EcoCyc: fusing model organism databases with systems biology.

EcoCyc (http://EcoCyc.org) is a model organism database built on the genome sequence of Escherichia coli K-12 MG1655. Expert manual curation of the functions of individual E. coli gene products in EcoCyc has been based on information found in the experimental literature for E. coli K-12-derived strains. Updates to EcoCyc content continue to improve the comprehensive picture of E. coli biology. The utility of EcoCyc is enhanced by new tools available on the EcoCyc web site, and the development of EcoCyc as a teaching tool is increasing the impact of the knowledge collected in EcoCyc

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Diagnosis of out-of-hospital cardiac arrest by Emergency Medical Dispatch : a diagnostic systematic review

Introduction Cardiac arrest is a time-sensitive condition requiring urgent intervention. Prompt and accurate recognition of cardiac arrest by emergency medical dispatchers at the time of the emergency call is a critical early step in cardiac arrest management allowing for initiation of dispatcher-assisted bystander CPR and appropriate and timely emergency response. The overall accuracy of dispatchers in recognizing cardiac arrest is not known. It is also not known if there are specific call characteristics that impact the ability to recognize cardiac arrest. Methods We performed a systematic review to examine dispatcher recognition of cardiac arrest as well as to identify call characteristics that may affect their ability to recognize cardiac arrest at the time of emergency call. We searched electronic databases for terms related to “emergency medical dispatcher”, “cardiac arrest’, and “diagnosis,” among others, with a focus on studies that allowed for calculating diagnostic test characteristics (e.g. sensitivity and specificity). The review was consistent with Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method for evidence evaluation. Results We screened 2520 article titles, resulting in 47 studies included in this review. There was significant heterogeneity between studies with a high risk of bias in 18 of the 47 which precluded performing meta-analyses. The reported sensitivities for cardiac arrest recognition ranged from 0.46 to 0.98 whereas specificities ranged from 0.32 to 1.00. There were no obvious differences in diagnostic accuracy between different dispatching criteria/algorithms or with the level of education of dispatchers. Conclusion The sensitivity and specificity of cardiac arrest recognition at the time of emergency call varied across dispatch centres and did not appear to differ by dispatch algorithm/criteria used or education of the dispatcher, although comparisons were hampered by heterogeneity across studies. Future efforts should focus on ways to improve sensitivity of cardiac arrest recognition to optimize patient care and ensure appropriate and timely resource utilizatio

Quantifying Sea-Ice Volume Flux using Moored Instrumentation in the Bering Strait

Thesis (Master's)--University of Washington, 2012The Bering Strait is the sole pathway linking the Pacific and Arctic Oceans, and carries one-third of the freshwater entering the Arctic. Although the strait's throughflow dominates the hydrography of the highly productive Chukchi Sea and affects the freshwater budget and thermal structure of the Arctic Ocean, the contribution of sea ice to the freshwater flux has never been satisfactorily quantified. We use data from an array of subsurface moored Acoustic Doppler Current Profilers (ADCPs) and other instruments deployed in the Bering Strait from 2007–2008 to calculate the sea ice and corresponding freshwater volume fluxes through the strait. Data from remote-sensing systems such as the Advanced Microwave Scanning Radiometer (AMSR) and modeled sea level pressure data provide a check of ADCP-derived measurements. We correct the ADCP sea-ice thickness records for instrument-based errors (instrument pitch and roll, ridge shadowing, beam footprint, beam averaging, range outliers) and environment-based errors (sound speed variation, instrument depth, sea-ice freeboard and snow loading), and determine the uncertainty in our volume flux calculations. We estimate the total error in ADCP ice thickness measurements to be of order 0.5 m, with ∼ 46% of this error resulting from beam footprint effects that would remain even if a more precise sonar instrument had been used in our study. We compare our estimates of sea-ice volume flux (190 ± 50 km3 yr-1) and corresponding freshwater transport (140 ± 40 km3 yr-1) through the strait to values from previous surveys, commenting on differences in methodology between the studies. Our findings allow us to assess the utility of subsurface moored ADCPs in quantifying sea-ice presence, thickness, and velocity; the ADCP signal correlation parameter appears to provide a particularly good indication of sea-ice presence. In addition, we consider the use of similar methods to evaluate historical ADCP records and develop a more complete understanding of interannual sea-ice flux variability through the Bering Strait

Learning to Learn from Data: Benchmarks and Instructional Communities

This article examines the use of interim assessments in elementary schools in the School District of Philadelphia. The article reports on the qualitative component of a multimethod study about the use of interim assessments in Philadelphia. The study used an organizational learning framework to explore how schools can best develop the capacity to utilize the potential benefits of interim assessments. The qualitative analysis draws on data from intensive fieldwork in 10 elementary schools and interviews with district staff and others who worked with the schools, as well as further in-depth case study analysis of 5 schools. This article examines how school leaders and grade groups made sense of data provided through interim assessments and how they were able to use these data to rethink instructional practice. We found substantial evidence that interim assessments have the potential to contribute to instructional coherence and instructional improvement if they are embedded in a robust feedback system. Such feedback systems were not the norm in the schools in our study, and their development requires skill, knowledge, and concerted attention on the part of school leaders

