Genetic influences on translation in yeast

Heritable differences in gene expression between individuals are an important source of phenotypic variation. The question of how closely the effects of genetic variation on protein levels mirror those on mRNA levels remains open. Here, we addressed this question by using ribosome profiling to examine how genetic differences between two strains of the yeast S. cerevisiae affect translation. Strain differences in translation were observed for hundreds of genes. Allele specific measurements in the diploid hybrid between the two strains revealed roughly half as many cis-acting effects on translation as were observed for mRNA levels. In both the parents and the hybrid, most effects on translation were of small magnitude, such that the direction of an mRNA difference was typically reflected in a concordant footprint difference. The relative importance of cis and trans acting variation on footprint levels was similar to that for mRNA levels. There was a tendency for translation to cause larger footprint differences than expected given the respective mRNA differences. This is in contrast to translational differences between yeast species that have been reported to more often oppose than reinforce mRNA differences. Finally, we catalogued instances of premature translation termination in the two yeast strains and also found several instances where erroneous reference gene annotations lead to apparent nonsense mutations that in fact reside outside of the translated gene body. Overall, genetic influences on translation subtly modulate gene expression differences, and translation does not create strong discrepancies between genetic influences on mRNA and protein levels

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Do general practitioners and psychiatrists agree about defining cure from depression? The DEsCRIBE™ survey

BACKGROUND: This study aimed to document the outcome dimensions that physicians see as important in defining cure from depression. The study also aimed to analyse physicians' attitudes about depression and to find out whether they affect their prescribing practices and/or the outcome dimensions that they view as important in defining cure. METHODS: A 51-item questionnaire based on six validated scales was used to rate the importance of several depression outcome dimensions. Physicians' attitudes about depression were also assessed using the Depression Attitude Scale. Overall, 369 Belgian physicians (264 general practitioners [GPs]; 105 psychiatrists) participated in the DEsCRIBE survey. RESULTS: GPs and psychiatrists strongly agreed that functioning and depressive symptomatology were most important in defining cure; anxious and somatic symptomatology was least important. GPs and psychiatrists differed in their attitudes about depression (p <0.001). Logistic regression revealed that the attitudes of GPs - but not psychiatrists - were significantly associated with their rates of antidepressant prescription (p < 0.001) and that certain attitudes predicted which outcome dimensions were seen as important in defining cure. CONCLUSIONS: Belgian GPs and psychiatrists strongly agreed on which criteria were important in defining cure from depression but differed in their attitudes about depression. The outcome dimensions that were considered important in defining cure were influenced by physicians' attitudes - this was more pronounced in GPs than in psychiatrists

The Osteopontin Level in Liver, Adipose Tissue and Serum Is Correlated with Fibrosis in Patients with Alcoholic Liver Disease

<div><h3>Background</h3><p>Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis.</p> <h3>Methodology/Principal Findings</h3><p>OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFβ expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F≥2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter® levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter® (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F≥2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury.</p> <h3>Conclusion/Significance</h3><p>OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease.</p> </div

Fine mapping and replication of QTL in outbred chicken advanced intercross lines

Background: Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F2 populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F2 animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature. Methods: We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F2 population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight. Results: Five of the nine QTL detected with the original F2 population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL. Conclusions: Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed

A classification of diabetic foot infections using ICD-9-CM codes: application to a large computerized medical database

<p>Abstract</p> <p>Background</p> <p>Diabetic foot infections are common, serious, and varied. Diagnostic and treatment strategies are correspondingly diverse. It is unclear how patients are managed in actual practice and how outcomes might be improved. Clarification will require study of large numbers of patients, such as are available in medical databases. We have developed and evaluated a system for identifying and classifying diabetic foot infections that can be used for this purpose.</p> <p>Methods</p> <p>We used the (VA) Diabetes Epidemiology Cohorts (DEpiC) database to conduct a retrospective observational study of patients with diabetic foot infections. DEpiC contains computerized VA and Medicare patient-level data for patients with diabetes since 1998. We determined which ICD-9-CM codes served to identify patients with different types of diabetic foot infections and ranked them in declining order of severity: Gangrene, Osteomyelitis, Ulcer, Foot cellulitis/abscess, Toe cellulitis/abscess, Paronychia. We evaluated our classification by examining its relationship to patient characteristics, diagnostic procedures, treatments given, and medical outcomes.</p> <p>Results</p> <p>There were 61,007 patients with foot infections, of which 42,063 were classifiable into one of our predefined groups. The different types of infection were related to expected patient characteristics, diagnostic procedures, treatments, and outcomes. Our severity ranking showed a monotonic relationship to hospital length of stay, amputation rate, transition to long-term care, and mortality.</p> <p>Conclusions</p> <p>We have developed a classification system for patients with diabetic foot infections that is expressly designed for use with large, computerized, ICD-9-CM coded administrative medical databases. It provides a framework that can be used to conduct observational studies of large numbers of patients in order to examine treatment variation and patient outcomes, including the effect of new management strategies, implementation of practice guidelines, and quality improvement initiatives.</p

