IMHOTEP A composite score integrating popular tools for predicting the functional consequences of non-synonymous sequence variants

The in silico prediction of the functional consequences of mutations is an important goal of human pathogenetics. However, bioinformatic tools that classify mutations according to their functionality employ different algorithms so that predictions may vary markedly between tools. We therefore integrated nine popular prediction tools (PolyPhen-2, SNPs&GO, MutPred, SIFT, MutationTaster2, Mutation Assessor and FATHMM as well as conservation-based Grantham Score and PhyloP) into a single predictor. The optimal combination of these tools was selected by means of a wide range of statistical modeling techniques, drawing upon 10 029 disease-causing single nucleotide variants (SNVs) from Human Gene Mutation Database and 10 002 putatively ‘benign’ non-synonymous SNVs from UCSC. Predictive performance was found to be markedly improved by model-based integration, whilst maximum predictive capability was obtained with either random forest, decision tree or logistic regression analysis. A combination of PolyPhen-2, SNPs&GO, MutPred, MutationTaster2 and FATHMM was found to perform as well as all tools combined. Comparison of our approach with other integrative approaches such as Condel, CoVEC, CAROL, CADD, MetaSVM and MetaLR using an independent validation dataset, revealed the superiority of our newly proposed integrative approach. An online implementation of this approach, IMHOTEP (‘Integrating Molecular Heuristics and Other Tools for Effect Prediction’), is provided at http://www.uni-kiel.de/medinfo/cgi-bin/predictor/

Effects of b-lactam antibiotics and fluoroquinolones on human gut microbiota in relation to clostridium difficile associated diarrhea

Clostridium difficile infections are an emerging health problem in the modern hospital environment. Severe alterations of the gut microbiome with loss of resistance to colonization against C. difficile are thought to be the major trigger, but there is no clear concept of how C. difficile infection evolves and which microbiological factors are involved. We sequenced 16S rRNA amplicons generated from DNA and RNA/cDNA of fecal samples from three groups of individuals by FLX technology: (i) healthy controls (no antibiotic therapy); (ii) individuals receiving antibiotic therapy (Ampicillin/Sulbactam, cephalosporins, and fluoroquinolones with subsequent development of C. difficile infection or (iii) individuals receiving antibiotic therapy without C. difficile infection. We compared the effects of the three different antibiotic classes on the intestinal microbiome and the effects of alterations of the gut microbiome on C. difficile infection at the DNA (total microbiota) and rRNA (potentially active) levels. A comparison of antibiotic classes showed significant differences at DNA level, but not at RNA level. Among individuals that developed or did not develop a C. difficile infection under antibiotics we found no significant differences. We identified single species that were up- or down regulated in individuals receiving antibiotics who developed the infection compared to non-infected individuals. We found no significant differences in the global composition of the transcriptionally active gut microbiome associated with C. difficile infections. We suggest that up- and down regulation of specific bacterial species may be involved in colonization resistance against C. difficile providing a potential therapeutic approach through specific manipulation of the intestinal microbiome.This work was supported by the ERANET Project PathoGenoMics program grant number 0315441A.Peer Reviewe

Effects of lower limb amputation on the mental rotation of feet

What happens to the mental representation of our body when the actual anatomy of our body changes? We asked 18 able-bodied controls, 18 patients with a lower limb amputation and a patient with rotationplasty to perform a laterality judgment task. They were shown illustrations of feet in different orientations which they had to classify as left or right limb. This laterality recognition task, originally introduced by Parsons in Cognit Psychol 19:178–241, (1987), is known to elicit implicit mental rotation of the subject’s own body part. However, it can also be solved by mental transformation of the visual stimuli. Despite the anatomical changes in the body periphery of the amputees and of the rotationplasty patient, no differences in their ability to identify illustrations of their affected versus contralateral limb were found, while the group of able-bodied controls showed clear laterality effects. These findings are discussed in the context of various strategies for mental rotation versus the maintenance of an intact prototypical body structural description

Data from: Conquering the inner couch potato: precommitment is an effective strategy to enhance motivation for effortful actions

