bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple methods of diet assessment reveal differences in Atlantic puffin adult and chick diets both between and within years
Authors: Kennerley William L. , Clucas Gemma V. , Lyons Donald E. 
Published: April 2024

AbstractAtlantic puffin (Fratercula arctica, hereafter “puffin”) reproductive success in the Gulf of Maine (GoM) has decreased following a recent oceanographic regime shift and subsequent rapid warming. Concurrent changes in both the regional forage fish community and puffin chick diet and provisioning rates suggest that inadequate prey resources may be driving this decline. To determine what prey GoM puffins were feeding on during two years of marine heatwave conditions, we assessed puffin diet using two methods: traditional, observational methods that utilize bill-load photography and emerging methods employing fecal DNA metabarcoding. We identified a strong correlation between the composition of chick diet as estimated through traditional and emerging methods, supporting the interpretation of DNA relative read abundance as a quantitative metric of diet composition. Both methods identified the same dominant prey groups, but metabarcoding identified a greater number of species and offered higher taxonomic resolution. Puffin adults and chicks fed on many of the same prey types, although adults consumed a greater variety of taxa and consumed more low quality prey than they provisioned chicks, as predicted by optimal foraging theory. For both age classes, diet varied both between and within years, likely reflecting changes in the local forage fish community in response to environmental variability. During these two years of marine heatwave conditions, puffins exploited unusual abundances of typically-uncommon prey, yet low puffin productivity suggests the observed dietary plasticity was not able to compensate for apparent prey shortages. Continued refinement of molecular tools and the interpretation of the data they provide will enable better assessments of how seabirds of diverse ages and breeding stages are compensating for changing forage fish communities in response to global climate change.
SLC25A46 is in contact with lysosomes and plays a role in mitochondrial cholesterol homeostasis
Authors: Schuettpelz Jana , Watt Kathleen , Antonicka Hana , Janer Alexandre , Larsson Ola , Shoubridge Eric A. 
Published: April 2024

ABSTRACTMitochondrial morphology reflects the dynamic equilibrium between fusion and fission events, controlled by cellular signaling. A cytoprotective response known as stress-induced mitochondrial hyperfusion (SIMH) is triggered by nutrient starvation and we show that the outer mitochondrial membrane protein SLC25A46 is required for this response. To unravel the cellular mechanisms involved, we conducted transcriptomic analysis on control human fibroblasts and SLC25A46 knock-out cells. Our analysis revealed a remarkable divergence in the transcriptional profile of proteins associated with lysosomal function and cholesterol binding and synthesis. Further investigations using live-cell imaging validated the presence of SLC25A46 at the majority of mitochondria-lysosome contact sites. Since mitochondria-lysosome contacts are linked to cholesterol transport, we investigated the involvement of SLC25A46 in cholesterol trafficking. The SLC25A46 knock-out cell line exhibited a decrease in mitochondrial cholesterol content and distinct alterations were observed in the pattern of cholesterol trafficking compared to control. Cholesterol supplementation in the SLC25A46 knock-out cell line rescued the mitochondrial fragmentation phenotype and restored the SIMH response, suggesting a role for SLC25A46 in maintaining mitochondrial cholesterol homeostasis.Summary blurbThe mitochondrial outer membrane protein SLC25A46 is required for SIMH triggered by nutrient starvation, localizes to lysosome contact sites and is involved in mitochondrial cholesterol homeostasis
Dynamic co-evolution of transposable elements and the piRNA pathway in African cichlid fishes
Authors: Almeida Miguel Vasconcelos , Blumer Moritz , Yuan Chengwei Ulrika , Sierra Pío , Price Jonathan L. , Quah Fu Xiang , Friman Aleksandr , Dallaire Alexandra , Vernaz Grégoire , Putman Audrey L. K. , Smith Alan M. , Joyce Domino A. , Butter Falk , Haase Astrid D. , Durbin Richard , Santos M. Emília , Miska Eric A. 
Published: April 2024

AbstractEast African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed an expansion ofpiwil1genes in Lake Malawi cichlids, likely driven by PiggyBac TEs. The expandedpiwil1copies have signatures of positive selection and retain amino acid residues essential for catalytic activity. Furthermore, the gonads of African cichlids express a Piwi-interacting RNA (piRNA) pathway that target TEs. We define the genomic sites of piRNA production in African cichlids and find divergence in closely related species, in line with fast evolution of piRNA-producing loci. Our findings suggest dynamic co-evolution of TEs and host silencing pathways in the African cichlid radiations. We propose that this co-evolution has contributed to cichlid genomic diversity.
A versatile information retrieval framework for evaluating profile strength and similarity
Authors: Kalinin Alexandr A. , Arevalo John , Serrano Erik , Vulliard Loan , Tsang Hillary , Bornholdt Michael , Sivagurunathan Suganya , Rajwa Bartek , Carpenter Anne E. , Way Gregory P. , Singh Shantanu 
Published: April 2024