Ethological principles predict the neuropeptides co-opted to influence parenting

Ethologists predicted that parental care evolves by modifying behavioural precursors in the asocial ancestor. As a corollary, we predict that the evolved mechanistic changes reside in genetic pathways underlying these traits. Here we test our hypothesis in female burying beetles, Nicrophorus vespilloides, an insect where caring adults regurgitate food to begging, dependent offspring. We quantify neuropeptide abundance in brains collected from three behavioural states: solitary virgins, individuals actively parenting or post-parenting solitary adults and quantify 133 peptides belonging to 18 neuropeptides. Eight neuropeptides differ in abundance in one or more states, with increased abundance during parenting in seven. None of these eight neuropeptides have been associated with parental care previously, but all have roles in predicted behavioural precursors for parenting. Our study supports the hypothesis that predictable traits and pathways are targets of selection during the evolution of parenting and suggests additional candidate neuropeptides to study in the context of parenting

Implementation of 3 T Lactate-Edited 3D 1H MR Spectroscopic Imaging with Flyback Echo-Planar Readout for Gliomas Patients

The purpose of this study was to implement a new lactate-edited 3D 1H magnetic resonance spectroscopic imaging (MRSI) sequence at 3 T and demonstrate the feasibility of using this sequence for measuring lactate in patients with gliomas. A 3D PRESS MRSI sequence incorporating shortened, high bandwidth 180° pulses, new dual BASING lactate-editing pulses, high bandwidth very selective suppression (VSS) pulses and a flyback echo-planar readout was implemented at 3 T. Over-prescription factor of PRESS voxels was optimized using phantom to minimize chemical shift artifacts. The lactate-edited flyback sequence was compared with lactate-edited MRSI using conventional elliptical k-space sampling in a phantom and volunteers, and then applied to patients with gliomas. The results demonstrated the feasibility of detecting lactate within a short scan time of 9.5 min in both phantoms and patients. Over-prescription of voxels gave less chemical shift artifacts allowing detection of lactate on the majority of the selected volume. The normalized SNR of brain metabolites using the flyback encoding were comparable to the SNR of brain metabolites using conventional phase encoding MRSI. The specialized lactate-edited 3D MRSI sequence was able to detect lactate in brain tumor patients at 3 T. The implementation of this technique means that brain lactate can be evaluated in a routine clinical setting to study its potential as a marker for prognosis and response to therapy

Terminology for Achilles tendon related disorders

The terminology of Achilles tendon pathology has become inconsistent and confusing throughout the years. For proper research, assessment and treatment, a uniform and clear terminology is necessary. A new terminology is proposed; the definitions hereof encompass the anatomic location, symptoms, clinical findings and histopathology. It comprises the following definitions: Mid-portion Achilles tendinopathy: a clinical syndrome characterized by a combination of pain, swelling and impaired performance. It includes, but is not limited to, the histopathological diagnosis of tendinosis. Achilles paratendinopathy: an acute or chronic inflammation and/or degeneration of the thin membrane around the Achilles tendon. There are clear distinctions between acute paratendinopathy and chronic paratendinopathy, both in symptoms as in histopathology. Insertional Achilles tendinopathy: located at the insertion of the Achilles tendon onto the calcaneus, bone spurs and calcifications in the tendon proper at the insertion site may exist. Retrocalcaneal bursitis: an inflammation of the bursa in the recess between the anterior inferior side of the Achilles tendon and the posterosuperior aspect of the calcaneus (retrocalcaneal recess). Superficial calcaneal bursitis: inflammation of the bursa located between a calcaneal prominence or the Achilles tendon and the skin. Finally, it is suggested that previous terms as Haglund’s disease; Haglund’s syndrome; Haglund’s deformity; pump bump (calcaneus altus; high prow heels; knobbly heels; cucumber heel), are no longer used