori selected sites that independently varied in the amount of vegetated area in the surrounding landscape at the 500-m scale and patch isolation at the 100-m scale, and we hold local patch characteristics constant. As indicator groups, we used bugs, beetles, leafhoppers, and spiders. Compared to intensively managed agricultural ecosystems, urban ecosystems supported a higher abundance of most indicator groups, a higher number of bug species, and a lower evenness of bug and beetle species. Within cities, a high amount of vegetated area increased species richness and abundance of most arthropod groups, whereas evenness showed no clear pattern. Patch isolation played only a limited role in urban ecosystems, which contrasts findings from agro-ecological studies. Our results show that urban areas can harbor a similar arthropod diversity and abundance compared to intensively managed agricultural ecosystems. Further, negative consequences of urbanization on arthropod diversity can be mitigated by providing sufficient vegetated space in the urban area, while patch connectivity is less important in an urban context. This highlights the need for applying a landscape ecological approach to understand the mechanisms shaping urban biodiversity and underlines the potential of appropriate urban planning for mitigating biodiversity loss. © 2015 John Wiley & Sons Ltd.

An Analysis of the Importance of Selected Functions of Counseling Centers in Public Colleges in the State of Maryland.

ERIC Educational Resources Information Center

Gross, Thomas S.; And Others

Counseling center directors at colleges in the state of Maryland were asked to rate the importance of several selected functions of their counseling centers. The functions rated were: (1) psychological problem counseling; (2) reading and study skills assistance; (3) testing; (4) academic advisement; (5) college orientation; (6) evening student…

Functional recovery is considered the most important target: a survey of dedicated professionals

PubMed Central

2014-01-01

Background The aim of this study was to survey the relative importance of postoperative recovery targets and perioperative care items, as perceived by a large group of international dedicated professionals. Methods A questionnaire with eight postoperative recovery targets and 13 perioperative care items was mailed to participants of the first international Enhanced Recovery After Surgery (ERAS) congress and to authors of papers with a clear relevance to ERAS in abdominal surgery. The responders were divided into categories according to profession and region. Results The recovery targets ‘To be completely free of nausea’, ‘To be independently mobile’ and ‘To be able to eat and drink as soon as possible’ received the highest score irrespective of the responder's profession or region of origin. Equally, the care items ‘Optimizing fluid balance’, ‘Preoperative counselling’ and ‘Promoting early and scheduled mobilisation’ received the highest score across all groups. Conclusions Functional recovery, as in tolerance of food without nausea and regained mobility, was considered the most important target of recovery. There was a consistent uniformity in the way international dedicated professionals scored the relative importance of recovery targets and care items. The relative rating of the perioperative care items was not dependent on the strength of evidence supporting the items. PMID:25089195

Lipoprotein(a): Biology and Clinical Importance

PubMed Central

McCormick, Sally P A

2004-01-01

Lipoprotein(a) [Lp(a)] is a unique lipoprotein that has emerged as an independent risk factor for developing vascular disease. Plasma Lp(a) levels above the common cut-off level of 300 mg/L place individuals at risk of developing heart disease particularly if combined with other lipid and thrombogenic risk factors. Studies in humans have shown Lp(a) levels to be hugely variable and under strict genetic control, largely by the apolipoprotein(a) [apo(a)] gene. In general, Lp(a) levels have proven difficult to manipulate, although some factors have been identified that can influence levels. Research has shown that Lp(a) has a high affinity for the arterial wall and displays many athero-thrombogenic properties. While a definite function for Lp(a) has not been identified, the last two decades of research have provided much information on the biology and clinical importance of Lp(a). PMID:18516206

Mango (Mangifera indica L.) cv. Kent fruit mesocarp de novo transcriptome assembly identifies gene families important for ripening

PubMed Central

Dautt-Castro, Mitzuko; Ochoa-Leyva, Adrian; Contreras-Vergara, Carmen A.; Pacheco-Sanchez, Magda A.; Casas-Flores, Sergio; Sanchez-Flores, Alejandro; Kuhn, David N.; Islas-Osuna, Maria A.

2015-01-01

Fruit ripening is a physiological and biochemical process genetically programmed to regulate fruit quality parameters like firmness, flavor, odor and color, as well as production of ethylene in climacteric fruit. In this study, a transcriptomic analysis of mango (Mangifera indica L.) mesocarp cv. “Kent” was done to identify key genes associated with fruit ripening. Using the Illumina sequencing platform, 67,682,269 clean reads were obtained and a transcriptome of 4.8 Gb. A total of 33,142 coding sequences were predicted and after functional annotation, 25,154 protein sequences were assigned with a product according to Swiss-Prot database and 32,560 according to non-redundant database. Differential expression analysis identified 2,306 genes with significant differences in expression between mature-green and ripe mango [1,178 up-regulated and 1,128 down-regulated (FDR ≤ 0.05)]. The expression of 10 genes evaluated by both qRT-PCR and RNA-seq data was highly correlated (R = 0.97), validating the differential expression data from RNA-seq alone. Gene Ontology enrichment analysis, showed significantly represented terms associated to fruit ripening like “cell wall,” “carbohydrate catabolic process” and “starch and sucrose metabolic process” among others. Mango genes were assigned to 327 metabolic pathways according to Kyoto Encyclopedia of Genes and Genomes database, among them those involved in fruit ripening such as plant hormone signal transduction, starch and sucrose metabolism, galactose metabolism, terpenoid backbone, and carotenoid biosynthesis. This study provides a mango transcriptome that will be very helpful to identify genes for expression studies in early and late flowering mangos during fruit ripening. PMID:25741352

Leveraging Comparative Genomics to Identify and Functionally Characterize Genes Associated with Sperm Phenotypes in Python bivittatus (Burmese Python)

PubMed Central

Rutllant, Josep

2016-01-01

Comparative genomics approaches provide a means of leveraging functional genomics information from a highly annotated model organism's genome (such as the mouse genome) in order to make physiological inferences about the role of genes and proteins in a less characterized organism's genome (such as the Burmese python). We employed a comparative genomics approach to produce the functional annotation of Python bivittatus genes encoding proteins associated with sperm phenotypes. We identify 129 gene-phenotype relationships in the python which are implicated in 10 specific sperm phenotypes. Results obtained through our systematic analysis identified subsets of python genes exhibiting associations with gene ontology annotation terms. Functional annotation data was represented in a semantic scatter plot. Together, these newly annotated Python bivittatus genome resources provide a high resolution framework from which the biology relating to reptile spermatogenesis, fertility, and reproduction can be further investigated. Applications of our research include (1) production of genetic diagnostics for assessing fertility in domestic and wild reptiles; (2) enhanced assisted reproduction technology for endangered and captive reptiles; and (3) novel molecular targets for biotechnology-based approaches aimed at reducing fertility and reproduction of invasive reptiles. Additional enhancements to reptile genomic resources will further enhance their value. PMID:27200191

In Vivo Functional Selection Identifies Cardiotrophin-1 as a Cardiac Engraftment Factor for Mesenchymal Stromal Cells.

PubMed

Bortolotti, Francesca; Ruozi, Giulia; Falcione, Antonella; Doimo, Sara; Dal Ferro, Matteo; Lesizza, Pierluigi; Zentilin, Lorena; Banks, Lawrence; Zacchigna, Serena; Giacca, Mauro

2017-10-17

Transplantation of cells into the infarcted heart has significant potential to improve myocardial recovery; however, low efficacy of cell engraftment still limits therapeutic benefit. Here, we describe a method for the unbiased, in vivo selection of cytokines that improve mesenchymal stromal cell engraftment into the heart both in normal conditions and after myocardial infarction. An arrayed library of 80 secreted factors, including most of the currently known interleukins and chemokines, were individually cloned into adeno-associated viral vectors. Pools from this library were then used for the batch transduction of bone marrow-derived mesenchymal stromal cells ex vivo, followed by intramyocardial cell administration in normal and infarcted mice. Three weeks after injection, vector genomes were recovered from the few persisting cells and identified by sequencing DNA barcodes uniquely labeling each of the tested cytokines. The most effective molecule identified by this competitive engraftment screening was cardiotrophin-1, a member of the interleukin-6 family. Intracardiac injection of mesenchymal stromal cells transiently preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size, parallel to the persistence of the transplanted cells in the healing hearts for at least 2 months after injection. Engraftment of cardiotrophin-1-treated mesenchymal stromal cells was consequent to signal transducer and activator of transcription 3-mediated activation of the focal adhesion kinase and its associated focal adhesion complex and the consequent acquisition of adhesive properties by the cells. These results support the feasibility of selecting molecules in vivo for their functional properties with adeno-associated viral vector libraries and identify cardiotrophin-1 as a powerful cytokine promoting cell engraftment and thus improving cell therapy of the infarcted myocardium. © 2017 American Heart Association, Inc.

Machine-learning scoring functions for identifying native poses of ligands docked to known and novel proteins.

PubMed

Ashtawy, Hossam M; Mahapatra, Nihar R

2015-01-01

Molecular docking is a widely-employed method in structure-based drug design. An essential component of molecular docking programs is a scoring function (SF) that can be used to identify the most stable binding pose of a ligand, when bound to a receptor protein, from among a large set of candidate poses. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited docking power (or ability to successfully identify the correct pose) has been a major impediment to cost-effective drug discovery. Therefore, in this work, we explore a range of novel SFs employing different machine-learning (ML) approaches in conjunction with physicochemical and geometrical features characterizing protein-ligand complexes to predict the native or near-native pose of a ligand docked to a receptor protein's binding site. We assess the docking accuracies of these new ML SFs as well as those of conventional SFs in the context of the 2007 PDBbind benchmark dataset on both diverse and homogeneous (protein-family-specific) test sets. Further, we perform a systematic analysis of the performance of the proposed SFs in identifying native poses of ligands that are docked to novel protein targets. We find that the best performing ML SF has a success rate of 80% in identifying poses that are within 1 Å root-mean-square deviation from the native poses of 65 different protein families. This is in comparison to a success rate of only 70% achieved by the best conventional SF, ASP, employed in the commercial docking software GOLD. In addition, the proposed ML SFs perform better on novel proteins that they were never trained on before. We also observed steady gains in the performance of these scoring functions as the training set size and number of features were increased by considering more protein-ligand complexes and/or more computationally-generated poses for each complex.

Machine-learning scoring functions for identifying native poses of ligands docked to known and novel proteins

PubMed Central

2015-01-01

Background Molecular docking is a widely-employed method in structure-based drug design. An essential component of molecular docking programs is a scoring function (SF) that can be used to identify the most stable binding pose of a ligand, when bound to a receptor protein, from among a large set of candidate poses. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited docking power (or ability to successfully identify the correct pose) has been a major impediment to cost-effective drug discovery. Therefore, in this work, we explore a range of novel SFs employing different machine-learning (ML) approaches in conjunction with physicochemical and geometrical features characterizing protein-ligand complexes to predict the native or near-native pose of a ligand docked to a receptor protein's binding site. We assess the docking accuracies of these new ML SFs as well as those of conventional SFs in the context of the 2007 PDBbind benchmark dataset on both diverse and homogeneous (protein-family-specific) test sets. Further, we perform a systematic analysis of the performance of the proposed SFs in identifying native poses of ligands that are docked to novel protein targets. Results and conclusion We find that the best performing ML SF has a success rate of 80% in identifying poses that are within 1 Å root-mean-square deviation from the native poses of 65 different protein families. This is in comparison to a success rate of only 70% achieved by the best conventional SF, ASP, employed in the commercial docking software GOLD. In addition, the proposed ML SFs perform better on novel proteins that they were never trained on before. We also observed steady gains in the performance of these scoring functions as the training set size and number of features were increased by considering more protein-ligand complexes and/or more computationally-generated poses for each complex. PMID:25916860

Disease-Associated Mutations Disrupt Functionally Important Regions of Intrinsic Protein Disorder

PubMed Central

Vacic, Vladimir; Markwick, Phineus R. L.; Oldfield, Christopher J.; Zhao, Xiaoyue; Haynes, Chad; Uversky, Vladimir N.; Iakoucheva, Lilia M.

2012-01-01

The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7–2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R→W, R→C, E→K, R→H, R→Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased α-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new

Perceived stress and cognitive function in older adults: which aspect of perceived stress is important?

PubMed

Korten, Nicole C M; Comijs, Hannie C; Penninx, Brenda W J H; Deeg, Dorly J H

2017-04-01

Few studies examined the association between perceived stress and cognitive function in older adults. This study will examine which aspects of perceived stress especially impact cognitive function. Cross-sectional data of 1099 older adults between 64 and 100 years from the Longitudinal Aging Study Amsterdam were used. Perceived stress and its subscales perceived helplessness and perceived self-efficacy were measured with the Perceived Stress Scale. Cognitive function was assessed regarding memory, processing speed and executive function. Univariate and multivariate linear regression analyses were performed between the stress measures and the domains of cognitive function. Perceived stress was associated with worse processing speed, direct and delayed recall, semantic fluency and digit span backwards (range β = -0.10; -0.11; p < 0.01). The subscale perceived helplessness showed negative associations only with processing speed (β = -0.06, p < 0.05) and delayed recall (β = -0.06, p < 0.05), which became nonsignificant after the adjustment for depressive symptoms or sense of mastery. The subscale perceived self-efficacy was significantly associated with better cognitive function, also after adjustment for depressive symptoms or sense of mastery (range β = 0.10; 0.18; p < 0.01). In older adults, especially perceived self-efficacy showed independent associations with a broad range of cognitive functions. Perceived self-efficacy might be an important factor in reducing stress and the prevention of cognitive decline. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis

PubMed Central

Du, Yushen; Wu, Nicholas C.; Jiang, Lin; Zhang, Tianhao; Gong, Danyang; Shu, Sara; Wu, Ting-Ting

2016-01-01

ABSTRACT Identification and annotation of functional residues are fundamental questions in protein sequence analysis. Sequence and structure conservation provides valuable information to tackle these questions. It is, however, limited by the incomplete sampling of sequence space in natural evolution. Moreover, proteins often have multiple functions, with overlapping sequences that present challenges to accurate annotation of the exact functions of individual residues by conservation-based methods. Using the influenza A virus PB1 protein as an example, we developed a method to systematically identify and annotate functional residues. We used saturation mutagenesis and high-throughput sequencing to measure the replication capacity of single nucleotide mutations across the entire PB1 protein. After predicting protein stability upon mutations, we identified functional PB1 residues that are essential for viral replication. To further annotate the functional residues important to the canonical or noncanonical functions of viral RNA-dependent RNA polymerase (vRdRp), we performed a homologous-structure analysis with 16 different vRdRp structures. We achieved high sensitivity in annotating the known canonical polymerase functional residues. Moreover, we identified a cluster of noncanonical functional residues located in the loop region of the PB1 β-ribbon. We further demonstrated that these residues were important for PB1 protein nuclear import through the interaction with Ran-binding protein 5. In summary, we developed a systematic and sensitive method to identify and annotate functional residues that are not restrained by sequence conservation. Importantly, this method is generally applicable to other proteins about which homologous-structure information is available. PMID:27803181

Forge into the Future: Identifying Core Competencies and Important Skills, Knowledge, and Abilities (SKAs) for Junior Navy Medical Service Corps Officers

DTIC Science & Technology

2008-10-20

operations and business practices, drug therapy management, and leadership, where as senior pharmacists placed a greater emphasis on the importance of SKAs...Commanders reviewed , sorted, and identified competencies from Wave I into 11 domains. From the expert analysis, the researcher developed a ...Y, a force of as many as 70 million are now beginning to embark on their career including the military health system. This generation as suggested

Identifying Breast Cancer Oncogenes

DTIC Science & Technology

2009-10-01

study by Boehm et al. (2007) identified IKBKE as a breast cancer oncogene that cooperates with HMLE -MEKDD to replace the function of myr-AKT in...1-0767 TITLE: Identifying Breast Cancer Oncogenes ~ PRINCIPAL INVESTIGATOR: Yashaswi Shrestha...Identifying Breast Cancer Oncogenes 5a. CONTRACT NUMBER W81XWH-08-1-0767 5b. GRANT NUMBER BC083061 - PreDoc 5c. PROGRAM ELEMENT NUMBER 6

Identifying transcription factor functions and targets by phenotypic activation

PubMed Central

Chua, Gordon; Morris, Quaid D.; Sopko, Richelle; Robinson, Mark D.; Ryan, Owen; Chan, Esther T.; Frey, Brendan J.; Andrews, Brenda J.; Boone, Charles; Hughes, Timothy R.

2006-01-01

Mapping transcriptional regulatory networks is difficult because many transcription factors (TFs) are activated only under specific conditions. We describe a generic strategy for identifying genes and pathways induced by individual TFs that does not require knowledge of their normal activation cues. Microarray analysis of 55 yeast TFs that caused a growth phenotype when overexpressed showed that the majority caused increased transcript levels of genes in specific physiological categories, suggesting a mechanism for growth inhibition. Induced genes typically included established targets and genes with consensus promoter motifs, if known, indicating that these data are useful for identifying potential new target genes and binding sites. We identified the sequence 5′-TCACGCAA as a binding sequence for Hms1p, a TF that positively regulates pseudohyphal growth and previously had no known motif. The general strategy outlined here presents a straightforward approach to discovery of TF activities and mapping targets that could be adapted to any organism with transgenic technology. PMID:16880382

Identifying Nanoscale Structure-Function Relationships Using Multimodal Atomic Force Microscopy, Dimensionality Reduction, and Regression Techniques.

PubMed

Kong, Jessica; Giridharagopal, Rajiv; Harrison, Jeffrey S; Ginger, David S

2018-05-31

Correlating nanoscale chemical specificity with operational physics is a long-standing goal of functional scanning probe microscopy (SPM). We employ a data analytic approach combining multiple microscopy modes, using compositional information in infrared vibrational excitation maps acquired via photoinduced force microscopy (PiFM) with electrical information from conductive atomic force microscopy. We study a model polymer blend comprising insulating poly(methyl methacrylate) (PMMA) and semiconducting poly(3-hexylthiophene) (P3HT). We show that PiFM spectra are different from FTIR spectra, but can still be used to identify local composition. We use principal component analysis to extract statistically significant principal components and principal component regression to predict local current and identify local polymer composition. In doing so, we observe evidence of semiconducting P3HT within PMMA aggregates. These methods are generalizable to correlated SPM data and provide a meaningful technique for extracting complex compositional information that are impossible to measure from any one technique.

NetCoffee: a fast and accurate global alignment approach to identify functionally conserved proteins in multiple networks.

PubMed

Hu, Jialu; Kehr, Birte; Reinert, Knut

2014-02-15

Owing to recent advancements in high-throughput technologies, protein-protein interaction networks of more and more species become available in public databases. The question of how to identify functionally conserved proteins across species attracts a lot of attention in computational biology. Network alignments provide a systematic way to solve this problem. However, most existing alignment tools encounter limitations in tackling this problem. Therefore, the demand for faster and more efficient alignment tools is growing. We present a fast and accurate algorithm, NetCoffee, which allows to find a global alignment of multiple protein-protein interaction networks. NetCoffee searches for a global alignment by maximizing a target function using simulated annealing on a set of weighted bipartite graphs that are constructed using a triplet approach similar to T-Coffee. To assess its performance, NetCoffee was applied to four real datasets. Our results suggest that NetCoffee remedies several limitations of previous algorithms, outperforms all existing alignment tools in terms of speed and nevertheless identifies biologically meaningful alignments. The source code and data are freely available for download under the GNU GPL v3 license at https://code.google.com/p/netcoffee/.

Integrating Genetic, Transcriptional, and Functional Analyses to Identify Five Novel Genes for Atrial Fibrillation

PubMed Central

Sinner, Moritz F.; Tucker, Nathan R.; Lunetta, Kathryn L.; Ozaki, Kouichi; Smith, J. Gustav; Trompet, Stella; Bis, Joshua C.; Lin, Honghuang; Chung, Mina K.; Nielsen, Jonas B.; Lubitz, Steven A.; Krijthe, Bouwe P.; Magnani, Jared W.; Ye, Jiangchuan; Gollob, Michael H.; Tsunoda, Tatsuhiko; Müller-Nurasyid, Martina; Lichtner, Peter; Peters, Annette; Dolmatova, Elena; Kubo, Michiaki; Smith, Jonathan D.; Psaty, Bruce M.; Smith, Nicholas L.; Jukema, J. Wouter; Chasman, Daniel I.; Albert, Christine M.; Ebana, Yusuke; Furukawa, Tetsushi; MacFarlane, Peter; Harris, Tamara B.; Darbar, Dawood; Dörr, Marcus; Holst, Anders G.; Svendsen, Jesper H.; Hofman, Albert; Uitterlinden, Andre G.; Gudnason, Vilmundur; Isobe, Mitsuaki; Malik, Rainer; Dichgans, Martin; Rosand, Jonathan; Van Wagoner, David R.; Benjamin, Emelia J.; Milan, David J.; Melander, Olle; Heckbert, Susan R.; Ford, Ian; Liu, Yongmei; Barnard, John; Olesen, Morten S.; Stricker, Bruno H.C.; Tanaka, Toshihiro; Kääb, Stefan; Ellinor, Patrick T.

2014-01-01

Background Atrial fibrillation (AF) affects over 30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods & Results To identify new AF-related genes, we utilized a multifaceted approach, combining large-scale genotyping in two ethnically distinct populations, cis-eQTL mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501, RR=1.18, 95%CI 1.13 – 1.23, p=6.5×10−16), GJA1 (rs13216675, RR=1.10, 95%CI 1.06 – 1.14, p=2.2×10−8), TBX5 (rs10507248, RR=1.12, 95%CI 1.08 – 1.16, p=5.7×10−11), and CAND2 (rs4642101, RR=1.10, 95%CI 1.06 – 1.14, p=9.8×10−9). In Japanese, novel loci were identified near NEURL (rs6584555, RR=1.32, 95%CI 1.26–1.39, p=2.0×10−25) and CUX2 (rs6490029, RR=1.12, 95%CI 1.08–1.16, p=3.9×10−9). The top SNPs or their proxies were identified as cis-eQTLs for the genes CAND2 (p=2.6×10−19), GJA1 (p=2.66×10−6), and TBX5 (p=1.36×10−05). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions We have identified five novel loci for AF. Our results further expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation. PMID:25124494

How important is importance for prospective memory? A review

PubMed Central

Walter, Stefan; Meier, Beat

2014-01-01

Forgetting to carry out an intention as planned can have serious consequences in everyday life. People sometimes even forget intentions that they consider as very important. Here, we review the literature on the impact of importance on prospective memory performance. We highlight different methods used to manipulate the importance of a prospective memory task such as providing rewards, importance relative to other ongoing activities, absolute importance, and providing social motives. Moreover, we address the relationship between importance and other factors known to affect prospective memory and ongoing task performance such as type of prospective memory task (time-, event-, or activity-based), cognitive loads, and processing overlaps. Finally, we provide a connection to motivation, we summarize the effects of task importance and we identify important venues for future research. PMID:25018743

Sensitivity of Ocean Reflectance Inversion Models for Identifying and Discriminating Between Phytoplankton Functional Groups

NASA Technical Reports Server (NTRS)

Werdell, P. Jeremy; Ooesler, Collin S.

2012-01-01

The daily, synoptic images provided by satellite ocean color instruments provide viable data streams for observing changes in the biogeochemistrY of marine ecosystems. Ocean reflectance inversion models (ORMs) provide a common mechanism for inverting the "color" of the water observed a satellite into marine inherent optical properties (lOPs) through a combination of empiricism and radiative transfer theory. lOPs, namely the spectral absorption and scattering characteristics of ocean water and its dissolved and particulate constituents, describe the contents of the upper ocean, information critical for furthering scientific understanding of biogeochemical oceanic processes. Many recent studies inferred marine particle sizes and discriminated between phytoplankton functional groups using remotely-sensed lOPs. While all demonstrated the viability of their approaches, few described the vertical distributions of the water column constituents under consideration and, thus, failed to report the biophysical conditions under which their model performed (e.g., the depth and thickness of the phytoplankton bloom(s)). We developed an ORM to remotely identifY Noctiluca miliaris and other phytoplankton functional types using satellite ocean color data records collected in the northern Arabian Sea. Here, we present results from analyses designed to evaluate the applicability and sensitivity of the ORM to varied biophysical conditions. Specifically, we: (1) synthesized a series of vertical profiles of spectral inherent optical properties that represent a wide variety of bio-optical conditions for the northern Arabian Sea under aN Miliaris bloom; (2) generated spectral remote-sensing reflectances from these profiles using Hydrolight; and, (3) applied the ORM to the synthesized reflectances to estimate the relative concentrations of diatoms and N Miliaris for each example. By comparing the estimates from the inversion model to those from synthesized vertical profiles, we were able to

Exome sequencing identifies novel compound heterozygous IFNA4 and IFNA10 mutations as a cause of impaired function in Crohn’s disease patients

PubMed Central

Xiao, Chuan-Xing; Xiao, Jing-Jing; Xu, Hong-Zhi; Wang, Huan-Huan; Chen, Xu; Liu, Yuan-Sheng; Li, Ping; Shi, Ying; Nie, Yong-Zhan; Li, Shao; Wu, Kai-Chun; Liu, Zhan-Ju; Ren, Jian-Lin; Guleng, Bayasi

2015-01-01

Previous studies have highlighted the role of genetic predispositions in disease, and several genes had been identified as important in Crohn’s disease (CD). However, many of these genes are likely rare and not associated with susceptibility in Chinese CD patients. We found 294 shared identical variants in the CD patients of which 26 were validated by Sanger sequencing. Two heterozygous IFN variants (IFNA10 c.60 T > A; IFNA4 c.60 A > T) were identified as significantly associated with CD susceptibility. The single-nucleotide changes alter a cysteine situated before the signal peptide cleavage site to a stop code (TGA) in IFNA10 result in the serum levels of IFNA10 were significantly decreased in the CD patients compared to the controls. Furthermore, the IFNA10 and IFNA4 mutants resulted in an impairment of the suppression of HCV RNA replication in HuH7 cells, and the administration of the recombinant IFN subtypes restored DSS-induced colonic inflammation through the upregulation of CD4+ Treg cells. We identified heterozygous IFNA10 and IFNA4 variants as a cause of impaired function and CD susceptibility genes in Chinese patients from multiple center based study. These findings might provide clues in the understanding of the genetic heterogeneity of CD and lead to better screening and improved treatment. PMID:26000985

Increased Range of Motion Is Important for Functional Outcome and Satisfaction After Total Knee Arthroplasty in Asian Patients.

PubMed

Ha, Chul-Won; Park, Yong-Beom; Song, Young-Suk; Kim, Jun-Ho; Park, Yong-Geun

2016-06-01

Although range of motion (ROM) is considered as an important factor for good outcome after total knee arthroplasty (TKA), the association of the degree of ROM with functional outcome and patient satisfaction is debated. We, therefore, investigated whether increased ROM would affect functional outcome and patient satisfaction after TKA in Asian patients. We reviewed 630 patients who underwent primary TKA with minimum 2-year follow-up. Clinical outcomes were evaluated by Knee Society (KS) score, Western Ontario and McMaster Universities osteoarthritis index, and high-flexion knee score. Patient satisfaction was evaluated using a validated questionnaire. The association of ROM and change in ROM (cROM) with clinical outcomes and satisfaction were analyzed using partial correlation analysis and multiple median regression analysis. All functional scores showed significant correlation with postoperative ROM (r = 0.129, P = .001 in Knee Society score; r = -0.101, P = .012 in Western Ontario and McMaster Universities osteoarthritis index; r = 0.183, P < .001 in high-flexion knee score). cROM correlated with satisfaction (r = 0.192, P = .005). Postoperative ROM and cROM were revealed as predisposing factors affecting function outcome using multivariable regression analysis. cROM was found as a predisposing factor affecting satisfaction. Based on the results of this study, ROM positively associated with functional outcome and cROM positively associated with patient satisfaction after TKA. These findings suggest that increased ROM after TKA is an important factor for functional outcome and satisfaction in Asian patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Importance of multi-modal approaches to effectively identify cataract cases from electronic health records.

PubMed

Peissig, Peggy L; Rasmussen, Luke V; Berg, Richard L; Linneman, James G; McCarty, Catherine A; Waudby, Carol; Chen, Lin; Denny, Joshua C; Wilke, Russell A; Pathak, Jyotishman; Carrell, David; Kho, Abel N; Starren, Justin B

2012-01-01

There is increasing interest in using electronic health records (EHRs) to identify subjects for genomic association studies, due in part to the availability of large amounts of clinical data and the expected cost efficiencies of subject identification. We describe the construction and validation of an EHR-based algorithm to identify subjects with age-related cataracts. We used a multi-modal strategy consisting of structured database querying, natural language processing on free-text documents, and optical character recognition on scanned clinical images to identify cataract subjects and related cataract attributes. Extensive validation on 3657 subjects compared the multi-modal results to manual chart review. The algorithm was also implemented at participating electronic MEdical Records and GEnomics (eMERGE) institutions. An EHR-based cataract phenotyping algorithm was successfully developed and validated, resulting in positive predictive values (PPVs) >95%. The multi-modal approach increased the identification of cataract subject attributes by a factor of three compared to single-mode approaches while maintaining high PPV. Components of the cataract algorithm were successfully deployed at three other institutions with similar accuracy. A multi-modal strategy incorporating optical character recognition and natural language processing may increase the number of cases identified while maintaining similar PPVs. Such algorithms, however, require that the needed information be embedded within clinical documents. We have demonstrated that algorithms to identify and characterize cataracts can be developed utilizing data collected via the EHR. These algorithms provide a high level of accuracy even when implemented across multiple EHRs and institutional boundaries.

Importance of multi-modal approaches to effectively identify cataract cases from electronic health records

PubMed Central

Rasmussen, Luke V; Berg, Richard L; Linneman, James G; McCarty, Catherine A; Waudby, Carol; Chen, Lin; Denny, Joshua C; Wilke, Russell A; Pathak, Jyotishman; Carrell, David; Kho, Abel N; Starren, Justin B

2012-01-01

Objective There is increasing interest in using electronic health records (EHRs) to identify subjects for genomic association studies, due in part to the availability of large amounts of clinical data and the expected cost efficiencies of subject identification. We describe the construction and validation of an EHR-based algorithm to identify subjects with age-related cataracts. Materials and methods We used a multi-modal strategy consisting of structured database querying, natural language processing on free-text documents, and optical character recognition on scanned clinical images to identify cataract subjects and related cataract attributes. Extensive validation on 3657 subjects compared the multi-modal results to manual chart review. The algorithm was also implemented at participating electronic MEdical Records and GEnomics (eMERGE) institutions. Results An EHR-based cataract phenotyping algorithm was successfully developed and validated, resulting in positive predictive values (PPVs) >95%. The multi-modal approach increased the identification of cataract subject attributes by a factor of three compared to single-mode approaches while maintaining high PPV. Components of the cataract algorithm were successfully deployed at three other institutions with similar accuracy. Discussion A multi-modal strategy incorporating optical character recognition and natural language processing may increase the number of cases identified while maintaining similar PPVs. Such algorithms, however, require that the needed information be embedded within clinical documents. Conclusion We have demonstrated that algorithms to identify and characterize cataracts can be developed utilizing data collected via the EHR. These algorithms provide a high level of accuracy even when implemented across multiple EHRs and institutional boundaries. PMID:22319176

New proteins identified in epididymal fluid from the platypus (Ornithorhynchus anatinus).

PubMed

Dacheux, Jean-Louis; Dacheux, Francoise; Labas, Valerie; Ecroyd, Heath; Nixon, Brett; Jones, Russell C

2009-01-01

The platypus epididymal proteome is being studied because epididymal proteins are essential for male fertility in mammals and it is considered that knowledge of the epididymal proteome in an early mammal would be informative in assessing the convergence and divergence of proteins that are important in the function of the mammalian epididymis. Few of the epididymal proteins that have been identified in eutherian mammals were found in platypus caudal epididymal fluid, and the major epididymal proteins in the platypus (PXN-FBPL, SPARC and E-OR20) have never been identified in the epididymis of any other mammal.

A meta-analysis of multiple myeloma risk regions in African and European ancestry populations identifies putatively functional loci

PubMed Central

Rand, Kristin A.; Song, Chi; Dean, Eric; Serie, Daniel J.; Curtin, Karen; Sheng, Xin; Hu, Donglei; Huff, Carol Ann; Bernal-Mizrachi, Leon; Tomasson, Michael H.; Ailawadhi, Sikander; Singhal, Seema; Pawlish, Karen; Peters, Edward S.; Bock, Cathryn H.; Stram, Alex; Van Den Berg, David J; Edlund, Christopher K.; V.Conti, David; Zimmerman, Todd; Hwang, Amie E.; Huntsman, Scott; Graff, John; Nooka, Ajay; Kong, Yinfei; Pregja, Silvana L.; Berndt, Sonja I.; Blot, William J.; Carpten, John; Casey, Graham; Chu, Lisa; Diver, W. Ryan; Stevens, Victoria L.; Lieber, Michael R.; Goodman, Phyllis J.; Hennis, Anselm J.M.; Hsing, Ann W.; Mehta, Jayesh; Kittles, Rick A.; Kolb, Suzanne; Klein, Eric A.; Leske, Cristina; Murphy, Adam B.; Nemesure, Barbara; Neslund-Dudas, Christine; Strom, Sara S.; Vij, Ravi; Rybicki, Benjamin A.; Stanford, Janet L.; Signorello, Lisa B.; Witte, John S.; Ambrosone, Christine B.; Bhatti, Parveen; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F.; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah J.; Bandera, Elisa V.; Birmann, Brenda M.; Ingles, Sue A.; Press, Michael F.; Atanackovic, Djordje; Glenn, Martha J.; Cannon-Albright, Lisa A.; Jones, Brandt; Tricot, Guido; Martin, Thomas G.; Kumar, Shaji K.; Wolf, Jeffrey L.; Deming, Sandra L.; Rothman, Nathaniel; Brooks-Wilson, Angela R.; Rajkumar, S. Vincent; Kolonel, Laurence N.; Chanock, Stephen J.; Slager, Susan L.; Severson, Richard K.; Janakiraman, Nalini; Terebelo, Howard R.; Brown, Elizabeth E.; De Roos, Anneclaire J.; Mohrbacher, Ann F.; Colditz, Graham A.; Giles, Graham G.; Spinelli, John J.; Chiu, Brian C.; Munshi, Nikhil C.; Anderson, Kenneth C.; Levy, Joan; Zonder, Jeffrey A.; Orlowski, Robert Z.; Lonial, Sagar; Camp, Nicola J.; Vachon, Celine M.; Ziv, Elad; Stram, Daniel O.; Hazelett, Dennis J.; Haiman, Christopher A.; Cozen, Wendy

2017-01-01

Background Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma (MM). Methods We performed association testing of common variation in eight regions in 1,264 MM patients and 1,479 controls of European ancestry (EA) and 1,305 MM patients and 7,078 controls of African ancestry (AA) and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (p<0.05) associated with MM risk in AAs and EAs and the variant in 3p22.1 was associated in EAs only. In a combined AA-EA meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically signficantly associated with MM risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR=1.32, p=2.93×10−7) in TNFRSF13B, encodes a lymphocyte-specific protein in the tumor necrosis factor receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions We found that reported MM susceptibility regions contain risk variants important across populations supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact A subset of reported risk loci for multiple myeloma have consistent affects across populations and are likely to be functional. PMID:27587788

The importance of trunk muscle strength for balance, functional performance, and fall prevention in seniors: a systematic review.

PubMed

Granacher, Urs; Gollhofer, Albert; Hortobágyi, Tibor; Kressig, Reto W; Muehlbauer, Thomas

2013-07-01

The aging process results in a number of functional (e.g., deficits in balance and strength/power performance), neural (e.g., loss of sensory/motor neurons), muscular (e.g., atrophy of type-II muscle fibers in particular), and bone-related (e.g., osteoporosis) deteriorations. Traditionally, balance and/or lower extremity resistance training were used to mitigate these age-related deficits. However, the effects of resistance training are limited and poorly translate into improvements in balance, functional tasks, activities of daily living, and fall rates. Thus, it is necessary to develop and design new intervention programs that are specifically tailored to counteract age-related weaknesses. Recent studies indicate that measures of trunk muscle strength (TMS) are associated with variables of static/dynamic balance, functional performance, and falls (i.e., occurrence, fear, rate, and/or risk of falls). Further, there is preliminary evidence in the literature that core strength training (CST) and Pilates exercise training (PET) have a positive influence on measures of strength, balance, functional performance, and falls in older adults. The objectives of this systematic literature review are: (a) to report potential associations between TMS/trunk muscle composition and balance, functional performance, and falls in old adults, and (b) to describe and discuss the effects of CST/PET on measures of TMS, balance, functional performance, and falls in seniors. A systematic approach was employed to capture all articles related to TMS/trunk muscle composition, balance, functional performance, and falls in seniors that were identified using the electronic databases PubMed and Web of Science (1972 to February 2013). A systematic approach was used to evaluate the 582 articles identified for initial review. Cross-sectional (i.e., relationship) or longitudinal (i.e., intervention) studies were included if they investigated TMS and an outcome-related measure of balance, functional

The importance of accounting for imperfect detection when estimating functional and phylogenetic community structure.

PubMed

Si, Xingfeng; Cadotte, Marc W; Zhao, Yuhao; Zhou, Haonan; Zeng, Di; Li, Jiaqi; Jin, Tinghao; Ren, Peng; Wang, Yanping; Ding, Ping; Tingley, Morgan W

2018-06-26

Incorporating imperfect detection when estimating species richness has become commonplace in the past decade. However, the question of how imperfect detection of species affects estimates of functional and phylogenetic community structure remains untested. We used long-term counts of breeding bird species that were detected at least once on islands in a land-bridge island system, and employed multi-species occupancy models to assess the effects of imperfect detection of species on estimates of bird diversity and community structure by incorporating species traits and phylogenies. Our results showed that taxonomic, functional, and phylogenetic diversity were all underestimated significantly as a result of species' imperfect detection, with taxonomic diversity showing the greatest bias. The functional and phylogenetic structure calculated from observed communities were both more clustered than those from the detection-corrected communities due to missed distinct species. The discrepancy between observed and estimated diversity differed according to the measure of biodiversity employed. Our study demonstrates the importance of accounting for species' imperfect detection in biodiversity studies, especially for functional and phylogenetic community ecology, and when attempting to infer community assembly processes. With datasets that allow for detection-corrected community structure, we can better estimate diversity and infer the underlying mechanisms that structure community assembly, and thus make reliable management decisions for the conservation of biodiversity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Functional brain activation differences in stuttering identified with a rapid fMRI sequence

PubMed Central

Kraft, Shelly Jo; Choo, Ai Leen; Sharma, Harish; Ambrose, Nicoline G.

2011-01-01

The purpose of this study was to investigate whether brain activity related to the presence of stuttering can be identified with rapid functional MRI (fMRI) sequences that involved overt and covert speech processing tasks. The long-term goal is to develop sensitive fMRI approaches with developmentally appropriate tasks to identify deviant speech motor and auditory brain activity in children who stutter closer to the age at which recovery from stuttering is documented. Rapid sequences may be preferred for individuals or populations who do not tolerate long scanning sessions. In this report, we document the application of a picture naming and phoneme monitoring task in three minute fMRI sequences with adults who stutter (AWS). If relevant brain differences are found in AWS with these approaches that conform to previous reports, then these approaches can be extended to younger populations. Pairwise contrasts of brain BOLD activity between AWS and normally fluent adults indicated the AWS showed higher BOLD activity in the right inferior frontal gyrus (IFG), right temporal lobe and sensorimotor cortices during picture naming and and higher activity in the right IFG during phoneme monitoring. The right lateralized pattern of BOLD activity together with higher activity in sensorimotor cortices is consistent with previous reports, which indicates rapid fMRI sequences can be considered for investigating stuttering in younger participants. PMID:22133409

Biodiversity and Resilience of Ecosystem Functions.

PubMed

Oliver, Tom H; Heard, Matthew S; Isaac, Nick J B; Roy, David B; Procter, Deborah; Eigenbrod, Felix; Freckleton, Rob; Hector, Andy; Orme, C David L; Petchey, Owen L; Proença, Vânia; Raffaelli, David; Suttle, K Blake; Mace, Georgina M; Martín-López, Berta; Woodcock, Ben A; Bullock, James M

2015-11-01

Accelerating rates of environmental change and the continued loss of global biodiversity threaten functions and services delivered by ecosystems. Much ecosystem monitoring and management is focused on the provision of ecosystem functions and services under current environmental conditions, yet this could lead to inappropriate management guidance and undervaluation of the importance of biodiversity. The maintenance of ecosystem functions and services under substantial predicted future environmental change (i.e., their 'resilience') is crucial. Here we identify a range of mechanisms underpinning the resilience of ecosystem functions across three ecological scales. Although potentially less important in the short term, biodiversity, encompassing variation from within species to across landscapes, may be crucial for the longer-term resilience of ecosystem functions and the services that they underpin. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identifying group-sensitive physical activities: a differential item functioning analysis of NHANES data.

PubMed

Gao, Yong; Zhu, Weimo

2011-05-01

The purpose of this study was to identify subgroup-sensitive physical activities (PA) using differential item functioning (DIF) analysis. A sub-unweighted sample of 1857 (men=923 and women=934) from the 2003-2004 National Health and Nutrition Examination Survey PA questionnaire data was used for the analyses. Using the Mantel-Haenszel, the simultaneous item bias test, and the ANOVA DIF methods, 33 specific leisure-time moderate and/or vigorous PA (MVPA) items were analyzed for DIF across race/ethnicity, gender, education, income, and age groups. Many leisure-time MVPA items were identified as large DIF items. When participating in the same amount of leisure-time MVPA, non-Hispanic blacks were more likely to participate in basketball and dance activities than non-Hispanic whites (NHW); NHW were more likely to participated in golf and hiking than non-Hispanic blacks; Hispanics were more likely to participate in dancing, hiking, and soccer than NHW, whereas NHW were more likely to engage in bicycling, golf, swimming, and walking than Hispanics; women were more likely to participate in aerobics, dancing, stretching, and walking than men, whereas men were more likely to engage in basketball, fishing, golf, running, soccer, weightlifting, and hunting than women; educated persons were more likely to participate in jogging and treadmill exercise than less educated persons; persons with higher incomes were more likely to engage in golf than those with lower incomes; and adults (20-59 yr) were more likely to participate in basketball, dancing, jogging, running, and weightlifting than older adults (60+ yr), whereas older adults were more likely to participate in walking and golf than younger adults. DIF methods are able to identify subgroup-sensitive PA and thus provide useful information to help design group-sensitive, targeted interventions for disadvantaged PA subgroups. © 2011 by the American College of Sports Medicine

Application of Think Aloud Protocols for Examining and Confirming Sources of Differential Item Functioning Identified by Expert Reviews

ERIC Educational Resources Information Center

Ercikan, Kadriye; Arim, Rubab; Law, Danielle; Domene, Jose; Gagnon, France; Lacroix, Serge

2010-01-01

This paper demonstrates and discusses the use of think aloud protocols (TAPs) as an approach for examining and confirming sources of differential item functioning (DIF). The TAPs are used to investigate to what extent surface characteristics of the items that are identified by expert reviews as sources of DIF are supported by empirical evidence…

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

PubMed Central

Artigas, María Soler; Wain, Louise V.; Miller, Suzanne; Kheirallah, Abdul Kader; Huffman, Jennifer E.; Ntalla, Ioanna; Shrine, Nick; Obeidat, Ma'en; Trochet, Holly; McArdle, Wendy L.; Alves, Alexessander Couto; Hui, Jennie; Zhao, Jing Hua; Joshi, Peter K.; Teumer, Alexander; Albrecht, Eva; Imboden, Medea; Rawal, Rajesh; Lopez, Lorna M.; Marten, Jonathan; Enroth, Stefan; Surakka, Ida; Polasek, Ozren; Lyytikäinen, Leo-Pekka; Granell, Raquel; Hysi, Pirro G.; Flexeder, Claudia; Mahajan, Anubha; Beilby, John; Bossé, Yohan; Brandsma, Corry-Anke; Campbell, Harry; Gieger, Christian; Gläser, Sven; González, Juan R.; Grallert, Harald; Hammond, Chris J.; Harris, Sarah E.; Hartikainen, Anna-Liisa; Heliövaara, Markku; Henderson, John; Hocking, Lynne; Horikoshi, Momoko; Hutri-Kähönen, Nina; Ingelsson, Erik; Johansson, Åsa; Kemp, John P.; Kolcic, Ivana; Kumar, Ashish; Lind, Lars; Melén, Erik; Musk, Arthur W.; Navarro, Pau; Nickle, David C.; Padmanabhan, Sandosh; Raitakari, Olli T.; Ried, Janina S.; Ripatti, Samuli; Schulz, Holger; Scott, Robert A.; Sin, Don D.; Starr, John M.; Deloukas, Panos; Hansell, Anna L.; Hubbard, Richard; Jackson, Victoria E.; Marchini, Jonathan; Pavord, Ian; Thomson, Neil C.; Zeggini, Eleftheria; Viñuela, Ana; Völzke, Henry; Wild, Sarah H.; Wright, Alan F.; Zemunik, Tatijana; Jarvis, Deborah L.; Spector, Tim D.; Evans, David M.; Lehtimäki, Terho; Vitart, Veronique; Kähönen, Mika; Gyllensten, Ulf; Rudan, Igor; Deary, Ian J.; Karrasch, Stefan; Probst-Hensch, Nicole M.; Heinrich, Joachim; Stubbe, Beate; Wilson, James F.; Wareham, Nicholas J.; James, Alan L.; Morris, Andrew P.; Jarvelin, Marjo-Riitta; Hayward, Caroline; Sayers, Ian; Strachan, David P.; Hall, Ian P.; Tobin, Martin D.

2015-01-01

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered. PMID:26635082

Structural requirements for interleukin-8 function identified by design of analogs and CXC chemokine hybrids.

PubMed

Clark-Lewis, I; Dewald, B; Loetscher, M; Moser, B; Baggiolini, M

1994-06-10

Structure-activity relationships of human interleukin-8 (IL-8) were probed using chemically synthesized analogs with single or double amino acid substitutions, as well as hybrids derived by substituting IL-8 regions into IP10, a related protein that lacks IL-8 activity. The analogs were tested for functional activity by measuring induction of elastase release from human neutrophils and competition for binding of radiolabeled IL-8. The hybrid studies indicated that Gly31 and Pro32, as well as the NH2-terminal region from IL-8 are required to convert IP10 into a fully functional protein, suggesting that these elements are critical for IL-8 activity. Both disulfide bridges, linking residue 7 to 34 and residue 9 to 50, were critical for function, as shown by substituting the cysteine pairs with alpha-aminobutyric acid. Single conservative substitutions were generally accepted into the 10-22 region of IL-8, which contrasts with the ELR motif (residues 4-6), previously shown to be essential for activity. The importance of residues within the 10-15 region and the 17-22 region was demonstrated with hybrids. In addition, some of the 4-22 residues have structural roles that may be important; for example, Tyr13, Phe17, and Phe21 are involved in aromatic interactions in the IL-8 structure, and are also moderately sensitive to modification. Except for Cys50, the results argue against a role for the 36-72 region, including the COOH-terminal alpha-helix, in receptor binding. We conclude that the disulfide bridges and 30-35 turn provide a structural scaffold for the NH2-terminal region which includes the primary receptor-binding site (the ELR motif) and secondary binding and conformational determinants between residues 10 and 22.

Incorporating deep learning with convolutional neural networks and position specific scoring matrices for identifying electron transport proteins.

PubMed

Le, Nguyen-Quoc-Khanh; Ho, Quang-Thai; Ou, Yu-Yen

2017-09-05

In several years, deep learning is a modern machine learning technique using in a variety of fields with state-of-the-art performance. Therefore, utilization of deep learning to enhance performance is also an important solution for current bioinformatics field. In this study, we try to use deep learning via convolutional neural networks and position specific scoring matrices to identify electron transport proteins, which is an important molecular function in transmembrane proteins. Our deep learning method can approach a precise model for identifying of electron transport proteins with achieved sensitivity of 80.3%, specificity of 94.4%, and accuracy of 92.3%, with MCC of 0.71 for independent dataset. The proposed technique can serve as a powerful tool for identifying electron transport proteins and can help biologists understand the function of the electron transport proteins. Moreover, this study provides a basis for further research that can enrich a field of applying deep learning in bioinformatics. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Fatty Aldehyde and Fatty Alcohol Metabolism: Review and Importance for Epidermal Structure and Function

PubMed Central

Rizzo, William B.

2014-01-01

Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. PMID:24036493

Melanoma Biomolecules: Independently Identified but Functionally Intertwined

PubMed Central

Dye, Danielle E.; Medic, Sandra; Ziman, Mel; Coombe, Deirdre R.

2013-01-01

The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (<1 mm thick) will have recurrence and die within 10 years, despite no evidence of local or metastatic spread at the time of diagnosis. Thus, there is a need for additional prognostic markers to help identify those patients that may be at risk of recurrent disease. Many studies and several meta-analyses have compared gene and protein expression in melanocytes, naevi, primary, and metastatic melanoma in an attempt to find informative prognostic markers for these patients. However, although a large number of putative biomarkers have been described, few of these molecules are informative when used in isolation. The best approach is likely to involve a combination of molecules. We believe one approach could be to analyze the expression of a group of interacting proteins that regulate different aspects of the metastatic pathway. This is because a primary lesion expressing proteins involved in multiple stages of metastasis may be more likely to lead to secondary disease than one that does not. This review focuses on five putative biomarkers – melanoma cell adhesion molecule (MCAM), galectin-3 (gal-3), matrix metalloproteinase 2 (MMP-2), chondroitin sulfate proteoglycan 4 (CSPG4), and paired box 3 (PAX3). The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology. PMID:24069584

Identifying Important Atlantic Areas for the conservation of Balearic shearwaters: Spatial overlap with conservation areas

NASA Astrophysics Data System (ADS)

Pérez-Roda, Amparo; Delord, Karine; Boué, Amélie; Arcos, José Manuel; García, David; Micol, Thierry; Weimerskirch, Henri; Pinaud, David; Louzao, Maite

2017-07-01

Marine protected areas (MPAs) are considered one of the main tools in both fisheries and conservation management to protect threatened species and their habitats around the globe. However, MPAs are underrepresented in marine environments compared to terrestrial environments. Within this context, we studied the Atlantic non-breeding distribution of the southern population of Balearic shearwaters (Puffinus mauretanicus) breeding in Eivissa during the 2011-2012 period based on global location sensing (GLS) devices. Our objectives were (1) to identify overall Important Atlantic Areas (IAAs) from a southern population, (2) to describe spatio-temporal patterns of oceanographic habitat use, and (3) to assess whether existing conservation areas (Natura 2000 sites and marine Important Bird Areas (IBAs)) cover the main IAAs of Balearic shearwaters. Our results highlighted that the Atlantic staging (from June to October in 2011) dynamic of the southern population was driven by individual segregation at both spatial and temporal scales. Individuals ranged in the North-East Atlantic over four main IAAs (Bay of Biscay: BoB, Western Iberian shelf: WIS, Gulf of Cadiz: GoC, West of Morocco: WoM). While most individuals spent more time on the WIS or in the GoC, a small number of birds visited IAAs at the extremes of their Atlantic distribution range (i.e., BoB and WoM). The chronology of the arrivals to the IAAs showed a latitudinal gradient with northern areas reached earlier during the Atlantic staging. The IAAs coincided with the most productive areas (higher chlorophyll a values) in the NE Atlantic between July and October. The spatial overlap between IAAs and conservation areas was higher for Natura 2000 sites than marine IBAs (areas with and without legal protection, respectively). Concerning the use of these areas, a slightly higher proportion of estimated positions fell within marine IBAs compared to designated Natura 2000 sites, with Spanish and Portuguese conservation

Seed-effect modeling improves the consistency of genome-wide loss-of-function screens and identifies synthetic lethal vulnerabilities in cancer cells.

