Assessing the pathogenicity of insertion and deletion variants with the Variant Effect Scoring Tool (VEST-Indel)

Insertion/deletion variants (indels) alter protein sequence and length, yet are highly prevalent in healthy populations, presenting a challenge to bioinformatics classifiers. Commonly used features—DNA and protein sequence conservation, indel length, and occurrence in repeat regions—are useful for inference of protein damage. However, these features can cause false positives when predicting the impact of indels on disease. Existing methods for indel classification suffer from low specificities, severely limiting clinical utility. Here, we further develop our variant effect scoring tool (VEST) to include the classification of in-frame and frameshift indels (VEST-indel) as pathogenic or benign. We apply 24 features, including a new “PubMed” feature, to estimate a gene's importance in human disease. When compared with four existing indel classifiers, our method achieves a drastically reduced false-positive rate, improving specificity by as much as 90%. This approach of estimating gene importance might be generally applicable to missense and other bioinformatics pathogenicity predictors, which often fail to achieve high specificity. Finally, we tested all possible meta-predictors that can be obtained from combining the four different indel classifiers using Boolean conjunctions and disjunctions, and derived a meta-predictor with improved performance over any individual method

A Multi-Lab Test of the Facial Feedback Hypothesis by the Many Smiles Collaboration

Following theories of emotional embodiment, the facial feedback hypothesis suggests that individuals’ subjective experiences of emotion are influenced by their facial expressions. However, evidence for this hypothesis has been mixed. We thus formed a global adversarial collaboration and carried out a preregistered, multicentre study designed to specify and test the conditions that should most reliably produce facial feedback effects. Data from n = 3,878 participants spanning 19 countries indicated that a facial mimicry and voluntary facial action task could both amplify and initiate feelings of happiness. However, evidence of facial feedback effects was less conclusive when facial feedback was manipulated unobtrusively via a pen-in-mouth task

A multi-lab test of the facial feedback hypothesis by the Many Smiles Collaboration

Following theories of emotional embodiment, the facial feedback hypothesis suggests that individuals' subjective experiences of emotion are influenced by their facial expressions. However, evidence for this hypothesis has been mixed. We thus formed a global adversarial collaboration and carried out a preregistered, multicentre study designed to specify and test the conditions that should most reliably produce facial feedback effects. Data from n = 3,878 participants spanning 19 countries indicated that a facial mimicry and voluntary facial action task could both amplify and initiate feelings of happiness. However, evidence of facial feedback effects was less conclusive when facial feedback was manipulated unobtrusively via a pen-in-mouth task

Assessing the Pathogenicity of Insertion and Deletion Variants with the Variant Effect Scoring Tool (VEST‐Indel)

Insertion/deletion variants (indels) alter protein sequence and length, yet are highly prevalent in healthy populations, presenting a challenge to bioinformatics classifiers. Commonly used features—DNA and protein sequence conservation, indel length, and occurrence in repeat regions—are useful for inference of protein damage. However, these features can cause false positives when predicting the impact of indels on disease. Existing methods for indel classification suffer from low specificities, severely limiting clinical utility. Here, we further develop our variant effect scoring tool (VEST) to include the classification of in-frame and frameshift indels (VEST-indel) as pathogenic or benign. We apply 24 features, including a new “PubMed” feature, to estimate a gene's importance in human disease. When compared with four existing indel classifiers, our method achieves a drastically reduced false-positive rate, improving specificity by as much as 90%. This approach of estimating gene importance might be generally applicable to missense and other bioinformatics pathogenicity predictors, which often fail to achieve high specificity. Finally, we tested all possible meta-predictors that can be obtained from combining the four different indel classifiers using Boolean conjunctions and disjunctions, and derived a meta-predictor with improved performance over any individual method

Clinical Escherichia coli isolates utilize alpha-hemolysin to inhibit in vitro epithelial cytokine production

Uropathogenic Escherichia coli is the primary cause of urinary tract infections, which affects over 60% of women during their lifetime. UPEC exhibits a number of virulence traits that facilitate colonization of the bladder, including inhibition of cytokine production by bladder epithelial cells. The goal of this study was to identify the mechanism of this inhibition. We observed that cytokine suppression was associated with rapid cytotoxicity toward epithelial cells. We found that cytotoxicity, cytokine suppression and alpha-hemolysin production were all tightly linked in clinical isolates. We screened a UPEC fosmid library and identified clones that gained the cytotoxicity and cytokine-suppression phenotypes. Both clones contained fosmids encoding a PAI II(J96)-like domain and expressed the alpha-hemolysin (hlyA) encoded therein. Mutation of the fosmid-encoded hly operon abolished cytotoxicity and cytokine suppression. Similarly, mutation of the chromosomal hlyCABD operon of UPEC isolate F11 also abolished these phenotypes, and they could be restored by introducing the PAI II(J96)-like domain-encoding fosmid. We also examined the role of alpha-hemolysin in cytokine production both in the murine UTI model as well as patient specimens. We conclude that E. coli utilizes alpha-hemolysin to inhibit epithelial cytokine production in vitro. Its contribution to inflammation during infection requires further study

Preservation of Amputated Extremities by Extracorporeal Blood Perfusion; a Feasibility Study in a Porcine Model

Successful extremity transplantations and replantations have to be performed within 6 h of amputation to avoid irreversible tissue loss. This study investigates ex vivo the technical feasibility and the limb preservation potential of extracorporeal whole blood perfusion in a porcine model

Bonding and structure.

Includes bibliographical references and index.Discriminating interactions between chiral molecules David P. Craig and David P. Mellor - No-bond-resonance compounds, structure, bonding, and properties / Rolf Gleiter and Ruedi Gygax - The molecular Zeeman effect / Dieter H. Sutter and W. H. Flygar