bluuebunny/crossref_metadata_2025_split huggingface dataset:
Personalised prediction of daily eczema severity scores using a mechanistic machine learning model
Authors: Hurault Guillem , Domínguez-Hüttinger Elisa , Langan Sinéad M. , Williams Hywel C. , Tanaka Reiko J. 
Published: January 2020

ABSTRACTBackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease with periods of flares and remission. Designing personalised treatment strategies for AD is challenging, given the apparent unpredictability and large variation in AD symptoms and treatment responses within and across individuals. Better prediction of AD severity over time for individual patients could help to select optimum timing and type of treatment for improving disease control.ObjectiveWe aimed to develop a mechanistic machine learning model that predicts the patient-specific evolution of AD severity scores on a daily basis.MethodsWe designed a probabilistic predictive model and trained it using Bayesian inference with the longitudinal data from two published clinical studies. The data consisted of daily recordings of AD severity scores and treatments used by 59 and 334 AD children over 6 months and 16 weeks, respectively. Internal and external validation of the predictive model was conducted in a forward-chaining setting.ResultsOur model was able to predict future severity scores at the individual level and improved chance-level forecast by 60%. Heterogeneous patterns in severity trajectories were captured with patient-specific parameters such as the short-term persistence of AD severity and responsiveness to topical steroids, calcineurin inhibitors and step-up treatment.ConclusionOur proof of principle model successfully predicted the daily evolution of AD severity scores at an individual level, and could inform the design of personalised treatment strategies that can be tested in future studies.
E-Cigarette Use and Subclinical Cardiac Effects
Authors: Rader Florian , Rashid Mohamad A. , Nguyen Trevor Trung , Luong Eric , Kim Andy , Kim Elizabeth H. , Elashhoff Robert , Davoren Katherine , Moy Norma B. , Nafeh Fida , Bairey Merz C. Noel , Ebinger Joseph E. , Hamburg Naomi M. , Lindner Jonathan R. , Cheng Susan 
Published: January 2020

ABSTRACTBACKGROUNDElectronic (e-) cigarettes are marketed as a safer alternative to conventional tobacco cigarettes. Although e-cigarettes contain a lower level of nicotine, the delivery method involves delivering an aerosolized bolus of poorly-characterized ultrafine particles that have unknown cardiovascular effects.METHODSWe studied apparently adult volunteers, free of any chronic disease, including: non-smoking controls, chronic e-cigarette users, and chronic tobacco cigarette smokers. After overnight abstinence, we used myocardial contrast echocardiography to measure acute increases in myocardial blood flow (MBF)induced by ischemic rhythmic handgrip stress, which causes sympathetically-mediated increases in myocardial work and oxygen demand and, in turn, shear stress, nitric oxide production, and coronary endothelial-dependent vasodilation.RESULTSIn non-smoking controls, handgrip stress increased myocardial blood flow, reflecting normal endothelial function. Chronic tobacco cigarette smokers demonstrated stress-induced blunting in myocardial blood flow change, when compared to non-smoking controls. Chronic e-cigarette smokers demonstrated a decrease, rather than increase, in myocardial blood flow change.CONCLUSIONChronic e-cigarette users demonstrated substantially impaired coronary microvascular endothelial function, even more pronounced than that seen in chronic tobacco cigarette users. These findings suggest that chronic e-cigarette use leads to measurable and persistent adverse vascular effects that are not directly related to nicotine.
Ethical Considerations When Creating Evidence from Real World Digital Health Data
Authors: Nebeker C. , Leavy Victoria , Roitmann Eva , Steinhubl Steven 
Published: January 2020

AbstractBackgroundPersonal health data (PHD) are collected using digital self-tracking technologies and present opportunities to increase self-knowledge and, also biometric surveillance. PHD become “big” data and are used in health-related research studies. We surveyed consumers regarding expectations regarding consent and sharing of PHD for biomedical research.MethodsData sharing preferences were assessed via an 11-item survey. The survey link was emailed to 89539 English-speaking Withings product users. Responses were accepted for 5 weeks.Descriptive statistics were calculated using Excel and qualitative data were analyzed to provide additional context.ResultsNearly 1640 people or 5.7% of invitees responded representing 62 countries with 80% identifying as Caucasian, 75% male with 78% being college educated. The majority were agreeable to having their data shared with researchers to advance knowledge and improve health care.Participants responding to open ended items (N=247) appeared unaware that the company had access to their personal health data.ConclusionsWhile the majority of respondents were in favor of data sharing, individuals expressed concerns about the ability to de-identify data and associated risks of re-identification as well as an interest in having some control over the use of “their” data. Given consumer misconception about data ownership, access and use, efforts to increase transparency when interacting with individual digital health data must be prioritized. Moreover, the basic ethical principle of “respect for persons” demonstrated via the informed consent process will be critical in advancing the adoption of digital technologies that create real-world evidence and advance opportunities for N-of-1 self-study.
Religious Belief and Cognitive Conflict Sensitivity: A Preregistered fMRI Study
Authors: Hoogeveen Suzanne , Snoek Lukas , van Elk Michiel 
Published: January 2020

AbstractIn the current preregistered fMRI study, we investigated the relationship between religiosity and behavioral and neural mechanisms of conflict processing, as a conceptual replication of the study by Inzlicht et al. (2009). Participants (N= 193) performed a gender-Stroop task and afterwards completed standardized measures to assess their religiosity. As expected, the task induced cognitive conflict at the behavioral level and at a neural level this was reflected in increased activity in the anterior cingulate cortex (ACC). However, individual differences in religiosity were not related to performance on the Stroop task as measured in accuracy and interference effects, nor to neural markers of response conflict (correct responses vs. errors) or informational conflict (congruent vs. incongruent stimuli). Overall, we obtained moderate to strong evidence in favor of the null hypotheses that religiosity is unrelated to cognitive conflict sensitivity. We discuss the implications for the neuroscience of religion and emphasize the importance of designing studies that more directly implicate religious concepts and behaviors in an ecologically valid manner.
Substrate-dependent accessibility changes in the Na+-dependent C4-dicarboxylate transporter, VcINDY, suggest differential substrate effects in a multistep mechanism
Authors: Sampson Connor D. D. , Stewart Matthew J. , Mindell Joseph A. , Mulligan Christopher 
Published: January 2020

AbstractMembers of thedivalentanionsodiumsymporter (DASS) family (SLC13 in humans) play critical roles in metabolic homeostasis, influencing many processes including fatty acid synthesis, insulin resistance, adiposity, and lifespan determination. DASS transporters catalyse the Na+-driven concentrative uptake of Krebs cycle intermediates and sulfate into cells; disrupting their function can protect against age-related metabolic diseases and can extend lifespan. An inward-facing crystal structure and an outward-facing model of a bacterial DASS family member, VcINDY fromVibrio cholerae, predict an elevator-like transport mechanism involving a large rigid body movement of the substrate binding site. How substrate binding influences the conformational state of VcINDY is currently unknown. Here, we probe the interaction between substrate binding and VcINDY conformation using a site-specific alkylation strategy to probe the solvent accessibility of several broadly distributed positions in VcINDY in the presence and absence of substrates (Na+and succinate). Our findings reveal that accessibility to all positions tested can be modulated by the presence of substrates, with the majority becoming less accessible in the presence of Na+. Mapping these solvent accessibility changes onto the known structures of VcINDY suggests that Na+binding drives the transporter into an as-yet-unidentified intermediate state. We also observe substantial, separable effects of Na+and succinate binding at several amino acid positions suggesting distinct effects of the two substrates. Furthermore, analysis of a solely succinate-sensitive residue indicates that VcINDY binds its substrate with a low affinity and proceeds via an ordered process in which one or more Na+ions must bind prior to succinate. These findings provide insight into the mechanism of VcINDY, which is currently the only structural-characterised representative of the entire DASS family.
Cortical tracking of speech in noise accounts for reading strategies in children
Authors: Destoky Florian , Bertels Julie , Niesen Maxime , Wens Vincent , Vander Ghinst Marc , Leybaert Jacqueline , Lallier Marie , Ince Robin A. A. , Gross Joachim , De Tiège Xavier , Bourguignon Mathieu 
Published: January 2020

AbstractHumans’ propensity to acquire literacy relates to several factors, among which, the ability to understand speech in noise (SiN). Still, the nature of the relation between reading and SiN perception abilities remains poorly understood. Here, we dissect the interplay between (i) reading abilities, (ii) classical behavioral predictors of reading (phonological awareness, phonological memory and lexical access), and (iii) electrophysiological markers of SiN perception in 99 elementary school children (26 with dyslexia). We demonstrate that cortical representation of phrasal content of SiN relates to the development of the lexical (but not sublexical) reading strategy. In contrast, classical behavioral predictors of reading abilities and the ability to benefit from visual speech to represent the syllabic content of SiN account for global reading performance (i.e., speed and accuracy of lexical and sublexical reading). Finally, we found that individuals with dyslexia properly integrate visual speech information to optimize processing of syntactic information, but not to sustain acoustic/phonemic processing. These results clarify the nature of the relation between SiN perception and reading abilities in typical and dyslexic child readers, and identified novel electrophysiological markers of emergent literacy.
Activation of cryptic splicing in bovineWDR19is associated with reduced semen quality and male fertility
Authors: Hiltpold Maya , Niu Guanglin , Kadri Naveen Kumar , Crysnanto Danang , Fang Zih-Hua , Spengeler Mirjam , Schmitz-Hsu Fritz , Fuerst Christian , Schwarzenbacher Hermann , Seefried Franz R. , Seehusen Frauke , Witschi Ulrich , Schnieke Angelika , Fries Ruedi , Bollwein Heinrich , Flisikowski Krzysztof , Pausch Hubert 
Published: January 2020

AbstractCattle are ideally suited to investigate the genetics of male reproduction, because semen quality and fertility are recorded for all ejaculates of artificial insemination bulls. We analysed 26,090 ejaculates of 794 Brown Swiss bulls to assess ejaculate volume, sperm concentration, sperm motility, sperm head and tail anomalies and insemination success. The heritability of the six semen traits was between 0 and 0.26. Genome-wide association testing on 607,511 SNPs revealed a QTL on bovine chromosome 6 that was associated with sperm motility (P = 2.5 × 10−27), head (P = 2.0 × 10−44) and tail anomalies (P = 7.2 × 10−49) and insemination success (P = 9.9 × 10−13). The QTL harbors a recessive allele that compromises semen quality and male fertility. We replicated the effect of the QTL on fertility (P = 7.1 × 10−32) in an independent cohort of 2481 Brown Swiss bulls. The analysis of whole-genome sequencing data revealed that a synonymous variant (BTA6:58373887C>T, rs474302732) inWDR19encoding WD repeat-containing protein 19 was in linkage disequilibrium with the fertility-associated haplotype. WD repeat-containing protein 19 is a constituent of the intraflagellar transport complex that is essential for the physiological function of motile cilia and flagella. Bioinformatic and transcription analyses revealed that the BTA6:58373887 T-allele activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from WDR19. Western blot analysis demonstrated that the BTA6:58373887 T-allele decreases protein expression. We make the remarkable observation that, in spite of negative effects on semen quality and bull fertility, the BTA6:58373887 T-allele has a frequency of 24 % in the Brown Swiss population. Our findings are the first to uncover a variant that is associated with quantitative variation in semen quality and male fertility in cattle.Author summaryIn cattle farming, artificial insemination is the most commonly used method of breeding. To ensure high fertilization rates, ejaculate quality and insemination success are closely monitored in artificial insemination bulls. We analyse semen quality, insemination success and microarray-called genotypes at more than 600,000 genome-wide SNP markers in 794 bulls to identify a recessive allele that compromises semen quality. We take advantage of whole-genome sequencing to pinpoint a variant in the coding sequence ofWDR19encoding WD repeat-containing protein 19 that activates a novel exonic splice site. Our results indicate that cryptic splicing inWDR19is associated with reduced male reproductive performance. This is the first report of a variant that contributes to quantitative variation in bovine semen quality.
In silicocharacterization of mechanisms positioning costimulatory and checkpoint complexes in immune synapses
Authors: Siokis Anastasios , Robert Philippe A. , Demetriou Philippos , Kvalvaag Audun , Valvo Salvatore , Mayya Viveka , Dustin Michael L. , Meyer-Hermann Michael 
Published: January 2020

