bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concert: Genome-wide prediction of sequence elements that modulate DNA replication timing
Authors: Yang Yang , Wang Yuchuan , Zhang Yang , Ma Jian 
Published: May 2022

AbstractProper control of replication timing (RT) is of vital importance to maintain genome and epigenome integrity. However, the genome-wide sequence determinants regulating RT remain unclear. Here, we develop a new machine learning method, named Concert, to simultaneously predict RT from sequence features and identify RT-modulating sequence elements in a genome-wide manner. Concert integrates two functionally cooperative modules, a selector, which performs importance estimationbased sampling to detect predictive sequence elements, and a predictor, which incorporates bidirectional recurrent neural networks and self-attention mechanism to achieve selective learning of longrange spatial dependencies across genomic loci. We apply Concert to predict RT in mouse embryonic stem cells and multiple human cell types with high accuracy. The identified RT-modulating sequence elements show novel connections with genomic and epigenomic features such as 3D chromatin interactions. In particular, Concert reveals a class of RT-modulating elements that are not transcriptional regulatory elements but are enriched with specific repetitive sequences. As a generic interpretable machine learning framework for predicting large-scale functional genomic profiles based on sequence features, Concert provides new insights into the potential sequence determinants of RT.
Cholesterol binds the amphipathic helix of IFITM3 and regulates antiviral activity
Authors: Rahman Kazi , Datta Siddhartha A.K. , Beaven Andrew H. , Jolley Abigail A. , Sodt Alexander J. , Compton Alex A. 
Published: May 2022

AbstractThe interferon-induced transmembrane (IFITM) proteins broadly inhibit the entry of diverse pathogenic viruses, including Influenza A virus (IAV), Zika virus, HIV-1, and SARS coronaviruses by inhibiting virus-cell membrane fusion. IFITM3 was previously shown to disrupt cholesterol trafficking, but the functional relationship between IFITM3 and cholesterol remains unclear. We previously showed that inhibition of IAV entry by IFITM3 is associated with its ability to promote cellular membrane rigidity, and these activities are functionally linked by a shared requirement for the amphipathic helix (AH) found in the intramembrane domain (IMD) of IFITM3. Furthermore, it has been shown that the AH of IFITM3 alters lipid membranes in vitro in a cholesterol-dependent manner. Therefore, we aimed to elucidate the relationship between IFITM3 and cholesterol in more detail. Using a fluorescence-based in vitro binding assay, we found that a peptide derived from the AH of IFITM3 directly interacted with the cholesterol analog, NBD-cholesterol, while other regions of the IFITM3 IMD did not, and native cholesterol competed with this interaction. In addition, recombinant full-length IFITM3 protein also exhibited NBD-cholesterol binding activity. Importantly, previously characterized mutations within the AH of IFITM3 that strongly inhibit antiviral function (F63Q and F67Q) disrupted AH structure in solution, inhibited cholesterol binding in vitro, and restricted bilayer insertion in silico. Our data suggest that direct interactions with cholesterol may contribute to the inhibition of membrane fusion pore formation by IFITM3. These findings may facilitate the design of therapeutic peptides for use in broad-spectrum antiviral therapy.
Systems-level identification of key transcription factors in immune cell specification
Authors: Liu Cong , Omilusik Kyla , Toma Clara , Kurd Nadia S. , Chang John T. , Goldrath Ananda W. , Wang Wei 
Published: May 2022

SummaryTranscription factors (TFs) are crucial for regulating cell differentiation during the development of the immune system. However, the key TFs for orchestrating the specification of distinct immune cells are not fully understood. Here, we integrated the transcriptomic and epigenomic measurements in 73 mouse and 61 human primary cell types, respectively, that span the immune cell differentiation pathways. We constructed the cell-type-specific transcriptional regulatory network and assessed the global importance of TFs based on the Taiji framework, which is a method we have previously developed that can infer the global impact of TFs using integrated transcriptomic and epigenetic data. Integrative analysis across cell types revealed putative driver TFs in cell lineage-specific differentiation in both mouse and human systems. We have also identified TF combinations that play important roles in specific developmental stages. Furthermore, we validated the functions of predicted novel TFs in murine CD8+ T cell differentiation and showed the importance of Elf1 and Prdm9 in the effector versus memory T cell fate specification and Kdm2b and Tet3 in promoting differentiation of CD8+ tissue resident memory (Trm) cells, validating the approach. Thus, we have developed a bioinformatic approach that provides a global picture of the regulatory mechanisms that govern cellular differentiation in the immune system and aids the discovery of novel mechanisms in cell fate decisions.
Great tits differ in glucocorticoid plasticity in response to spring temperature
Authors: Hau Michaela , Deimel Caroline , Moiron Maria 
Published: May 2022

AbstractFluctuations in environmental temperature affect energy metabolism, stimulating the expression of phenotypic plasticity in behavioral and physiological traits. Vertebrate hormonal signals like glucocorticoids underpin environmentally-induced phenotypic plasticity, with changes in circulating concentrations orchestrating plastic changes in diverse traits. Climate change is predicted to alter temperature variation globally, making it imperative to evaluate whether free-living animal populations can cope adaptively. To evaluate their potential to respond to ongoing global change, we quantified individual variation in glucocorticoid plasticity to ambient temperature in wild great tits (Parus major). Using a reaction norm approach, we repeatedly sampled individuals for circulating glucocorticoid concentrations across five years. As expected, baseline and stress-induced glucocorticoid concentrations increased with lower ambient temperatures at the population and within-individual level. Moreover, we provide unique evidence that free-living individuals differ significantly in their plastic responses to temperature variation for both glucocorticoid traits, with some displaying greater plasticity than others. Average concentrations and degree of plasticity covaried for baseline glucocorticoids, indicating that these two reaction norm components are linked. Hence, individual variation in glucocorticoid plasticity to an important environmental factor exists in a wild population, representing a crucial step to assess the adaptive potential of vertebrates to endure current temperature fluctuations.
OptoRheo: Simultaneousin situmicro-mechanical sensing and imaging of live 3D biological systems
Authors: Mendonca Tania , Lis-Slimak Katarzyna , Matheson Andrew B. , Smith Matthew G. , Anane-Adjei Akosua B. , Ashworth Jennifer C. , Cavanagh Robert , Paterson Lynn , Dalgarno Paul A. , Alexander Cameron , Tassieri Manlio , Merry Catherine L. R. , Wright Amanda J. 
Published: May 2022

AbstractBiomechanical cues from the extracellular matrix (ECM) are essential for directing many cellular processes, from normal development and repair, to disease progression. To better understand cell-matrix interactions, we have developed a new instrument named ‘OptoRheo’ that combines light sheet fluorescence microscopy with particle tracking microrheology. OptoRheo lets us image cells in 3D as they proliferate over several days while simultaneously sensing the mechanical properties of the surrounding extracellular and pericellular matrix at a sub-cellular length scale. OptoRheo can be used in two operational modalities (with and without an optical trap) to extend the dynamic range of microrheology measurements. We corroborated this by characterising the ECM surrounding live breast cancer cells in two distinct culture systems, cell clusters in 3D hydrogels and spheroids in suspension culture. This cutting-edge instrument will transform the exploration of drug transport through complex cell culture matrices and optimise the design of the next-generation of disease models.
Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis
Authors: Taylor Henry J. , Hung Yu-Han , Narisu Narisu , Erdos Michael R. , Kanke Matthew , Yan Tingfen , Grenko Caleb M. , Swift Amy J. , Bonnycastle Lori L. , Sethupathy Praveen , Collins Francis S. , Taylor D. Leland 
Published: May 2022

AbstractGenetic studies have identified ≥240 loci associated with risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, representing the largest sequencing-based analysis of miRNA expression in human islets to date. We characterize the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression (miRNA-eQTLs). We find (i) 81 heritable miRNAs, primarily regulated by trans-acting genetic effects, and (ii) 5 miRNA-eQTLs. We also use several different strategies to identify T2D-associated miRNAs. First, we colocalize miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersect miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and find 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we perform differential expression analysis and identify 13 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.
Upregulated Ca2+ release from the endoplasmic reticulum leads to impaired presynaptic function in Alzheimer’s disease
Authors: Adeoye Temitope , Shah Syed I , Demuro Angelo , Rabson David A , Ullah Ghanim 
Published: May 2022

AbstractNeurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca2+ influx through membrane-resident voltage-gated Ca2+ channels (VGCCs). Also, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in synaptic transmission by regulating Ca2+ levels. Alzheimer’s disease (AD) is marked by enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins. However, the precise consequence of impaired Ca2+ signalling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in-silico experiments of intracellular Ca2+ signalling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca2+ signalling on neurotransmitter release in AD. Our model predicts that enhanced Ca2+ release from the ER increases the probability of neurotransmitter release in AD. Moreover, over very short timescales (30-60 msec), the model exhibits activity-dependent and enhanced short-term plasticity in AD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 msec), pathological Ca2+ signalling increases depression and desynchronization with stimulus, causing affected synapses to operate unreliably. Overall, our work provides direct evidence in support of a crucial role played by altered Ca2+ homeostasis mediated by intracellular stores in AD.
Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer disease
Authors: Brymer Kyle J , Hurley Emily P , Barron Jessica C , Mukherjee Bandhan , Barnes Jocelyn R , Nafar Firoozeh , Parsons Matthew P 
Published: May 2022

SummaryMost research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric: astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.
Landscape change and alien invasions drive shifts in native lady beetle communities over a century
Authors: Perry Kayla I , Bahlai Christie A , Assal Timothy J , Riley Christopher B , Turo Katherine J , Taylor Leo , Radl James , Delgado de la flor Yvan A , Sivakoff Frances S , Gardiner Mary M 
Published: May 2022

AbstractAimUnderstanding drivers of insect population declines is essential for the development of successful conservation plans, but data limitations restrict assessment across spatial and temporal scales. Museum records represent a unique source of historical data that can be leveraged to investigate temporal trends in insect communities. Native lady beetle decline has been attributed to competition with established alien species and landscape change, but the relative importance of these drivers is difficult to measure with short-term field-based studies. Here we assessed distribution patterns for native lady beetle species over 12 decades using museum records and evaluated the relative importance of alien species and landscape change as long-term drivers contributing to changes in lady beetle communities.LocationOhio, USA.MethodsWe compiled occurrence records for 28 lady beetle species collected in Ohio, USA from 1900-2018. Incidence-based measures of taxonomic beta-diversity were used to evaluate changes in lady beetle community composition over time. To evaluate the relative influence of temporal, spatial, landscape, and community drivers on the captures of native lady beetles, we constructed negative binomial generalized additive models.ResultsWe report evidence of declines in captures for several native species, includingAdalia bipunctata, Coccinella novemnotata, Hippodamia convergens, andColeomegilla maculata. Importantly, the timing, severity, and drivers of these documented declines were species-specific. Changes in lady beetle species composition began in the 1980s, when processes of species loss/gain and turnover shifted communities towards dominance by a few alien lady beetle species. Land cover change also was associated with declines in captures, particularly forC. novemnotatawhich declined prior to the arrival of alien species in the state.Main conclusionsOur study documented shifts in Ohio’s lady beetle communities beginning in the 1980s as alien species supplanted natives. Drivers of declines in captures of native lady beetle species were highly species-specific, emphasizing that mechanisms driving population losses cannot be generalized even among closely related species. These findings also indicate the importance of museum holdings and the analysis of species-level data when studying temporal trends in insect populations.
Impaired immune response drives age-dependent severity of COVID-19
Authors: Beer Julius , Crotta Stefania , Breithaupt Angele , Ohnemus Annette , Becker Jan , Sachs Benedikt , Kern Lisa , Llorian Miriam , Ebert Nadine , Labroussaa Fabien , Thao Tran Thi Nhu , Trueeb Bettina Salome , Jores Joerg , Thiel Volker , Beer Martin , Fuchs Jonas , Kochs Georg , Wack Andreas , Schwemmle Martin , Schnepf Daniel 
Published: May 2022

AbstractSARS-CoV-2 is a highly contagious respiratory virus and the causative agent for COVID-19. The severity of disease varies from mildly symptomatic to lethal and shows an extraordinary correlation with increasing age, which represents the major risk factor for severe COVID-191. However, the precise pathomechanisms leading to aggravated disease in the elderly are currently unknown. Delayed and insufficient antiviral immune responses early after infection as well as dysregulated and overshooting immunopathological processes late during disease were suggested as possible mechanisms. Here we show that the age-dependent increase of COVID-19 severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) responses. To overcome the limitations of mechanistic studies in humans, we generated a mouse model for severe COVID-19 and compared the kinetics of the immune responses in adult and aged mice at different time points after infection. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice.Mimicking impaired type I IFN immunity in adult and aged mice, a second major risk factor for severe COVID-192–4, we found that therapeutic treatment with IFN-λ in adult and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1-/-mice was highly efficient in protecting against severe disease.Our findings provide an explanation for the age-dependent disease severity of COVID-19 and clarify the nonredundant antiviral functions of type I, II and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Based on our data, we suggest that highly vulnerable individuals combining both risk factors, advanced age and an impaired type I IFN immunity, may greatly benefit from immunotherapy combining IFN-γ and IFN-λ.
Increased spinal excitation causes decreased locomotor complexity
Authors: de Graaf Myriam Lauren , Mochizuki Luis , Wagner Heiko , Le Mouel Charlotte 
Published: May 2022

AbstractAnimals display rich and coordinated motor patterns during walking and running, that are generated and controlled within the central nervous system. Previous computational and experimental results suggest that the balance between excitation and inhibition in neural circuits may be critical for generating such structured motor patterns. In this paper, we explore the influence of this balance on the ability of a reservoir computing artificial neural network to learn human locomotor patterns, using mean-field theory analysis and simulations. We varied the numbers of neurons, connection percentages and connection strengths of excitatory and inhibitory neuron populations, and introduced the anatomicalimbalancethat quantifies their combined overall effect. Our results indicate that network dynamics and performance depend critically on the anatomical imbalance in the network. Inhibition-dominated networks work well, displaying balanced input to the neurons and good firing rate variability. Excitation-dominated networks, however, lead to saturated firing rates, thereby reducing the effective dimensionality of the networks and leading to simplified motor output patterns. This suggests that motor pattern generation may be robust to increased inhibition but not increased excitation in neural networks.
scTagger: Fast and accurate matching of cellular barcodes across short- and long-reads of single-cell RNA-seq experiments
Authors: Ebrahimi Ghazal , Orabi Baraa , Robinson Meghan , Chauve Cedric , Flannigan Ryan , Hach Faraz 
Published: May 2022

SummarySingle-cell RNA sequencing allows for characterizing the gene expression landscape at the cell type level. However, because of its use of short-reads, it is severely limited at detecting full-length features of transcripts such as alternative splicing. New library preparation techniques attempt to extend single-cell sequencing by utilizing both long-and short-reads. These techniques split the library material, after it is tagged with cellular barcodes, into two pools: one for short-read sequencing and one for long-read sequencing. However, the challenge of utilizing these techniques is that they require matching the cellular barcodes sequenced by the erroneous long-reads to the cellular barcodes detected by the short-reads. To overcome this challenge, we introduce scTagger, a computational method to match cellular barcodes data from long-and short-reads. We tested scTagger against another state-of-the-art tool on both real and simulated datasets and we demonstrate that scTagger has both significantly better accuracy and time efficiency.
A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence
Authors: Kang Taekyu , Moore Emily C. , Kopania Emily E. K. , King Christina D. , Schilling Birgit , Campisi Judith , Good Jeffrey M. , Brem Rachel B. 
Published: May 2022

AbstractCellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-kB, p53, and C/EBPβ. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouseMus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratoryM. musculus. We used allele-specific expression profiling to catalog senescence-dependentcis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, USF2, for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program—shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.