bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene-methylation interactions: Discovering region-wise DNA methylation levels that modify SNP-associated disease risk
Authors: Romanowska Julia , Haaland Øystein A. , Jugessur Astanand , Gjerdevik Miriam , Xu Zongli , Taylor Jack , Wilcox Allen J. , Jonassen Inge , Lie Rolv Terje , Gjessing Håkon K. 
Published: April 2019

AbstractThe genetic code is tightly linked to epigenetic instructions as to what genes to express, and when and where to express them. The most studied epigenetic mark is DNA methylation at CpG dinucleotides. Today’s technology enables a rapid assessment of DNA sequence and methylation levels at a single-site resolution for hundreds of thousands of sites in the human genome, in thousands of individuals at a time. Recent years have seen a rapid increase in epigenome-wide association studies (EWAS) searching for the causes of risk for genetic diseases that previous genome-wide association studies (GWAS) could not pinpoint. However, those single-omics data analyses led to even more questions and it has become clear that only by integrating data one can get closer to answers. Here, we propose two new methods within genetic association analyses that treat the level of DNA methylation at a given CpG site as environmental exposure. Our analyses search for statistical interactions between a given allele and DNA methylation (G×Me), and between a parent-of-origin effect and DNA methylation (PoO× Me). The new methods were implemented in the R package Haplin and were tested on a dataset comprising genotype data from mother-father-child triadsm with DNA methylation data from the children only. The phenotype here was orofacial clefts (OFC), a relatively common birth defect in humans, which is known to have a genetic origin and an environmental component possibly mediated by DNA methylation. We found no significant PoO×Me interactions and a few significant G×Me interactions. Our results show that the significance of these interaction effects depends on the genomic region in which the CpGs reside and on the number of strata of methylation level. We demonstrate that, by including the methylation level around the SNP in the analyses, the estimated relative risk of OFC can change significantly. We also discuss the importance of including control data in such analyses. The new methods will be of value for all the researchers who want to explore genome- and epigenome-wide datasets in an integrative manner. Moreover, thanks to the implementation in a popular R package, the methods are easily accessible and enable fast scans of the genome- and epigenome-wide datasets.
Comparing open-source toolboxes for processing and analysis of spike and local field potentials data
Authors: Unakafova Valentina A. , Gail Alexander 
Published: April 2019

ABSTRACTAnalysis of spike and local field potential (LFP) data is an essential part of neuroscientific research. Today there exist many open-source toolboxes for spike and LFP data analysis implementing various functionality. Here we aim to provide a practical guidance for neuroscientists in the choice of an open-source toolbox best satisfying their needs. We overview major open-source toolboxes for spike and LFP data analysis as well as toolboxes with tools for connectivity analysis, dimensionality reduction and generalized linear modeling. We focus on comparing toolboxes functionality, statistical and visualization tools, documentation and support quality. To give a better insight, we compare and illustrate functionality of the toolboxes on open-access dataset or simulated data and make corresponding MATLAB scripts publicly available.
The Dialysis Procedure Triggers Autonomic Imbalance and Cardiac Arrhythmias: Insights from Continuous 14-day ECG Monitoring
Authors: Rogovoy Nichole M. , Howell Stacey J. , Lee Tiffany L. , Hamilton Christopher , Perez-Alday Erick A. , Kabir Muammar M. , Li-Pershing Yin , Zhang Yanwei , Kim Esther D. , Fitzpatrick Jessica , Monroy-Trujillo Jose M. , Estrella Michelle M. , Sozio Stephen M. , Jaar Bernard G. , Parekh Rulan S. , Tereshchenko Larisa G. 
Published: April 2019

AbstractBackgroundIn end-stage kidney disease the dialytic cycle relates to the rate of sudden cardiac death. We hypothesized that circadian, dialytic cycles, paroxysmal arrhythmias, and cardiovascular risk factors are associated with periodic changes in heart rate and heart rate variability (HRV) in incident dialysis patients.MethodsWe conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease cohort (n=28; age 54±13 y; 57% men; 96% black; 33% with a history of structural heart disease; left ventricular ejection fraction 70±9%). Continuous ECG monitoring was performed using an ECG patch (Zio Patch, iRhythm) and short-term HRV was measured for three minutes every hour. HRV was measured by root mean square of the successive normal-to-normal intervals (rMSSD), high and low frequency power, Poincaré plot, and sample and Renyi entropy.ResultsArrhythmias were detected in 46% (n=13). Non-sustained ventricular tachycardia (VT) was more frequent during dialysis or within 6 hours post-dialysis, as compared to pre-or between-dialysis (63% vs. 37%, P=0.015), whereas supraventricular tachycardia was more frequent pre-/ between-dialysis, as compared to during-/ post-dialysis (84% vs. 16%, P=0.015). In adjusted for cardiovascular disease and its risk factors autoregressive conditional heteroscedasticity panel (ARCH) model, VT events were associated with increased heart rate by 11.2 (95%CI 10.1-12.3) bpm (P<0.0001). During regular dialytic cycle, rMSSD demonstrated significant circadian pattern (Mesor 10.6(0.9-11.2) ms; Amplitude 1.5(1.0-3.1) ms; Peak at 02:01(20:22-03:16) am; P<0.0001), which was abolished on a second day interdialytic extension (adjusted ARCH trend for rMSSD −1.41(−1.67 to −1.15) ms per 24h; P<0.0001).ConclusionCardiac arrhythmias associate with dialytic phase. Regular dialytic schedule preserves physiological circadian rhythm, but the second day without dialysis is characterized by parasympathetic withdrawal and a steady increase in sympathetic predominance.Subject TermsArrhythmias, Autonomic Nervous System, Electrocardiology (ECG), Treatment.
Interdisciplinary and disciplinary identities: towards a theory of forms of knowledge change1
Authors: van den Besselaar Peter 
Published: April 2019

AbstractThe concept of interdisciplinarity lacks theoretical understanding, and consequently, the number of indicators for interdisciplinarity is booming: out of field citations, betweenness centrality, or the set coherence, diversity, mediation, to mention a few. However, these indicators focus on characteristics of papers and journals, without referring clearly to the processes of knowledge production, communication and stabilization. Without understanding of the nature of interdisciplinarity and its various forms, the choice of indicators seems rather arbitrary. In this paper we argue that interdisciplinarity is one of the forms of development of research fields. We will show that interdisciplinarity is a temporary phase in knowledge dynamics. New fields emerge at the boundaries of existing fields as multidisciplinary research activities, and either develop through an interdisciplinary phase into a ‘new’ discipline’, or remain multidisciplinary for a while and generally disappear.We use the analysis of journal-journal citation relations to map the identity and development of disciplinary, multidisciplinary and interdisciplinary research fields. A comparison results in three types of identities: (1) disciplinary fields, (2) interdisciplinarity as a developmental phase from multidisciplinary to disciplinary fields, and (3) unstable temporal multidisciplinary research topics at the boundaries between research fields. We conclude that the main difference between a mature interdisciplinary field and ‘normal’ disciplinary fields is that the former is newer than the latter. We propose to focus on change in the research landscape, instead of on indicators for what is only one (early or long term unstable) stage of interdisciplinarity. The mapping approach can be used to identify the nature of cognitive change in general, such as the emergence, growth, differentiation, merger, and decline of research fields.
Exploring dimension-reduced embeddings with Sleepwalk
Authors: Ovchinnikova Svetlana , Anders Simon 
Published: April 2019

AbstractDimension-reduction methods, such as t-SNE or UMAP, are widely used when exploring high-dimensional data describing many entities, e.g., RNA-seq data for many single cells. However, dimension reduction is commonly prone to introducing artefacts, and we hence need means to see where a dimension-reduced embedding is a faithful representation of the local neighbourhood and where it is not.We present Sleepwalk, a simple but powerful tool that allows the user to interactively explore an embedding, using colour to depict original or any other distances from all points to the cell under the mouse cursor. We show how this approach not only highlights distortions, but also reveals otherwise hidden characteristics of the data, and how Sleep-walk’s comparative modes help integrate multi-sample data and understand differences between embedding and preprocessing methods. Sleepwalk is a versatile and intuitive tool that unlocks the full power of dimension reduction and will be of value not only in single-cell RNA-seq but also in any other area with matrix-shaped big data.
Natural hypothalamic circuit dynamics underlying object memorization
Authors: Kosse Christin , Burdakov Denis 
Published: April 2019

SummaryMemorizing encountered objects is fundamental for normal life, but the underlying natural brain activity remains poorly understood. The hypothalamus is historically implicated in memory disorders, but whether and how its endogenous real-time activity affects object memorization remains unknown. We found that upon self-initiated object encounters, hypothalamic melanin-concentrating hormone (MCH) neurons emit dynamic, object-encounter-associated signals encoding object novelty. Optosilencing of these signals, performed in closed-loop with object encounters selectively during object memory acquisition, prevented the ability to recognize the previously encountered objects. Optogenetic and chemogenetic connectivity analyses demonstrated that local GAD65 neurons form an inhibitory GAD65→MCH microcircuit that controls the object-encounter-associated MCH cell signals. GAD65 cell optosilencing during object memory acquisition enhanced future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that natural, object-associated signals in genetically-distinct but interacting hypothalamic neurons differentially control whether the brain forms object memories.
Macroevolutionary integration of phenotypes within and across ant worker castes
Authors: Friedman Nicholas R. , Bennet Beatrice Lecroq , Fischer Georg , Sarnat Eli M. , Huang Jen-Pan , Lacey Knowles L. , Economo Evan P. 
Published: April 2019

AbstractPhenotypic traits are often integrated into evolutionary modules: sets of organismal parts that evolve together. In social insect colonies the concepts of integration and modularity apply to sets of traits both within and among functionally and phenotypically differentiated castes. On macroevolutionary timescales, patterns of integration and modularity within and across castes can be clues to the selective and ecological factors shaping their evolution and diversification. We develop a set of hypotheses describing contrasting patterns of worker integration and apply this framework in a broad (246 species) comparative analysis of major and minor worker evolution in the hyperdiverse ant genusPheidole. Using geometric morphometrics in a phylogenetic framework, we inferred fast and tightly integrated evolution of mesosoma shape between major and minor workers, but slower and more independent evolution of head shape between the two worker castes. Thus,Pheidoleworkers are evolving as a mixture of intra- and inter-caste integration and rate heterogeneity. The decoupling of homologous traits across worker castes may represent an important process facilitating the rise of social complexity.
A data-driven, meaningful, easy to interpret, population-independent accelerometer outcome variable for global surveillance
Authors: Rowlands Alex V. , Sherar Lauren B. , Fairclough Stuart J. , Yates Tom , Edwardson Charlotte L. , Harrington Deirdre M. , Davies Melanie J. , Munir Fehmidah , Khunti Kamlesh , Stiles Victoria H. 
Published: April 2019

AbstractBackgroundAccelerometer-driven physical activity guidelines are not available, likely due to the lack of consensus on meaningful and interpretable accelerometer outcomes. The aim of this paper is to demonstrate how a data-driven accelerometer metric, the acceleration above which a person’s most active minutes are accumulated, can a) quantify the prevalence of meeting current physical activity guidelines for global surveillance and b) moving forward, could inform accelerometer-driven physical activity guidelines. Unlike cut-point methods, the metric is population-independent (e.g. age) and comparable across datasets.MethodsSecondary data analyses were carried out on five datasets using wrist-worn accelerometers: children (N=145), adolescent girls (N=1669), office workers (N=114), pre- (N=1218) and post- (N=1316) menopausal women, and adults with type 2 diabetes (N=475). Open-source software (GGIR) was used to generate the magnitude of acceleration above which a person’s most active 60, 30 and 2 minutes are accumulated: M60ACC; M30ACCand M2ACC, respectively.ResultsThe proportion of participants with M60ACC(children) and M30ACC(adults) values higher than accelerations indicative of brisk walking (i.e., moderate-to-vigorous physical activity) ranged from 17-68% in children and 15%-81% in adults, tending to decline with age. The proportion of pre-and post-menopausal women with M2ACCvalues indicative of running and thus meeting recently presented thresholds for bone health ranged from 6-13%.ConclusionThese metrics can be used for global surveillance of physical activity, including assessing prevalence of meeting the current physical activity guidelines, across the lifespan. Translation of acceleration magnitudes into indicative activities provides a public health friendly interpretation of results. As accelerometer and corresponding health data accumulate it will be possible to interpret the metrics relative to age- and sex-specific norms and derive evidence-based physical activity guidelines directly from accelerometer data for use in future global surveillance. This is where the key advantages of these metrics lie.
A microtubule-mediated mechanical feedback controls leaf blade development in three dimensions
Authors: Zhao Feng , Du Fei , Oliveri Hadrien , Zhou Lüwen , Ali Olivier , Chen Wenqian , Feng Shiliang , Wang Qingqing , Lü Shouqin , Long Mian , Schneider René , Sampathkumar Arun , Godin Christophe , Traas Jan , Jiao Yuling 
Published: April 2019