Letting effort-free gratification derail us from effort-requiring goals is one reason why we fail to realize health-relevant intentions like ‘exercise regularly’. We tested the effectiveness of the self-control strategy precommitment in such effort-related conflicts, using a novel laboratory choice paradigm, where participants could precommit to an effort-requiring large reward by pre-eliminating an effort-free small reward from their choice set. Our participants used precommitment frequently and effectively, such that they reached effort-requiring large rewards more often. Using computational modelling and Bayesian model comparisons, we assessed whether participants employed precommitment to avoid anticipated willpower failures (i.e. as a self-regulatory measure) or to maximize their motivation to choose the effort-requiring option (i.e. as a self-motivational measure). Observed choices and precommitment decisions were consistent with the motivation maximization hypothesis, but not the willpower hypothesis. Our findings show that offering precommitment is effective in helping individuals optimize their motivation and choice behaviour and thereby achieve effort-requiring goals, and strongly encourage application of precommitment schemes in exercise and rehabilitation interventions. This article is part of the theme issue ‘Risk taking and impulsive behaviour: fundamental discoveries, theoretical perspectives and clinical implications’

Modelling codes and raw data for the effort and delay tasks

The zipped folder contains the Matlab modelling codes (choice and precommitment models as specified in Table 1 of the article) and the respective raw data (one file per participant) for each of the two experimental task

A Challenge to the Reigning Theory of the Just War

Troubled times often gives rise to great art that reflects those troubles. So too with political theory. The greatest work of twentieth century political theory, John Rawls's A theory of justice, was inspired in various respects by extreme social and economic inequality, racialized slavery and racial segregation in the United States. Arguably the most influential work of political theory since Rawls—Michael Walzer's Just and unjust wars—a sustained and historically informed reflection on the morality of interstate armed conflict—was written in the midst of the Vietnam War. It should be no surprise, then, that the bellicose period of the past 20 years should give rise to a robust new literature in political theory on the morality of armed conflict. It has been of uneven quality, and to some extent episodic, responding to particular challenges—the increased prevalence of asymmetric warfare and the permissibility of preventive or preemptive war—that have arisen as a result of specific events. In the past decade, however, a group of philosophers has begun to pose more fundamental questions about the reigning theory of the morality of armed conflict warfare—just war theory—as formulated by Walzer and others. Jeff McMahan's concise, inventive and tightly argued work Killing in war is without doubt the most important of these challenges to the reigning theory of the just war. This review article discusses McMahan's work, some of the critical attention it has received, and its potential implications for practice

Effects of β-Lactam Antibiotics and Fluoroquinolones on Human Gut Microbiota in Relation to <i>Clostridium difficile</i> Associated Diarrhea

<div><p><i>Clostridium difficile</i> infections are an emerging health problem in the modern hospital environment. Severe alterations of the gut microbiome with loss of resistance to colonization against <i>C. difficile</i> are thought to be the major trigger, but there is no clear concept of how <i>C. difficile</i> infection evolves and which microbiological factors are involved. We sequenced 16S rRNA amplicons generated from DNA and RNA/cDNA of fecal samples from three groups of individuals by FLX technology: (i) healthy controls (no antibiotic therapy); (ii) individuals receiving antibiotic therapy (Ampicillin/Sulbactam, cephalosporins, and fluoroquinolones with subsequent development of <i>C. difficile</i> infection or (iii) individuals receiving antibiotic therapy without <i>C. difficile</i> infection. We compared the effects of the three different antibiotic classes on the intestinal microbiome and the effects of alterations of the gut microbiome on <i>C. difficile</i> infection at the DNA (total microbiota) and rRNA (potentially active) levels. A comparison of antibiotic classes showed significant differences at DNA level, but not at RNA level. Among individuals that developed or did not develop a <i>C. difficile</i> infection under antibiotics we found no significant differences. We identified single species that were up- or down regulated in individuals receiving antibiotics who developed the infection compared to non-infected individuals. We found no significant differences in the global composition of the transcriptionally active gut microbiome associated with <i>C. difficile</i> infections. We suggest that up- and down regulation of specific bacterial species may be involved in colonization resistance against <i>C. difficile</i> providing a potential therapeutic approach through specific manipulation of the intestinal microbiome.</p></div