bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variation in diel timing in great tits is affected by the timing of their social mate
Authors: Strauß Aurelia F. T. , Tomotani Barbara M. , Visser Marcel E. , Helm Barbara 
Published: August 2024

AbstractDiel rhythms are driven by genetic and environmental components. These rhythms are mediated by the circadian clock, and entail rhythmicity of various physiological and behavioural traits. Although individuals show to some extent repeatable timing (i.e., chronotype), there is ample variation of diel timing observed within and between individuals of the same species. Here, we investigated various environmental factors, including timing of the social partner, that could explain day-to-day variation within individuals. Synchronisation with the social partner during provisioning timing could increase breeding success, and decrease extrapair paternity opportunities for females during the fertile period in case of consistent timing across the breeding stages. Therefore, we also investigated fitness consequences of between-individual variation. We first assessed the magnitude of between- and within-individual variation in the timing of nest visits by great tits (Parus major). We monitored nest visits of males and females in 37 broods during chick provisioning in 2020 and 2021. Next, we explored the responsiveness of the diel timing to environmental variables, specifically comparing abiotic and social factors. The onset of nest visits varied significantly with day within the breeding season, rainfall and the diel timing of the breeding partner but not with night temperature. In response to the partner’s onset, females responded stronger compared to males. By contrast, offset was generally more variable within individuals and less variation was explained by the environmental variables. Both males and females delayed their activity offset with the progressing season and females also had a later onset with more daytime rainfall. Further, the reproductive output and extrapair paternity were independent of parental chronotype and their synchronisation within pairs. It is possible that consistency of chronotypes is less important for reproductive success than the ability to plastically respond to changing environmental conditions. Thus, the next step could be to investigate potential individual differences in plasticity which could be even linked to specific chronotypes. This information might be crucial to predict how species can cope with unpredictable environmental conditions.
LAT encodes T cell activation pathway balance
Authors: Rubin Adam J. , Dao Tyler T. , Schueppert Amelia V. , Regev Aviv , Shalek Alex K. 
Published: August 2024

AbstractImmune cells transduce environmental stimuli into responses essential for host health via complex signaling cascades. T cells, in particular, leverage their unique T cell receptors (TCRs) to detect specific Human Leukocyte Antigen (HLA)-presented peptides. TCR activation is then relayed via linker for activation of T cells (LAT), a TCR-proximal disordered adapter protein, which organizes protein partners and mediates the propagation of signals down diverse pathways including NFAT and AP-1. Here, we studied how balanced downstream pathway activation is encoded in the amino acid sequence of LAT. To comprehensively profile the sequence-function relationship of LAT, we developed a pooled, single-cell, high-content screening approach in which a large series of mutants in the LAT protein were analyzed to characterize their effects on T cell activation. Measuring epigenetic, transcriptomic, and cell surface protein dynamics of single cells harboring distinct LAT mutants, we found functional regions spanning over 40% of the LAT amino acid sequence. Conserved sequence motifs for protein interactions along with charge distribution are critical sequence features, and contribute to interpretation of human genetic variation in LAT. While mutant defect severity spans from moderate to complete loss of function, nearly all defective mutants, irrespective of their position in LAT, confer balanced defects across all downstream pathways. To understand the molecular basis for this observation, we performed proximal protein labeling which demonstrated that disruption of LAT interaction with a single partner protein indirectly disrupts other partner interactions, likely through the dual roles of these proteins as effectors of downstream pathways and bridging factors between LAT molecules. Overall, we report widely distributed functional regions throughout a disordered adapter and a precise physical organization of LAT and interacting molecules which constrains signaling outputs. More broadly, we describe an approach for interrogating sequence-function relationships for proteins with complex activities across regulatory layers of the cell.
Cell cycle re-entry in the agingDrosophilabrain
Authors: Damschroder Deena , Sun Jenny , McDonald Katherine O. , Buttitta Laura 
Published: August 2024

AbstractThe brain is an organ comprised mostly of long-lived, quiescent cells that perform vital functions throughout an animal’s life. Due to the brain’s limited regenerative ability, these long-lived cells must engage unique mechanisms to cope with accumulated damage over time. We have shown that a subset of differentiated neuronal and glial cells in the fruit fly brain become polyploid during adulthood. Cell cycle re-entry in the brain has previously been associated with neurodegeneration, but there may be a more complex relationship between polyploidy and cell fitness in the brain. Here, we examine how known lifespan modifiers influence the accumulation of polyploidy in the aging fly brain. Flies aged at a low temperature, or with a low protein diet, accumulate polyploid cells in the brain more slowly than expected if this phenotype were solely regulated by lifespan mechanisms. Despite the slower accumulation of polyploid cells, animals under conditions that extend lifespan eventually reach similar levels of polyploidy in the brain as controls. Our work suggests known lifespan modifiers can influence the timing of cell cycle re-entry in the adult brain, indicating there is a flexible window of cell cycle plasticity in the aging brain.
Genomic signatures and demographic history of the widespread and critically endangered yellow-breasted bunting
Authors: Chen Guoling , Sin Simon Yung Wa 
Published: August 2024

AbstractPopulation declines may have long-term genetic consequences, including genetic erosion and inbreeding depression, which could affect species’ evolutionary potential and increase their risk of extinction. Small populations are more vulnerable to genetic threats than common species, but even species with large populations can also be at risk of extinction. The yellow-breasted bunting (Emberiza aureola) is a common and widespread songbird in the northern Palearctic regions, but its population has drastically declined by around 90% throughout the past 30 years, leading to an upgrade of its conservation status to critically endangered. In this study, we identified three populations within this species using whole-genome resequencing data, but the genetic differentiation between populations was shallow. These populations underwent similar population fluctuations but differed in the extent of population decline, resulting in lower genetic diversity and more homozygous deleterious mutations in a population comprising individuals on islands. The ancient demographic history was mainly associated with the climate, while recent population declines are likely due to human activities. Our results suggest that the yellow-breasted bunting population before the recent population collapse faced relatively low genetic threats and had high evolutionary potential. However, we should be vigilant about the genetic threats faced by this species as our sampling time occurred at the onset of its recent global population collapse. This study provides valuable genetic information for appropriate conservation management of the yellow-breasted bunting and sheds light on the extinction risks and genetic consequences common species face.
The landscape of cellular clearance systems across human tissues and cell types is shaped by tissue-specific proteome needs
Authors: Vinogradov Ekaterina , Ravkaie Lior , Edri Bar , Jubran Juman , Ben-Zvi Anat , Yeger-Lotem Esti 
Published: August 2024

ABSTRACTProtein clearance is fundamental to proteome health. In eukaryotes, it is carried by two highly conserved proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). Despite their pivotal role, the basal organization of the human protein clearance systems across tissues and cell types remains uncharacterized. Here, we interrogated this organization using diverse omics datasets. Relative to other protein-coding genes, UPS and ALP genes were more widely expressed, encoded more housekeeping proteins, and were more essential for growth, in accordance with their fundamental roles. Most of the UPS and ALP genes were nevertheless differentially expressed across tissues, and their tissue-specific upregulation was associated with tissue-specific functions, phenotypes, and disease susceptibility. The small subset of UPS and ALP genes that was stably expressed across tissues was more highly and widely expressed and more essential for growth than other UPS and ALP genes, suggesting that it acts as a core. Lastly, we compared protein clearance to other branches of the proteostasis network. Protein clearance and folding were closely coordinated across tissues, yet both were less pivotal than protein synthesis. Taken together, we propose that the proteostasis network is organized hierarchically and is tailored to the proteome needs. This organization could contribute to and illuminate tissue-selective phenotypes.
The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites
Authors: Lo Joelle , Vaeth Katherine F. , Bhardwaj Gurprit , Mukherjee Neelanjan , Russ Holger A. , Moore Jeffrey K. , Taliaferro J. Matthew 
Published: August 2024

ABSTRACTRNA molecules are localized to subcellular regions through interactions between localization-regulatory cis-elements and trans-acting RNA binding proteins (RBPs). However, the identities of RNAs whose localization is regulated by a specific RBP as well as the impacts of that RNA localization on cell function have generally remained unknown. Here, we demonstrate that the RBP HNRNPA2B1 acts to keep specific RNAs out of neuronal projections. Using subcellular fractionation, high-throughput sequencing, and single molecule RNA FISH, we find that hundreds of RNAs demonstrate markedly increased abundance in neurites in HNRNPA2B1 knockout cells. These RNAs often encode motor proteins and are enriched for known HNRNPA2B1 binding sites and motifs in their 3′ UTRs. The speed and processivity of microtubule-based transport is impaired in these cells, specifically in their neurites. HNRNPA2B1 point mutations that increase its cytoplasmic abundance relative to wildtype lead to stronger suppression of RNA mislocalization defects than seen with wildtype HNRNPA2B1. We further find that the subcellular localizations of HNRNPA2B1 target RNAs are sensitive to perturbations of RNA decay machinery, suggesting that it is HNRNPA2B1’s known role in regulating RNA stability that may explain these observations. These findings establish HNRNPA2B1 as a negative regulator of neurite RNA abundance and link the subcellular activities of motor proteins with the subcellular abundance of the RNAs that encode them.
Dynamic modeling of EEG responses to natural speech reveals earlier processing of predictable words
Authors: Dou Jin , Anderson Andrew J. , White Aaron S. , Norman-Haignere Samuel V. , Lalor Edmund C. 
Published: August 2024

AbstractIn recent years, it has become clear that EEG indexes the comprehension of natural, narrative speech. One particularly compelling demonstration of this fact can be seen by regressing EEG responses to speech against measures of how individual words in that speech linguistically relate to their preceding context. This approach produces a so-called temporal response function that displays a centro-parietal negativity reminiscent of the classic N400 component of the event-related potential. One shortcoming of previous implementations of this approach is that they have typically assumed a linear, time-invariant relationship between the linguistic speech features and the EEG responses. In other words, the analysis typically assumes that the response has the same shape and timing for every word – and only varies (linearly) in terms of its amplitude. In the present work, we relax this assumption under the hypothesis that responses to individual words may be processed more rapidly when they are predictable. Specifically, we introduce a framework wherein the standard linear temporal response function can be modulated in terms of its amplitude, latency, and temporal scale based on the expectedness of the current and prior words. We use the proposed approach to model EEG recorded from a set of participants who listened to an audiobook narrated by a single talker, and a separate set of participants who attended to one of two concurrently presented audiobooks. We show that expected words are processed faster – evoking lower amplitude N400-like responses with earlier peaks – and that this effect is driven both by the word’s own predictability and the predictability of the immediately preceding word. Additional analysis suggests that this finding is not simply explained based on how quickly words can be disambiguated from their phonetic neighbors. As such, our study demonstrates that the timing and amplitude of brain responses to words in natural speech depend on their predictability. By accounting for these effects, our framework also improves the accuracy with which neural responses to natural speech can be modeled.
Peptide therapeutic leads for multi-target inhibition of inflammatory cytokines in Inflammatory Bowel Disease - computational design and in-vitro validation
Authors: Tsaban Tomer , Kariv-Attias Gali , Khramushin Alisa , Gover Ofer , Hayouka Zvi , Schueler-Furman Ora , Schwartz Betty 
Published: August 2024

AbstractInflammatory Bowel Disease (IBD) are chronic and recurrent inflammatory disorders affecting the gastrointestinal tract, characterized by the involvement of numerous pro-inflammatory cytokines. These conditions profoundly impact both immune system dynamics and intestinal tissue integrity. Current therapeutic approaches predominantly rely on monoclonal antibodies, and frequently encounter limitations such as non-responsiveness, loss of efficacy over time, immunogenicity, adverse effects, and substantial cost. Consequently, there is a critical need for novel, targeted anti-inflammatory strategies. We present the computational structure guided design of peptidic inhibitors aimed at attenuating the activity of pivotal pro-inflammatory cytokines implicated in IBD pathogenesis, namely TNFα, IL-1β, and IL-6. These peptides were engineered to disrupt specific cytokine - receptor interactions, to block the release of pro-inflammatory cytokines. We structurally characterized key features in the studied interactions and used these to guide two computational design strategies, one based on the identification of dominant segments using our PeptiDerive approach, and one based on complementing fragments detected using our PatchMAN protocol. The designed peptides were synthesized and their efficacy was validated on Caco-2 intestinal epithelial cells and THP-1 macrophages, representative of the epithelial and immunological alterations typical of active IBD. The majority of the novel peptides effectively suppressed release of pro-inflammatory cytokines by both macrophages and intestinal epithelial cells, thereby reducing the risk of inflammation. This study underscores the efficacy of a rational design approach rooted in structural insights into inflammatory signaling complexes. Our findings demonstrate the potential of targeting key cytokines and receptor interaction with designed peptides as a promising therapeutic avenue for managing IBD and other inflammatory disorders.
A diverse landscape of FGFR alterations and co-mutations defines novel therapeutic strategies in pediatric low-grade gliomas
Authors: Morin Eric , Apfelbaum April A. , Sturm Dominik , Ayoub Georges , DiGiacomo Jeromy , Bahadur Sher , Chandarana Bhavyaa , Power Phoebe C. , Cusick Margaret M. , Novikov Dana , Jones Robert , Vogelzang Jayne , Bossi Connor C. , Malinowski Seth , Jeang John , Collins Jared , Oh Sehee , Jeon Hyesung , Cameron Amy , Rechter Patrick , Deleon Angela , Murugesan Karthikeyan , Montesion Meagan , Albacker Lee A. , Ramkissoon Shakti H. , Tilburg Cornelis M. , Hardin Emily C. , Sievers Philipp , Sahm Felix , Yeo Kee Kiat , Rosenberg Tom , Chi Susan , Wright Karen , Hébert Steve , Peck Sydney , Picca Alberto , Larouche Valérie , Renzi Samuele , Bale Tejus , Smith Amy A. , Touat Mehdi , Jabado Nada , Fischer Eric S. , Eck Michael J. , Baird Lissa , Witt Olaf , Kleinman Claudia , Nguyen Quang-De , Alexandrescu Sanda , Jones David T.W. , Ligon Keith L. , Bandopadhayay Pratiti 
Published: August 2024