AbstractIntegrin and small immunoglobulin superfamily (sIGSF) adhesion complexes function physiologically in human immunological synapses (IS) wherein sIGSF complexes form a corolla of microdomains around an integrin ring and secretory core. The corolla recruits and retains the major costimulatory and checkpoint complexes that regulate the response to T cell receptor (TCR) engagement, making forces that govern corolla formation of particular interest. We developed a phenomenological agent-based model in order to test different hypotheses concerning the mechanisms underlying molecular reorganization during IS formation. The model showed that sIGSF complexes are passively excluded to the distal aspect of the IS as long as their interaction with the ramified F-actin transport network is absent or weaker than that of integrins. An attractive force between sIGSF adhesion and costimulatory/checkpoint complexes relocates the latter from the centre of the IS to the corolla. The simulations suggest that size based sorting interactions with large glycocalyx components as well as a short-range self-attraction between sIGSF complexes explain the corolla “petals”. These molecular and mechanistic features establish a general model that can recapitulate complex pattern formation processes observed in cell-bilayer and cell-cell interfaces.One Sentence SummaryComputer simulations of immunological synapses reveal the localization mechanisms of immunoglobulin superfamily adhesion and costimulatory/checkpoint complexes.
Relating the past with the present: Information integration and segregation during ongoing narrative processing
Authors: Chang Claire H. C. , Lazaridi Christina , Yeshurun Yaara , Norman Kenneth A. , Hasson Uri 
Published: January 2020

AbstractThis study examined how the brain dynamically updates event representations by integrating new information over multiple minutes while segregating irrelevant input. A professional writer custom-designed a narrative with two independent storylines, interleaving across minute-long segments (ABAB). In the last (C) part, characters from the two storylines meet and their shared history is revealed. Part C is designed to induce the spontaneous recall of past events, upon the recurrence of narrative motifs from A/B, and to shed new light on them. Our fMRI results showed storyline-specific neural patterns, which were reinstated (i.e. became more active) during storyline transitions. This effect increased along the processing timescale hierarchy, peaking in the default mode network. Similarly, the neural reinstatement of motifs was found during part C. Furthermore, participants showing stronger motif reinstatement performed better in integrating A/B and C events, demonstrating the role of memory reactivation in information integration over intervening irrelevant events.
The hippocampal formation as a hierarchical generative model supporting generative replay and continual learning
Authors: Stoianov Ivilin , Maisto Domenico , Pezzulo Giovanni 
Published: January 2020

AbstractWe advance a novel computational theory of the hippocampal formation as a hierarchical generative model that organizes sequential experiences, such as rodent trajectories during spatial navigation, into coherent spatiotemporal contexts. We propose that the hippocampal generative model is endowed with inductive biases to identify individual items of experience (first hierarchical layer), organize them into sequences (second layer) and cluster them into maps (third layer). This theory entails a novel characterization of hippocampal reactivations asgenerative replay: the offline resampling of fictive sequences from the generative model, which supports the continual learning of multiple sequential experiences. We show that the model learns and efficiently retains multiple spatial navigation trajectories, by organizing them into spatial maps. Furthermore, the model reproduces flexible and prospective aspects of hippocampal dynamics that are challenging to explain within existing frameworks. This theory reconciles multiple roles of the hippocampal formation in map-based navigation, episodic memory and imagination.
Benchmarking kinetic models ofEscherichia colimetabolism
Authors: Shepelin Denis , Machado Daniel , Nielsen Lars K. , Herrgård Markus J. 
Published: January 2020

