Collagen Fiber Regulation in Human Pediatric Aortic Valve Development and Disease

Congenital aortic valve stenosis (CAVS) affects up to 10% of the world population without medical therapies to treat the disease. New molecular targets are continually being sought that can halt CAVS progression. Collagen deregulation is a hallmark of CAVS yet remains mostly undefined. Here, histological studies were paired with high resolution accurate mass (HRAM) collagen-targeting proteomics to investigate collagen fiber production with collagen regulation associated with human AV development and pediatric end-stage CAVS (pCAVS). Histological studies identified collagen fiber realignment and unique regions of high-density collagen in pCAVS. Proteomic analysis reported specific collagen peptides are modified by hydroxylated prolines (HYP), a post-translational modification critical to stabilizing the collagen triple helix. Quantitative data analysis reported significant regulation of collagen HYP sites across patient categories. Non-collagen type ECM proteins identified (26 of the 44 total proteins) have direct interactions in collagen synthesis, regulation, or modification. Network analysis identified BAMBI (BMP and Activin Membrane Bound Inhibitor) as a potential upstream regulator of the collagen interactome. This is the first study to detail the collagen types and HYP modifications associated with human AV development and pCAVS. We anticipate that this study will inform new therapeutic avenues that inhibit valvular degradation in pCAVS and engineered options for valve replacement

Metrics for optimising the multi-dimensional value of resources recovered from waste in a circular economy: A critical review

© 2017 The Authors - Established assessment methods focusing on resource recovery from waste within a circular economy context consider few or even a single domain/s of value, i.e. environmental, economic, social and technical domains. This partial approach often delivers misleading messages for policy- and decision-makers. It fails to accurately represent systems complexity, and obscures impacts, trade-offs and problem shifting that resource recovery processes or systems intended to promote circular economy may cause. Here, we challenge such partial approaches by critically reviewing the existing suite of environmental, economic, social and technical metrics that have been regularly observed and used in waste management and resource recovery systems' assessment studies, upstream and downstream of the point where waste is generated. We assess the potential of those metrics to evaluate ‘complex value’ of materials, components and products, i.e., the holistic sum of their environmental, economic, social and technical benefits and impacts across the system. Findings suggest that the way resource recovery systems are assessed and evaluated require simplicity, yet must retain a suitable minimum level of detail across all domains of value, which is pivotal for enabling sound decision-making processes. Criteria for defining a suitable set of metrics for assessing resource recovery from waste require them to be simple, transparent and easy to measure, and be both system- and stakeholder-specific. Future developments must focus on providing a framework for the selection of metrics that accurately describe (or at least reliably proxy for) benefits and impacts across all domains of value, enabling effective and transparent analysis of resource recovery form waste in circular economy systems.We gratefully acknowledge support of the UK Natural Environ-ment Research Council (NERC) and the UK Economic and SocialResearch Council (ESRC) who funded this work in the context of‘Complex Value Optimisation for Resource Recovery’(CVORR)project (Grant No. NE/L014149/1)

Systematic review of tools to measure outcomes for young children with autism spectrum disorder

Background: The needs of children with autism spectrum disorder (ASD) are complex and this is reflected in the number and diversity of outcomes assessed and measurement tools used to collect evidence about children's progress. Relevant outcomes include improvement in core ASD impairments, such as communication, social awareness, sensory sensitivities and repetitiveness, skills such as social functioning and play, participation outcomes such as social inclusion, and parent and family impact. Objectives: To examine the measurement properties of tools used to measure progress and outcomes in children with ASD up to the age of 6 years. To identify outcome areas regarded as important by people with ASD and parents. Methods: The MeASURe (Measurement in Autism Spectrum disorder Under Review) research collaboration included ASD experts and review methodologists. We undertook systematic review of tools used in ASD early intervention and observational studies from 1992 to 2013, systematic review, using the COSMIN checklist (Consensus-based Standards for the selection of health Measurement Instruments) of papers addressing the measurement properties of identified tools in children with ASD, and synthesis of evidence and gaps. The review design and process was informed throughout by consultation with stakeholders including parents, young people with ASD, clinicians and researchers. Results: The conceptual framework developed for the review was drawn from the International Classification of Functioning, Disability and Health, including the domains 'Impairments', 'Activity Level Indicators', 'Participation', and 'Family Measures'. In review 1, 10,154 papers were sifted - 3091 by full text - and data extracted from 184, in total, 131 tools were identified, excluding observational coding, study-specific measures and those not in English. In review 2, 2665 papers were sifted and data concerning measurement properties of 57 (43%) tools were extracted from 128 papers. Evidence for the measurement properties of the reviewed tools was combined with information about their accessibility and presentation. Twelve tools were identified as having the strongest supporting evidence, the majority measuring autism characteristics and problem behaviour. The patchy evidence and limited scope of outcomes measured mean these tools do not constitute a 'recommended battery' for use. In particular,there is little evidence that the identified tools would be good at detecting change in intervention studies. The obvious gaps in available outcome measurement include well-being and participation outcomes for children, and family quality-of-life outcomes, domains particularly valued by our informants (young people with ASD and parents). Conclusions: This is the first systematic review of the quality and appropriateness of tools designed to monitor progress and outcomes of young children with ASD. Although it was not possible to recommend fully robust tools at this stage, the review consolidates what is known about the field and will act as a benchmark for future developments. With input from parents and other stakeholders, recommendations are made about priority targets for research. Future work: Priorities include development of a tool to measure child quality of life in ASD, and validation of a potential primary outcome tool for trials of early social communication intervention. Study registration: This study is registered as PROSPERO CRD42012002223. Funding: The National Institute for Health Research Health Technology Assessment programme

BM-Map: an efficient software package for accurately allocating multireads of RNA-sequencing data

Abstract Background RNA sequencing (RNA-seq) has become a major tool for biomedical research. A key step in analyzing RNA-seq data is to infer the origin of short reads in the source genome, and for this purpose, many read alignment/mapping software programs have been developed. Usually, the majority of mappable reads can be mapped to one unambiguous genomic location, and these reads are called unique reads. However, a considerable proportion of mappable reads can be aligned to more than one genomic location with the same or similar fidelities, and they are called "multireads". Allocating these multireads is challenging but critical for interpreting RNA-seq data. We recently developed a Bayesian stochastic model that allocates multireads more accurately than alternative methods (Ji et al. Biometrics 2011). Results In order to serve a greater biological community, we have implemented this method in a stand-alone, efficient, and user-friendly software package, BM-Map. BM-Map takes SAM (Sequence Alignment/Map), the most popular read alignment format, as the standard input; then based on the Bayesian model, it calculates mapping probabilities of multireads for competing genomic loci; and BM-Map generates the output by adding mapping probabilities to the original SAM file so that users can easily perform downstream analyses. The program is available in three common operating systems, Linux, Mac and PC. Moreover, we have built a dedicated website, http://bioinformatics.mdanderson.org/main/BM-Map, which includes free downloads, detailed tutorials and illustration examples. Conclusions We have developed a stand-alone, efficient, and user-friendly software package for accurately allocating multireads, which is an important addition to our previous methodology paper. We believe that this bioinformatics tool will greatly help RNA-seq and related applications reach their full potential in life science research.</p