miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis.MethodsGWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes.ResultsMIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility

Risk of symptomatic COVID-19 due to aircraft transmission: a retrospective cohort study of contact-traced flights during England's containment phase.

BACKGROUND: Knowledge gaps remain regarding SARS-CoV-2 transmission on flights. We conducted a retrospective cohort study to estimate risk of acquiring symptomatic SARS-CoV-2 on aircraft, to inform contact tracing and infection control efforts. METHODS: We identified co-passengers of infectious passengers on 18 England-bound flights from European cities up to 12/03/2020, using manifests received for contact tracing. Infectious passengers were laboratory-confirmed cases with symptom onset from 7 days before to 2 days after the flight. Possible aircraft-acquired cases were laboratory-confirmed with onset 3-14 days post-flight with no known non-flight exposure. Manifests was merged with the national case management dataset (identifying cases, onset dates, contact tracing status) and the national COVID-19 linelist. Contact tracing notes were reviewed to identify non-flight exposures. We calculated attack rates (ARs) among all co-passengers and within subgroups, including by distance from infectious cases and number of infectious cases on-board. RESULTS: There were 55 infectious passengers and 2313 co-passengers, including 2221 flight-only contacts. Five possible aircraft-acquired cases were identified; ARs of 0.2% (95%CI 0.1-0.5) among all flight-only contacts and 3.8% (95%CI 1.3-10.6) among contact-traced flight-only contacts sat within a two-seat radius. The AR among 92 co-travellers with known non-flight exposure to infectious cases was 13.0% (95%CI 7.6%-21.4%). There were insufficient numbers to assess differences between subgroups. CONCLUSION: We conclude that risk of symptomatic COVID-19 due to transmission on short to medium-haul flights is low, and recommend prioritising contact-tracing of close contacts and co-travellers where resources are limited. Further research on risk on aircraft is encouraged

Tech Home

El desarrollo de la tecnología ha evolucionado la oferta de servicios e incrementado el uso de las plataformas digitales, convirtiéndo a estas en un gran aliado de los negocios. A partir de esto, surgió TechHome, un aplicativo que busca atender las demandas y necesidades del mercado en base a la oferta de servicios dirigidos a dos segmentos conformados por amas de casa y trabajadores técnicos relacionados a tareas de hogar. Para el primer segmento, esperamos brindarles un medio en el que puedan conseguir de manera rápida y segura, ayuda para desarrollar o resolver problemas relacionados a bienes del hogar; por otro lado, para nuestro segundo segmento, se busca brindarle un medio en el que puedan ofertar sus servicios y aumentar su cartera de clientes. Por todo lo mencionado anteriormente, el presente trabajo busca evaluar las acciones y decisiones que se van a tomar en torno a la implementación del aplicativo, así como de evaluar el factor financiero que permita analizar la viabilidad y ejecución del proyecto. Para llegar a este punto, a lo largo del proyecto se han desarrollado diversas investigaciones y validaciones de cada uno de los segmentos con el objetivo de brindar una mejor experiencia. Asimismo, se han desarrollado concierges e investigaciones de crecimiento del sector para elaborar las proyecciones de las ventas que finalmente fueron evaluadas en el plan financiero. Finalmente, a partir de todo lo anterior, hemos podido llegar a la conclusión de que este proyecto es rentable y viable.The development of technology has evolved the offer of services and increased the use of digital platforms, making them a great ally of business. From this, TechHome emerged, an application that seeks to meet the demands and needs of the market based on the offer of services aimed at two segments made up of housewives and technical workers related to household chores. For the first segment, we hope to provide them with a means in which they can quickly and safely get help to develop or solve problems related to household goods; on the other hand, for our second segment, we seek to provide a means in which they can offer their services and increase their client portfolio. For all the above, this work seeks to evaluate the actions and decisions that will be taken around the implementation of the application, as well as evaluate the financial factor that allows analyzing the viability and execution of the project. To reach this point, throughout the project various investigations and validations of each of the segments have been developed with the aim of providing a better experience. Likewise, concierges and research on the growth of the sector have been developed to elaborate the projections of the sales that were finally evaluated in the financial plan. Finally, from all of the above, we have been able to come to the conclusion that this project is profitable and viable.Trabajo de investigació

Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents

Background: Inactivation of the Fanconi anemia (FA) pathway through defects in one of 13 FA genes occurs at low frequency in various solid cancer entities among the general population. As FA pathway inactivation confers a distinct hypersensitivity towards DNA interstrand-crosslinking (ICL)-agents, FA defects represent rational targets for individualized therapeutic strategies. Except for pancreatic cancer, however, the prevalence of FA defects in gastrointestinal (GI) tumors has not yet been systematically explored. Results: A panel of GI cancer cell lines was screened for FA pathway inactivation applying FANCD2 monoubiquitination and FANCD2/RAD51 nuclear focus formation and a newly identified FA pathway-deficient cell line was functionally characterized. The hepatocellular carcinoma (HCC) line HuH-7 was defective in FANCD2 monoubiquitination and FANCD2 nuclear focus formation but proficient in RAD51 focus formation. Gene complementation studies revealed that this proximal FA pathway inactivation was attributable to defective FANCC function in HuH-7 cells. Accordingly, a homozygous inactivating FANCC nonsense mutation (c.553C > T, p.R185X) was identified in HuH-7, resulting in partial transcriptional skipping of exon 6 and leading to the classic cellular FA hypersensitivity phenotype; HuH-7 cells exhibited a strongly reduced proliferation rate and a pronounced G2 cell cycle arrest at distinctly lower concentrations of ICL-agents than a panel of non-isogenic, FA pathway-proficient HCC cell lines. Upon retroviral transduction of HuH-7 cells with FANCC cDNA, FA pathway functions were restored and ICL-hypersensitivity abrogated. Analyses of 18 surgical HCC specimens yielded no further examples for genetic or epigenetic inactivation of FANCC, FANCF, or FANCG in HCC, suggesting a low prevalence of proximal FA pathway inactivation in this tumor type. Conclusions: As the majority of HCC are chemoresistant, assessment of FA pathway function in HCC could identify small subpopulations of patients expected to predictably benefit from individualized treatment protocols using ICL-agents

Virtual pathway explorer (viPEr) and pathway enrichment analysis tool (PEANuT): creating and analyzing focus networks to identify cross-talk between molecules and pathways

BACKGROUND: Interpreting large-scale studies from microarrays or next-generation sequencing for further experimental testing remains one of the major challenges in quantitative biology. Combining expression with physical or genetic interaction data has already been successfully applied to enhance knowledge from all types of high-throughput studies. Yet, toolboxes for navigating and understanding even small gene or protein networks are poorly developed. RESULTS: We introduce two Cytoscape plug-ins, which support the generation and interpretation of experiment-based interaction networks. The virtual pathway explorer viPEr creates so-called focus networks by joining a list of experimentally determined genes with the interactome of a specific organism. viPEr calculates all paths between two or more user-selected nodes, or explores the neighborhood of a single selected node. Numerical values from expression studies assigned to the nodes serve to score identified paths. The pathway enrichment analysis tool PEANuT annotates networks with pathway information from various sources and calculates enriched pathways between a focus and a background network. Using time series expression data of atorvastatin treated primary hepatocytes from six patients, we demonstrate the handling and applicability of viPEr and PEANuT. Based on our investigations using viPEr and PEANuT, we suggest a role of the FoxA1/A2/A3 transcriptional network in the cellular response to atorvastatin treatment. Moreover, we find an enrichment of metabolic and cancer pathways in the Fox transcriptional network and demonstrate a patient-specific reaction to the drug. CONCLUSIONS: The Cytoscape plug-in viPEr integrates –omics data with interactome data. It supports the interpretation and navigation of large-scale datasets by creating focus networks, facilitating mechanistic predictions from –omics studies. PEANuT provides an up-front method to identify underlying biological principles by calculating enriched pathways in focus networks. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2017-z) contains supplementary material, which is available to authorized users

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements