Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Fashion retailing – past, present and future

This issue of Textile Progress reviews the way that fashion retailing has developed as a result of the application of the World Wide Web and information and communications technology (ICT) by fashion-retail companies. The review therefore first considers how fashion retailing has evolved, analysing retail formats, global strategies, emerging and developing economies, and the factors that are threatening and driving growth in the fashion-retail market. The second part of the review considers the emergence of omni-channel retailing, analysing how retail has progressed and developed since the adoption of the Internet and how ICT initiatives such as mobile commerce (m-commerce), digital visualisation online, and in-store and self-service technologies have been proven to support the progression and expansion of fashion retailing. The paper concludes with recommendations on future research opportunities for gaining a better understanding of the impacts of ICT and omni-channel retailing, through which it may be possible to increase and develop knowledge and understanding of the way the sector is developing and provide fresh impetus to an already-innovative and competitive industr

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Deepening Inclusive and Community-Engaged Education in Three Schools: A Teachers' Resource

In 2009 the Toronto District School Board (TDSB) initiated the Inclusive Schools three-year pilot project with the intent to engage teachers, teacher educators, students, parents, staff, and administrators in investigating and developing effective inclusive curriculum and instructional practices that could be implemented in classrooms and school-wide. In addition, the project aimed to identify practices and factors that contribute to improved student engagement and learning and that strengthen community connections. Over a three-year period, three TDSB elementary schools - Carleton Village Public School, Flemington Public School, and Grey Owl Junior Public School - carried out 19 school-based inquiries. School-based inquiries were grounded in a professional learning process that emphasized inquiry, partnership, collaboration, action and reflection, and professional choice and responsibility. Participants had different understandings and experiences, which they brought to their particular investigations. This teachers’ resource contains reports on school-based inquiries into effective inclusive curriculum practices. It is intended for teachers who are considering the integration of inclusive approaches in their day-to-day work in schools. As such, the purpose of this resource is to contribute toward understanding how to support student learning and ongoing teacher education in ways that are responsive to today’s educational context

Engineering Antibody Reactivity for Efficient Derivatization to Generate Na_V1.7 Inhibitory GpTx‑1 Peptide–Antibody Conjugates

The voltage-gated sodium channel Na_V1.7 is a genetically validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain; however functional Na_V1.7 targeting antibodies are not known. In this report, we describe Na_V1.7 inhibitory peptide–antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified Na_V1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity. Tethering GpTx-1 peptides to antibodies bifunctionally couples FcRn-based antibody recycling attributes to the Na_V1.7 targeting function of the peptide warhead. Herein, we conjugated a GpTx-1 peptide to specific engineered cysteines in a carrier anti-2,4-dinitrophenol monoclonal antibody using polyethylene glycol linkers. The reactivity of 13 potential cysteine conjugation sites in the antibody scaffold was tuned using a model alkylating agent. Subsequent reactions with the peptide identified cysteine locations with the highest conversion to desired conjugates, which blocked Na_V1.7 currents in whole cell electrophysiology. Variations in attachment site, linker, and peptide loading established design parameters for potency optimization. Antibody conjugation led to <i>in vivo</i> half-life extension by 130-fold relative to a nonconjugated GpTx-1 peptide and differential biodistribution to nerve fibers in wild-type but not Na_V1.7 knockout mice. This study describes the optimization and application of antibody derivatization technology to functionally inhibit Na_V1.7 in engineered and neuronal cells

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10(-4), with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10(-6); odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10(-8)), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10(-9); OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio