bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global discovery of lupus genetic risk variant allelic enhancer activity
Authors: Lu Xiaoming , Chen Xiaoting , Forney Carmy , Donmez Omer , Miller Daniel , Parameswaran Sreeja , Hong Ted , Huang Yongbo , Pujato Mario , Cazares Tareian , Miraldi Emily R. , Ray John P. , de Boer Carl G. , Harley John B. , Weirauch Matthew T. , Kottyan Leah C. 
Published: March 2021

AbstractGenome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we construct a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into the Epstein-Barr virus-transformed B cell line GM12878 reveals 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Comparison of MPRA results in GM12878 and Jurkat T cell lines highlights shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around allelic variants identifies one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second class of TFs that bind allelically without direct alteration of their motif by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.
Interplay of BAF and MLL4 promotes cell type-specific enhancer activation
Authors: Park Young-Kwon , Lee Ji-Eun , Yan Zhijiang , McKernan Kaitlin , O’Haren Tommy , Wang Weidong , Peng Weiqun , Ge Kai 
Published: March 2021

AbstractCell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. The SWI/SNF chromatin remodeling complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) are both implicated in enhancer activation. However, the interplay between BAF and MLL4 in enhancer activation remains unclear. Using adipogenesis as a model system, we identify BAF as the major SWI/SNF complex that colocalizes with MLL4 and LDTFs on active enhancers and is required for cell differentiation. In contrast, the promoter enriched SWI/SNF complex PBAF is dispensable for adipogenesis. By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BAF and MLL4 reciprocally regulate each other’s binding on active enhancers before and during adipogenesis. By focusing on enhancer activation by the adipogenic pioneer transcription factor C/EBPβ without inducing cell differentiation, we provide direct evidence for an interdependent relationship between BAF and MLL4 in activating cell type-specific enhancers. Together, these findings reveal a positive feedback between BAF and MLL4 in promoting LDTF-dependent activation of cell type-specific enhancers.
Theory of optical responses in clean multi-band superconductors
Authors: Ahn Junyeong , Nagaosa Naoto 
Published: March 2021

AbstractElectromagnetic responses in superconductors provide valuable information on the pairing symmetry as well as physical quantities such as the superfluid density. However, at the superconducting gap energy scale, optical excitations of the Bogoliugov quasiparticles are forbidden in conventional Bardeen-Cooper-Schrieffer superconductors when momentum is conserved. Accordingly, far-infrared optical responses have been understood in the framework of a dirty-limit theory by Mattis and Bardeen for over 60 years. Here we show, by investigating the selection rules imposed by particle-hole symmetry and unitary symmetries, that intrinsic momentum-conserving optical excitations can occur in clean multi-band superconductors when one of the following three conditions is satisfied: (i) inversion symmetry breaking, (ii) symmetry protection of the Bogoliubov Fermi surfaces, or (iii) simply finite spin-orbit coupling with unbroken time reversal and inversion symmetries. This result indicates that clean-limit optical responses are common beyond the straightforward case of broken inversion symmetry. We apply our theory to optical responses in FeSe, a clean multi-band superconductor with inversion symmetry and significant spin-orbit coupling. This result paves the way for studying clean-limit superconductors through optical measurements.
Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications
Authors: Xiao Nan , Nie Meng , Pang Huanhuan , Wang Bohong , Hu Jieli , Meng Xiangjun , Li Ke , Ran Xiaorong , Long Quanxin , Deng Haijun , Chen Na , Li Shao , Tang Ni , Huang Ailong , Hu Zeping 
Published: March 2021

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.
SARS-CoV and SARS-CoV-2 are transmitted through the air between ferrets over more than one meter distance
Authors: Kutter Jasmin S. , de Meulder Dennis , Bestebroer Theo M. , Lexmond Pascal , Mulders Ard , Richard Mathilde , Fouchier Ron A. M. , Herfst Sander 
Published: March 2021

AbstractSARS-CoV-2 emerged in late 2019 and caused a pandemic, whereas the closely related SARS-CoV was contained rapidly in 2003. Here, an experimental set-up is used to study transmission of SARS-CoV and SARS-CoV-2 through the air between ferrets over more than a meter distance. Both viruses cause a robust productive respiratory tract infection resulting in transmission of SARS-CoV-2 to two of four indirect recipient ferrets and SARS-CoV to all four. A control pandemic A/H1N1 influenza virus also transmits efficiently. Serological assays confirm all virus transmission events. Although the experiments do not discriminate between transmission via small aerosols, large droplets and fomites, these results demonstrate that SARS-CoV and SARS-CoV-2 can remain infectious while traveling through the air. Efficient virus transmission between ferrets is in agreement with frequent SARS-CoV-2 outbreaks in mink farms. Although the evidence for virus transmission via the air between humans under natural conditions is absent or weak for SARS-CoV and SARS-CoV-2, ferrets may represent a sensitive model to study interventions aimed at preventing virus transmission.
Adeno-associated virus capsid assembly is divergent and stochastic
Authors: Wörner Tobias P. , Bennett Antonette , Habka Sana , Snijder Joost , Friese Olga , Powers Thomas , Agbandje-McKenna Mavis , Heck Albert J. R. 
Published: March 2021

AbstractAdeno-associated viruses (AAVs) are increasingly used as gene therapy vectors. AAVs package their genome in a non-enveloped T = 1 icosahedral capsid of ~3.8 megaDalton, consisting of 60 subunits of 3 distinct viral proteins (VPs), which vary only in their N-terminus. While all three VPs play a role in cell-entry and transduction, their precise stoichiometry and structural organization in the capsid has remained elusive. Here we investigate the composition of several AAV serotypes by high-resolution native mass spectrometry. Our data reveal that the capsids assemble stochastically, leading to a highly heterogeneous population of capsids of variable composition, whereby even the single-most abundant VP stoichiometry represents only a small percentage of the total AAV population. We estimate that virtually every AAV capsid in a particular preparation has a unique composition. The systematic scoring of the simulations against experimental native MS data offers a sensitive new method to characterize these therapeutically important heterogeneous capsids.
Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures
Authors: Li Jiao , Seidlitz Jakob , Suckling John , Fan Feiyang , Ji Gong-Jun , Meng Yao , Yang Siqi , Wang Kai , Qiu Jiang , Chen Huafu , Liao Wei 
Published: March 2021

AbstractMajor depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.
Evaluating the impact of curfews and other measures on SARS-CoV-2 transmission in French Guiana
Authors: Andronico Alessio , Tran Kiem Cécile , Paireau Juliette , Succo Tiphanie , Bosetti Paolo , Lefrancq Noémie , Nacher Mathieu , Djossou Félix , Sanna Alice , Flamand Claude , Salje Henrik , Rousseau Cyril , Cauchemez Simon 
Published: March 2021

AbstractWhile general lockdowns have proven effective to control SARS-CoV-2 epidemics, they come with enormous costs for society. It is therefore essential to identify control strategies with lower social and economic impact. Here, we report and evaluate the control strategy implemented during a large SARS-CoV-2 epidemic in June–July 2020 in French Guiana that relied on curfews, targeted lockdowns, and other measures. We find that the combination of these interventions coincided with a reduction in the basic reproduction number of SARS-CoV-2 from 1.7 to 1.1, which was sufficient to avoid hospital saturation. We estimate that thanks to the young demographics, the risk of hospitalisation following infection was 0.3 times that of metropolitan France and that about 20% of the population was infected by July. Our model projections are consistent with a recent seroprevalence study. The study showcases how mathematical modelling can be used to support healthcare planning in a context of high uncertainty.
A deep learning method for HLA imputation and trans-ethnic MHC fine-mapping of type 1 diabetes
Authors: Naito Tatsuhiko , Suzuki Ken , Hirata Jun , Kamatani Yoichiro , Matsuda Koichi , Toda Tatsushi , Okada Yukinori 
Published: March 2021

AbstractConventional human leukocyte antigen (HLA) imputation methods drop their performance for infrequent alleles, which is one of the factors that reduce the reliability of trans-ethnic major histocompatibility complex (MHC) fine-mapping due to inter-ethnic heterogeneity in allele frequency spectra. We develop DEEP*HLA, a deep learning method for imputing HLA genotypes. Through validation using the Japanese and European HLA reference panels (n = 1,118 and 5,122), DEEP*HLA achieves the highest accuracies with significant superiority for low-frequency and rare alleles. DEEP*HLA is less dependent on distance-dependent linkage disequilibrium decay of the target alleles and might capture the complicated region-wide information. We apply DEEP*HLA to type 1 diabetes GWAS data from BioBank Japan (n = 62,387) and UK Biobank (n = 354,459), and successfully disentangle independently associated class I and II HLA variants with shared risk among diverse populations (the top signal at amino acid position 71 of HLA-DRβ1; P = 7.5 × 10−120). Our study illustrates the value of deep learning in genotype imputation and trans-ethnic MHC fine-mapping.
A systematic review of movement and muscular activity biomarkers to discriminate non-specific chronic low back pain patients from an asymptomatic population
Authors: Moissenet Florent , Rose-Dulcina Kevin , Armand Stéphane , Genevay Stéphane 
Published: March 2021

AbstractThe identification of relevant and valid biomarkers to distinguish patients with non-specific chronic low back pain (NSCLBP) from an asymptomatic population in terms of musculoskeletal factors could contribute to patient follow-up and to evaluate therapeutic strategies. Several parameters related to movement and/or muscular activity impairments have been proposed in the literature in that respect. In this article, we propose a systematic and comprehensive review of these parameters (i.e. potential biomarkers) and related measurement properties. This systematic review (PROSPERO registration number: CRD42020144877) was conducted in Medline, Embase, and Web of Knowledge databases until July 2019. In the included studies, all movements or muscular activity parameters having demonstrated at least a moderate level of construct validity were defined as biomarkers, and their measurement properties were assessed. In total, 92 studies were included. This allowed to identify 121 movement and 150 muscular activity biomarkers. An extensive measurement properties assessment was found in 31 movement and 14 muscular activity biomarkers. On the whole, these biomarkers support the primary biomechanical concepts proposed for low back pain. However, a consensus concerning a robust and standardised biomechanical approach to assess low back pain is needed.
Wireless power transfer system rigid to tissue characteristics using metamaterial inspired geometry for biomedical implant applications
Authors: Pokharel Ramesh K. , Barakat Adel , Alshhawy Shimaa , Yoshitomi Kuniaki , Sarris Costas 
Published: March 2021

AbstractConventional resonant inductive coupling wireless power transfer (WPT) systems encounter performance degradation while energizing biomedical implants. This degradation results from the dielectric and conductive characteristics of the tissue, which cause increased radiation and conduction losses, respectively. Moreover, the proximity of a resonator to the high permittivity tissue causes a change in its operating frequency if misalignment occurs. In this report, we propose a metamaterial inspired geometry with near-zero permeability property to overcome these mentioned problems. This metamaterial inspired geometry is stacked split ring resonator metamaterial fed by a driving inductive loop and acts as a WPT transmitter for an in-tissue implanted WPT receiver. The presented demonstrations have confirmed that the proposed metamaterial inspired WPT system outperforms the conventional one. Also, the resonance frequency of the proposed metamaterial inspired TX is negligibly affected by the tissue characteristics, which is of great interest from the design and operation prospects. Furthermore, the proposed WPT system can be used with more than twice the input power of the conventional one while complying with the safety regulations of electromagnetic waves exposure.
Ketone body 3-hydroxybutyrate as a biomarker of aggression
Authors: Whipp A. M. , Vuoksimaa E. , Korhonen T. , Pool R. , But A. , Ligthart L. , Hagenbeek F. A. , Bartels M. , Bogl L. H. , Pulkkinen L. , Rose R. J. , Boomsma D. I. , Kaprio J. 
Published: March 2021

AbstractHuman aggression is a complex behaviour, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983–1987, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the response variable and aggression ratings as predictor variables, and included several potential confounders. All metabolites showed low correlations with aggression, with only one—3-hydroxybutyrate, a ketone body produced during fasting—showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated (age 14) aggression were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher aggression (self-rated) was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.
Associations between the gut microbiome and fatigue in cancer patients
Authors: Hajjar Joud , Mendoza Tito , Zhang Liangliang , Fu Siqing , Piha-Paul Sarina A. , Hong David S. , Janku Filip , Karp Daniel D. , Ballhausen Alexej , Gong Jing , Zarifa Abdulrazzak , Peterson Christine B. , Meric-Bernstam Funda , Jenq Robert , Naing Aung 
Published: March 2021