Expression de gènes viraux de l'herpès virus OsHV-1 sous sa forme µVar chez l'huître creuse, Crassostrea gigas

Le premier cas d'infection à virus de type herpès a été rapporté en 1972, aux Etats Unis, chez l'huître américaine, Crassostrea virginica (Farley et al, 1972). A partir de 1991, des mortalités massives associées à la détection de virus de type herpes ont été observées chez plusieurs espèces de bivalves marins, à différents stades de développement (essentiellement chez les larves et le naissain) et dans différentes régions du monde. Sur la base d’observation en microscopie électronique à transmission, ces virus présentaient des caractéristiques morphologiques identiques à celles des Herpesvirus (Roizman, 1982). Les connaissances acquises concernant la taille, la structure et le séquençage du génome d’un virus infectant les larves d’huîtres creuses en France ont confirmé l'hypothèse que ce virus, appelé Ostreid herpesvirus 1 appartient à l’ordre des Herpesviales et à la famille des Malacoherpesviridae (Le Deuff & Renault, 1999 ; Davison et al., en 2005 ; Davison et al., 2009). Le séquençage complet a montré que la structure de l'ADN viral est comparable à l'herpès simplex virus de type 1, HSV-1. La taille du génome d'OsHV-1 est estimée à 207 kpb et comprend de 124 cadres de lecture (ORFs). Depuis 2008, des épisodes de surmortalités ont été rapportés dans différentes régions de production d’huîtres creuses, C. gigas, en France, en Irlande et au Royaume Uni. Les données disponibles suggèrent que le virus est une cause prépondérante avec la détection un génotype viral particulier, appelé OsHV-1 µVar à partir de 2008 (Segarra et al. 2010). Bien que les facteurs climatiques seuls n’apparaissent pas comme une cause suffisante pour expliquer le phénomène, les surmortalités sont bien saisonnières en termes d’apparition. Une augmentation rapide de la température de l’eau au printemps a été clairement identifiée comme un facteur de risque majeur. Pour diminuer les effets de ce virus, les moyens de lutte sont relativement restreints. Au vue des conditions d'élevage des huîtres en milieu ouvert, l'utilisation de traitements médicamenteux reste inadaptée. De plus, l'absence de mémoire immunitaire chez les invertébrés ne permet pas d'utiliser la vaccination pour combattre l’infection virale. Ainsi, les moyens de lutte reposent essentiellement sur (1) la surveillance des stocks et des transferts afin de limiter la propagation de la maladie et (2) sur le développement d'animaux résistants à l'infection se traduisant par une meilleure survie. Ces différentes approches nécessitent des outils de diagnostic adaptés, une bonne connaissance du cycle viral, et plus particulièrement des interactions entre l’hôte, le virus et l’environnement. Dans ce contexte, il apparaît indispensable de mieux connaître l'expression des gènes viraux au cours de l'infection chez l'huître creuse, Crassostrea gigas. Il a été choisi de suivre l’expression de gènes viraux lors d’une infection expérimentale. En effet, très récemment, Schikorski et al. (2011) ont développé un protocole d’infection expérimentale rendant possible la reproduction de l'infection virale en laboratoire chez le naissain d'huîtres creuses. D'autre part, le séquençage complet d'OsHV-1 (Davison et al., 2005) permettait de sélectionner des gènes d’intérêt ( 41 gènes candidats). Afin d'étudier la cinétique d'expression des gènes sélectionnés, la PCR en temps réel à été optimisé pour chacun couple d'amorces. La présente étude a été réalisée chez des huîtres de moins d’un an appartenant de 2 familles présentant un comportement contrastées en terme de résistance à l’infection en condition expérimentale : une famille résistante (10% de mortalité 6 jours post infection) et une famille sensible (100% de mortalité 3 jours post infection). Suite à l'infection, un fragment de manteau a été prélevé sur 12 individus pour chaque condition et chaque temps de prélèvement. Les temps de prélèvements post injection sélectionnés étaient : 0h, 4h, 8h, 12h et 26h. Les premiers résultats obtenus en PCR en temps réel mettent en évidence la détection de gènes très précoces mais également plus tardifs. Dans cette étude, après 26h d'infection, les 41 gènes viraux semblent tous être exprimés chez la famille sensible. Ainsi, l'expression des gènes d'OsHV-1 semble avoir une cinétique similaire à ceux des herpesvirus de vertébrés. En effet, l’expression des gènes viraux chez les herpersvirus comporte trois phases au cours de l’infection : (1) des gènes sont exprimés très précocement avec synthèse de protéines activatrices, (2) d’autres gènes précocement avec la synthèse d’enzymatiques impliquées dans la réplication dont l'ADN polymérase et (3) et enfin un troisième groupe de gènes tardivement avec la synthèse des composants protéiques de la capside et des glycoprotéines d'enveloppe. Ainsi, cette étude a permis de détecter la présence d'ARN transcrits durant une infection expérimentale à OsHV-1 chez le naissain d'huître creuse Crassostrea gigas. Enfin, ceci confirme la réplication du virus au sein même de son hôte et par conséquent renseigne sur le cycle de vie viral d'OsHV-1