bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial Epigenome Sequencing at Tissue Scale and Cellular Level
Authors: Deng Yanxiang , Zhang Di , Liu Yang , Su Graham , Enninful Archibald , Bai Zhiliang , Fan Rong 
Published: March 2021

AbstractSpatial biology is emerging as a new frontier of biomedical research in development and disease, but currently limited to transcriptome and a panel of proteins. Here we present spatial epigenome profiling for three histone modifications (H3K27me3, H3K4me3, H3K27ac) via next-generation sequencing by combining in-tissue CUT&Tag chemistry and microfluidic deterministic barcoding. Spatial chromatin states in mouse embryos or olfactory bulbs revealed tissue type-specific epigenetic regulations, in concordance with ENCODE reference data, but providing spatially resolved genome-wide profiles at tissue scale. Using fluorescence imaging to identify the tissue pixels (20μm) each containing one nucleus allowed us to extract single-cell epigenomes in situ. Spatial chromatin state profiling in tissue may enable unprecedented opportunities to study epigenetic regulation, cell function and fate decision in normal physiology and pathogenesis.
Loss of TCF-1 regulates production of noncanonical Tregs in a prion-like manner
Authors: Harris Rebecca , Mammadli Mahinbanu , Karimi Mobin 
Published: March 2021

AbstractRegulatory T cells (Tregs) are suppressive immune cells used for a variety of clinical and therapeutic applications. Canonical Tregs express CD4, FOXP3, and CD25, which are considered definitive markers of Treg status when used together. However, a subset of noncanonical Tregs expressing only CD4 and FOXP3 have recently been described in some infection contexts. The transcriptional regulation of these cells is still unclear. We found that loss of TCF-1 in all T cells in mice leads to expansion of these cells in multiple tissues in a cell-intrinsic fashion. This effect was not due to aberrant expression of FOXP3, as other functional Treg markers were also expressed. In addition, presence of TCF-1-deficient cells in a chimeric mouse induced increased production of noncanonical Tregs from WT donor cells. Therefore, targeting of TCF-1 may remove suppression on this Treg lineage, increasing the yield of these cells for use in the clinic.Summary sentenceLoss of TCF-1 causes expansion of CD25- FOXP3+ noncanonical Tregs, and TCF-1-deficient T cells induce increased production of CD25- Tregs from WT cells.
DNA methylation aging and transcriptomic studies in horses
Authors: Horvath Steve , Haghani Amin , Peng Sichong , Hales Erin N. , Zoller Joseph A. , Raj Ken , Larison Brenda , Petersen Jessica L. , Bellone Rebecca R. , Finno Carrie J. 
Published: March 2021

ABSTRACTHuman DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging (“epigenetic clocks”). Here, we describe epigenetic clocks for horses, based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs were measured using a custom-designed Infinium array (HorvathMammalMethylChip40). We generated 336 DNA methylation profiles from 42 different horse tissues and body parts, which we used to develop five epigenetic clocks for horses: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. Epigenetic age measured by these clocks show that while castration affects the basal methylation levels of individual cytosines, it does not exert a significant impact on the epigenetic aging rate of the horse. We observed that most age-related CpGs are adjacent to developmental genes. Consistently, these CpGs reside in bivalent chromatin domains and polycomb repressive targets, which are elements that control expression of developmental genes. The availability of an RNA expression atlas of these tissues allowed us to correlate CpG methylation, their corresponding contextual chromatin features and gene expression. This analysis revealed that while increased methylation of CpGs in enhancers is likely to repress gene expression, methylation of CpGs in bivalent chromatin domains on the other hand is likely to stimulate expression of the corresponding downstream loci, which are often developmental genes. This supports the notion that aging may be accompanied by increased expression of developmental genes. It is expected that the epigenetic clocks will be useful for identifying and validating anti-aging interventions for horses.
Evaluation of critical data processing steps for reliable prediction of gene co-expression from large collections of RNA-seq data
Authors: Vandenbon Alexis 
Published: March 2021

AbstractMotivationGene co-expression analysis is an attractive tool for leveraging enormous amounts of public RNA-seq datasets for the prediction of gene functions and regulatory mechanisms. However, the optimal data processing steps for the accurate prediction of gene co-expression from such large datasets remain unclear. Especially the importance of batch effect correction is understudied.ResultsWe processed RNA-seq data of 68 human and 76 mouse cell types and tissues using 50 different workflows into 7,200 genome-wide gene co-expression networks. We then conducted a systematic analysis of the factors that result in high-quality co-expression predictions, focusing on normalization, batch effect correction, and measure of correlation. We confirmed the key importance of high sample counts for high-quality predictions. However, choosing a suitable normalization approach and applying batch effect correction can further improve the quality of co-expression estimates, equivalent to a >80% and >40% increase in samples. In larger datasets, batch effect removal was equivalent to a more than doubling of the sample size. Finally, Pearson correlation appears more suitable than Spearman correlation, except for smaller datasets.ConclusionA key point for accurate prediction of gene co-expression is the collection of many samples. However, paying attention to data normalization, batch effects, and the measure of correlation can significantly improve the quality of co-expression estimates.
Delayed Start of the Respiratory Syncytial Virus Epidemic at the End of the 20/21 Northern Hemisphere Winter Season, Lyon, France
Authors: Casalegno Jean-sebastien , Javouhey Etienne , Ploin Dominique , Valette Martine , Fanget Remi , Targe Sandrine Couray , Myar-Dury Anne-Florence , Doret-Dion Muriel , Massoud Mona , Vanhems Phillipe , Claris Olivier , Butin Marine , Ader Florence , Bin Sylvie , Gaymard Alexandre , Lina Bruno , Morfin Florence ,   VRS study group in Lyon, Gillet Yves 
Published: March 2021

AbstractThe implementation of Non Pharmaceutical Interventions (NPI), triggered by the emergence of covid-19, decrease the RSV circulation. Data, from our ongoing surveillance; show a late introduction of RSV at the end of December and a 4 month delayed epidemic start without significant change in our NPI policy. This data indicates that RSV still have the potential to give a late season outbreak in northern hemisphere. RSV surveillance should be reinforced and RSV Pharmaceutical Interventions maintained for at risk neonate
Reconstitution of Kinesin-1 Activation
Authors: Chiba Kyoko , Ori-McKenney Kassandra M. , Niwa Shinsuke , McKenney Richard J. 
Published: March 2021

AbstractAutoinhibition is an important regulatory mechanism for cytoskeletal motor proteins. Kinesin-1 (kinesin hereafter), the ubiquitous plus-end directed microtubule motor, is thought to be controlled by a complicated autoinihibition mechanism, but the molecular details remain unclear. Conformational changes mediated by intramolecular interactions between the C-terminal tail and N-terminal motor domains of the kinesin heavy chain (KHC) are proposed to be one facet of motor regulation. The dimeric KHC also binds two copies of the kinesin light chains (KLCs), which have been implicated in both autoinhibition and cargo-dependent activation of the tetrameric motor complex, although the precise mechanisms remain opaque. Using in vitro reconstitution, we show that the KLC strongly inhibits the kinesin-microtubule interaction via an independent mechanism from the tail-motor interaction within KHC. Kinesin cargo-adaptor proteins that bind KLC activated processive movement of the kinesin tetramer but the landing rate of these activated complexes remained low. The addition of MAP7, which specifically binds to the KHC, strongly enhanced activated motor motility by dramatically increasing the landing rate and processivity of the activated kinesin motors. Our results support a model whereby the activity of the kinesin tetramer is regulated by independent tail- and KLC-based inhibition mechanisms, and that cargo-adaptor binding to the KLC directly releases both of these inhibitions. However, we find that a third component, a non-motor MAP is required for robust activity of the activated motor. Thus, human kinesin activity is regulated by a two-factor mechanism comprised of intramolecular allosteric regulation, as well as intermolecular kinesin-adaptor and kinesin-MAP interactions.
Gene-Gene Interaction Detection with Deep Learning
Authors: Cui Tianyu , El Mekkaoui Khaoula , Reinvall Jaakko , Havulinna Aki S. , Marttinen Pekka , Kaski Samuel 
Published: March 2021

ABSTRACTWe do not know the extent to which genetic interactions affect the observed phenotype in diseases, because the current interaction detection approaches are limited: they only consider interactions between the top SNPs of each gene, and only simple forms of interaction. We introduce methods for increasing the statistical power of interaction detection by taking into account all SNPs andcomplex interactionsbetween them, beyond only the currently considered multiplicative relationships. In brief, the relation between SNPs and a phenotype is captured by a gene interaction neural network (NN), and the interactions are quantified by the Shapley score between hidden nodes, which are gene representations that optimally combine information from all SNPs in the gene. Additionally, we design a new permutation procedure tailored for NNs to assess the significance of interactions. The new approach outperformed existing alternatives on simulated datasets, and in a cholesterol study on the UK Biobank it detected six interactions which replicated on an independent FINRISK dataset, four of them novel findings.
TP53loss initiates chromosomal instability in high-grade serous ovarian cancer
Authors: Bronder Daniel , Wangsa Darawalee , Zong Dali , Meyer Thomas J. , Wardenaar René , Minshall Paul , Tighe Anthony , Hirsch Daniela , Heselmeyer-Haddad Kerstin , Nelson Louisa , Spierings Diana , McGrail Joanne C. , Cam Maggie , Nussenzweig André , Foijer Floris , Ried Thomas , Taylor Stephen S. 
Published: March 2021

ABSTRACTHigh-grade serous ovarian cancer (HGSOC) originates in the fallopian tube epithelium and is characterized by ubiquitousTP53mutation and extensive chromosomal instability (CIN). While the direct causes of CIN are errors during DNA replication and/or chromosome segregation, mutations in genes encoding DNA replication and mitotic factors are rare in HGSOC. Thus, the drivers of CIN remain undefined. We therefore asked whether the oncogenic lesions that are frequently observed in HGSOC are capable of driving CIN via indirect mechanisms. To address this question, we genetically manipulated non-transformedhTERT-immortalized human fallopian tube epithelial cells to model homologous recombination deficiency (HRD) and oncogenic signalling in HGSOC. Using CRISPR/Cas9-mediated gene editing, we sequentially mutagenized the tumour suppressorsTP53andBRCA1, followed by overexpression of theMYConcogene. Single-cell shallow-depth whole-genome sequencing revealed that loss of p53 function was sufficient to lead to the emergence of heterogenous karyotypes harbouring whole chromosome and chromosome arm aneuploidies, a phenomenon exacerbated by subsequent loss of BRCA1 function. In addition, whole-genome doubling events were observed in independent p53/BRCA1-deficient subclones. Global transcriptomics showed thatTP53mutation was also sufficient to deregulate gene expression modules involved in cell cycle commitment, DNA replication, G2/M checkpoint control and mitotic spindle function, suggesting that p53-deficiency induces cell cycle distortions that could precipitate CIN. Again, loss of BRCA1 function and MYC overexpression exacerbated these patterns of transcriptional deregulation. Thus, our observations support a model whereby the initial loss of the key tumour suppressorTP53is sufficient to deregulate gene expression networks governing multiple cell cycle controls, and that this in turn is sufficient to drive CIN in pre-malignant fallopian tube epithelial cells.SUMMARY STATEMENTHigh-grade serous ovarian cancer is defined byTP53mutation and chromosomal instability, the cause of which remains poorly understood. We developed a novel model system that implicates cell cycle deregulation upon p53-loss as cause of CIN.
Markov State Models of Proton- and Gate-Dependent Activation in a Pentameric Ligand-Gated Ion Channel
Authors: Bergh Cathrine , Heusser Stephanie A. , Howard Rebecca J. , Lindahl Erik 
Published: March 2021

AbstractLigand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels the mechanistic details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating transitions. Consistent with new functional recordings reported here in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed-versus open-like states enabled estimation of open probabilities and transition rates in each condition, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization among subunits. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they correctly reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.
Examination of the contribution of Nav1.7 to axonal propagation in nociceptors
Authors: Goodwin George , McMurray Sheridan , Stevens Edward B , Denk Franziska , McMahon Stephen B 
Published: March 2021

AbstractNav1.7 is a promising drug target for the treatment of pain because individuals with Nav1.7 loss-of-function mutations are insensitive to pain and do not have other serious neurological deficits. However, current peripherally restricted Nav1.7 inhibitors have not performed well in clinical pain trials, which may reflect a lack of understanding of the function of Nav1.7 in the transmission of nociceptive information. Although numerous studies have reported that Nav1.7 has a moderate role in peripheral transduction, the precise contribution of Nav1.7 to axonal propagation in nociceptors is not clearly defined, particularly for afferents innervating deep structures.In this study, we examined the contribution of Nav1.7 to axonal propagation in nociceptors utilising sodium channel blockers inin vivoelectrophysiological and calcium imaging recordings from L4 in the mouse. Using the sodium channel blocker TTX (1-10μM) to inhibit Nav1.7 and other TTX-S sodium channels along the sciatic nerve, we first showed that around 2/3rdsof nociceptive neurons innervating the skin, but a lower proportion innervating the muscle (45%), are blocked by TTX. In contrast, nearly all large-sized A-fibre cutaneous afferents (95-100%) were blocked by axonal TTX. Characterisation of TTX resistant cutaneous nociceptors revealed that many were polymodal (57%) and capsaicin sensitive (57%).Next, we examined the role of Nav1.7 in axonal propagation in nociceptive neurons by applying the selective channel blocker PF-05198007 (300nM-1μM) to the sciatic nerve between stimulating and recording sites. 100-300nM PF-05198007 blocked propagation in 63% of C-fibre sensory neurons, whereas similar concentrations did not affect propagation in rapidly conducting A-fibre neurons. We conclude that Nav1.7 has an essential contribution to axonal propagation in only around 2/3rdsof nociceptive C-fibre neurons, and a lower proportion (≤45%) of nociceptive neurons innervating muscle.
Systemic application of the TRPV4 antagonist GSK2193874 induces tail vasodilation in a mouse model of thermoregulation
Authors: O’Brien Fiona , Staunton Caroline A , Barrett-Jolley Richard 
Published: March 2021

AbstractIn humans the skin is a primary thermoregulatory organ, with vasodilation leading to rapid body cooling, whereas in Rodentia the tail performs an analogous function. Many thermodetection mechanisms are likely to be involved including transient receptor potential vanilloid-type 4 (TRPV4), a widely distributed ion channel with both mechanical and thermosensitive properties. Previous studies have shown that TRPV4 can act as a vasodilator by local action in blood vessels, and in this study, we investigated whether TRPV4 activity effectsmus muscularistail vascular tone and thermoregulation. We measured tail blood flow by pressure plethysmography in lightly sedatedmus muscularis(CD1 strain) at a range of ambient temperatures, with and without intraperitoneal administration of the blood brain barrier crossing TRPV4 antagonist GSK2193874. We also measured heart rate and blood pressure with and without GSK2193874. As expected for a thermoregulatory organ, we found that tail blood flow increased with temperature. However, unexpectedly we found that the TRPV4 antagonist GSK2193874 increased tail blood flow at all temperatures, and we observed changes in heart rate variability. Since TRPV4 activation stimulates the relaxation of peripheral resistance arteries (vasodilation) that would increase tail blood flow, these data suggest that increases in tail blood flow resulting from the TRPV4 antagonist may arise from a site other than the blood vessels themselves, perhaps in central cardiovascular control centres such as the hypothalamus.
Green information quality and green brand evaluation: the moderating effects of eco-label credibility and consumer knowledge
Authors: Kumar Prashant , Polonsky Michael , Dwivedi Yogesh K. , Kar Arpan 
Published: March 2021

Purpose
This study aims to examine the effects of three green information quality dimensions – persuasiveness, completeness and credibility – on green brand evaluation and whether this is mediated by green brand credibility. It also examines the moderating effects of eco-label credibility and consumer knowledge on green information quality dimensions and green brand credibility relationships.

