bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
Authors: Bandaru Manoj K , Emmanouilidou Anastasia , Ranefall Petter , von der Heyde Benedikt , Mazzaferro Eugenia , Klingström Tiffany , Masiero Mauro , Dethlefsen Olga , Ledin Johan , Larsson Anders , Brooke Hannah L , Wählby Carolina , Ingelsson Erik , den Hoed Marcel 
Published: December 2018

AbstractBackgroundHundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.MethodsWe developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384), and used it to characterize three candidate genes in a GWAS-identified pleiotropic locus on chr 19p13.11 (n>500).ResultsOur results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1). Finally, our pipeline helped identify putative causal genes for circulating lipids and early-stage atherosclerosis (LPAR2andGATAD2A).ConclusionsIn summary, our pipeline facilitates systematic,in vivocharacterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.
Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress responses
Authors: Szewczyk Magdalena M , Ishikawa Yoshinori , Organ Shawna , Sakai Nozomu , Li Fengling , Ackloo Suzanne , Eram Mohammad , Dilworth David , Fukushi Hideto , Harding Rachel , Seña Carlo C dela , Sugo Tsukasa , Hayashi Kozo , Macleod David , Zepeda Carlos , Takagi Shinji , Al-Awar Rima , Richard Stephane , Takizawa Masayuki , Arrowsmith Cheryl H , Vedadi Masoud , Brown Peter J , Nara Hiroshi , Barsyte-Lovejoy Dalia 
Published: December 2018

AbstractProtein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective and cell active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells, is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 resulted in drastically reduced levels of arginine monomethylation of HSP70 family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibited methylation of both constitutive and inducible forms of HSP70, and led to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
Community venomics reveals intra-species variations in venom composition of a local population ofVipera kaznakoviin Northeastern Turkey
Authors: Petras Daniel , Hempel Benjamin-Florian , Göçmen Bayram , Karis Mert , Whiteley Gareth , Wagstaff Simon C. , Heiss Paul , Casewell Nicholas R. , Nalbantsoy Ayse , Süssmuth Roderich D. 
Published: December 2018

AbstractWe report on the variable venom composition of a population of the Caucasus viper (Vipera kaznakovi) in Northeastern Turkey. We applied a combination of venom gland transcriptomics, as well as de-complexing bottom-up and top-down venomics, enabling the comparison of the venom proteomes from multiple individuals. In total, we identified peptides and proteins from 15 toxin families, including snake venom metalloproteinases (svMP; 37.8%), phospholipases A2(PLA2; 19.0%), snake venom serine proteinases (svSP; 11.5%), C-type lectins (CTL; 6.9%) and cysteine-rich secretory proteins (CRISP; 5.0%), in addition to several low abundant toxin families. Furthermore, we identified intra-species variations of theV. kaznakovivenom composition, and find these were mainly driven by the age of the animals, with lower svSP abundance in juveniles. On a proteoform level, several small molecular weight toxins between 5 and 8 kDa in size, as well as PLA2s, drove the difference between juvenile and adult individuals. This study provides first insights into venom variability ofV. kaznakoviand highlights the utility of intact mass profiling for a fast and detailed comparison of snake venoms of individuals from a community.Biological SignificancePopulation level and ontogenetic venom variation (e.g. diet, habitat, sex or age) can cause a loss of antivenom efficacy against snake bites from wide ranging snake populations. The state of the art for the analysis of snake venoms are de-complexing bottom-up proteomics approaches. While useful, these have the significant drawback of being time-consuming and following costly protocols, and consequently are often applied to pooled venom samples. To overcome these shortcomings and to enable rapid and detailed profiling of large numbers of individual venom samples, we integrated an intact protein analysis workflow into a transcriptomics-guided bottom-up approach. The application of this workflow to snake individuals of a local population ofV. kaznakovirevealed intra-species variations in venom composition, which are primarily explained by the age of the animals, and highlighted svSP abundance to be one of the molecular drivers for the compositional differences.HighlightsFirst community venomic analysis of a local population of the Caucasian viper (Vipera kaznakovi).The venom gland transcriptome ofV. kaznakoviidentified 46 toxin genes relating to 15 venom toxin families.Bottom-up venomics revealed the identification of 25 proteins covering 7 toxin families mainly dominated by snake venom metalloproteinases (svMP).Community venomics by top-down mass profiling revealed ontogenetic shifts between juvenile and adult snakes.
The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination within heterochromatin
Authors: Kollarovic G. , Topping C. E. , Shaw E. P. , Chambers A. L. 
Published: December 2018

ABSTRACTEfficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes can facilitate different DNA repair pathways, during different stages of the cell cycle and in a range of chromatin environments. The contribution of remodelling factors to break repair within heterochromatin during G2 is unclear.The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We find that HELLS facilitates homologous recombination at two-ended breaks within heterochromatic regions during G2. HELLS enables end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.
VikNGS: A C++ Variant Integration Kit for Next Generation Sequencing association analysis
Authors: Baskurt Zeynep , Mastromatteo Scott , Gong Jiafen , Wintle Richard F. , Scherer Stephen W. , Strug Lisa J. 
Published: December 2018

AbstractMotivationIntegration of next generation sequencing data (NGS) across different research studies can improve the power of genetic association testing by increasing sample size and can obviate the need for sequencing controls. Unfortunately, if differential genotype uncertainty across studies is not accounted for, combining data sets can also produce spurious association results. The robust variance score statistic (RVS) for genetic association of rare and common variants has been shown to effectively adjust for bias caused by the differences in read depth in case-control genetic association studies when the two groups were sequenced using different experimental designs. To enable consortium research, the aggregation of several data sets for genetic association analysis of quantitative and binary traits with covariate adjustment is required, and we developed the Variant Integration Kit for NGS (VikNGS) that expands the functionality of RVS (vRVS) for this purpose.ResultsVikNGS is a fast and computationally efficient cross-platform software package that provides an implementation for vRVS, as well as conventional rare and common variant genotype-based association analysis approaches. The package includes a graphical user interface that contains power simulation functionality and data visualization tools.Availability and ImplementationThe VikNGS package can be downloaded at http://www.tcag.ca/tools/index.htmlDocumentation can be found at https://VikNGSdocs.readthedocs.io/en/latest/Contactlisa.strug@sickkids.caSupplementary informationSupplementary data are available at Bioinformatics online.
The redefined DNA-binding domain of human xeroderma pigmentosum complementation group A: production, crystallization and structure solution
Authors: Lian Fu-Ming , Yang Xiangwei , Yang Wancai , Jiang Yong-Liang , Qian Chengmin 
Published: December 2018

Human xeroderma pigmentosum complementation group A (XPA) is a scaffold protein that plays significant roles in DNA-damage verification and in recruiting downstream endonucleases to facilitate the repair of DNA lesions in nucleotide-excision repair. XPA98–219 (residues 98–219) has been identified as a DNA-binding domain and has been extensively studied in the last two decades. However, the most recent studies have redefined the DNA-binding domain as XPA98–239 (residues 98–239); it exerts a remarkably higher DNA-binding affinity than XPA98–219 and has a binding affinity that is quite similar to that of the full-length protein. Here, the production, crystallization and structure solution of human XPA98–239 are described. Crystals were obtained using a precipitant composed of 1.8 M ammonium citrate tribasic pH 7.0. Native X-ray diffraction data and zinc single-wavelength anomalous diffraction (SAD) data were collected to 1.93 and 2.06 Å resolution, respectively. The crystals belonged to space group P3, with unit-cell parameters a = 67.1, b = 67.1, c = 35.6 Å, γ = 120.0°. Crystal-content analysis showed the presence of one molecule in the asymmetric unit, corresponding to a Matthews coefficient of 2.65 Å3 Da−1 and a solvent content of 53.6%. The initial phases were solved and the structure model was automatically built by zinc SAD using the AutoSol program. The initial structure model covered 119 of 142 residues in the asymmetric unit, with an R
work of 22.15% and an R
free of 25.82%. Compared with a previously obtained truncated solution NMR structure of XPA (residues 98–210), a 19-residue C-terminal extension (residues 211–229, corresponding to 10 of the 20 extra C-terminal residues in the redefined domain for enhanced DNA binding) was contained in this initial model. Refinement of the atomic coordinates of XPA is ongoing.
The associations between audit firm attributes and audit quality-specific indicators
Authors: Alareeni Bahaaeddin Ahmed 
Published: December 2018

PurposeThis study aims to investigate the associations between audit firm attributes (i.e. audit firm size, non-audit services, auditor industry specialization and auditor-client tenure) and specific indicators of audit quality. It also aims to test whether these relationships are moderated by a set of other factors like legal system and US versus non-US settings.Design/methodology/approachThe method of Hunter et al. (1982) is used as a meta-analysis technique to test the study hypotheses and achieve the study aims. A total of 71 published papers from 1992 to 2017 are included.FindingsThere are significant positive relationships between all audit firm attributes and audit quality. Additionally, the associations between all audit firm attributes and audit quality are moderated by proxies for audit quality. Furthermore, these associations are moderated by other variables, such as US and non-US studies, pre-SOX and post-SOX periods, the legal system, the strength of auditing and reporting standards and country classification (developed or developing country).Research limitations/implicationsThe number of studies is insufficient for some variables, and therefore, the results should be interpreted with caution. In addition, the analyzed studies include several proxies, and thus, the number of studies is inadequate for the incorporation of other factors in the meta-analysis (e.g. audit firm experience and audit firm reputation).Originality/valueThis study contributes to audit quality research by providing empirical evidence of the associations between a specific set of audit firm attributes and audit quality using the meta-analysis method. More importantly, the study provides evidence on factors that moderate these associations.
Subjective memory complaints and difficulty performing activities of daily living among older women in Australia
Authors: Cordier Reinie , Chen Yu‐Wei , Clemson Lindy , Byles Julie , Mahoney Natasha 
Published: December 2018

Background/aimIncreased age and cognitive decline have been linked to difficulties with activities of daily living (ADL) and instrumental activities of daily living (IADL). Cognitive decline can often be signalled by complaints about one's cognition, such as memory. With older Australians living longer, there is an increasing proportion of the population at risk of declined performance in daily tasks. The aim of this study was to identify if subjective memory complaints in later life among older women predict changes in independence in performing ADL and IADL.MethodsData were from 3721 women born 1921–1926, who completed Surveys 4–6 of the Australian Longitudinal Study on Women's Health. Memory complaints and difficulties on ADL were measured at each survey, using the Memory Complaint Questionnaire and 16 questions regarding specific ADL. Latent growth modelling examined correlations between initial scores on each measure, changes in measures, and the association between memory complaints and changes in ADL and IADL.ResultsThere was a significant association between baseline scores for subjective memory difficulty and baseline ADL and IADL scores. Initial memory difficulty was also associated with increase in ADL and IADL difficulty.ConclusionsSubjective memory complaints may be a risk factor for decline in performance on ADL. Attention to these concerns may be important in identifying functional decline in older age.
Altered fine motor control and manual dexterity in people with cocaine dependence: An observational study
Authors: Sánchez‐Camarero Carlos , Ortega‐Santiago Ricardo , Arias‐Horcajadas Francisco , Madoz‐Gúrpide Agustín , Miangolarra‐Page Juan Carlos , Palacios‐Ceña Domingo 
Published: December 2018

