bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplex Confounding Factor Correction for Genomic Association Mapping with Squared Sparse Linear Mixed Model
Authors: Wang Haohan , Liu Xiang , Xiao Yunpeng , Xu Ming , Xing Eric P. 
Published: December 2017

AbstractGenome-wide Association Study has presented a promising way to understand the association between human genomes and complex traits. Many simple polymorphic loci have been shown to explain a significant fraction of phenotypic variability. However, challenges remain in the non-triviality of explaining complex traits associated with multifactorial genetic loci, especially considering the confounding factors caused by population structure, family structure, and cryptic relatedness. In this paper, we propose a Squared-LMM (LMM2) model, aiming to jointly correct population and genetic confounding factors. We offer two strategies of utilizing LMM2 for association mapping: 1) It serves as an extension of univariate LMM, which could effectively correct population structure, but consider each SNP in isolation. 2) It is integrated with the multivariate regression model to discover association relationship between complex traits and multifactorial genetic loci. We refer to this second model as sparse Squared-LMM (sLMM2). Further, we extend LMM2/sLMM2 by raising the power of our squared model to the LMMn/sLMMn model. We demonstrate the practical use of our model with synthetic phenotypic variants generated from genetic loci of Arabidopsis Thaliana. The experiment shows that our method achieves a more accurate and significant prediction on the association relationship between traits and loci. We also evaluate our models on collected phenotypes and genotypes with the number of candidate genes that the models could discover. The results suggest the potential and promising usage of our method in genome-wide association studies.
A novel method for estimating LDC levels: total cholesterol and non-HDLC can be used to predict the normal LDLC level in apparently healthy population
Authors: Zhang Guo-Ming , Bai Shumei , Zhang Gao-Ming , Ma Xiao-Bo 
Published: December 2017

ABSTRACTBackgroundTriglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), and low-density lipoprotein cholesterol (LDLC) are usually ordered together to test lipid metabolism in physical examination and clinical application. LDLC is a component of TC and its change is closely correlated to TC.ObjectiveWe aim to predict the normal LDLC level by using TG, TC, HDLC and non-HDLC (nonHDLC) in this study.MethodsTG, TC, HDLC, and LDLC data were obtained from Laboratory Information System (LIS) based on 4 years (Octo, 1, 2013-Sept, 30, 2017) period health check-up TG, TC, HDLC, and LDLC(direct clearance method) were measured using TBA2000FR biochemical analyzer. The nonHDLC was calculated with TC minus HDLC. Correlation between TG, TC, nonHDLC, and LDLC were analyzed using Spearman’s rank approach. Receiver operating characteristics curve analysis was used to evaluate the predictive of TG, TC and nonHDLC for the normal LDLC level(less than 130mg/dL).ResultsBoth TC(r = 0.870) and nonHDLC (r = 0.893) were significantly positively correlated with LDLC. Area under curve of TC and nonHDLC can be used to predict normal LDLC level. Optimal thresholds were 182.5 mg/dL(4.72 mmol/L) for TC and 135.3 mg/dL(3.50 mmol/L) for nonHDLC. Based on these optimal thresholds, less than 0.5% and 0.4% of tests with elevated LDLC might be missed, but the missing elevated LDLC is not too high(less than 147.3 mg/dL).ConclusionIf the nonHDLC is less than 135.3mg/dL(3.50 mmol/L) and/or TC is less than 182.5mg/dL(4.72 mmol/L) for the apparently healthy populations the LDLC level will be less than 130mg/dL(3.36 mmol/L). Total cholesterol and non-HDLC can be used to predict the normal LDLC level in apparently healthy population is a novel method for estimating LDC level.
Altered transcription factor binding events predict personalized gene expression and confer insight into functional cis-regulatory variants
Authors: Shi Wenqiang , Fornes Oriol , Wasserman Wyeth W. 
Published: December 2017

AbstractDeciphering the functional roles of cis-regulatory variants is a critical challenge in genome analysis and interpretation. We hypothesize that altered transcription factor (TF) binding events are a central mechanism by which cis-regulatory variants impact gene expression. We present TF2Exp, the first gene-based framework (to our knowledge) to predict the impact of altered TF binding on personalized gene expression based on cis-regulatory variants. Using data from lymphoblastoid cell lines, TF2Exp models achieved suitable performance for 3,060 genes. Alterations within DNase I hypersensitive, CTCF-bound, and tissue-specific TF-bound regions were the greatest contributors to the models. Our cis-regulatory variant-based TF2Exp models performed as well as the state-of-the-art SNP-based models, both in cross-validation and external validation. In addition, unlike SNP-based models, our TF2Exp models have the unique advantages to evaluate impact of uncommon variants and distinguish the functional roles of variants in linkage disequilibrium, showing broader utility for future human genetic studies.
Dynamical model of the CLC-2 ion channel exhibits a two-step gating mechanism
Authors: McKiernan Keri A. , Koster Anna K. , Maduke Merritt , Pande Vijay S. 
Published: December 2017

AbstractThis work reports a dynamical Markov state model of CLC-2 “fast” (pore) gating, based on 600 microseconds of molecular dynamics (MD) simulation. In the starting conformation of our CLC-2 model, both outer and inner channel gates are closed. The first conformational change in our dataset involves rotation of the inner-gate backbone along residues S168-G169-I170. This change is strikingly similar to that observed in the cryo-EM structure of the bovine CLC-K channel, though the volume of the intracellular (inner) region of the ion conduction pathway is further expanded in our model. From this state (inner gate open and outer gate closed), two additional states are observed, each involving a unique rotameric flip of the outer-gate residue GLUex. Both additional states involve conformational changes that orient GLUexaway from the extracellular (outer) region of the ion conduction pathway. In the first additional state, the rotameric flip of GLUexresults in an open, or near-open, channel pore. The equilibrium population of this state is low (∼1%), consistent with the low open probability of CLC-2 observed experimentally in the absence of a membrane potential stimulus (0 mV). In the second additional state, GLUexrotates to occlude the channel pore. This state, which has a low equilibrium population (∼1%), is only accessible when GLUexis protonated. Together, these pathways model the opening of both an inner and outer gate within the CLC-2 selectivity filter, as a function of GLUexprotonation. Collectively, our findings are consistent with published experimental analyses of CLC-2 gating and provide a high-resolution structural model to guide future investigations.Author summaryIn the brain, the roles and mechanisms of sodium-, potassium-, and calcium-selective ion channels are well established. In contrast, chloride-selective channels have been studied much less and are not sufficiently understood, despite known associations of chloride-channel defects with brain disorders. The most broadly expressed voltage-activated chloride channel in the brain is CLC-2 (one of 9 human CLC homologs). In this work, we use simulations to model the conformational dynamics of the CLC-2 chloride ion channel selectivity filter (SF), which is the part of the protein that controls whether the channel is in an ion-conducting or non-conducting state. Our analysis identifies four primary conformational states and a specific progression through these states. Our results are consistent with structural and functional data in the literature and provide a high-resolution model for guiding further studies of CLC-2. These results will inform our understanding of how CLC-2 governs electrical activity and ion homeostasis in the brain.
Social and non-social autism symptom and trait domains are genetically dissociable
Authors: Warrier Varun , Toro Roberto , Won Hyejung , Leblond Claire S , Cliquet Freddy , Delorme Richard , De Witte Ward , Bralten Janita , Chakrabarti Bhismadev , Børglum Anders D , Grove Jakob , Poelmans Geert ,   the 23andMe Research Team, Hinds David A. , Bourgeron Thomas , Baron-Cohen Simon 
Published: December 2017

AbstractThe core diagnostic criteria for autism comprise two symptom domains – social and communication difficulties, and unusually repetitive and restricted behaviour, interests and activities. There is some evidence to suggest that these two domains are dissociable, yet, this hypothesis has not been tested using molecular genetics. We test this using a GWAS of a non-social autistic trait, systemizing (N = 51,564), defined as the drive to analyse and build systems. We demonstrate that systemizing is heritable and genetically correlated with autism. In contrast, we do not identify significant genetic correlations between social autistic traits and systemizing. Supporting this, polygenic scores for systemizing are significantly positively associated with restricted and repetitive behaviour but not with social difficulties in autistic individuals. These findings strongly suggest that the two core domains of autism are genetically dissociable, and point at how to fractionate the genetics of autism.
On-line Optimization of Hamiltonian Replica Exchange Simulations
Authors: MacCallum Justin L. , Muniyat Mir Ishruna , Gaalswyk Kari 
Published: December 2017

AbstractReplica exchange is a widely used sampling strategy in molecular simulation. While a variety of methods exist for optimizing temperature replica exchange, less is known about how to optimize more general Hamiltonian replica exchange simulations. We present an algorithm for the on-line optimization of both temperature and Hamiltonian replica exchange simulations that draws on techniques from the optimization of deep neural networks in machine learning. We optimize a heuristic-based objective function capturing the efficiency of replica exchange. Our approach is general, and has several desirable properties, including: (1) it makes few assumptions about the system of interest; (2) optimization occurs on-line wihout the requirement of pre-simulation; and (3) it readily generalizes to systems where there are multiple control parameters per replica. We explore some general properties of the algorithm on a simple harmonic oscillator system, and demonstrate its effectiveness on a more complex data-guided protein folding simulation.
Combined aptamer and transcriptome sequencing of single cells
Authors: Delley Cyrille L. , Liu Leqian , Sarhan Maen F. , Abate Adam R. 
Published: December 2017