Design/methodology/approach
Using a structured questionnaire on environmentally-friendly electrical goods/electronics, cosmetic and apparel product advertisements, involving an elaboration task, this study collected usable data from 1,282 Indian consumers across 50 cities. It also undertook an assessment for three different product groups using structural equation modelling to examine proposed hypotheses and assessed moderated mediation using the Hays process model.

Findings
The study indicates that: green brand credibility mediates the effects of green information quality dimensions on green brand evaluation; consumer knowledge moderates the effects of persuasiveness and completeness on green brand credibility and eco-label credibility moderates the effects of persuasiveness and credibility on green brand credibility.

Research limitations/implications
In green information processing, this study supports the relevance of the elaboration likelihood model and the mediation effect of green brand credibility. It also presents evidence that credible eco-labels enhance green information processing. While the results are broadly consistent across the three product categories, the results may only generalizable to the environmentally-aware urban populations.

Practical implications
Help brand managers to design advertisements that add brand credibility in environmentally-aware urban markets.

Originality/value
It helps to define green information quality and the interacting effects of eco-label credibility and consumer knowledge in green information processing.
Two-phase model for mixed convection and flow enhancement of a nanofluid in an inclined channel patterned with heated slip stripes
Authors: Dutta Subhasree , Bhattacharyya Somnath , Pop Ioan 
Published: March 2021

Purpose
The purpose of this study is to analyze the heat transfer and flow enhancement of an Al2O3-water nanofluid filling an inclined channel whose lower wall is embedded with periodically placed discrete hydrophobic heat sources. Formation of a thin depletion layer of low viscosity over each hydrophobic heated patch leads to the velocity slip and temperature jump condition at the interface of the hydrophobic patch.

Design/methodology/approach
The mixed convection of the nanofluid is analysed based on the two-phase non-homogeneous model. The governing equations are solved numerically through a control volume approach. A periodic boundary condition is adopted along the longitudinal direction of the modulated channel. A velocity slip and temperature jump condition are imposed along with the hydrophobic heated stripes. The paper has validated the present non-homogeneous model with existing experimental and numerical results for particular cases. The impact of temperature jump condition and slip velocity on the flow and thermal field of the nanofluid in mixed convection is analysed for a wide range of governing parameters, namely, Reynolds number (50 ≤ Re ≤ 150), Grashof number (

103≤Gr≤5×104), nanoparticle bulk volume fraction (

0.01≤φb≤0.05), nanoparticle diameter (

30≤dp≤60) and the angle of inclination (

−60°≤σ≤60°).

Findings
The presence of the thin depletion layer above the heated stripes reduces the heat transfer and augments the volume flow rate. Consideration of the nanofluid as a coolant enhances the rate of heat transfer, as well as the entropy generation and friction factor compared to the clear fluid. However, the rate of increment in heat transfer suppresses by a significant margin of the loss due to enhanced entropy generation and friction factor. Heat transfer performance of the channel diminishes as the channel inclination angle with the horizontal is increased. The paper has also compared the non-homogeneous model with the corresponding homogeneous model. In the non-homogeneous formulation, the nanoparticle distribution is directly affected by the slip conditions by virtue of the no-normal flux of nanoparticles on the slip planes. For this, the slip stripes augment the impact of nanoparticle volume fraction compared to the no-slip case.

Originality/value
This paper finds that the periodically arranged hydrophobic heat sources on the lower wall of the channel create a significant augmentation in the volume flow rate, which may be crucial to augment the transport process in mini- or micro-channels. This type of configuration has not been addressed in the existing literature.