AbstractAlterations in Fibroblast growth factor receptor (FGFR)-family proteins frequently occur as oncogenes in many cancers, including a subset of pediatric gliomas. Here, we performed a genomic analysis of 11,635 gliomas across ages and found that 4.5% of all gliomas harbor FGFR alterations including structural variants (SV) and single nucleotide variants (SNV), with an incidence of almost 10% in pediatric gliomas. FGFR family members are differentially enriched by age, tumor grade, and histological subtype, with FGFR1-alterations associated with glioneuronal histologies and pediatric low-grade gliomas. Across development, we findFGFR1expression in both neuronal and glial precursors, whileFGFR3expression is largely restricted to astrocytic lineages. Leveraging novel isogenic model systems, we confirm FGFR1 alterations to be sufficient to activate MAPK and mTOR signaling, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway inhibitors, including pan-FGFR inhibitors. Models driven by FGFR1 SVs exhibited different patterns of sensitivity compared to those driven by SNVs. Finally, we performed a retrospective analysis of clinical responses in children diagnosed with FGFR-driven gliomas and found that targeted MAPK or FGFR-inhibition with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome.
Synovial Transcriptome Profiling for Predicting Biological Treatment Response in Rheumatoid Arthritis: A Feasibility study
Authors: d’Ailly P.N. , Schäffers O.J.M. , Deugd C. , Versnel M.A. , van de Werken H.J.G. , Bindels E.M.J. , Tas S.W. , Gribnau J. , Schep N.W.L. , Bisoendial R.J. 
Published: August 2024

ABSTRACTIntroductionDisease-Modifying Anti-Rheumatic Drug (DMARD) treatment fails to achieve clinical remission in a substantial proportion of patients with rheumatoid arthritis (RA). Patient-derived synovial tissue (ST)-signatures, thought to determine this heterogeneity of treatment responses, can be studied by single-cell RNA sequencing (scRNA-seq).Study aimsThe first aim was to obtain viable ST from RA patients using wrist arthroscopy. The second aim was to identify patient-specific transcriptome signatures from the ST omics data that relate to clinical course and treatment responses in RA.MethodsRadiocarpal and midcarpal synovectomy was performed using a standard set-up wrist arthroscopy. Single-cell suspensions of ST from affected wrists of two RA patients and a control subject were processed on the 10X Genomics Chromium Platform. Seurat was used for downstream analysis.ResultsIn two RA patients and one non-inflammatory control, ST was successfully removed during wrist arthroscopy. No surgical complications occurred. For the RA patients and control, 17,176 and 7,884 high-quality cells were analyzed, respectively. Apart from enrichment of cell compartments in RA, including those of B- and plasma cells, T cell populations, NK cells, and macrophages, we observed interpatient variability that may influence the relationship between RA synovial signature and clinical phenotype, potentially also affecting treatment response and outcome. In-depth analysis of the prevailing cell-type abundance phenotype (CTAP) in the RA patients, as described previously, provided insights into the extent to which these CTAPs may be used to predict treatment responses.ConclusionIn this feasibility study, we demonstrated that wrist arthroscopy successfully retrieves ST with good tissue viability, which may provide informative and high-quality transcriptomic data for predicting therapy response at an individual level.
Post-processing and weighted combination of infectious disease nowcasts
Authors: Amaral André Victor Ribeiro , Wolffram Daniel , Moraga Paula , Bracher Johannes 
Published: August 2024

AbstractIn infectious disease surveillance, incidence data are frequently subject to reporting delays and retrospective corrections, making it hard to assess current trends in real time. A variety of probabilistic nowcasting methods have been suggested to correct for the resulting biases. Building upon a recent comparison of eight of these methods in an application to COVID-19 hospitalization data from Germany, the objective of this paper is twofold. Firstly, we investigate how nowcasts from different models can be improved using statistical post-processing methods as employed, e.g., in weather forecasting. Secondly, we assess the potential of weighted ensemble nowcasts, i.e., weighted combinations of different probabilistic nowcasts. These are a natural extension of unweighted nowcast ensembles, which have previously been found to outperform most individual models. Both in post-processing and ensemble building, specific challenges arise from the fact that data are constantly revised, hindering the use of standard approaches. We find that post-processing can improve the individual performance of almost all considered models both in terms of evaluation scores and forecast interval coverage. Improving upon the performance of unweighted ensemble nowcasts via weighting schemes, on the other hand, poses a substantial challenge. Across an array of approaches, we find modest improvement in scores for some and decreased performance for most, with overall more favorable results for simple methods. In terms of forecast interval coverage, however, our methods lead to rather consistent improvements over the unweighted ensembles.