AbstractPredicting phenotype from genotype is the holy grail of quantitative systems biology. Kinetic models of metabolism are among the most mechanistically detailed tools for phenotype prediction. Kinetic models describe changes in metabolite concentrations as a function of enzyme concentration, reaction rates, and concentrations of metabolic effectors uniquely enabling integration of multiple omics data types in a unifying mechanistic framework. While development of such models forEscherichia colihas been going on for almost twenty years, multiple separate models have been established and systematic independent benchmarking studies have not been performed on the full set of models available. In this study we compared systematically all recently published kinetic models of the central carbon metabolism ofEscherichia coli. We assess the ease of use of the models, their ability to include omics data as input, and the accuracy of prediction of central carbon metabolic flux phenotypes. We conclude that there is no clear winner among the models when considering the resulting tradeoffs in performance and applicability to various scenarios. This study can help to guide further development of kinetic models, and to demonstrate how to apply such models in real-world setting, ultimately enabling the design of efficient cell factories.Author summaryKinetic modeling is a promising method to predict cell metabolism. Such models provide mechanistic description of how concentrations of metabolites change in the cell as a function of time, cellular environment and the genotype of the cell. In the past years there have been several kinetic models published for various organisms. We want to assess how reliably models ofEscherichia colimetabolism could predict cellular metabolic state upon genetic or environmental perturbations. We test selected models in the ways that represent common metabolic engineering practices including deletion and overexpression of genes. Our results suggest that all published models have tradeoffs and the model to use should be chosen depending on the specific application. We show in which cases users could expect the best performance from published models. Our benchmarking study should help users to make a better informed choice and also provides systematic training and testing dataset for model developers.
Resolving mechanisms of immune-mediated disease in primary CD4 T cells
Authors: Bourges C , Groff AF , Burren OS , Gerhardinger C , Mattioli K , Hutchinson A , Hu T , Anand T , Epping MW , Wallace C , Smith KGC , Rinn JL , Lee JC 
Published: January 2020

ABSTRACTDeriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by linkage disequilibrium. To determine whether causal variants could be identified via their functional effects, we adapted a massively-parallel reporter assay for use in primary CD4 T-cells, key effectors of many immune-mediated diseases. Using the results to guide further study, we provide a generalisable framework for resolving disease mechanisms from non-coding associations – illustrated by a locus linked to 6 immune-mediated diseases, where the lead functional variant causally disrupts a super-enhancer within an NF-κB-driven regulatory circuit, triggering unrestrained T-cell activation.
The relationship between longevity and diet is genotype dependent and sensitive to desiccation
Authors: McCracken Andrew W , Buckle Eleanor , Simons Mirre J. P. 
Published: January 2020

SummaryDietary restriction (DR) is a key focus in ageing research. Specific conditions and genotypes were recently found to negate lifespan extension by DR, questioning its universal relevance. However, the conceptual framework of dietary reaction norms explains why DR’s effects might not be apparent in some situations. We tested comprehensively the importance of dietary reaction norms by measuring longevity and fecundity on five diets in five genotypes, with and without water supplementation in the fly (N>25,000). We found substantial genetic variation in the reaction norm between diet and lifespan. Environments supplemented with water rescued putative desiccation stress but only at the richest diets. Fecundity declined at these richest diets, but was unaffected by water and is thus most likely caused by nutritional toxicity. Our results demonstrate empirically that any conclusion on the absence of DR is only justified when a range of diets is considered in a reaction norm framework.
DrawAlignR: An interactive tool for across run chromatogram alignment visualization
Authors: Gupta Shubham , Sing Justin , Mahmoodi Arshia , Röst Hannes 
Published: January 2020

AbstractMulti-run alignment is widely used in proteomics to establish analyte correspondence across runs. Generally alignment algorithms return a cumulative score, which may not be easily interpretable for each peptide. Here we present a novel tool, DrawAlignR, to visualize each chromatographic alignment for DIA/SWATH data. Furthermore, we have developed a novel C++ based implementation of raw chromatogram alignment which is 35 times faster than the previously published algorithm. This not only enables users to plot alignment interactively by DrawAlignR, but also allows other software platforms to use the algorithm. DrawAlignR is an open-source web application using R Shiny that can be hosted using the source-code available athttps://github.com/Roestlab/DrawAlignR.