PubMed

Jaiswal, Alok; Peddinti, Gopal; Akimov, Yevhen; Wennerberg, Krister; Kuznetsov, Sergey; Tang, Jing; Aittokallio, Tero

2017-06-01

Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity. We performed a systematic, quantitative analysis of the consistency between two genome-wide shRNA screens conducted on a compendium of cancer cell lines, and also compared several gene summarization methods for inferring gene essentiality from shRNA level data. We then devised novel concepts of seed essentiality and shRNA family, based on seed region sequences of shRNAs, to study in-depth the contribution of seed-mediated off-target effects to the consistency of the two screens. We further investigated two seed-sequence properties, seed pairing stability, and target abundance in terms of their capability to minimize the off-target effects in post-screening data analysis. Finally, we applied this novel methodology to identify genetic interactions and synthetic lethal partners of cancer drivers, and confirmed differential essentiality phenotypes by detailed CRISPR/Cas9 experiments. Using the novel concepts of seed essentiality and shRNA family, we demonstrate how genome-wide loss-of-function profiling of a common set of cancer cell lines can be actually made fairly reproducible when considering seed-mediated off-target effects. Importantly, by excluding shRNAs having higher propensity for off-target effects, based on their seed-sequence properties, one can remove noise from the genome-wide shRNA datasets. As a translational application case, we demonstrate enhanced reproducibility of genetic interaction partners of common cancer drivers, as well as identify novel

Comprehensive analysis of the functional microRNA–mRNA regulatory network identifies miRNA signatures associated with glioma malignant progression

PubMed Central

Li, Yongsheng; Xu, Juan; Chen, Hong; Bai, Jing; Li, Shengli; Zhao, Zheng; Shao, Tingting; Jiang, Tao; Ren, Huan; Kang, Chunsheng; Li, Xia

2013-01-01

Glioma is the most common and fatal primary brain tumour with poor prognosis; however, the functional roles of miRNAs in glioma malignant progression are insufficiently understood. Here, we used an integrated approach to identify miRNA functional targets during glioma malignant progression by combining the paired expression profiles of miRNAs and mRNAs across 160 Chinese glioma patients, and further constructed the functional miRNA–mRNA regulatory network. As a result, most tumour-suppressive miRNAs in glioma progression were newly discovered, whose functions were widely involved in gliomagenesis. Moreover, three miRNA signatures, with different combinations of hub miRNAs (regulations≥30) were constructed, which could independently predict the survival of patients with all gliomas, high-grade glioma and glioblastoma. Our network-based method increased the ability to identify the prognostic biomarkers, when compared with the traditional method and random conditions. Hsa-miR-524-5p and hsa-miR-628-5p, shared by these three signatures, acted as protective factors and their expression decreased gradually during glioma progression. Functional analysis of these miRNA signatures highlighted their critical roles in cell cycle and cell proliferation in glioblastoma malignant progression, especially hsa-miR-524-5p and hsa-miR-628-5p exhibited dominant regulatory activities. Therefore, network-based biomarkers are expected to be more effective and provide deep insights into the molecular mechanism of glioma malignant progression. PMID:24194606

COMPARABLE MEASURES OF COGNITIVE FUNCTION IN HUMAN INFANTS AND LABORATORY ANIMALS TO IDENTIFY ENVIRONMENTAL HEALTH RISKS TO CHILDREN

EPA Science Inventory

The importance of including neurodevelopmental end points in environmental studies is clear. A validated measure of cognitive function in human infants that also has a homologous or parallel test in laboratory animal studies will provide a valuable approach for large-scale studie...

Annotating Protein Functional Residues by Coupling High-Throughput Fitness Profile and Homologous-Structure Analysis.

PubMed

Du, Yushen; Wu, Nicholas C; Jiang, Lin; Zhang, Tianhao; Gong, Danyang; Shu, Sara; Wu, Ting-Ting; Sun, Ren

2016-11-01

Identification and annotation of functional residues are fundamental questions in protein sequence analysis. Sequence and structure conservation provides valuable information to tackle these questions. It is, however, limited by the incomplete sampling of sequence space in natural evolution. Moreover, proteins often have multiple functions, with overlapping sequences that present challenges to accurate annotation of the exact functions of individual residues by conservation-based methods. Using the influenza A virus PB1 protein as an example, we developed a method to systematically identify and annotate functional residues. We used saturation mutagenesis and high-throughput sequencing to measure the replication capacity of single nucleotide mutations across the entire PB1 protein. After predicting protein stability upon mutations, we identified functional PB1 residues that are essential for viral replication. To further annotate the functional residues important to the canonical or noncanonical functions of viral RNA-dependent RNA polymerase (vRdRp), we performed a homologous-structure analysis with 16 different vRdRp structures. We achieved high sensitivity in annotating the known canonical polymerase functional residues. Moreover, we identified a cluster of noncanonical functional residues located in the loop region of the PB1 β-ribbon. We further demonstrated that these residues were important for PB1 protein nuclear import through the interaction with Ran-binding protein 5. In summary, we developed a systematic and sensitive method to identify and annotate functional residues that are not restrained by sequence conservation. Importantly, this method is generally applicable to other proteins about which homologous-structure information is available. To fully comprehend the diverse functions of a protein, it is essential to understand the functionality of individual residues. Current methods are highly dependent on evolutionary sequence conservation, which is

Structural RNAs of known and unknown function identified in malaria parasites by comparative genomics and RNA analysis

PubMed Central

Chakrabarti, Kausik; Pearson, Michael; Grate, Leslie; Sterne-Weiler, Timothy; Deans, Jonathan; Donohue, John Paul; Ares, Manuel

2007-01-01

As the genomes of more eukaryotic pathogens are sequenced, understanding how molecular differences between parasite and host might be exploited to provide new therapies has become a major focus. Central to cell function are RNA-containing complexes involved in gene expression, such as the ribosome, the spliceosome, snoRNAs, RNase P, and telomerase, among others. In this article we identify by comparative genomics and validate by RNA analysis numerous previously unknown structural RNAs encoded by the Plasmodium falciparum genome, including the telomerase RNA, U3, 31 snoRNAs, as well as previously predicted spliceosomal snRNAs, SRP RNA, MRP RNA, and RNAse P RNA. Furthermore, we identify six new RNA coding genes of unknown function. To investigate the relationships of the RNA coding genes to other genomic features in related parasites, we developed a genome browser for P. falciparum (http://areslab.ucsc.edu/cgi-bin/hgGateway). Additional experiments provide evidence supporting the prediction that snoRNAs guide methylation of a specific position on U4 snRNA, as well as predicting an snRNA promoter element particular to Plasmodium sp. These findings should allow detailed structural comparisons between the RNA components of the gene expression machinery of the parasite and its vertebrate hosts. PMID:17901154

Identifying Country-Specific Cultures of Physics Education: A differential item functioning approach

NASA Astrophysics Data System (ADS)

Mesic, Vanes

2012-11-01

In international large-scale assessments of educational outcomes, student achievement is often represented by unidimensional constructs. This approach allows for drawing general conclusions about country rankings with respect to the given achievement measure, but it typically does not provide specific diagnostic information which is necessary for systematic comparisons and improvements of educational systems. Useful information could be obtained by exploring the differences in national profiles of student achievement between low-achieving and high-achieving countries. In this study, we aimed to identify the relative weaknesses and strengths of eighth graders' physics achievement in Bosnia and Herzegovina in comparison to the achievement of their peers from Slovenia. For this purpose, we ran a secondary analysis of Trends in International Mathematics and Science Study (TIMSS) 2007 data. The student sample consisted of 4,220 students from Bosnia and Herzegovina and 4,043 students from Slovenia. After analysing the cognitive demands of TIMSS 2007 physics items, the correspondent differential item functioning (DIF)/differential group functioning contrasts were estimated. Approximately 40% of items exhibited large DIF contrasts, indicating significant differences between cultures of physics education in Bosnia and Herzegovina and Slovenia. The relative strength of students from Bosnia and Herzegovina showed to be mainly associated with the topic area 'Electricity and magnetism'. Classes of items which required the knowledge of experimental method, counterintuitive thinking, proportional reasoning and/or the use of complex knowledge structures proved to be differentially easier for students from Slovenia. In the light of the presented results, the common practice of ranking countries with respect to universally established cognitive categories seems to be potentially misleading.

The requirement of iron transport for lymphocyte function.

PubMed

Lo, Bernice

2016-01-01

Iron is essential in multiple cellular processes and is especially critical for cellular respiration and division. A new study identified a mutation affecting the iron import receptor TfR1 as the cause of a human primary immunodeficiency, illuminating the importance of iron in immune cell function.

Identifying Similarities in Cognitive Subtest Functional Requirements: An Empirical Approach

ERIC Educational Resources Information Center

Frisby, Craig L.; Parkin, Jason R.

2007-01-01

In the cognitive test interpretation literature, a Rational/Intuitive, Indirect Empirical, or Combined approach is typically used to construct conceptual taxonomies of the functional (behavioral) similarities between subtests. To address shortcomings of these approaches, the functional requirements for 49 subtests from six individually…

Functional Expression of Two Neuronal Nicotinic Acetylcholine Receptors from cDNA Clones Identifies a Gene Family

NASA Astrophysics Data System (ADS)

Boulter, Jim; Connolly, John; Deneris, Evan; Goldman, Dan; Heinemann, Steven; Patrick, Jim

1987-11-01

A family of genes coding for proteins homologous to the α subunit of the muscle nicotinic acetylcholine receptor has been identified in the rat genome. These genes are transcribed in the central and peripheral nervous systems in areas known to contain functional nicotinic receptors. In this paper, we demonstrate that three of these genes, which we call alpha3, alpha4, and beta2, encode proteins that form functional nicotinic acetylcholine receptors when expressed in Xenopus oocytes. Oocytes expressing either alpha3 or alpha4 protein in combination with the beta2 protein produced a strong response to acetylcholine. Oocytes expressing only the alpha4 protein gave a weak response to acetylcholine. These receptors are activated by acetylcholine and nicotine and are blocked by Bungarus toxin 3.1. They are not blocked by α -bungarotoxin, which blocks the muscle nicotinic acetylcholine receptor. Thus, the receptors formed by the alpha3, alpha4, and beta2 subunits are pharmacologically similar to the ganglionic-type neuronal nicotinic acetylcholine receptor. These results indicate that the alpha3, alpha4, and beta2 genes encode functional nicotinic acetylcholine receptor subunits that are expressed in the brain and peripheral nervous system.

Immune Selection In Vitro Reveals Human Immunodeficiency Virus Type 1 Nef Sequence Motifs Important for Its Immune Evasion Function In Vivo

PubMed Central

Lee, Patricia; Ng, Hwee L.; Yang, Otto O.

2012-01-01

Human immunodeficiency virus type 1 (HIV-1) Nef downregulates major histocompatibility complex class I (MHC-I), impairing the clearance of infected cells by CD8+ cytotoxic T lymphocytes (CTLs). While sequence motifs mediating this function have been determined by in vitro mutagenesis studies of laboratory-adapted HIV-1 molecular clones, it is unclear whether the highly variable Nef sequences of primary isolates in vivo rely on the same sequence motifs. To address this issue, nef quasispecies from nine chronically HIV-1-infected persons were examined for sequence evolution and altered MHC-I downregulatory function under Gag-specific CTL immune pressure in vitro. This selection resulted in decreased nef diversity and strong purifying selection. Site-by-site analysis identified 13 codons undergoing purifying selection and 1 undergoing positive selection. Of the former, only 6 have been reported to have roles in Nef function, including 4 associated with MHC-I downregulation. Functional testing of naturally occurring in vivo polymorphisms at the 7 sites with no previously known functional role revealed 3 mutations (A84D, Y135F, and G140R) that ablated MHC-I downregulation and 3 (N52A, S169I, and V180E) that partially impaired MHC-I downregulation. Globally, the CTL pressure in vitro selected functional Nef from the in vivo quasispecies mixtures that predominately lacked MHC-I downregulatory function at the baseline. Overall, these data demonstrate that CTL pressure exerts a strong purifying selective pressure for MHC-I downregulation and identifies novel functional motifs present in Nef sequences in vivo. PMID:22553319

Identifying Turbulent Structures through Topological Segmentation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bremer, Peer-Timo; Gruber, Andrea; Bennett, Janine C.

2016-01-01

A new method of extracting vortical structures from a turbulent flow is proposed whereby topological segmentation of an indicator function scalar field is used to identify the regions of influence of the individual vortices. This addresses a long-standing challenge in vector field topological analysis: indicator functions commonly used produce a scalar field based on the local velocity vector field; reconstructing regions of influence for a particular structure requires selecting a threshold to define vortex extent. In practice, the same threshold is rarely meaningful throughout a given flow. By also considering the topology of the indicator field function, the characteristics ofmore » vortex strength and extent can be separated and the ambiguity in the choice of the threshold reduced. The proposed approach is able to identify several types of vortices observed in a jet in cross-flow configuration simultaneously where no single threshold value for a selection of common indicator functions appears able to identify all of these vortex types.« less

Molecular mimicry: an important virulence strategy employed by Legionella pneumophila to subvert host functions.

PubMed

Nora, Tamara; Lomma, Mariella; Gomez-Valero, Laura; Buchrieser, Carmen

2009-08-01

It is 32 years since Legionella pneumophila was identified and recognized as a human pathogen, causing the severe form of pneumonia termed Legionnaires' disease, or legionellosis. This bacterium is found in freshwater reservoirs where it replicates in aquatic protozoa and can invade man-made water distribution systems. Although the disease can be treated by antibiotherapy and prevented through surveillance and control measures, reported cases of Legionnaires' disease continue to rise across Europe and outbreaks of major public health significance still occur. Genome sequencing and analyses led to a giant step forward by suggesting new ways by which this intracellular bacterium might subvert host functions. One particular feature revealed was the presence of many eukaryotic-like proteins, possibly mimicking host proteins to allow intracellular replication of Legionella. Here, we describe the identification and analysis of these proteins and report on recent advances detailing the mechanisms by which these proteins function. Finally, comparative and evolutionary genomic aspects regarding the eukaryotic-like proteins are presented. Collectively, these data have shed new light on the virulence strategies of L. pneumophila, a major aspect of which is molecular mimicry.

Cognitive Function | Science Inventory | US EPA

EPA Pesticide Factsheets

Because chemicals can adversely affect cognitive function in humans, considerable effort has been made to characterize their effects using animal models. Information from such models will be necessary to: evaluate whether chemicals identified as potentially neurotoxic by screening methods actually do affect cognitive function; identify and characterize the mechanisms or pathways by which effects at these targets lead to cognitive dysfunction; address issues of susceptibility and variability, which require understanding the compensations and interactions that only a whole organism can engage; and improve our understanding of the neurobiological underpinnings of cognitive function.This chapter has several purposes. First, it provides working definitions of cognitive functions, such as learning, memory and attention, in terms frequently used by behavioral toxicologists. It is important to have a common vocabulary to assess methods used in this area of research. Second, it presents an overview of some of the procedures commonly used in behavioral toxicology to assess the effects of chemicals on cognitive function in animals. It should be noted that this overview is not intended to be comprehensive or complete, but is intended to illustrate specific points by discussing examples. Finally, this chapter discusses some critical experimental and conceptual variables that are important for studies on chemical-induced cognitive dysfunction, and touches on the potential p

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

PubMed

Emdin, Connor A; Khera, Amit V; Chaffin, Mark; Klarin, Derek; Natarajan, Pradeep; Aragam, Krishna; Haas, Mary; Bick, Alexander; Zekavat, Seyedeh M; Nomura, Akihiro; Ardissino, Diego; Wilson, James G; Schunkert, Heribert; McPherson, Ruth; Watkins, Hugh; Elosua, Roberto; Bown, Matthew J; Samani, Nilesh J; Baber, Usman; Erdmann, Jeanette; Gupta, Namrata; Danesh, John; Chasman, Daniel; Ridker, Paul; Denny, Joshua; Bastarache, Lisa; Lichtman, Judith H; D'Onofrio, Gail; Mattera, Jennifer; Spertus, John A; Sheu, Wayne H-H; Taylor, Kent D; Psaty, Bruce M; Rich, Stephen S; Post, Wendy; Rotter, Jerome I; Chen, Yii-Der Ida; Krumholz, Harlan; Saleheen, Danish; Gabriel, Stacey; Kathiresan, Sekar

2018-04-24

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease

PubMed Central

McDonald, Jacqueline U.; Kaforou, Myrsini; Clare, Simon; Hale, Christine; Ivanova, Maria; Huntley, Derek; Dorner, Marcus; Wright, Victoria J.; Levin, Michael; Martinon-Torres, Federico; Herberg, Jethro A.

2016-01-01

ABSTRACT Greater understanding of the functions of host gene products in response to infection is required. While many of these genes enable pathogen clearance, some enhance pathogen growth or contribute to disease symptoms. Many studies have profiled transcriptomic and proteomic responses to infection, generating large data sets, but selecting targets for further study is challenging. Here we propose a novel data-mining approach combining multiple heterogeneous data sets to prioritize genes for further study by using respiratory syncytial virus (RSV) infection as a model pathogen with a significant health care impact. The assumption was that the more frequently a gene is detected across multiple studies, the more important its role is. A literature search was performed to find data sets of genes and proteins that change after RSV infection. The data sets were standardized, collated into a single database, and then panned to determine which genes occurred in multiple data sets, generating a candidate gene list. This candidate gene list was validated by using both a clinical cohort and in vitro screening. We identified several genes that were frequently expressed following RSV infection with no assigned function in RSV control, including IFI27, IFIT3, IFI44L, GBP1, OAS3, IFI44, and IRF7. Drilling down into the function of these genes, we demonstrate a role in disease for the gene for interferon regulatory factor 7, which was highly ranked on the list, but not for IRF1, which was not. Thus, we have developed and validated an approach for collating published data sets into a manageable list of candidates, identifying novel targets for future analysis. IMPORTANCE Making the most of “big data” is one of the core challenges of current biology. There is a large array of heterogeneous data sets of host gene responses to infection, but these data sets do not inform us about gene function and require specialized skill sets and training for their utilization. Here we

Soft Skills in Higher Education: Importance and Improvement Ratings as a Function of Individual Differences and Academic Performance

ERIC Educational Resources Information Center

Chamorro-Premuzic, Tomas; Arteche, Adriane; Bremner, Andrew J.; Greven, Corina; Furnham, Adrian

2010-01-01

Three UK studies on the relationship between a purpose-built instrument to assess the importance and development of 15 "soft skills" are reported. "Study 1" (N = 444) identified strong latent components underlying these soft skills, such that differences "between-skills" were over-shadowed by differences…

The Importance of Dispersal for Bacterial Community Composition and Functioning

PubMed Central

Lindström, Eva S.; Östman, Örjan

2011-01-01

We conducted a metacommunity experiment to investigate the role of dispersal for bacterial community composition (BCC) and function of freshwater bacteria. Bacteria were dispersed from a common source pool into three different lake communities in their natural lake water. The experiment was conducted in dialysis bags to enable a decoupling between a change in the local environment and dispersal. BCC was determined by terminal restriction fragment length polymorphism (tRFLP) of the 16S rRNA gene. We show that the greatest changes in BCC occurred between 10% and 43% of dispersal of standing stock per day. Functioning, measured as growth rate, was also affected by dispersal in all three communities but the qualitative pattern differed between communities, sometimes showing a hump-shaped relationship to dispersal and sometimes decreasing with increasing dispersal. In all waters, functioning was related to BCC. Our results show that dispersal does affect BCC and functioning but that high dispersal rates are needed. Further, the effect of dispersal on BCC and function seem to depend on the quality of the habitat to which bacteria disperse into. PMID:21998714

The importance of phrenic nerve preservation and its effect on long-term postoperative lung function after pneumonectomy.