AbstractIn profiling assays, thousands of biological properties are measured in a single test, yielding biological discoveries by capturing the state of a cell population, often at the single-cell level. However, for profiling datasets, it has been challenging to evaluate the phenotypic activity of a sample and the phenotypic consistency among samples, due to profiles’ high dimensionality, heterogeneous nature, and non-linear properties. Existing methods leave researchers uncertain where to draw boundaries between meaningful biological response and technical noise. Here, we developed a statistical framework that uses the well-established mean average precision (mAP) as a single, data-driven metric to bridge this gap. We validated the mAP framework against established metrics through simulations and real-world data applications, revealing its ability to capture subtle and meaningful biological differences in cell state. Specifically, we used mAP to assess both phenotypic activity for a given perturbation (or a sample) as well as consistency within groups of perturbations (or samples) across diverse high-dimensional datasets. We evaluated the framework on different profile types (image, protein, and mRNA profiles), perturbation types (CRISPR gene editing, gene overexpression, and small molecules), and profile resolutions (single-cell and bulk). Our open-source software allows this framework to be applied to identify interesting biological phenomena and promising therapeutics fromlarge-scale profiling data.
Group Heteroscedasticity - A Silent Saboteur of Power and False Discovery in RNA-Seq Differential Expression
Authors: Chatterjee Suvo , Fadikar Arindam , Hanumesh Vrushab , Meshram Siddhant Sunil , Zoh Roger S , Ma Siyuan , Arunkumar Ganesan , Mallick Himel 
Published: April 2024

AbstractDespite the availability of several high-profile, state-of-the-art methods, analyzing bulk RNA-Seq data continues to face significant challenges. Evidence from recent studies has highlighted that popular differential expression (DE) tools, such as edgeR and DESeq2, are susceptible to an alarmingly high false discovery rate (FDR). These studies suggest that the FDR inflation observed in these models could be attributed to issues such as violations of parametric assumptions or an inability to effectively handle outliers in the data. Here, we argue that group heteroscedasticity can also contribute to this elevated FDR, a phenomenon largely overlooked by the research community. We introduce a novel statistical model, Robseq, designed for effective per-feature modeling in differential analysis, particularly when the assumption of group homoscedasticity is unmet. Robseq utilizes well-established statistical machinery from the robust statistics literature, including M-estimators to robustly estimate gene expression level changes and Huber-Cameron variance estimators to calculate robust standard errors in heteroscedastic settings. Additionally, it incorporates a degrees of freedom adjustment for the Welch t-statistic, based on Bell-McCaffrey’s recommendation, for inferential purposes, effectively addressing the problem of FDR inflation in RNA-Seq differential expression. Through detailed simulations and comprehensive benchmarking, we show that Robseq successfully maintains the false discovery and type-I error rates at nominal levels while retaining high statistical power compared to well-known DE methods. Analysis of population-level RNA-Seq data further demonstrates that Robseq is capable of identifying biologically significant signals and pathways implicated in complex human diseases that otherwise cannot be revealed by published methods. The implementation of Robseq is publicly available as an R package athttps://github.com/schatterjee30/Robseq.
Dysregulation in Spatiotemporal Expression ofHMX1Coordinated by Multifaceted Enhancers Drives an Auricular Disorder
Authors: Xu Xiaopeng , Chen Qi , Huang Qingpei , Cox Timothy C. , Zhu Hao , Hu Jintian , Han Xi , Meng Ziqiu , Wang Bingqing , Liao Zhiying , Xu Wenxin , Xiao Baichuan , Lang Ruirui , Liu Jiqiang , Li Qiang , Zhang Qingguo , Antonarakis Stylianos E. , Zhang Jiao , Fan Xiaoying , Liu Huisheng , Zhang Yong-Biao 
Published: April 2024