Background/aimCocaine consumption may result in irreversible structural changes in the brain. The long‐term effects of cocaine are related to a wide range of deteriorated cognitive functions. This study aimed to examine the fine motor control and hand‐function in cocaine users compared to healthy controls.MethodsAn observational study was conducted. Sociodemographic variables, substance consumption, the Purdue Pegboard and the Jebsen–Taylor Hand‐function Test were evaluated bilaterally in 35 participants who were cocaine users and in 35 healthy participants. Differences between sides (dominant and non‐dominant hands) and groups were analysed with analysis of variance (ANOVA).ResultsThe ANOVA revealed significant differences between groups (P < 0.001) and between sides (dominant and non‐dominant hands) (P = 0.005) for the one‐hand pin placement subtest of the Purdue Pegboard Test. Also, ANOVA tests showed significant differences between sides, but not groups, for the simulated feeding (P < 0.001) and stacking checkers (P < 0.001) Jebsen–Taylor subtests. Cocaine user participants exhibited significantly lower scores in bilateral pin placement and required more time for the Jebsen–Taylor subtests compared to healthy participants.ConclusionsCocaine user participants display deficits of fine motor control and some aspects of manual dexterity when compared to healthy controls. These findings show the convenience of incorporating functional rehabilitation by occupational therapists as a key component within the treatment of cocaine users. This study therefore opens a new field of practice for occupational therapy based on the assessment and treatment of motor deficits in the hand and the upper limb of people who consume cocaine.
Long non‐coding RNA TUG1 regulates the migration and invasion of trophoblast‐like cells through sponging miR‐204‐5p
Authors: Yu Yang , Wang Leilei , Gao Man , Guan Hongbo 
Published: December 2018

SummaryPreeclampsia (PE) is a leading cause of maternal and perinatal death. Accumulated evidence suggests that many long non‐coding RNAs (lncRNAs) are abnormally expressed in placentas from PE patients, and they may play functional roles in the development of PE. The present study aimed to investigate the functional role TUG1 in PE and explore the potential molecular mechanisms. Clinically, the expression of TUG1 in placental tissues from PE and normal controls was determined. In vitro, human trophoblast HTR‐8/SVneo and JAR cells were employed for loss or gain‐of‐function assays. Our results demonstrate that TUG1 was downregulated in PE placental tissues compared with normal controls. Moreover, downregulation of TUG1 inhibited the migration and invasion of trophoblast‐like cells. Bioinformatics analysis and functional assays showed that TUG1 interacted with miR‐204‐5p and negatively regulated the expression and function of miR‐204‐5p in trophoblast cells. Furthermore, TUG1‐mediated migration and invasion of trophoblast cells was regulated by miR‐204‐5p. Together, our results suggested that TUG1 regulates trophoblast migration and invasion partly through sponging miR‐204‐5p, and the TUG1/miR‐204‐5p axis could be a potential therapeutic target for the treatment of PE.
Socio‐spatial mobilities and narratives of class identity in Britain
Authors: Miles Andrew , Leguina Adrian 
Published: December 2018

AbstractIn this article we carry out the most comprehensive analysis of social and spatial mobility in the UK to date and the first to directly link different dimensions of mobility to processes of social class formation. Using new analytical techniques in this field, we integrate quantitative and qualitative data from the 1958 Birth Cohort Study, combining text‐mining and correspondence analysis in order to examine the intersection of geographical and social mobility with class identities. This work reflects a revival of interest in the spatialization of class inequalities, which is connected to policy concerns about the regional dimension of Britain’s mobility ‘crisis’ that have intensified in the wake of the ‘Brexit’ vote. We find that the South’s role as an ‘escalator’ region for upward mobility has continued and that the relationship between social and spatial mobility both confirms and qualifies the role of London and the South East in generating inequalities. We show that different migration‐mobility transitions are associated with distinctive and contrasting class identity narratives. Those who move from North to South stand out in particular for the way their ‘class talk’ reveals the social disorientation that attends their success. The contrasting ways in which other groups express their social identities suggests that the interplay of geographical and social mobilities performs a significant role in regional cultural divisions.
Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe
Authors: Spencer R , Rossi C , Lees M , Peebles D , Brocklehurst P , Martin J , Hansson SR , Hecher K , Marsal K , Figueras F , Gratacos E , David AL ,   on behalf of the EVERREST Consortium
Published: December 2018

ObjectiveTo determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation.DesignIncidence estimation based on literature review and published national and EU statistics.Setting and populationEuropean Union.MethodsData were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched.ResultsThe proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93–3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07–3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population.ConclusionsMaternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life‐threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits.Tweetable abstractPlacental insufficiency meets the European Medicines Agency requirements for orphan disease designation.