PubMed

Kocher, Gregor J; Poulson, Jannie Lysgaard; Blichfeldt-Eckhardt, Morten Rune; Elle, Bo; Schmid, Ralph A; Licht, Peter B

2016-04-01

The importance of phrenic nerve preservation during pneumonectomy remains controversial. We previously demonstrated that preservation of the phrenic nerve in the immediate postoperative period preserved lung function by 3-5% but little is known about its long-term effects. We, therefore, decided to investigate the effect of temporary ipsilateral cervical phrenic nerve block on dynamic lung volumes in mid- to long-term pneumonectomy patients. We investigated 14 patients after a median of 9 years post pneumonectomy (range: 1-15 years). Lung function testing (spirometry) and fluoroscopic and/or sonographic assessment of diaphragmatic motion on the pneumonectomy side were performed before and after ultrasonographic-guided ipsilateral cervical phrenic nerve block by infiltration with lidocaine. Ipsilateral phrenic nerve block was successfully achieved in 12 patients (86%). In the remaining 2 patients, diaphragmatic motion was already paradoxical before the nerve block. We found no significant difference on dynamic lung function values (FEV1 'before' 1.39 ± 0.44 vs FEV1 'after' 1.38 ± 0.40; P = 0.81). Induction of a temporary diaphragmatic palsy did not significantly influence dynamic lung volumes in mid- to long-term pneumonectomy patients, suggesting that preservation of the phrenic nerve is of greater importance in the immediate postoperative period after pneumonectomy. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Functional β-Adrenoceptors Are Important for Early Muscle Regeneration in Mice through Effects on Myoblast Proliferation and Differentiation

PubMed Central

Church, Jarrod E.; Trieu, Jennifer; Sheorey, Radhika; Chee, Annabel Y. -M.; Naim, Timur; Baum, Dale M.; Ryall, James G.; Gregorevic, Paul; Lynch, Gordon S.

2014-01-01

Muscles can be injured in different ways and the trauma and subsequent loss of function and physical capacity can impact significantly on the lives of patients through physical impairments and compromised quality of life. The relative success of muscle repair after injury will largely determine the extent of functional recovery. Unfortunately, regenerative processes are often slow and incomplete, and so developing novel strategies to enhance muscle regeneration is important. While the capacity to enhance muscle repair by stimulating β2-adrenoceptors (β-ARs) using β2-AR agonists (β2-agonists) has been demonstrated previously, the exact role β-ARs play in regulating the regenerative process remains unclear. To investigate β-AR-mediated signaling in muscle regeneration after myotoxic damage, we examined the regenerative capacity of tibialis anterior and extensor digitorum longus muscles from mice lacking either β1-AR (β1-KO) and/or β2-ARs (β2-KO), testing the hypothesis that muscles from mice lacking the β2-AR would exhibit impaired functional regeneration after damage compared with muscles from β1-KO or β1/β2-AR null (β1/β2-KO) KO mice. At 7 days post-injury, regenerating muscles from β1/β2-KO mice produced less force than those of controls but muscles from β1-KO or β2-KO mice did not exhibit any delay in functional restoration. Compared with controls, β1/β2-KO mice exhibited an enhanced inflammatory response to injury, which delayed early muscle regeneration, but an enhanced myoblast proliferation later during regeneration ensured a similar functional recovery (to controls) by 14 days post-injury. This apparent redundancy in the β-AR signaling pathway was unexpected and may have important implications for manipulating β-AR signaling to improve the rate, extent and efficacy of muscle regeneration to enhance functional recovery after injury. PMID:25000590

Identifying functional communities for use in forest planning and decisionmaking

Treesearch

Pamela J. Jakes; Thomas E. Fish

1998-01-01

Public land managers are searching for frameworks for organizing and displaying social information that will make it useful in forest management and decisionmaking. On the Chequamegon-Nicolet National Forests in Wisconsin, managers and researchers have used the concept of functional communities to develop such a framework. Functional communities define geographic areas...

A parallel genome-wide RNAi screening strategy to identify host proteins important for entry of Marburg virus and H5N1 influenza virus.

PubMed

Cheng, Han; Koning, Katie; O'Hearn, Aileen; Wang, Minxiu; Rumschlag-Booms, Emily; Varhegyi, Elizabeth; Rong, Lijun

2015-11-24

Genome-wide RNAi screening has been widely used to identify host proteins involved in replication and infection of different viruses, and numerous host factors are implicated in the replication cycles of these viruses, demonstrating the power of this approach. However, discrepancies on target identification of the same viruses by different groups suggest that high throughput RNAi screening strategies need to be carefully designed, developed and optimized prior to the large scale screening. Two genome-wide RNAi screens were performed in parallel against the entry of pseudotyped Marburg viruses and avian influenza virus H5N1 utilizing an HIV-1 based surrogate system, to identify host factors which are important for virus entry. A comparative analysis approach was employed in data analysis, which alleviated systematic positional effects and reduced the false positive number of virus-specific hits. The parallel nature of the strategy allows us to easily identify the host factors for a specific virus with a greatly reduced number of false positives in the initial screen, which is one of the major problems with high throughput screening. The power of this strategy is illustrated by a genome-wide RNAi screen for identifying the host factors important for Marburg virus and/or avian influenza virus H5N1 as described in this study. This strategy is particularly useful for highly pathogenic viruses since pseudotyping allows us to perform high throughput screens in the biosafety level 2 (BSL-2) containment instead of the BSL-3 or BSL-4 for the infectious viruses, with alleviated safety concerns. The screening strategy together with the unique comparative analysis approach makes the data more suitable for hit selection and enables us to identify virus-specific hits with a much lower false positive rate.

Spider Transcriptomes Identify Ancient Large-Scale Gene Duplication Event Potentially Important in Silk Gland Evolution

PubMed Central

Clarke, Thomas H.; Garb, Jessica E.; Hayashi, Cheryl Y.; Arensburger, Peter; Ayoub, Nadia A.

2015-01-01

The evolution of specialized tissues with novel functions, such as the silk synthesizing glands in spiders, is likely an influential driver of adaptive success. Large-scale gene duplication events and subsequent paralog divergence are thought to be required for generating evolutionary novelty. Such an event has been proposed for spiders, but not tested. We de novo assembled transcriptomes from three cobweb weaving spider species. Based on phylogenetic analyses of gene families with representatives from each of the three species, we found numerous duplication events indicative of a whole genome or segmental duplication. We estimated the age of the gene duplications relative to several speciation events within spiders and arachnids and found that the duplications likely occurred after the divergence of scorpions (order Scorpionida) and spiders (order Araneae), but before the divergence of the spider suborders Mygalomorphae and Araneomorphae, near the evolutionary origin of spider silk glands. Transcripts that are expressed exclusively or primarily within black widow silk glands are more likely to have a paralog descended from the ancient duplication event and have elevated amino acid replacement rates compared with other transcripts. Thus, an ancient large-scale gene duplication event within the spider lineage was likely an important source of molecular novelty during the evolution of silk gland-specific expression. This duplication event may have provided genetic material for subsequent silk gland diversification in the true spiders (Araneomorphae). PMID:26058392

Relating genes to function: identifying enriched transcription factors using the ENCODE ChIP-Seq significance tool.

PubMed

Auerbach, Raymond K; Chen, Bin; Butte, Atul J

2013-08-01

Biological analysis has shifted from identifying genes and transcripts to mapping these genes and transcripts to biological functions. The ENCODE Project has generated hundreds of ChIP-Seq experiments spanning multiple transcription factors and cell lines for public use, but tools for a biomedical scientist to analyze these data are either non-existent or tailored to narrow biological questions. We present the ENCODE ChIP-Seq Significance Tool, a flexible web application leveraging public ENCODE data to identify enriched transcription factors in a gene or transcript list for comparative analyses. The ENCODE ChIP-Seq Significance Tool is written in JavaScript on the client side and has been tested on Google Chrome, Apple Safari and Mozilla Firefox browsers. Server-side scripts are written in PHP and leverage R and a MySQL database. The tool is available at http://encodeqt.stanford.edu. abutte@stanford.edu Supplementary material is available at Bioinformatics online.

Rice functional genomics research in China.

PubMed

Han, Bin; Xue, Yongbiao; Li, Jiayang; Deng, Xing-Wang; Zhang, Qifa

2007-06-29

Rice functional genomics is a scientific approach that seeks to identify and define the function of rice genes, and uncover when and how genes work together to produce phenotypic traits. Rapid progress in rice genome sequencing has facilitated research in rice functional genomics in China. The Ministry of Science and Technology of China has funded two major rice functional genomics research programmes for building up the infrastructures of the functional genomics study such as developing rice functional genomics tools and resources. The programmes were also aimed at cloning and functional analyses of a number of genes controlling important agronomic traits from rice. National and international collaborations on rice functional genomics study are accelerating rice gene discovery and application.

Identifying functional zones of denitrification in heterogeneous aquifer systems by numerical simulations - a case study

NASA Astrophysics Data System (ADS)

Jang, E.; Kalbacher, T.; He, W.; Shao, H.; Schueth, C.; Kolditz, O.

2014-12-01

Nitrate contamination in shallow groundwater is still one of the common problems in many countries. Because of its high solubility and anionic nature, nitrate can easily leach through soil and persist in groundwater for decades. High nitrate concentration has been suggested as a major cause of accelerated eutrophication, methemoglobinemia and gastric cancer. There are several factors influencing the fate of nitrate in groundwater system, which is e.g. distribution of N- sources to soil and groundwater, distribution and amount of reactive substances maintaining denitrification, rate of nitrate degradation and its kinetics, and geological characteristics of the aquifer. Nitrate transport and redox transformation processes are closely linked to complex and spatially distributed physical and chemical interaction, therefore it is difficult to predict and quantify in the field and laboratory experiment. Models can play a key role in elucidation of nitrate reduction pathway in groundwater system and in the design and evaluation of field tests to investigate in situ remediation technologies as well. The goal of the current study is to predict groundwater vulnerability to nitrate, to identify functional zones of denitrification in heterogeneous aquifer systems and to describe the uncertainty of the predictions due to scale effects. For this aim, we developed a kinetic model using multi-component mass transport code OpenGeoSys coupling with IPhreeqc module of the geochemical solver PHREEQC. The developed model included sequential aerobic and nitrate-based respiration, multi-Monod kinetics, multi-species biogeochemical reactions, and geological characteristics of the groundwater aquifer. Moreover water-rock interaction such as secondary mineral precipitation was also included in this model. In this presentation, we focused on the general modelling approach and present the simulation results of nitrate transport simulation in a hypothetical aquifer systems based on data from

Combining Methods to Describe Important Marine Habitats for Top Predators: Application to Identify Biological Hotspots in Tropical Waters.

PubMed

Thiers, Laurie; Louzao, Maite; Ridoux, Vincent; Le Corre, Matthieu; Jaquemet, Sébastien; Weimerskirch, Henri

2014-01-01

In tropical waters resources are usually scarce and patchy, and predatory species generally show specific adaptations for foraging. Tropical seabirds often forage in association with sub-surface predators that create feeding opportunities by bringing prey close to the surface, and the birds often aggregate in large multispecific flocks. Here we hypothesize that frigatebirds, a tropical seabird adapted to foraging with low energetic costs, could be a good predictor of the distribution of their associated predatory species, including other seabirds (e.g. boobies, terns) and subsurface predators (e.g., dolphins, tunas). To test this hypothesis, we compared distribution patterns of marine predators in the Mozambique Channel based on a long-term dataset of both vessel- and aerial surveys, as well as tracking data of frigatebirds. By developing species distribution models (SDMs), we identified key marine areas for tropical predators in relation to contemporaneous oceanographic features to investigate multi-species spatial overlap areas and identify predator hotspots in the Mozambique Channel. SDMs reasonably matched observed patterns and both static (e.g. bathymetry) and dynamic (e.g. Chlorophyll a concentration and sea surface temperature) factors were important explaining predator distribution patterns. We found that the distribution of frigatebirds included the distributions of the associated species. The central part of the channel appeared to be the best habitat for the four groups of species considered in this study (frigatebirds, brown terns, boobies and sub-surface predators).

Authentic early experience in Medical Education: a socio-cultural analysis identifying important variables in learning interactions within workplaces.

PubMed

Yardley, Sarah; Brosnan, Caragh; Richardson, Jane; Hays, Richard

2013-12-01

This paper addresses the question 'what are the variables influencing social interactions and learning during Authentic Early Experience (AEE)?' AEE is a complex educational intervention for new medical students. Following critique of the existing literature, multiple qualitative methods were used to create a study framework conceptually orientated to a socio-cultural perspective. Study participants were recruited from three groups at one UK medical school: students, workplace supervisors, and medical school faculty. A series of intersecting spectra identified in the data describe dyadic variables that make explicit the parameters within which social interactions are conducted in this setting. Four of the spectra describe social processes related to being in workplaces and developing the ability to manage interactions during authentic early experiences. These are: (1) legitimacy expressed through invited participation or exclusion; (2) finding a role-a spectrum from student identity to doctor mindset; (3) personal perspectives and discomfort in transition from lay to medical; and, (4) taking responsibility for 'risk'-moving from aversion to management through graded progression of responsibility. Four further spectra describe educational consequences of social interactions. These spectra identify how the reality of learning is shaped through social interactions and are (1) generic-specific objectives, (2) parallel-integrated-learning, (3) context specific-transferable learning and (4) performing or simulating-reality. Attention to these variables is important if educators are to maximise constructive learning from AEE. Application of each of the spectra could assist workplace supervisors to maximise the positive learning potential of specific workplaces.

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

PubMed

Rand, Kristin A; Song, Chi; Dean, Eric; Serie, Daniel J; Curtin, Karen; Sheng, Xin; Hu, Donglei; Huff, Carol Ann; Bernal-Mizrachi, Leon; Tomasson, Michael H; Ailawadhi, Sikander; Singhal, Seema; Pawlish, Karen; Peters, Edward S; Bock, Cathryn H; Stram, Alex; Van Den Berg, David J; Edlund, Christopher K; Conti, David V; Zimmerman, Todd; Hwang, Amie E; Huntsman, Scott; Graff, John; Nooka, Ajay; Kong, Yinfei; Pregja, Silvana L; Berndt, Sonja I; Blot, William J; Carpten, John; Casey, Graham; Chu, Lisa; Diver, W Ryan; Stevens, Victoria L; Lieber, Michael R; Goodman, Phyllis J; Hennis, Anselm J M; Hsing, Ann W; Mehta, Jayesh; Kittles, Rick A; Kolb, Suzanne; Klein, Eric A; Leske, Cristina; Murphy, Adam B; Nemesure, Barbara; Neslund-Dudas, Christine; Strom, Sara S; Vij, Ravi; Rybicki, Benjamin A; Stanford, Janet L; Signorello, Lisa B; Witte, John S; Ambrosone, Christine B; Bhatti, Parveen; John, Esther M; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah J; Bandera, Elisa V; Birmann, Brenda M; Ingles, Sue A; Press, Michael F; Atanackovic, Djordje; Glenn, Martha J; Cannon-Albright, Lisa A; Jones, Brandt; Tricot, Guido; Martin, Thomas G; Kumar, Shaji K; Wolf, Jeffrey L; Deming Halverson, Sandra L; Rothman, Nathaniel; Brooks-Wilson, Angela R; Rajkumar, S Vincent; Kolonel, Laurence N; Chanock, Stephen J; Slager, Susan L; Severson, Richard K; Janakiraman, Nalini; Terebelo, Howard R; Brown, Elizabeth E; De Roos, Anneclaire J; Mohrbacher, Ann F; Colditz, Graham A; Giles, Graham G; Spinelli, John J; Chiu, Brian C; Munshi, Nikhil C; Anderson, Kenneth C; Levy, Joan; Zonder, Jeffrey A; Orlowski, Robert Z; Lonial, Sagar; Camp, Nicola J; Vachon, Celine M; Ziv, Elad; Stram, Daniel O; Hazelett, Dennis J; Haiman, Christopher A; Cozen, Wendy

2016-12-01

Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10 -7 ) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR. ©2016 American Association for Cancer Research.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

PubMed

Chasman, Daniel I; Fuchsberger, Christian; Pattaro, Cristian; Teumer, Alexander; Böger, Carsten A; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C; O'Seaghdha, Conall M; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V; O'Connell, Jeffrey R; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D; Gierman, Hinco J; Feitosa, Mary F; Hwang, Shih-Jen; Atkinson, Elizabeth J; Lohman, Kurt; Cornelis, Marilyn C; Johansson, Asa; Tönjes, Anke; Dehghan, Abbas; Lambert, Jean-Charles; Holliday, Elizabeth G; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y; Murgia, Federico; Trompet, Stella; Imboden, Medea; Coassin, Stefan; Pistis, Giorgio; Harris, Tamara B; Launer, Lenore J; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank; Demirkan, Ayse; Oostra, Ben A; de Andrade, Mariza; Turner, Stephen T; Ding, Jingzhong; Andrews, Jeanette S; Freedman, Barry I; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Meisinger, Christa; Gieger, Christian; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H; Wright, Alan F; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G; Rivadeneira, Fernando; Aulchenko, Yurii S; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K; Portas, Laura; Ford, Ian; Buckley, Brendan M; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J Wouter; Probst-Hensch, Nicole M; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S; van Duijn, Cornelia M; Borecki, Ingrid B; Kardia, Sharon L R; Liu, Yongmei; Curhan, Gary C; Rudan, Igor; Gyllensten, Ulf; Wilson, James F; Franke, Andre; Pramstaller, Peter P; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M; Parsa, Afshin; Bochud, Murielle; Heid, Iris M; Kao, W H Linda; Fox, Caroline S; Köttgen, Anna

2012-12-15

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

PubMed Central

Chasman, Daniel I.; Fuchsberger, Christian; Pattaro, Cristian; Teumer, Alexander; Böger, Carsten A.; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; O'Seaghdha, Conall M.; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V.; O'Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D.; Gierman, Hinco J.; Feitosa, Mary F.; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Lambert, Jean-Charles; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Coassin, Stefan; Pistis, Giorgio; Harris, Tamara B.; Launer, Lenore J.; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D.; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank; Demirkan, Ayse; Oostra, Ben A.; de Andrade, Mariza; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Meisinger, Christa; Gieger, Christian; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E.; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H.; Wright, Alan F.; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K.; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K.; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J. Wouter; Probst-Hensch, Nicole M.; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R.; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S.; van Duijn, Cornelia M.; Borecki, Ingrid B.; Kardia, Sharon L.R.; Liu, Yongmei; Curhan, Gary C.; Rudan, Igor; Gyllensten, Ulf; Wilson, James F.; Franke, Andre; Pramstaller, Peter P.; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M; Parsa, Afshin; Bochud, Murielle; Heid, Iris M.; Kao, W.H. Linda; Fox, Caroline S.; Köttgen, Anna

2012-01-01

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general. PMID:22962313

Functional networks in parallel with cortical development associate with executive functions in children.

PubMed

Zhong, Jidan; Rifkin-Graboi, Anne; Ta, Anh Tuan; Yap, Kar Lai; Chuang, Kai-Hsiang; Meaney, Michael J; Qiu, Anqi

2014-07-01

Children begin performing similarly to adults on tasks requiring executive functions in late childhood, a transition that is probably due to neuroanatomical fine-tuning processes, including myelination and synaptic pruning. In parallel to such structural changes in neuroanatomical organization, development of functional organization may also be associated with cognitive behaviors in children. We examined 6- to 10-year-old children's cortical thickness, functional organization, and cognitive performance. We used structural magnetic resonance imaging (MRI) to identify areas with cortical thinning, resting-state fMRI to identify functional organization in parallel to cortical development, and working memory/response inhibition tasks to assess executive functioning. We found that neuroanatomical changes in the form of cortical thinning spread over bilateral frontal, parietal, and occipital regions. These regions were engaged in 3 functional networks: sensorimotor and auditory, executive control, and default mode network. Furthermore, we found that working memory and response inhibition only associated with regional functional connectivity, but not topological organization (i.e., local and global efficiency of information transfer) of these functional networks. Interestingly, functional connections associated with "bottom-up" as opposed to "top-down" processing were more clearly related to children's performance on working memory and response inhibition, implying an important role for brain systems involved in late childhood. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Health and role functioning: the use of focus groups in the development of an item bank.

PubMed

Anatchkova, Milena D; Bjorner, Jakob B

2010-02-01

Role functioning is an important part of health-related quality of life. However, assessment of role functioning is complicated by the wide definition of roles and by fluctuations in role participation across the life-span. The aim of this study is to explore variations in role functioning across the lifespan using qualitative approaches, to inform the development of a role functioning item bank and to pilot test sample items from the bank. Eight focus groups were conducted with a convenience sample of 38 English-speaking adults recruited in Rhode Island. Participants were stratified by gender and four age groups. Focus groups were taped, transcribed, and analyzed for thematic content. Participants of all ages identified family roles as the most important. There was age variation in the importance of social life roles, with younger and older adults rating them as more important. Occupational roles were identified as important by younger and middle-aged participants. The potential of health problems to affect role participation was recognized. Participants found the sample items easy to understand, response options identical in meaning and preferred five response choices. Participants identified key aspects of role functioning and provided insights on their perception of the impact of health on their role participation. These results will inform item bank generation.

OXPHOS-Dependent Cells Identify Environmental Disruptors of Mitochondrial Function

EPA Science Inventory

Mitochondrial dysfunction is associated with numerous chronic diseases including metabolic syndrome. Environmental chemicals can impair mitochondrial function through numerous mechanisms such as membrane disruption, complex inhibition and electron transport chain uncoupling. Curr...

Identifying Corridors among Large Protected Areas in the United States.

PubMed

Belote, R Travis; Dietz, Matthew S; McRae, Brad H; Theobald, David M; McClure, Meredith L; Irwin, G Hugh; McKinley, Peter S; Gage, Josh A; Aplet, Gregory H

2016-01-01

Conservation scientists emphasize the importance of maintaining a connected network of protected areas to prevent ecosystems and populations from becoming isolated, reduce the risk of extinction, and ultimately sustain biodiversity. Keeping protected areas connected in a network is increasingly recognized as a conservation priority in the current era of rapid climate change. Models that identify suitable linkages between core areas have been used to prioritize potentially important corridors for maintaining functional connectivity. Here, we identify the most "natural" (i.e., least human-modified) corridors between large protected areas in the contiguous Unites States. We aggregated results from multiple connectivity models to develop a composite map of corridors reflecting agreement of models run under different assumptions about how human modification of land may influence connectivity. To identify which land units are most important for sustaining structural connectivity, we used the composite map of corridors to evaluate connectivity priorities in two ways: (1) among land units outside of our pool of large core protected areas and (2) among units administratively protected as Inventoried Roadless (IRAs) or Wilderness Study Areas (WSAs). Corridor values varied substantially among classes of "unprotected" non-core land units, and land units of high connectivity value and priority represent diverse ownerships and existing levels of protections. We provide a ranking of IRAs and WSAs that should be prioritized for additional protection to maintain minimal human modification. Our results provide a coarse-scale assessment of connectivity priorities for maintaining a connected network of protected areas.

Which outcomes are most important to people with aphasia and their families? an international nominal group technique study framed within the ICF.

PubMed

Wallace, Sarah J; Worrall, Linda; Rose, Tanya; Le Dorze, Guylaine; Cruice, Madeline; Isaksen, Jytte; Kong, Anthony Pak Hin; Simmons-Mackie, Nina; Scarinci, Nerina; Gauvreau, Christine Alary

2017-07-01

To identify important treatment outcomes from the perspective of people with aphasia and their families using the ICF as a frame of reference. The nominal group technique was used with people with aphasia and their family members in seven countries to identify and rank important treatment outcomes from aphasia rehabilitation. People with aphasia identified outcomes for themselves; and family members identified outcomes for themselves and for the person with aphasia. Outcomes were analysed using qualitative content analysis and ICF linking. A total of 39 people with aphasia and 29 family members participated in one of 16 nominal groups. Inductive qualitative content analysis revealed the following six themes: (1) Improved communication; (2) Increased life participation; (3) Changed attitudes through increased awareness and education about aphasia; (4) Recovered normality; (5) Improved physical and emotional well-being; and (6) Improved health (and support) services. Prioritized outcomes for both participant groups linked to all ICF components; primary activity/participation (39%) and body functions (36%) for people with aphasia, and activity/participation (49%) and environmental factors (28%) for family members. Outcomes prioritized by family members relating to the person with aphasia, primarily linked to body functions (60%). People with aphasia and their families identified treatment outcomes which span all components of the ICF. This has implications for research outcome measurement and clinical service provision which currently focuses on the measurement of body function outcomes. The wide range of desired outcomes generated by both people with aphasia and their family members, highlights the importance of collaborative goal setting within a family-centred approach to rehabilitation. These results will be combined with other stakeholder perspectives to establish a core outcome set for aphasia treatment research. Implications for Rehabilitation Important

A Human Proteome Array Approach to Identifying Key Host Proteins Targeted by Toxoplasma Kinase ROP18*

PubMed Central

Yang, Zhaoshou; Hou, Yongheng; Hao, Taofang; Rho, Hee-Sool; Wan, Jun; Luan, Yizhao; Gao, Xin; Yao, Jianping; Pan, Aihua; Xie, Zhi; Qian, Jiang; Liao, Wanqin; Zhu, Heng; Zhou, Xingwang

2017-01-01

Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates, we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions, including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1, were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser-187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and provide new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface. PMID:28087594

N-Glycosylation Is Important for Proper Haloferax volcanii S-Layer Stability and Function.

PubMed

Tamir, Adi; Eichler, Jerry

2017-03-15

N-Glycosylation, the covalent linkage of glycans to select Asn residues of target proteins, is an almost universal posttranslational modification in archaea. However, whereas roles for N-glycosylation have been defined in eukarya and bacteria, the function of archaeal N-glycosylation remains unclear. Here, the impact of perturbed N-glycosylation on the structure and physiology of the haloarchaeon Haloferax volcanii was considered. Cryo-electron microscopy was used to examine right-side-out membrane vesicles prepared from cells of a parent strain and from strains lacking genes encoding glycosyltransferases involved in assembling the N-linked pentasaccharide decorating the surface layer (S-layer) glycoprotein, the sole component of the S-layer surrounding H. volcanii cells. Whereas a regularly repeating S-layer covered the entire surface of vesicles prepared from parent strain cells, vesicles from the mutant cells were only partially covered. To determine whether such N-glycosylation-related effects on S-layer assembly also affected cell function, the secretion of a reporter protein was addressed in the parent and N-glycosylation mutant strains. Compromised S-layer glycoprotein N-glycosylation resulted in impaired transfer of the reporter past the S-layer and into the growth medium. Finally, an assessment of S-layer glycoprotein susceptibility to added proteases in the mutants revealed that in cells lacking AglD, which is involved in adding the final pentasaccharide sugar, a distinct S-layer glycoprotein conformation was assumed in which the N-terminal region was readily degraded. Perturbed N-glycosylation thus affects S-layer glycoprotein folding. These findings suggest that H. volcanii could adapt to changes in its surroundings by modulating N-glycosylation so as to affect S-layer architecture and function. IMPORTANCE Long held to be a process unique to eukaryotes, it is now accepted that bacteria and archaea also perform N-glycosylation, namely, the covalent

Measuring use of electronic health record functionality using system audit information.

PubMed

Bowes, Watson A

2010-01-01

Meaningful and efficient methods for measuring Electronic Health Record (EHR) adoption and functional usage patterns have recently become important for hospitals, clinics, and health care networks in the United State due to recent government initiatives to increase EHR use. To date, surveys have been the method of choice to measure EHR adoption. This paper describes another method for measuring EHR adoption which capitalizes on audit logs, which are often common components of modern EHRs. An Audit Data Mart is described which identified EHR functionality within 836 Departments, within 22 Hospitals and 170 clinics at Intermountain Healthcare, a large integrated delivery system. The Audit Data Mart successfully identified important and differing EHR functional usage patterns. These patterns were useful in strategic planning, tracking EHR implementations, and will likely be utilized to assist in documentation of "Meaningful Use" of EHR functionality.

The Body of Knowledge & Content Framework. Identifying the Important Knowledge Required for Productive Performance of a Plastics Machine Operator. Blow Molding, Extrusion, Injection Molding, Thermoforming.

ERIC Educational Resources Information Center

Society of the Plastics Industry, Inc., Washington, DC.

Designed to guide training and curriculum development to prepare machine operators for the national certification exam, this publication identifies the important knowledge required for productive performance by a plastics machine operator. Introductory material discusses the rationale for a national standard, uses of the Body of Knowledge,…

Sensing a Sensor: Identifying the Mechanosensory Function of Primary Cilia

PubMed Central

Prasad, Rahul M.; Jin, Xingjian; Nauli, Surya M.

2014-01-01

Over the past decade, primary cilia have emerged as the premier means by which cells sense and transduce mechanical stimuli. Primary cilia are sensory organelles that have been shown to be vitally involved in the mechanosensation of urine in the renal nephron, bile in the hepatic biliary system, digestive fluid in the pancreatic duct, dentin in dental pulp, lacunocanalicular fluid in bone and cartilage, and blood in vasculature. The prevalence of primary cilia among mammalian cell types is matched by the tremendously varied disease states caused by both structural and functional defects in cilia. In the process of delineating the mechanisms behind these disease states, calcium fluorimetry has been widely utilized as a means of quantifying ciliary function to both fluid flow and pharmacological agents. In this review, we will discuss the approaches used in associating calcium levels to cilia function. PMID:24839551

Functional Status Score for the Intensive Care Unit (FSS-ICU): An International Clinimetric Analysis of Validity, Responsiveness, and Minimal Important Difference

PubMed Central

Huang, Minxuan; Chan, Kitty S.; Zanni, Jennifer M.; Parry, Selina M.; Neto, Saint-Clair G. B.; Neto, Jose A. A.; da Silva, Vinicius Z. M.; Kho, Michelle E.; Needham, Dale M.

2017-01-01

Objective To evaluate the internal consistency, validity, responsiveness, and minimal important difference of the Functional Status Score for the Intensive Care Unit (FSS-ICU), a physical function measure designed for the intensive care unit (ICU). Design Clinimetric analysis. Settings Five international data sets from the United States, Australia, and Brazil. Patients 819 ICU patients. Intervention None. Measurements and Main Results Clinimetric analyses were initially conducted separately for each data source and time point to examine generalizability of findings, with pooled analyses performed thereafter to increase power of analyses. The FSS-ICU demonstrated good to excellent internal consistency. There was good convergent and discriminant validity, with significant and positive correlations (r = 0.30 to 0.95) between FSS-ICU and other physical function measures, and generally weaker correlations with non-physical measures (|r| = 0.01 to 0.70). Known group validity was demonstrated by significantly higher FSS-ICU scores among patients without ICU-acquired weakness (Medical Research Council sumscore ≥48 versus <48) and with hospital discharge to home (versus healthcare facility). FSS-ICU at ICU discharge predicted post-ICU hospital length of stay and discharge location. Responsiveness was supported via increased FSS-ICU scores with improvements in muscle strength. Distribution-based methods indicated a minimal important difference of 2.0 to 5.0. Conclusions The FSS-ICU has good internal consistency and is a valid and responsive measure of physical function for ICU patients. The estimated minimal important difference can be used in sample size calculations and in interpreting studies comparing the physical function of groups of ICU patients. PMID:27488220

Functional importance of GLP-1 receptor species and expression levels in cell lines.

PubMed

Knudsen, Lotte Bjerre; Hastrup, Sven; Underwood, Christina Rye; Wulff, Birgitte Schjellerup; Fleckner, Jan

2012-04-10

Of the mammalian species, only the GLP-1 receptors of rat and human origin have been described and characterized. Here, we report the cloning of the homologous GLP-1 receptors from mouse, rabbit, pig, cynomolgus monkey and chimp. The GLP-1 receptor is highly conserved across species, thus underlining the physiological importance of the peptide hormone and its receptor across a wide range of mammals. We expressed the receptors by stable transfection of BHK cells, both in cell lines with high expression levels of the cloned receptors, as well as in cell lines with lower expression levels, more comparable to endogenous expression of these receptors. High expression levels of cloned GLP-1 receptors markedly increased the potency of GLP-1 and other high affinity ligands, whereas the K(d) values were not affected. For a low affinity ligand like the ago-allosteric modulator Compound 2, expression levels of the human GLP-1 receptor were important for maximal efficacy as well as potency. The two natural metabolites of GLP-1, GLP-1(9-37) and GLP-1(9-36)amide were agonists when tested on a cell line with high expression of the recombinant human GLP-1 receptor, whereas they behaved as (low potent) antagonists on a cell line that expressed the receptor endogenously, as well as cells expressing a moderate level of the recombinant human GLP-1 receptor. The amide form was a more potent agonist than the free acid from. In conclusion, receptor expression level is an important parametre for selecting cell lines with cloned GLP-1 receptors for functional characterization of physiological and pharmaceutical ligands. Copyright © 2011 Elsevier B.V. All rights reserved.

Voluntary pulmonary function screening identifies high rates of undiagnosed asymptomatic chronic obstructive pulmonary disease.

