Enskog Theory for Polydisperse Granular Mixtures. I. Navier-Stokes order Transport

A hydrodynamic description for an $s$-component mixture of inelastic, smooth hard disks (two dimensions) or spheres (three dimensions) is derived based on the revised Enskog theory for the single-particle velocity distribution functions. In this first portion of the two-part series, the macroscopic balance equations for mass, momentum, and energy are derived. Constitutive equations are calculated from exact expressions for the fluxes by a Chapman-Enskog expansion carried out to first order in spatial gradients, thereby resulting in a Navier-Stokes order theory. Within this context of small gradients, the theory is applicable to a wide range of restitution coefficients and densities. The resulting integral-differential equations for the zeroth- and first-order approximations of the distribution functions are given in exact form. An approximate solution to these equations is required for practical purposes in order to cast the constitutive quantities as algebraic functions of the macroscopic variables; this task is described in the companion paper.Comment: 36 pages, to be published in Phys. Rev.

Evolutionary relationships among barley and <i>Arabidopsis</i> core circadian clock and clock-associated genes

The circadian clock regulates a multitude of plant developmental and metabolic processes. In crop species, it contributes significantly to plant performance and productivity and to the adaptation and geographical range over which crops can be grown. To understand the clock in barley and how it relates to the components in the Arabidopsis thaliana clock, we have performed a systematic analysis of core circadian clock and clock-associated genes in barley, Arabidopsis and another eight species including tomato, potato, a range of monocotyledonous species and the moss, Physcomitrella patens. We have identified orthologues and paralogues of Arabidopsis genes which are conserved in all species, monocot/dicot differences, species-specific differences and variation in gene copy number (e.g. gene duplications among the various species). We propose that the common ancestor of barley and Arabidopsis had two-thirds of the key clock components identified in Arabidopsis prior to the separation of the monocot/dicot groups. After this separation, multiple independent gene duplication events took place in both monocot and dicot ancestors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00239-015-9665-0) contains supplementary material, which is available to authorized users

Functional characterization of a GGPPS variant indentified in atypical femoral fracture patients and delineation of the role of GGPPS in bone-relevant cell types

Atypical femoral fractures (AFFs) are a rare but potentially devastating event, often but not always linked to bisphosphonate (BP) therapy. The pathogenic mechanisms underlying AFFs remain obscure, and there are no tests available that might assist in identifying those at high risk of AFF. We previously used exome sequencing to explore the genetic background of three sisters with AFFs and three additional unrelated AFF cases, all previously treated with BPs. We detected 37 rare mutations (in 34 genes) shared by the three sisters. Notably, we found a p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase, a component of the mevalonate pathway, which is critical to osteoclast function and is inhibited by N-BPs. In addition, the CYP1A1 gene, responsible for the hydroxylation of 17β-estradiol, estrone, and vitamin D, was also mutated in all three sisters and one unrelated patient. Here we present a detailed list of the variants found and report functional analyses of the GGPS1 p.Asp188Tyr mutation, which showed a severe reduction in enzyme activity together with oligomerization defects. Unlike BP treatment, this genetic mutation will affect all cells in the carriers. RNAi knockdown of GGPS1 in osteoblasts produced a strong mineralization reduction and a reduced expression of osteocalcin, osterix, and RANKL, whereas in osteoclasts, it led to a lower resorption activity. Taken together, the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for AFF susceptibility. We speculate that other genes such as CYP1A1 might be involved in AFF pathogenesis, which remains to be functionally proved. The identification of the genetic background for AFFs provides new insights for future development of novel risk assessment tools. © 2018 American Society for Bone and Mineral Research

GGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates

Atypical femoral fractures have been associated with long-term bisphosphonate treatment.1,2 However, the underlying mechanisms remain obscure. We studied three sisters who had atypical femoral fractures after receiving various oral bisphosphonates for 6 years. Two of the sisters had a single fracture (at the ages of 64 and 73 years), and one had bilateral fractures (one at the age of 60 years and the other at the age of 61 years). Given the low incidence of atypical femoral fractures in the general population (5.9 per 10,000 person-years),3 we hypothesized that these sisters might have an underlying genetic background that contributed to these fractures

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Structural Basis for Substrate Specificity in Human Monomeric Carbonyl Reductases

Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a very broad substrate spectrum. A paralog, carbonyl reductase 3 (CBR3) has about 70% sequence identity and has not been sufficiently characterized to date. Screening of a focused xenobiotic compound library revealed that CBR3 has narrower substrate specificity and acts on several orthoquinones, as well as isatin or the anticancer drug oracin. To further investigate structure-activity relationships between these enzymes we crystallized CBR3, performed substrate docking, site-directed mutagenesis and compared its kinetic features to CBR1. Despite high sequence similarities, the active sites differ in shape and surface properties. The data reveal that the differences in substrate specificity are largely due to a short segment of a substrate binding loop comprising critical residues Trp229/Pro230, Ala235/Asp236 as well as part of the active site formed by Met141/Gln142 in CBR1 and CBR3, respectively. The data suggest a minor role in xenobiotic metabolism for CBR3. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing

Child-report measures of occupational performance: A systematic review

© Copyright 2016 Cordier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Improving occupational performance is a key service of occupational therapists and client-centred approach to care is central to clinical practice. As such it is important to comprehensively evaluate the quality of psychometric properties reported across measures of occupational performance; in order to guide assessment and treatment planning. Objective To systematically review the literature on the psychometric properties of child-report measures of occupational performance for children ages 2-18 years. Methods A systematic search of the following six electronic databases was conducted: CINAHL; Psy-cINFO; EMBASE; PubMed; the Health and Psychosocial Instruments (HAPI) database; and Google Scholar. The quality of the studies was evaluated against the COSMIN taxonomy of measurement properties and the overall quality of psychometric properties was evaluated using pre-set psychometric criteria. Results Fifteen articles and one manual were reviewed to assess the psychometric properties of the six measures-the PEGS, MMD, CAPE, PAC, COSA, and OSA- which met the inclusion criteria. Most of the measures had conducted good quality studies to evaluate the psychometric properties of measures (PEGS, CAPE, PAC, OSA); however, the quality of the studies for two of these measures was relatively weak (MMD, COSA). When integrating the quality of the psychometric properties of the measures with the quality of the studies, the PAC stood out as having superior psychometric qualities. Conclusions The overall quality of the psychometric properties of most measures was limited. There is a need for continuing research into the psychometric properties of child-report measures of occupational performance, and to revise and improve the psychometric properties of existing measures

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome.METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants.RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving.CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.</p

A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginine reader domains and was identified as a putative onco-gene and transcriptional co-activator. Here we report a SPIN1 chemi-cal probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, iden-tified genes which are transcriptionally regulated by SPIN1 in squa-mous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis