ResponseNet: revealing signaling and regulatory networks linking genetic transcriptomic screening data

Cellular response to stimuli is typically complex and involves both regulatory and metabolic processes. Large-scale experimental efforts to identify components of these processes often comprise of genetic screening and transcriptomic profiling assays. We previously established that in yeast genetic screens tend to identify response regulators, while transcriptomic profiling assays tend to identify components of metabolic processes. ResponseNet is a network-optimization approach that integrates the results from these assays with data of known molecular interactions. Specifically, ResponseNet identifies a high-probability sub-network, composed of signaling and regulatory molecular interaction paths, through which putative response regulators may lead to the measured transcriptomic changes. Computationally, this is achieved by formulating a minimum-cost flow optimization problem and solving it efficiently using linear programming tools. The ResponseNet web server offers a simple interface for applying ResponseNet. Users can upload weighted lists of proteins and genes and obtain a sparse, weighted, molecular interaction sub-network connecting their data. The predicted sub-network and its gene ontology enrichment analysis are presented graphically or as text. Consequently, the ResponseNet web server enables researchers that were previously limited to separate analysis of their distinct, large-scale experiments, to meaningfully integrate their data and substantially expand their understanding of the underlying cellular response. ResponseNet is available at http://bioinfo.bgu.ac.il/respnet.Seventh Framework Programme (European Commission) (FP7-PEOPLE-MCA-IRG)United States-Israel Binational Science Foundation (Grant 2009323

Idiopathic Gastric Rupture in a Child: Critical Situation

Idiopathic gastric rupture is extremely rare condition in children. We report herein a 4-years-old girl with Idiopathic GR who presented with shock. Resuscitation and early surgical intervention led to saving the child's life. Index Word: Gastric rupture, Pneumoperitoneum, Abdominal distension, Resuscitation

Post-transplant liver biopsies: a concise and practical approach for beginners

Exposure to post-transplant liver biopsies varies among pathology residencies and largely depends on the institution's training program, particularly if the hospital has a liver transplant program. The interpretation of biopsies from transplanted livers presents its own set of challenges, even for those with a solid understanding of non-transplant medical liver biopsies. In this review, we aim to provide a succinct, step-by-step approach to help you interpret liver transplant biopsies. This article may be beneficial for residents interested in liver pathology, gastrointestinal and liver pathology fellows in the early stages of training, clinical gastroenterology and hepatology fellows, hepatologists and general pathologists who are curious about this niche

Cultural difference in attitudes towards stuttering among British, Arab and Chinese students: considering home and host cultures

Background Geographical and cultural differences have been shown to affect public attitudes towards stuttering. However, increasingly for many individuals in the world one's birthplace culture (or home culture) and culture in their local geographical environment (or host culture) are not the same. Aims The effects of home culture and host culture in shaping the attitudes towards stuttering among students with British, Arab and Chinese home cultures attending one British university were explored. The effects of host culture were investigated by considering the time lived in the UK for Arab and Chinese students. Methods & Procedures The study used a descriptive survey design that included a standardized self‐delivered questionnaire: the Public Opinion Survey of Human Attributes—Stuttering (POSHA‐S). Purposive sampling was carried out thorough volunteer mailing lists, student societies and personal contact. The final sample of 156 university students included 51 British, 52 Arab and 53 Chinese students. Outcomes & Results Overall stuttering score (OSS), which is indicative of attitudes towards stuttering, was highest for British participants (mean = 30) and lowest for Chinese participants (mean = 13), with Arab participants falling in the middle (mean = 21). The differences in attitudes between the three groups were statistically significant, suggesting that home culture is a contributor to attitudes towards stuttering. A post‐hoc item analysis of the POSHA‐S revealed numerous specific differences in attitudes towards stuttering between the three groups, including differences in the attribution of the aetiology of stuttering, their role in helping people who stutter (PWS) and sympathy toward PWS. Time lived in the UK—a proxy measure for the role of host culture—did not significantly influence the attitudes of Arab and Chinese respondents. Conclusions & Implications To varying degrees, all three groups had evidence of stereotypical stuttering attitudes. Nevertheless, given similar ages and student status in the same university, observed respondent differences confirm previous research documenting geographical influences on stuttering attitudes in Western versus East Asian and Middle Eastern samples. The study also provides evidence that home culture was influential in shaping attitudes towards stuttering, but host culture was not a significant contributor. What this paper adds What is already known on the subject Public stereotypical beliefs towards stuttering are found across the world and hinder the quality of life among PWS. Different cultures have unique stereotypical beliefs towards PWS. What this study adds to existing knowledge To the best of our knowledge, no other study has investigated specifically if individuals who live in the same geographical location but have different home cultures, have similar or differing attitudes towards PWS. Results provide preliminary evidence that the home culture of an individual was influential in shaping attitudes towards PWS, but host culture, measured as the length of time living in the current geographical location, did not have a significant relationship with attitudes towards stuttering. What are the potential or actual clinical implications of this work This study highlights that culturally sensitive clinical practice should not be based on just the culture of the region but should take home culture into consideration as well, and clinicians should discuss cultural perceptions of stuttering with clients in clinical practice