AbstractMany plant species have thin leaf blades, which is an important adaptation that optimizes the exchanges with the environment. Here, we provide evidence that their three-dimensional geometry is governed by microtubule alignment along mechanical stress patterns in internal walls. Depending on the primary shape of the primordium, this process has the potential to amplify an initial degree of flatness, or promote the formation of nearly axisymmetric, mostly elongating organs, such as stems and roots. This mechanism may explain leaf evolution from branches, which is alternative to Zimmermann’s influential, but widely questioned,telometheory.One Sentence SummaryMechanical feedback controls leaf development in three dimensions
Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues Fludarabine and Vidarabine
Authors: Holzer Sandro , Rzechorzek Neil J. , Short Isobel R. , Jenkyn-Bedford Michael , Pellegrini Luca , Kilkenny Mairi L. 
Published: April 2019

SUMMARYNucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as Fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of theirin vivotargets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for inhibition by arabinose nucleotides of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of Fludarabine could be modified to improve its specificity and affinity towards primase, possibly leading to less toxic and more effective therapeutic agents.
Toxicity drives facilitation between four bacterial species
Authors: Piccardi Philippe , Vessman Björn , Mitri Sara 
Published: April 2019

AbstractCompetition between microbes is extremely common, with many investing in a wide range of mechanisms to harm other strains and species. Yet positive interactions between species have also been documented. What makes species help or harm each other is currently unclear. Here, we studied the interactions between four bacterial species capable of degrading Metal-Working Fluids (MWF), an industrial coolant and lubricant, which contains growth substrates as well as toxic biocides. We were surprised to find only positive or neutral interactions between the four species. Using mathematical modeling and further experiments, we show that positive interactions in this community are likely due to the toxicity of MWF, whereby each species’ detoxification benefited the others by facilitating their survival, such that they could grow and degrade MWF better when together. The addition of nutrients, the reduction of toxicity or the addition of more species instead resulted in competitive behavior. Our work provides support to the stress gradient hypothesis by showing how harsh, toxic environments can strongly favor facilitation between microbial species and mask underlying competitive interactions.
Endocrine, metabolic, and endocannabinoid alterations in rats exhibiting high anxiety-related behaviors
Authors: Vega-Torres Julio David , Kalyan-Masih Priya , Argueta Donovan A. , DiPatrizio Nicholas V. , Figueroa Johnny D. 
Published: April 2019

AbstractAnxiety disorders are major risk factors for obesity. However, the mechanisms accounting for this susceptibility remain unclear. Animal models have proved to be useful tools for understanding the role of emotional functioning in the development and maintenance of metabolic alterations implicated in obesity. Here we sought to determine the predictive value of behavioral indices of anxiety for hormonal and metabolic imbalances in rats. Adult Lewis rats were screened on the elevated plus maze (EPM). K-means clustering was used to divide the rats into two groups based on their anxiety index in the EPM: low (LA) and high anxiety (HA) rats. This proxy of anxiety combines individual EPM parameters and accepted ratios into a single score. Four weeks later, we measured markers of endocrine and metabolic function. We found that relative LA rats, the HA rats exhibited reduced latencies to exit a modified light-dark conflict test. Our results show that the HA rats displayed increased corticosterone levels when compared to LA rats. Furthermore, the HA rats weighted more and exhibited an enhanced glycemic response to exogenously administered glucose during the glucose tolerance test, indicating glucose intolerance. Notably, when compared to LA rats, the HA rats showed higher circulating levels of the endogenous cannabinoid, 2-arachidonoyl-sn-glycerol (2-AG). Together, these data indicate that patterns of emotional reactivity associated with anxiety may share common pathological pathways with metabolic complications implicated in obesity. Uncovering metabolic risk factors for anxiety disorders have the potential to strongly impact how we treat mental illnesses.ObjectiveTo test the hypothesis that indices of anxiety in the elevated plus maze have predictive value for alterations implicated in obesity, which include heightened emotional reactivity, and dysregulated corticosterone, glucose metabolism, and circulating endocannabinoid levels.
BreakCA, a method to discover indels using ChIP-seq and ATAC-seq reads, finds recurrent indels in regulatory regions of neuroblastoma genomes
Authors: Sen Arko , Tyndale Sélène T. , Fu Yi , Erikson Galina , McVicker Graham 
Published: April 2019

AbstractMost known cancer driver mutations are within protein coding regions of the genome, however, there are several important examples of oncogenic non-coding regulatory mutations. We developed a method to identify insertions and deletions (indels) in regulatory regions using aligned reads from chromatin immunoprecipitation followed by sequencing (ChIP-seq) or the assay for transposase-accessible chromatin (ATAC-seq). Our method, which we call BreakCA for Breaks in Chromatin Accessible regions, allows non-coding indels to be discovered in the absence of whole genome sequencing data, out-performs popular variant callers such as the GATK-HaplotypeCaller and VarScan2, and detects known oncogenic regulatory mutations in T-cell acute lymphoblastic leukemia cell lines. We apply BreakCA to identify indels in H3K27ac ChIP-seq peaks in 23 neuroblastoma cell lines and, after removing common germline variants, we identify 23 rare germline or somatic indels that occur in multiple neuroblastoma cell lines. Among them, 4 indels are candidate oncogenic drivers that are present in 4 or 5 cell lines, absent from the genome aggregation database of over 15,000 whole genome sequences, and within the promoters or first introns of known genes (PHF21A, ADAMTS19, GPR85andRALGDS). In addition, we observe a rare 7bp germline deletion in two cell lines, which is associated with high expression of the histone demethylaseKDM5B. Overexpression ofKDM5Bis prognostic for many cancers and further characterization of this indel as a potential oncogenic risk factor is therefore warranted.
Interplay between gene nucleotide composition bias and splicing
Authors: Lemaire Sébastien , Fontrodona Nicolas , Claude Jean-Baptiste , Polvèche Hélène , Aubé Fabien , Modolo Laurent , Bourgeois Cyril F. , Mortreux Franck , Auboeuf Didier 
Published: April 2019

AbstractTo characterize the rules governing exon recognition during splicing, we analysed dozens of RNA-seq datasets and identified ~3,200 GC-rich exons and ~4,000 AT-rich exons whose inclusion depends on different sets of splicing factors. We show that GC-rich exons have predicted RNA secondary structures at 5’-ss, and are dependent on U1 snRNP–associated proteins. In contrast, AT-rich exons have a large number of branchpoints and SF1-or U2AF2-binding sites and are dependent on U2 snRNP–associated proteins. Nucleotide composition bias also influences local chromatin organization, with consequences for exon recognition during splicing. As the GC content of exons correlates with that of their hosting genes, isochores and topologically-associated domains, we propose that regional nucleotide composition bias leaves a local footprint at the exon level and induces constraints during splicing that can be alleviated by local chromatin organization and recruitment of specific splicing factors. Therefore, nucleotide composition bias establishes a direct link between genome organization and local regulatory processes, like alternative splicing.