AbstractFatigue is the most prevalent symptom of cancer and its treatments. Changes in the intestinal microbiome have been identified in chronic fatigue syndrome and other neuropsychiatric disorders, and cancer patients. However, the association between intestinal microbiome and fatigue in patients with advanced cancers has not been evaluated. Understanding the connection between intestinal microbiome and fatigue will provide interventional and therapeutic opportunities to manipulate the microbiome to improve fatigue and other patients’ reported outcomes. In this project, we aimed to identify associations between microbiome composition and fatigue in advanced cancer patients. In this cross-sectional observational study at a tertiary cancer care center, we included 88 patients with advanced, metastatic, unresectable cancers who were in a washout period from chemotherapy. We measured fatigue using the MD Anderson Symptom Inventory—Immunotherapy fatigue score, and used 16srRNA to analyze intestinal microbiome. Using correlation analysis we found that Eubacterium hallii was negatively associated with fatigue severity scores (r = − 0.30, p = 0.005), whereas Cosenzaea was positively associated with fatigue scores (r = 0.33, p = 0.0002). We identified microbial species that exhibit distinct composition between high-fatigued and low-fatigued cancer patients. Further studies are warranted to investigate whether modulating the microbiome reduces cancer patients’ fatigue severity and improves their quality of life.
Human milk extracellular vesicle miRNA expression and associations with maternal characteristics in a population-based cohort from the Faroe Islands
Authors: Kupsco Allison , Prada Diddier , Valvi Damaskini , Hu Lisa , Petersen Maria Skaalum , Coull Brent , Grandjean Philippe , Weihe Pal , Baccarelli Andrea A. 
Published: March 2021

AbstractHuman milk plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. Milk contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). We aimed to characterize milk EV-miRNA profiles in a human population cohort, assess potential pathways and ontology, and investigate associations with maternal characteristics. We conducted the first study to describe the EV miRNA profile of human milk in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1523 miRNAs with ≥ one read in 70% of samples. Using hierarchical clustering, we determined five EV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster human milk EV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. miRNA expression was associated with time to milk collection post-delivery, maternal body mass index, and maternal smoking, but not maternal parity. Future studies investigating determinants of human EV-miRNAs and associated health outcomes are needed to elucidate the role of human milk EV-miRNAs in health and disease.
Quantifying mechanical loading and elastic strain energy of the human Achilles tendon during walking and running
Authors: Kharazi Mohamadreza , Bohm Sebastian , Theodorakis Christos , Mersmann Falk , Arampatzis Adamantios 
Published: March 2021

AbstractThe purpose of the current study was to assess in vivo Achilles tendon (AT) mechanical loading and strain energy during locomotion. We measured AT length considering its curve-path shape. Eleven participants walked at 1.4 m/s and ran at 2.5 m/s and 3.5 m/s on a treadmill. The AT length was defined as the distance between its origin at the gastrocnemius medialis myotendinous junction (MTJ) and the calcaneal insertion. The MTJ was tracked using ultrasonography and projected to the reconstructed skin surface to account for its misalignment. Skin-to-bone displacements were assessed during a passive rotation (5°/s) of the ankle joint. Force and strain energy of the AT during locomotion were calculated by fitting a quadratic function to the experimentally measured tendon force–length curve obtained from maximum voluntary isometric contractions. The maximum AT strain and force were affected by speed (p < 0.05, ranging from 4.0 to 4.9% strain and 1.989 to 2.556 kN), yet insufficient in magnitude to be considered as an effective stimulus for tendon adaptation. Besides the important tendon energy recoil during the propulsion phase (7.8 to 11.3 J), we found a recoil of elastic strain energy at the beginning of the stance phase of running (70–77 ms after touch down) between 1.7 ± 0.6 and 1.9 ± 1.1 J, which might be functionally relevant for running efficiency.