AbstractEnhancers, through the combinatorial action of transcription factors (TFs), dictate both the spatial specificity and the levels of gene expression, and their aberrations can result in diseases. The association betweenHMX1and its downstream enhancer with ear deformities has been previously documented. However, the pathogenic variations and molecular mechanisms underlying the bilateral constricted ear (BCE) malformations remain unclear. This study identifies a copy number variation (CNV) encompassing three enhancers that induces BCE. These enhancers, collectively termed the positional identity hierarchical enhancer cluster (PI-HEC), co-regulate spatiotemporal expression of theHMX1gene in a coordinated and synergistic mode, each displaying unique activity-location-structure characteristics. A thorough exploration of this regulatory locus reveals that specific motif clusters within the PI-HEC variably modulate its activity and specificity, with the high mobility group (HMG) box combined with Coordinator and homeodomain (HD)-TFs notably influencing them respectively. Our findings based on various types of mouse models, reveal that both aberrantHmx1expression in the fibroblasts of the basal pinna, originating from neural crest cells, and ectopic expression in the distal pinna structures contribute to the abnormal development of the outer ear, including the cartilage, muscle, and epidermis tissues. This study deepens our understanding of mammalian ear morphogenesis and sheds light on the complexity of gene expression regulation by enhancers and specific sequence motifs.
A specific and portable gene expression program underlies antigen archiving by lymphatic endothelial cells
Authors: Sheridan Ryan M. , Doan Thu A. , Lucas Cormac , Forward Tadg S. , Uecker-Martin Aspen , Morrison Thomas E. , Hesselberth Jay R. , Tamburini Beth A. Jirón 
Published: April 2024

AbstractAntigens from protein subunit vaccination traffic from the tissue to the draining lymph node, either passively via the lymph or carried by dendritic cells at the local injection site. Lymph node (LN) lymphatic endothelial cells (LEC) actively acquire and archive foreign antigens, and archived antigen can be released during subsequent inflammatory stimulus to improve immune responses. Here, we answer questions about how LECs achieve durable antigen archiving and whether there are transcriptional signatures associated with LECs containing high levels of antigen. We used single cell sequencing in dissociated LN tissue to quantify antigen levels in LEC and dendritic cell populations at multiple timepoints after immunization, and used machine learning to define a unique transcriptional program within archiving LECs that can predict LEC archiving capacity in independent data sets. Finally, we validated this modeling, showing we could predict antigen archiving from a transcriptional dataset of CHIKV infected mice and demonstratedin vivothe accuracy of our prediction. Collectively, our findings establish a unique transcriptional program in LECs that promotes antigen archiving that can be translated to other systems.
SPLICER: A Highly Efficient Base Editing Toolbox That EnablesIn VivoTherapeutic Exon Skipping
Authors: Miskalis Angelo , Shirguppe Shraddha , Winter Jackson , Elias Gianna , Swami Devyani , Nambiar Ananthan , Stilger Michelle , Woods Wendy S. , Gosstola Nicholas , Gapinske Michael , Zeballos Alejandra , Moore Hayden , Maslov Sergei , Gaj Thomas , Perez-Pinera Pablo 
Published: April 2024

AbstractExon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which has broad applications in molecular biology, medicine, and biotechnology. Existing exon skipping techniques include antisense oligonucleotides, targetable nucleases, and base editors, which, while effective for specific applications at some target exons, remain hindered by shortcomings, including transient effects for oligonucleotides, genotoxicity for nucleases and inconsistent exon skipping for base editors. To overcome these limitations, we created SPLICER, a toolbox of next-generation base editors consisting of near-PAMless Cas9 nickase variants fused to adenosine or cytosine deaminases for the simultaneous editing of splice acceptor (SA) and splice donor (SD) sequences. Synchronized SA and SD editing with SPLICER improves exon skipping, reduces aberrant outcomes, including cryptic splicing and intron retention, and enables skipping of exons refractory to single splice-site editing. To demonstrate the therapeutic potential of SPLICER, we targetedAPPexon 17, which encodes the amino acid residues that are cleaved to form the Aβ plaques in Alzheimer’s disease. SPLICER reduced the formation of Aβ42 peptidesin vitroand enabled efficient exon skipping in a mouse model of Alzheimer’s disease. Overall, SPLICER is a widely applicable and efficient toolbox for exon skipping with broad therapeutic applications.
Single molecule tracking reveals nanodomains in biomolecular condensates
Authors: Gao Guoming , Sumrall Emily R. , Walter Nils G. 
Published: April 2024