Network-Free Inference of Knockout Effects in Yeast

Perturbation experiments, in which a certain gene is knocked out and the expression levels of other genes are observed, constitute a fundamental step in uncovering the intricate wiring diagrams in the living cell and elucidating the causal roles of genes in signaling and regulation. Here we present a novel framework for analyzing large cohorts of gene knockout experiments and their genome-wide effects on expression levels. We devise clustering-like algorithms that identify groups of genes that behave similarly with respect to the knockout data, and utilize them to predict knockout effects and to annotate physical interactions between proteins as inhibiting or activating. Differing from previous approaches, our prediction approach does not depend on physical network information; the latter is used only for the annotation task. Consequently, it is both more efficient and of wider applicability than previous methods. We evaluate our approach using a large scale collection of gene knockout experiments in yeast, comparing it to the state-of-the-art SPINE algorithm. In cross validation tests, our algorithm exhibits superior prediction accuracy, while at the same time increasing the coverage by over 25-fold. Significant coverage gains are obtained also in the annotation of the physical network

A Parsimony Approach to Biological Pathway Reconstruction/Inference for Genomes and Metagenomes

A common biological pathway reconstruction approach—as implemented by many automatic biological pathway services (such as the KAAS and RAST servers) and the functional annotation of metagenomic sequences—starts with the identification of protein functions or families (e.g., KO families for the KEGG database and the FIG families for the SEED database) in the query sequences, followed by a direct mapping of the identified protein families onto pathways. Given a predicted patchwork of individual biochemical steps, some metric must be applied in deciding what pathways actually exist in the genome or metagenome represented by the sequences. Commonly, and straightforwardly, a complete biological pathway can be identified in a dataset if at least one of the steps associated with the pathway is found. We report, however, that this naïve mapping approach leads to an inflated estimate of biological pathways, and thus overestimates the functional diversity of the sample from which the DNA sequences are derived. We developed a parsimony approach, called MinPath (Minimal set of Pathways), for biological pathway reconstructions using protein family predictions, which yields a more conservative, yet more faithful, estimation of the biological pathways for a query dataset. MinPath identified far fewer pathways for the genomes collected in the KEGG database—as compared to the naïve mapping approach—eliminating some obviously spurious pathway annotations. Results from applying MinPath to several metagenomes indicate that the common methods used for metagenome annotation may significantly overestimate the biological pathways encoded by microbial communities

Discovering pathways by orienting edges in protein interaction networks

Modern experimental technology enables the identification of the sensory proteins that interact with the cells’ environment or various pathogens. Expression and knockdown studies can determine the downstream effects of these interactions. However, when attempting to reconstruct the signaling networks and pathways between these sources and targets, one faces a substantial challenge. Although pathways are directed, high-throughput protein interaction data are undirected. In order to utilize the available data, we need methods that can orient protein interaction edges and discover high-confidence pathways that explain the observed experimental outcomes. We formalize the orientation problem in weighted protein interaction graphs as an optimization problem and present three approximation algorithms based on either weighted Boolean satisfiability solvers or probabilistic assignments. We use these algorithms to identify pathways in yeast. Our approach recovers twice as many known signaling cascades as a recent unoriented signaling pathway prediction technique and over 13 times as many as an existing network orientation algorithm. The discovered paths match several known signaling pathways and suggest new mechanisms that are not currently present in signaling databases. For some pathways, including the pheromone signaling pathway and the high-osmolarity glycerol pathway, our method suggests interesting and novel components that extend current annotations