AbstractThe transcriptome and proteome encode distinct information that is important for characterizing heterogeneous biological systems. We demonstrate a method to simultaneously characterize the transcriptomes and proteomes of single cells at high throughput using aptamer probes and droplet-based single cell sequencing. With our method, we differentiate distinct cell types based on aptamer surface binding and gene expression patterns. Aptamers provide advantages over antibodies for single cell protein characterization, including rapid, in vitro, and high-purity generation via SELEX, and the ability to amplify and detect them with PCR and sequencing.
Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease
Authors: Song Wan , Zsindely Nóra , Faragó Anikó , Marsh J. Lawrence , Bodai László 
Published: December 2017

ABSTRACTHuntington’s Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in aDrosophila melanogasterHD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT induced pathology while reducing PRC2 complex core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.
Disruptive innovation at the base-of-the-pyramid
Authors: Adegbile Abiodun , Sarpong David 
Published: December 2017

PurposeThe authors aim to examine the potential opportunities and challenges multinationals operating in Africa are likely to encounter when they seek to pioneer disruptive innovations at the base of the pyramid (BoP) in African emerging markets.Design/methodology/approachDrawing on the extant literature on the BoP, disruptive innovation and the African business context, the authors explore the pioneering of disruptive innovations in the African socio-economic context.FindingsThis study develops various hypotheses to extend our understanding of disruptive innovations at the BoP. The authors also delineate potential managerial and institutional challenges multinational corporations (MNCs) are likely to encounter in their efforts to pioneering disruptive innovations for BoP customers in African emerging markets.Practical implicationsThe authors develop some recommendations for MNCs on how to create and capture value from disruptive innovations in African emerging marketsOriginality/valueThe authors delineate African context-specific managerial and institutional challenges that MNCs might encounter when seeking to develop disruptive innovation at the BoP.
How do Italian vocational teachers educate for a sense of initiative and entrepreneurship? Development and initial application of the SIE questionnaire
Authors: Morselli Daniele 
Published: December 2017

PurposeThe purpose of this paper is to examine how educators can teach the key competence of a sense of initiative and entrepreneurship (SIE) as a cross-curricular subject in compulsory education. It draws both on the literature relating to entrepreneurial education and on competence-based education to set out five features of entrepreneurial teaching. For illustrative purposes, these five characteristics are explored in a questionnaire put to a small group of teaching staff.Design/methodology/approachThis study employs a qualitative approach, seeking to understand the personal perspectives of participants, and drawing out the complexities of their behaviour, whilst also providing a holistic interpretation of such behaviour.FindingsThe literature review identifies five features of entrepreneurial teaching: embedding learning outcomes for a SIE within taught subjects; active entrepreneurial teaching; educating for entrepreneurial attitudes; networking activities; being entrepreneurial as part of lifelong learning. It can be hypothesised that teaching staff teach different aspects of the SIE depending on the subject they teach (vocational or more traditional) and their role (teacher or workshop assistant).Originality/valueDevelopment of the SIE and the five characteristics of entrepreneurial teaching is a first step towards understanding how secondary vocational teachers and workshop assistants understand and teach the SIE as cross-curricular subject. In line with Fayolle and Gailly who called for deeper investigation of the most effective combinations of objectives, content and teaching methods, the paper seeks to establish a relationship between teaching methods, development of entrepreneurial attitudes and assessment.
Information as signs
Authors: Thellefsen Martin Muderspach , Thellefsen Torkild , Sørensen Bent 
Published: December 2017

PurposeThe purpose of this paper is to formulate an analytical framework for the information concept based on the semiotic theory.Design/methodology/approachThe paper is motivated by the apparent controversy that still surrounds the information concept. Information, being a key concept within LIS, suffers from being anchored in various incompatible theories. The paper suggests that information is signs, and it demonstrates how the concept of information can be understood within C.S. Peirce’s phenomenologically rooted semiotic. Hence, from there, certain ontological conditions as well epistemological consequences of the information concept can be deduced.FindingsThe paper argues that an understanding of information, as either objective or subjective/discursive, leads to either objective reductionism and signal processing, that fails to explain how information becomes meaningful at all, or conversely, information is understood only relative to subjective/discursive intentions, agendas, etc. To overcome the limitations of defining information as either objective or subjective/discursive, a semiotic analysis shows that information understood as signs is consistently sensitive to both objective and subjective/discursive features of information. It is consequently argued that information as concept should be defined in relation to ontological conditions having certain epistemological consequences.Originality/valueThe paper presents an analytical framework, derived from semiotics, that adds to the developments of the philosophical dimensions of information within LIS.
Effect of Hazardous Alcohol Use During Pregnancy on Growth Outcomes at Birth: Findings from a South African Cohort Study
Authors: Myers Bronwyn , Koen Nastassja , Donald Kirsten A. , Nhapi Raymond T. , Workman Lesley , Barnett Whitney , Hoffman Nadia , Koopowitz Sheri , Zar Heather J. , Stein Dan J. 
Published: December 2017

BackgroundCohort studies have noted associations between hazardous alcohol use during pregnancy and infant growth outcomes, but many have not controlled for potential psychosocial confounders. To assess the unique contribution of hazardous alcohol use, we examined its effect on infant growth outcomes while controlling for maternal psychosocial stressors and hazardous tobacco and drug use in a cohort of 986 pregnant South African women enrolled into the Drakenstein Child Health Study between 2012 and 2015.MethodsData on psychosocial stressors and maternal risk behaviors were collected between 28 and 32 weeks of gestation. Participants were categorized as hazardous alcohol users if they obtained moderate or high scores (>10) on the Alcohol, Smoking and Substance Involvement Screening Test at this assessment or retrospectively reported drinking at least 2 drinks weekly during any trimester of pregnancy. Infant growth outcomes were recorded at delivery. Multivariable regression models examined correlates of hazardous alcohol use and associations between hazardous alcohol use and birth outcomes.ResultsOverall, 13% of mothers reported hazardous alcohol use. Recent exposure to intimate partner violence (adjusted odds ratio (aOR) = 2.08; 95% confidence interval (CI): 1.37, 3.18) and hazardous tobacco use (aOR = 5.03; 95% CI: 2.97, 8.52) were significant correlates of hazardous alcohol use. After controlling for potential psychosocial confounders, hazardous alcohol use remained associated with lower infant weight‐for‐age (B = −0.35, 95% CI: −0.56, −0.14), height‐for‐age (B = −0.46, 95% CI: −0.76, −0.17), and head‐circumference‐for‐age z‐scores (B = −0.43, 95% CI: −0.69, −0.17).ConclusionsInterventions to reduce hazardous alcohol use among pregnant women in South Africa are needed to prevent alcohol‐related infant growth restrictions. As these growth deficits may lead to neurodevelopmental consequences, it is critical to identify alcohol‐related growth restrictions at birth and link exposed infants to early interventions for neurodevelopment.
Intra‐ocular diathermy forceps
Authors: van Overdam Koen A. , Kilic Emine , Verdijk Robert M. , Manning Sonia 
Published: December 2017

AbstractPurposeThe purpose of this study was to develop intra‐ocular diathermy forceps and test them on perfused porcine cadaver eyes.MethodsWe designed two types of 23‐gauge intra‐ocular bipolar diathermy forceps by modifying commercially available membrane peeling forceps. In the first type, the emitting electrode is connected to one‐half of the core and the return electrode to the other half, with one jaw of the forceps attached to each half. In the second type, the emitting electrode is attached to the core and both jaws of the forceps, and the return electrode to the surrounding tube. We compared the new diathermy forceps to conventional intra‐ocular diathermy, on perfused porcine cadaver eyes. First‐order retinal artery and vein closure was confirmed both by a perfusion study and by histology of the treated vessels.ResultsType 1 diathermy forceps closed retinal arteries and veins more successfully (five of five and five of five successful treatments, respectively) than Type 2 diathermy forceps (five of five and four of five, respectively) and conventional diathermy (three of five and four of five, respectively). Less energy was used with Type 1 compared to Type 2 and conventional for artery closure (1.5 ± 0.0 versus 4.6 ± 3.3 versus 2.1 ± 0.8 joules, respectively) and vein closure (1.5 ± 0.0 versus 5.4 ± 4.6 versus 2.4 ± 0.8 joules, respectively). Histology of the treated vessels confirmed the perfusion study results.ConclusionWe designed two types of a new multifunctional intra‐ocular instrument with the ability to peel membranes and to grasp, compress and coagulate retinal blood vessels. Both types pose operational advantages compared to current conventional intra‐ocular diathermy.