PubMed

Wang, Shengyu; Gong, Wei; Tian, Yao

2016-05-01

Chronic obstructive pulmonary disease (COPD) is projected to be the third leading cause of death by 2020. Early detection and screening may alter the course and prognosis associated with lung disease. We investigated the effectiveness of a voluntary public lung function screening program and factors that had a predictive value for asymptomatic COPD in Xi'an, China. Pulmonary function testing (PFT) was conducted on volunteers recruited from four community centers in Xi'an, China, between July and August 2012. Participants underwent three forced vital capacity maneuvers. The maneuver with the best forced expiratory volume in first second was retained. Participants filled out a medical history and environmental exposure survey before undergoing the PFT. Patients who self-reported lung disease on the health survey were excluded from the analysis. Logistical regression was used to determine associations with airway obstruction. A total of 803 volunteers participated in this study, and 33 subjects were excluded as the participants did not meet the requirements of PFT. Of the 770 volunteers, 44 participants had been diagnosed with chronic respiratory diseases previously, and 144 participants (18.7%) met COPD criteria. Four hundred forty-four participants did not self-report any respiratory symptoms, and the remaining 282 participants self-reported respiratory symptoms. Of the asymptomatic participants, 98 volunteers had PFT results that were consistent with COPD and 68.1% of asymptomatic participants were undiagnosed. A greater percentage of women than men had moderate or severe airway obstruction (p = 0.004).Only smoking status (odds ratio = 2.64, 95% confidence interval 1.20-6.04) was associated with asymptomatic COPD. Voluntary public lung function screening programs in China are likely to identify a large number of undiagnosed, asymptomatic COPD. Smoking status is associated with airway obstruction and a greater percentage of women than men had moderate or severe

Identifying Neural Patterns of Functional Dyspepsia Using Multivariate Pattern Analysis: A Resting-State fMRI Study

PubMed Central

Liu, Peng; Qin, Wei; Wang, Jingjing; Zeng, Fang; Zhou, Guangyu; Wen, Haixia; von Deneen, Karen M.; Liang, Fanrong; Gong, Qiyong; Tian, Jie

2013-01-01

Background Previous imaging studies on functional dyspepsia (FD) have focused on abnormal brain functions during special tasks, while few studies concentrated on the resting-state abnormalities of FD patients, which might be potentially valuable to provide us with direct information about the neural basis of FD. The main purpose of the current study was thereby to characterize the distinct patterns of resting-state function between FD patients and healthy controls (HCs). Methodology/Principal Findings Thirty FD patients and thirty HCs were enrolled and experienced 5-mintue resting-state scanning. Based on the support vector machine (SVM), we applied multivariate pattern analysis (MVPA) to investigate the differences of resting-state function mapped by regional homogeneity (ReHo). A classifier was designed by using the principal component analysis and the linear SVM. Permutation test was then employed to identify the significant contribution to the final discrimination. The results displayed that the mean classifier accuracy was 86.67%, and highly discriminative brain regions mainly included the prefrontal cortex (PFC), orbitofrontal cortex (OFC), supplementary motor area (SMA), temporal pole (TP), insula, anterior/middle cingulate cortex (ACC/MCC), thalamus, hippocampus (HIPP)/parahippocamus (ParaHIPP) and cerebellum. Correlation analysis revealed significant correlations between ReHo values in certain regions of interest (ROI) and the FD symptom severity and/or duration, including the positive correlations between the dmPFC, pACC and the symptom severity; whereas, the positive correlations between the MCC, OFC, insula, TP and FD duration. Conclusions These findings indicated that significantly distinct patterns existed between FD patients and HCs during the resting-state, which could expand our understanding of the neural basis of FD. Meanwhile, our results possibly showed potential feasibility of functional magnetic resonance imaging diagnostic assay for FD. PMID

Differential activation of an identified motor neuron and neuromodulation provide Aplysia's retractor muscle an additional function.

PubMed

McManus, Jeffrey M; Lu, Hui; Cullins, Miranda J; Chiel, Hillel J

2014-08-15

To survive, animals must use the same peripheral structures to perform a variety of tasks. How does a nervous system employ one muscle to perform multiple functions? We addressed this question through work on the I3 jaw muscle of the marine mollusk Aplysia californica's feeding system. This muscle mediates retraction of Aplysia's food grasper in multiple feeding responses and is innervated by a pool of identified neurons that activate different muscle regions. One I3 motor neuron, B38, is active in the protraction phase, rather than the retraction phase, suggesting the muscle has an additional function. We used intracellular, extracellular, and muscle force recordings in several in vitro preparations as well as recordings of nerve and muscle activity from intact, behaving animals to characterize B38's activation of the muscle and its activity in different behavior types. We show that B38 specifically activates the anterior region of I3 and is specifically recruited during one behavior, swallowing. The function of this protraction-phase jaw muscle contraction is to hold food; thus the I3 muscle has an additional function beyond mediating retraction. We additionally show that B38's typical activity during in vivo swallowing is insufficient to generate force in an unmodulated muscle and that intrinsic and extrinsic modulation shift the force-frequency relationship to allow contraction. Using methods that traverse levels from individual neuron to muscle to intact animal, we show how regional muscle activation, differential motor neuron recruitment, and neuromodulation are key components in Aplysia's generation of multifunctionality. Copyright © 2014 the American Physiological Society.

Nationwide outbreak of Salmonella Montevideo infections associated with contaminated imported black and red pepper: warehouse membership cards provide critical clues to identify the source.

PubMed

Gieraltowski, L; Julian, E; Pringle, J; Macdonald, K; Quilliam, D; Marsden-Haug, N; Saathoff-Huber, L; Von Stein, D; Kissler, B; Parish, M; Elder, D; Howard-King, V; Besser, J; Sodha, S; Loharikar, A; Dalton, S; Williams, I; Barton Behravesh, C

2013-06-01

In November 2009, we initiated a multistate investigation of Salmonella Montevideo infections with pulsed-field gel electrophoresis pattern JIXX01.0011. We identified 272 cases in 44 states with illness onset dates ranging from 1 July 2009 to 14 April 2010. To help generate hypotheses, warehouse store membership card information was collected to identify products consumed by cases. These records identified 19 ill persons who purchased company A salami products before onset of illness. A case-control study was conducted. Ready-to-eat salami consumption was significantly associated with illness (matched odds ratio 8·5, 95% confidence interval 2·1-75·9). The outbreak strain was isolated from company A salami products from an environmental sample from one manufacturing plant, and sealed containers of black and red pepper at the facility. This outbreak illustrates the importance of using membership card information to assist in identifying suspect vehicles, the potential for spices to contaminate ready-to-eat products, and preventing raw ingredient contamination of these products.

Individuals with knee impairments identify items in need of clarification in the Patient Reported Outcomes Measurement Information System (PROMIS®) pain interference and physical function item banks - a qualitative study.

PubMed

Lynch, Andrew D; Dodds, Nathan E; Yu, Lan; Pilkonis, Paul A; Irrgang, James J

2016-05-11

The content and wording of the Patient Reported Outcome Measurement Information System (PROMIS) Physical Function and Pain Interference item banks have not been qualitatively assessed by individuals with knee joint impairments. The purpose of this investigation was to identify items in the PROMIS Physical Function and Pain Interference Item Banks that are irrelevant, unclear, or otherwise difficult to respond to for individuals with impairment of the knee and to suggest modifications based on cognitive interviews. Twenty-nine individuals with knee joint impairments qualitatively assessed items in the Pain Interference and Physical Function Item Banks in a mixed-methods cognitive interview. Field notes were analyzed to identify themes and frequency counts were calculated to identify items not relevant to individuals with knee joint impairments. Issues with clarity were identified in 23 items in the Physical Function Item Bank, resulting in the creation of 43 new or modified items, typically changing words within the item to be clearer. Interpretation issues included whether or not the knee joint played a significant role in overall health and age/gender differences in items. One quarter of the original items (31 of 124) in the Physical Function Item Bank were identified as irrelevant to the knee joint. All 41 items in the Pain Interference Item Bank were identified as clear, although individuals without significant pain substituted other symptoms which interfered with their life. The Physical Function Item Bank would benefit from additional items that are relevant to individuals with knee joint impairments and, by extension, to other lower extremity impairments. Several issues in clarity were identified that are likely to be present in other patient cohorts as well.

Understanding identifiability as a crucial step in uncertainty assessment

NASA Astrophysics Data System (ADS)

Jakeman, A. J.; Guillaume, J. H. A.; Hill, M. C.; Seo, L.

2016-12-01

The topic of identifiability analysis offers concepts and approaches to identify why unique model parameter values cannot be identified, and can suggest possible responses that either increase uniqueness or help to understand the effect of non-uniqueness on predictions. Identifiability analysis typically involves evaluation of the model equations and the parameter estimation process. Non-identifiability can have a number of undesirable effects. In terms of model parameters these effects include: parameters not being estimated uniquely even with ideal data; wildly different values being returned for different initialisations of a parameter optimisation algorithm; and parameters not being physically meaningful in a model attempting to represent a process. This presentation illustrates some of the drastic consequences of ignoring model identifiability analysis. It argues for a more cogent framework and use of identifiability analysis as a way of understanding model limitations and systematically learning about sources of uncertainty and their importance. The presentation specifically distinguishes between five sources of parameter non-uniqueness (and hence uncertainty) within the modelling process, pragmatically capturing key distinctions within existing identifiability literature. It enumerates many of the various approaches discussed in the literature. Admittedly, improving identifiability is often non-trivial. It requires thorough understanding of the cause of non-identifiability, and the time, knowledge and resources to collect or select new data, modify model structures or objective functions, or improve conditioning. But ignoring these problems is not a viable solution. Even simple approaches such as fixing parameter values or naively using a different model structure may have significant impacts on results which are too often overlooked because identifiability analysis is neglected.

Systemic analysis of different colorectal cancer cell lines and TCGA datasets identified IGF-1R/EGFR-PPAR-CASPASE axis as important indicator for radiotherapy sensitivity.

PubMed

Chen, Lin; Zhu, Zhe; Gao, Wei; Jiang, Qixin; Yu, Jiangming; Fu, Chuangang

2017-09-05

Insulin-like growth factor 1 receptor (IGF-1R) is proved to contribute the development of many types of cancers. But, little is known about its roles in radio-resistance of colorectal cancer (CRC). Here, we demonstrated that low IGF-1R expression value was associated with the better radiotherapy sensitivity of CRC. Besides, through Quantitative Real-time PCR (qRT-PCR), the elevated expression value of epidermal growth factor receptor (EGFR) was observed in CRC cell lines (HT29, RKO) with high radio-sensitivity compared with those with low sensitivity (SW480, LOVO). The irradiation induced apoptosis rates of wild type and EGFR agonist (EGF) or IGF-1R inhibitor (NVP-ADW742) treated HT29 and SW480 cells were quantified by flow cytometry. As a result, the apoptosis rate of EGF and NVP-ADW742 treated HT29 cells was significantly higher than that of those wild type ones, which indicated that high EGFR and low IGF-1R expression level in CRC was associated with the high sensitivity to radiotherapy. We next conducted systemic bioinformatics analysis of genome-wide expression profiles of CRC samples from the Cancer Genome Atlas (TCGA). Differential expression analysis between IGF-1R and EGFR abnormal CRC samples, i.e. CRC samples with higher IGF-1R and lower EGFR expression levels based on their median expression values, and the rest of CRC samples identified potential genes contribute to radiotherapy sensitivity. Functional enrichment of analysis of those differential expression genes (DEGs) in the Database for Annotation, Visualization and Integrated Discovery (DAVID) indicated PPAR signaling pathway as an important pathway for the radio-resistance of CRC. Our study identified the potential biomarkers for the rational selection of radiotherapy for CRC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Longitudinal Changes in Functioning and Disability in Patients with Disorders of Consciousness: The Importance of Environmental Factors

PubMed Central

Willems, Michelle; Sattin, Davide; Vingerhoets, Ad J.J.M.; Leonardi, Matilde

2015-01-01

Disorders of consciousness are neurological conditions associated with low levels of functioning which pose a serious challenge to public health systems. The current study aimed to examine longitudinal changes in functioning in patients with disorders of consciousness and to identify associated biopsychosocial factors using the International Classification of Functioning, Disability, and Health. An Italian sample of 248 patients was assessed longitudinally. Differences in relative variability (an index of change that controls for baseline levels) between acute and chronic patients and predictors of relative variability in “Activities & Participation” were examined. Results showed that there were subgroups of patients whose functioning improved over time. The number of problems in “Activities & Participation” decreased in acute patients over time, whereas in chronic patients, an increase was found. The significant difference in relative variability for the environmental factor “support and relationships” reflects the increase in facilitators in acute patients, whereas the number of facilitators in chronic patients remained unchanged over time. Age at event, time from event, and relative variability in “Environmental Factors” were significant predictors of relative variability in “Activities & Participation”. It is of clinical relevance that patients with disorders of consciousness are kept in a supportive and facilitative environment, in order to prevent a decline in their functioning. Moreover, caregivers should receive tailored support in order to enhance and facilitate appropriate care of patients with disorders of consciousness. PMID:25837348

Application of unsteady flow rate evaluations to identify the dynamic transfer function of a cavitatingVenturi

NASA Astrophysics Data System (ADS)

Marie-Magdeleine, A.; Fortes-Patella, R.; Lemoine, N.; Marchand, N.

2012-11-01

This study concerns the simulation of the implementation of the Kinetic Differential Pressure (KDP) method used for the unsteady mass flow rate evaluation in order to identify the dynamic transfer matrix of a cavitatingVenturi. Firstly, the equations of the IZ code used for this simulation are introduced. Next, the methodology for evaluating unsteady pressures and mass flow rates at the inlet and the outlet of the cavitatingVenturi and for identifying the dynamic transfer matrix is presented. Later, the robustness of the method towards measurement uncertainties implemented as a Gaussian white noise is studied. The results of the numerical simulations let us estimate the system linearity domain and to perform the Empirical Transfer Function Evaluation on the inlet frequency per frequency signal and on the chirp signal tests. Then the pressure data obtained with the KDP method is taken and the identification procedure by ETFE and by the user-made Auto-Recursive Moving-Average eXogenous algorithms is performed and the obtained transfer matrix coefficients are compared with those obtained from the simulated input and output data.

Exome capture sequencing identifies a novel mutation in BBS4

PubMed Central

Wang, Hui; Chen, Xianfeng; Dudinsky, Lynn; Patenia, Claire; Chen, Yiyun; Li, Yumei; Wei, Yue; Abboud, Emad B.; Al-Rajhi, Ali A.; Lewis, Richard Alan; Lupski, James R.; Mardon, Graeme; Gibbs, Richard A.; Perkins, Brian D.

2011-01-01

Purpose Leber congenital amaurosis (LCA) is one of the most severe eye dystrophies characterized by severe vision loss at an early stage and accounts for approximately 5% of all retinal dystrophies. The purpose of this study was to identify a novel LCA disease allele or gene and to develop an approach combining genetic mapping with whole exome sequencing. Methods Three patients from King Khaled Eye Specialist Hospital (KKESH205) underwent whole genome single nucleotide polymorphism genotyping, and a single candidate region was identified. Taking advantage of next-generation high-throughput DNA sequencing technologies, whole exome capture sequencing was performed on patient KKESH205#7. Sanger direct sequencing was used during the validation step. The zebrafish model was used to examine the function of the mutant allele. Results A novel missense mutation in Bardet-Biedl syndrome 4 protein (BBS4) was identified in a consanguineous family from Saudi Arabia. This missense mutation in the fifth exon (c.253G>C;p.E85Q) of BBS4 is likely a disease-causing mutation as it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, or matching normal controls. Functional analysis of this mutation in zebrafish indicates that the G253C allele is pathogenic. Coinjection of the G253C allele cannot rescue the mislocalization of rhodopsin in the retina when BBS4 is knocked down by morpholino injection. Immunofluorescence analysis in cell culture shows that this missense mutation in BBS4 does not cause obvious defects in protein expression or pericentriolar localization. Conclusions This mutation likely mainly reduces or abolishes BBS4 function in the retina. Further studies of this allele will provide important insights concerning the pleiotropic nature of BBS4 function. PMID:22219648

Spectroscopy methods for identifying the country of origin

NASA Astrophysics Data System (ADS)

Hondrogiannis, Ellen; Ehrlinger, Erin; Miziolek, Andrzej W.

2013-05-01

There is a need in many industries and government functions to identify the source of origin for various materials. For example, the food industry needs to ensure that the claimed source of some of the food products (e.g. coffee, spices) are in fact legitimate due to the variation of quality from different source locations world-wide. Another example is to identify the source country for imported commodities going through Customs so as to assess the correct tariff which varies depending on the source country. Laser Induced Breakdown Spectroscopy (LIBS) holds promise for being a field-portable tool for rapid identification of the country of origin of various materials. Recent research at Towson University has identified the elemental markers needed for discrimination of select spices back to their country of origin using wavelength dispersive X-ray fluorescence (WDXRF). The WDXRF device, however, is not particularly suitable for convenient and fast field analysis. We are extending this study to evaluate the potential of a benchtop commercial LIBS device that could be located at ports of entry and to compare its performance with WDXRF. Our initial study on the spice cumin has demonstrated that discriminant function models can not only be created with 100% separation between the 4 countries of origin (China, India, Syria, and Turkey), but also when tested they show 100% correct matching to the country of origin. This study adds to the growing number of publications that indicate the power of LIBS elemental fingerprinting for provenance determinations.

Structural-Functional Properties of Identified Excitatory and Inhibitory Interneurons within Pre-Bötzinger Complex Respiratory Microcircuits

PubMed Central

Koizumi, Hidehiko; Koshiya, Naohiro; Chia, Justine X.; Cao, Fang; Nugent, Joseph; Zhang, Ruli

2013-01-01

We comparatively analyzed cellular and circuit properties of identified rhythmic excitatory and inhibitory interneurons within respiratory microcircuits of the neonatal rodent pre-Bötzinger complex (pre-BötC), the structure generating inspiratory rhythm in the brainstem. We combined high-resolution structural–functional imaging, molecular assays for neurotransmitter phenotype identification in conjunction with electrophysiological property phenotyping, and morphological reconstruction of interneurons in neonatal rat and mouse slices in vitro. This approach revealed previously undifferentiated structural–functional features that distinguish excitatory and inhibitory interneuronal populations. We identified distinct subpopulations of pre-BötC glutamatergic, glycinergic, GABAergic, and glycine-GABA coexpressing interneurons. Most commissural pre-BötC inspiratory interneurons were glutamatergic, with a substantial subset exhibiting intrinsic oscillatory bursting properties. Commissural excitatory interneurons projected with nearly planar trajectories to the contralateral pre-BötC, many also with axon collaterals to areas containing inspiratory hypoglossal (XII) premotoneurons and motoneurons. Inhibitory neurons as characterized in the present study did not exhibit intrinsic oscillatory bursting properties, but were electrophysiologically distinguished by more pronounced spike frequency adaptation properties. Axons of many inhibitory neurons projected ipsilaterally also to regions containing inspiratory XII premotoneurons and motoneurons, whereas a minority of inhibitory neurons had commissural axonal projections. Dendrites of both excitatory and inhibitory interneurons were arborized asymmetrically, primarily in the coronal plane. The dendritic fields of inhibitory neurons were more spatially compact than those of excitatory interneurons. Our results are consistent with the concepts of a compartmental circuit organization, a bilaterally coupled excitatory

Identifying obstacles and ranking common biological control research priorities for Europe to manage most economically important pests in arable, vegetable and perennial crops.

PubMed

Lamichhane, Jay Ram; Bischoff-Schaefer, Monika; Bluemel, Sylvia; Dachbrodt-Saaydeh, Silke; Dreux, Laure; Jansen, Jean-Pierre; Kiss, Jozsef; Köhl, Jürgen; Kudsk, Per; Malausa, Thibaut; Messéan, Antoine; Nicot, Philippe C; Ricci, Pierre; Thibierge, Jérôme; Villeneuve, François

2017-01-01

EU agriculture is currently in transition from conventional crop protection to integrated pest management (IPM). Because biocontrol is a key component of IPM, many European countries recently have intensified their national efforts on biocontrol research and innovation (R&I), although such initiatives are often fragmented. The operational outputs of national efforts would benefit from closer collaboration among stakeholders via transnationally coordinated approaches, as most economically important pests are similar across Europe. This paper proposes a common European framework on biocontrol R&I. It identifies generic R&I bottlenecks and needs as well as priorities for three crop types (arable, vegetable and perennial crops). The existing gap between the market offers of biocontrol solutions and the demand of growers, the lengthy and expensive registration process for biocontrol solutions and their varying effectiveness due to variable climatic conditions and site-specific factors across Europe are key obstacles hindering the development and adoption of biocontrol solutions in Europe. Considering arable, vegetable and perennial crops, a dozen common target pests are identified for each type of crop and ranked by order of importance at European level. Such a ranked list indicates numerous topics on which future joint transnational efforts would be justified. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

The Importance of Behavioral Thresholds and Objective Functions in Contaminant Transport Uncertainty Analysis

NASA Astrophysics Data System (ADS)

Sykes, J. F.; Kang, M.; Thomson, N. R.

2007-12-01

methodology that inherently accounts for parameter correlations and does not require assumptions regarding parameter distributions. For uncertainty analysis, multiple parameter sets were obtained using a modified Cauchy's M-estimator. Penalty functions had to be incorporated into the objective function definitions to generate a sufficient number of acceptable parameter sets. The combined effect of optimization and the application of the physical criteria perform the function of behavioral thresholds by reducing anomalies and by removing parameter sets with high objective function values. The factors that are important to the creation of an uncertainty envelope for TCE arrival at wells are outlined in the work. In general, greater uncertainty appears to be present at the tails of the distribution. For a refinement of the uncertainty envelopes, the application of additional physical criteria or behavioral thresholds is recommended.

Multi-functional roles for the polypeptide transport associated domains of Toc75 in chloroplast protein import

PubMed Central

Paila, Yamuna D; Richardson, Lynn GL; Inoue, Hitoshi; Parks, Elizabeth S; McMahon, James; Inoue, Kentaro; Schnell, Danny J

2016-01-01

Toc75 plays a central role in chloroplast biogenesis in plants as the membrane channel of the protein import translocon at the outer envelope of chloroplasts (TOC). Toc75 is a member of the Omp85 family of bacterial and organellar membrane insertases, characterized by N-terminal POTRA (polypeptide-transport associated) domains and C-terminal membrane-integrated β-barrels. We demonstrate that the Toc75 POTRA domains are essential for protein import and contribute to interactions with TOC receptors, thereby coupling preprotein recognition at the chloroplast surface with membrane translocation. The POTRA domains also interact with preproteins and mediate the recruitment of molecular chaperones in the intermembrane space to facilitate membrane transport. Our studies are consistent with the multi-functional roles of POTRA domains observed in other Omp85 family members and demonstrate that the domains of Toc75 have evolved unique properties specific to the acquisition of protein import during endosymbiotic evolution of the TOC system in plastids. DOI: http://dx.doi.org/10.7554/eLife.12631.001 PMID:26999824

Mechanisms and function of autophagy in intestinal disease.

PubMed

Lassen, Kara G; Xavier, Ramnik J

2018-01-01

The discovery of numerous genetic variants in the human genome that are associated with inflammatory bowel disease (IBD) has revealed critical pathways that play important roles in intestinal homeostasis. These genetic studies have identified a critical role for macroautophagy/autophagy and more recently, lysosomal function, in maintaining the intestinal barrier and mucosal homeostasis. This review highlights recent work on the functional characterization of IBD-associated human genetic variants in cell type-specific functions for autophagy.

Challenges in Identifying Patients with Type 2 Diabetes for Quality-Improvement Interventions in Primary Care Settings and the Importance of Valid Disease Registries.

PubMed

Wozniak, Lisa; Soprovich, Allison; Rees, Sandra; Johnson, Steven T; Majumdar, Sumit R; Johnson, Jeffrey A

2015-10-01

Patient registries are considered an important foundation of chronic disease management, and diabetes patient registries are associated with better processes and outcomes of care. The purpose of this article is to describe the development and use of registries in the Alberta's Caring for Diabetes (ABCD) project to identify and reach target populations for quality-improvement interventions in the primary care setting. We applied the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) framework and expanded the definition of reach beyond the individual (i.e. patient) level to include the ability to identify target populations at an organizational level. To characterize reach and the implementation of registries, semistructured interviews were conducted with key informants, and a usual-care checklist was compiled for each participating Primary Care Network (PCN). Content analysis was used to analyze qualitative data. Using registries to identify and recruit participants for the ABCD interventions proved challenging. The quality of the registries depended on whether physicians granted PCN access to patient lists, the strategies used in development, the reliability of diagnostic information and the data elements collected. In addition, once a diabetes registry was developed, there was limited ability to update it. Proactive management of chronic diseases like diabetes requires the ability to reach targeted patients at the population level. We observed several challenges to the development and application of patient registries. Given the importance of valid registries, strong collaborations and novel strategies that involve policy-makers, PCNs and providers are needed to help find solutions to improve registry quality and resolve maintenance issues. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

A survey of single nucleotide polymorphisms identified from whole-genome sequencing and their functional effect in the porcine genome.

PubMed

Keel, B N; Nonneman, D J; Rohrer, G A

2017-08-01

Genetic variants detected from sequence have been used to successfully identify causal variants and map complex traits in several organisms. High and moderate impact variants, those expected to alter or disrupt the protein coded by a gene and those that regulate protein production, likely have a more significant effect on phenotypic variation than do other types of genetic variants. Hence, a comprehensive list of these functional variants would be of considerable interest in swine genomic studies, particularly those targeting fertility and production traits. Whole-genome sequence was obtained from 72 of the founders of an intensely phenotyped experimental swine herd at the U.S. Meat Animal Research Center (USMARC). These animals included all 24 of the founding boars (12 Duroc and 12 Landrace) and 48 Yorkshire-Landrace composite sows. Sequence reads were mapped to the Sscrofa10.2 genome build, resulting in a mean of 6.1 fold (×) coverage per genome. A total of 22 342 915 high confidence SNPs were identified from the sequenced genomes. These included 21 million previously reported SNPs and 79% of the 62 163 SNPs on the PorcineSNP60 BeadChip assay. Variation was detected in the coding sequence or untranslated regions (UTRs) of 87.8% of the genes in the porcine genome: loss-of-function variants were predicted in 504 genes, 10 202 genes contained nonsynonymous variants, 10 773 had variation in UTRs and 13 010 genes contained synonymous variants. Approximately 139 000 SNPs were classified as loss-of-function, nonsynonymous or regulatory, which suggests that over 99% of the variation detected in our pigs could potentially be ignored, allowing us to focus on a much smaller number of functional SNPs during future analyses. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Novel subgroups of attention-deficit/hyperactivity disorder identified by topological data analysis and their functional network modular organizations

PubMed Central

Kyeong, Sunghyon; Kim, Jae-Jin; Kim, Eunjoo

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a clinically heterogeneous condition and identification of clinically meaningful subgroups would open up a new window for personalized medicine. Thus, we aimed to identify new clinical phenotypes in children and adolescents with ADHD and to investigate whether neuroimaging findings validate the identified phenotypes. Neuroimaging and clinical data from 67 children with ADHD and 62 typically developing controls (TDCs) from the ADHD-200 database were selected. Clinical measures of ADHD symptoms and intelligence quotient (IQ) were used as input features into a topological data analysis (TDA) to identify ADHD subgroups within our sample. As external validators, graph theoretical measures obtained from the functional connectome were compared to address the biological meaningfulness of the identified subtypes. The TDA identified two unique subgroups of ADHD, labelled as mild symptom ADHD (mADHD) and severe symptom ADHD (sADHD). The output topology shape was repeatedly observed in the independent validation dataset. The graph theoretical analysis showed a decrease in the degree centrality and PageRank in the bilateral posterior cingulate cortex in the sADHD group compared with the TDC group. The mADHD group showed similar patterns of intra- and inter-module connectivity to the sADHD group. Relative to the TDC group, the inter-module connectivity between the default mode network and executive control network were significantly increased in the sADHD group but not in the mADHD group. Taken together, our results show that the data-driven TDA is potentially useful in identifying objective and biologically relevant disease phenotypes in children and adolescents with ADHD. PMID:28829775

High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding.

PubMed

Chiang, Wei-Chung; Wei, Yongjie; Kuo, Yi-Chun; Wei, Shuguang; Zhou, Anwu; Zou, Zhongju; Yehl, Jenna; Ranaghan, Matthew J; Skepner, Adam; Bittker, Joshua A; Perez, Jose R; Posner, Bruce A; Levine, Beth

2018-06-21

Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. We sought to establish a method for developing new chemical compounds that specifically induce autophagy. To do this, we developed two assays to identify compounds that target a key regulatory node of autophagy induction-specifically, the binding of Bcl-2 (a negative regulator of autophagy) to Beclin 1 (an allosteric modulator of the Beclin 1/VPS34 lipid kinase complex that functions in autophagy initiation). These assays use either a split-luciferase assay to measure Beclin 1/Bcl-2 binding in cells or an AlphaLISA assay to directly measure direct Beclin 1/Bcl-2 binding in vitro. We screened two different chemical compound libraries, comprising ∼300 K compounds, to identify small molecules that disrupt Beclin 1/Bcl-2 binding and induce autophagy. Three novel compounds were identified that directly inhibit Beclin 1/Bcl-2 interaction with an IC 50 in the micromolar range and increase autophagic flux. These compounds do not demonstrate significant cytotoxicity, and they exert selectivity for disruption of Bcl-2 binding to the BH3 domain of Beclin 1 compared with the BH3 domain of the pro-apoptotic Bcl-2 family members, Bax and Bim. Thus, we have identified candidate molecules that serve as lead templates for developing potent and selective Beclin 1/Bcl-2 inhibitors that may be clinically useful as autophagy-inducing agents.

Dynamics in microbial communities: Unraveling mechanisms to identify principles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konopka, Allan; Lindemann, Stephen R.; Fredrickson, Jim K.

2015-07-01

Diversity begets higher order properties such as functional stability and robustness in microbial communities, but principles that inform conceptual (and eventually predictive) models of community dynamics are lacking. Recent work has shown that selection as well as dispersal and drift shape communities, but the mechanistic bases for assembly of communities and the forces that maintain their function in the face of environmental perturbation are not well understood. Conceptually, some interactions among community members could generate endogenous dynamics in composition, even in the absence of environmental changes. These endogenous dynamics are further perturbed by exogenous forcing factors to produce a richermore » network of community interactions, and it is this “system” that is the basis for higher order community properties. Elucidation of principles that follow from this conceptual model requires identifying the mechanisms that (a) optimize diversity within a community and (b) impart community stability. The network of interactions between organisms can be an important element by providing a buffer against disturbance beyond the effect of functional redundancy, as alternative pathways with different combinations of microbes can be recruited to fulfill specific functions.« less

Importance of β-defensins in sperm function.

PubMed

Dorin, Julia R; Barratt, Christopher L R

2014-09-01

Recent work in humans and mouse has confirmed the involvement of the host defence β-defensin peptides in male fertility. We discuss here the work that has implicated β-defensins in sperm function including the identification of the epididymis as the predominant site of expression of the peptides and the in vivo consequences of mutation and deletion. The potential dual role of these peptides in the regulation of infection and control of sperm maturation is compelling and may combine their antimicrobial activity with the ability of these molecules to interact with cell membrane receptors and modulate ion transport. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Measuring Frailty Can Help Emergency Departments Identify Independent Seniors at Risk of Functional Decline After Minor Injuries

PubMed Central

Griffith, Lauren; Perry, Jeffrey; Daoust, Raoul; Veillette, Nathalie; Lee, Jacques; Pelletier, Mathieu; Wilding, Laura; Émond, Marcel

2017-01-01

Background. This study aims to (i) describe frailty in the subgroup of independent community-dwelling seniors consulting emergency departments (EDs) for minor injuries, (ii) examine the association between frailty and functional decline 3 months postinjury, (iii) ascertain the predictive accuracy of frailty measures and emergency physicians’ for functional decline. Method. Prospective cohort in 2011–2013 among 1,072 seniors aged 65 years or older, independent in basic daily activities, evaluated in Canadian EDs for minor injuries. Frailty was assessed at EDs using the Canadian Study of Health and Aging-Clinical Frailty scale (CSHA-CFS) and the Study of Osteoporotic Fracture frailty index (SOF). Functional decline was defined as a loss ≥2/28 on the Older American Resources Services scale 3 months postinjury. Generalized mixed models were used to explore differences in functional decline across frailty levels. Areas under the receiver operating characteristic curve were used to ascertain the predictive accuracy of frailty measures and emergency physicians’ clinical judgment. Results. The SOF and CSHA-CFS were available in 342 and 1,058 participants, respectively. The SOF identified 55.6%, 32.7%, 11.7% patients as robust, prefrail, and frail. These CSHA-CFS (n = 1,058) proportions were 51.9%, 38.3%, and 9.9%. The 3-month incidence of functional decline was 12.1% (10.0%−14.6%). The Areas under the receiver operating characteristic curves of the CSHA-CFS and the emergency physicians’ were similar (0.548–0.777), while the SOF was somewhat higher (0.704–0.859). Conclusion. Measuring frailty in community-dwelling seniors with minor injuries in EDs may enhance current risk screening for functional decline. However, before implementation in usual care, feasibility issues such as inter-rater reliability and acceptability of frailty tools in the EDs have to be addressed. PMID:26400735

Spider Transcriptomes Identify Ancient Large-Scale Gene Duplication Event Potentially Important in Silk Gland Evolution.

PubMed

Clarke, Thomas H; Garb, Jessica E; Hayashi, Cheryl Y; Arensburger, Peter; Ayoub, Nadia A

2015-06-08

The evolution of specialized tissues with novel functions, such as the silk synthesizing glands in spiders, is likely an influential driver of adaptive success. Large-scale gene duplication events and subsequent paralog divergence are thought to be required for generating evolutionary novelty. Such an event has been proposed for spiders, but not tested. We de novo assembled transcriptomes from three cobweb weaving spider species. Based on phylogenetic analyses of gene families with representatives from each of the three species, we found numerous duplication events indicative of a whole genome or segmental duplication. We estimated the age of the gene duplications relative to several speciation events within spiders and arachnids and found that the duplications likely occurred after the divergence of scorpions (order Scorpionida) and spiders (order Araneae), but before the divergence of the spider suborders Mygalomorphae and Araneomorphae, near the evolutionary origin of spider silk glands. Transcripts that are expressed exclusively or primarily within black widow silk glands are more likely to have a paralog descended from the ancient duplication event and have elevated amino acid replacement rates compared with other transcripts. Thus, an ancient large-scale gene duplication event within the spider lineage was likely an important source of molecular novelty during the evolution of silk gland-specific expression. This duplication event may have provided genetic material for subsequent silk gland diversification in the true spiders (Araneomorphae). © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Three novel approaches to structural identifiability analysis in mixed-effects models.

PubMed

Janzén, David L I; Jirstrand, Mats; Chappell, Michael J; Evans, Neil D

2016-05-06

Structural identifiability is a concept that considers whether the structure of a model together with a set of input-output relations uniquely determines the model parameters. In the mathematical modelling of biological systems, structural identifiability is an important concept since biological interpretations are typically made from the parameter estimates. For a system defined by ordinary differential equations, several methods have been developed to analyse whether the model is structurally identifiable or otherwise. Another well-used modelling framework, which is particularly useful when the experimental data are sparsely sampled and the population variance is of interest, is mixed-effects modelling. However, established identifiability analysis techniques for ordinary differential equations are not directly applicable to such models. In this paper, we present and apply three different methods that can be used to study structural identifiability in mixed-effects models. The first method, called the repeated measurement approach, is based on applying a set of previously established statistical theorems. The second method, called the augmented system approach, is based on augmenting the mixed-effects model to an extended state-space form. The third method, called the Laplace transform mixed-effects extension, is based on considering the moment invariants of the systems transfer function as functions of random variables. To illustrate, compare and contrast the application of the three methods, they are applied to a set of mixed-effects models. Three structural identifiability analysis methods applicable to mixed-effects models have been presented in this paper. As method development of structural identifiability techniques for mixed-effects models has been given very little attention, despite mixed-effects models being widely used, the methods presented in this paper provides a way of handling structural identifiability in mixed-effects models previously not