AbstractProtein-rich biomolecular condensates formed by phase separation1play a crucial role in cellular RNA regulation by the selective recruitment and processing of RNA molecules2. The functional impact of condensates on RNA biology relies on the residence time of individual RNA molecules within a condensate3, which is governed by intra-condensate diffusion4– the slower or more confined the diffusion, the longer the residence time. However, the spatiotemporal organization of RNA and protein diffusion within a single condensate remains largely unknown due to the challenge of accurately profiling intra-condensate diffusion behaviors down to the single-molecule level. Here we introduced a general condensate-tethering approach that allows single molecule tracking (SMT) of fluorescently labeled proteins and RNAs within non-wetted spherical 3D condensates without the interference of condensate motions. We found that a significant fraction of RNA and protein molecules are locally confined, rather than freely diffusive, within a model condensate formed by full-length, tag-free, RNA-binding protein Fused-in-Sarcoma (FUS), known for its critical roles in RNA biology under both physiological and pathological conditions5. Dynamic Point Accumulation for Imaging in Nanoscale Topography (PAINT)6reconstruction further revealed that RNA and proteins are confined to distinct slow-moving nanometer-scale regions, termed nanodomains, within a single condensate. Remarkably, nanodomains affect the diffusion but not the density of the confined biomolecules, supporting local percolation1,7rather than a secondary phase separation within the condensate as their origin. Beyond their regulatory roles on RNA residence time, nanodomains engender both elevated local connectivity and altered chemical environment, a prerequisite for pathological liquid-to-solid transition of FUS during aging. In summary, our study uncovers a patterned spatial organization of both protein and RNA molecules within a single condensate, revealing distinct diffusion dynamics that affect molecular retention time and interactions underlying cellular function and pathology.
Probiotic treatment causes sex-specific neuroprotection after traumatic brain injury in mice
Authors: Holcomb Morgan , Marshall Austin , Flinn Hannah , Lozano Mariana , Soriano Sirena , Gomez-Pinilla Fernando , Treangen Todd J. , Villapol Sonia 
Published: April 2024

ABSTRACTBackgroundRecent studies have shed light on the potential role of gut dysbiosis in shaping traumatic brain injury (TBI) outcomes. Changes in the levels and types ofLactobacillusbacteria present might impact the immune system disturbances, neuroinflammatory responses, anxiety and depressive-like behaviors, and compromised neuroprotection mechanisms triggered by TBI.ObjectiveThis study aimed to investigate the effects of a daily pan-probiotic (PP) mixture in drinking water containing strains ofLactobacillus plantarum, L. reuteri, L. helveticus, L. fermentum, L. rhamnosus, L. gasseri,andL. casei, administered for either two or seven weeks before inducing TBI on both male and female mice.MethodsMice were subjected to controlled cortical impact (CCI) injury. Short-chain fatty acids (SCFAs) analysis was performed for metabolite measurements. The taxonomic profiles of murine fecal samples were evaluated using 16S rRNA V1-V3 sequencing analysis. Histological analyses were used to assess neuroinflammation and gut changes post-TBI, while behavioral tests were conducted to evaluate sensorimotor and cognitive functions.ResultsOur findings suggest that PP administration modulates the diversity and composition of the microbiome and increases the levels of SCFAs in a sex-dependent manner. We also observed a reduction of lesion volume, cell death, and microglial and macrophage activation after PP treatment following TBI in male mice. Furthermore, PP-treated mice show motor function improvements and decreases in anxiety and depressive-like behaviors.ConclusionOur findings suggest that PP administration can mitigate neuroinflammation and ameliorate motor and anxiety and depressive-like behavior deficits following TBI. These results underscore the potential of probiotic interventions as a viable therapeutic strategy to address TBI-induced impairments, emphasizing the need for gender-specific treatment approaches.
Transfer Learning Of Gene Expression Using Reactome
Authors: Belgadi Siham , Zhang David Yu , Gopinath Ashwin 
Published: April 2024

AbstractIn clinical research, translating findings from model organisms to human applications remains challenging due to biological differences between species as well as limitations of orthologous, and homologous, gene comparisons, which is fraugt with information loss as well as many-to-many mapping. To address these issues, we introduce a novel Universal Gene Embedding (UGE) model that leverages transformer-based few-shot learning for species-agnostic transfer learning with heterogeneous domain adaptation. The UGE model, trained on a dataset of gene expression from ten organs across rats and mice, establishes a unified biological latent space that effectively represents genes from any organ or species. By focusing on reactomes—comprehensive profiles of gene expression responses to drugs—the UGE model enables functional gene mapping across species based on the similarities of these profiles. Our contributions include a gene reactome vector prediction module, a robust framework for mapping drug-induced gene expression patterns across species, strategies for optimizing experimental design, and enhanced gene mapping precision. These advancements provide a new tool for genetic research and a new paradigm for cross-species insights, potentially revolutionizing our understanding of gene function, drug responses, and the translation of findings from model organisms to human clinical applications.
mTORC1-dependent SOCE activity regulates synaptic gene expression and muscle response to denervation
Authors: Prola Alexandre , Dupont Olivier , Rajendran Jayasimman , Chabry Florent , Koenig Stéphane , Frieden Maud , Castets Perrine 
Published: April 2024

AbstractNeuromuscular junction (NMJ) instability is central in muscle dysfunction occurring in neuromuscular disorders and aging. NMJ maintenance requires regionalized regulation of synaptic genes, previously associated with Ca2+-dependent pathways. However, what sustains Ca2+micro-domains in myofibers and allows a rapid response to denervation is not known. Here, we identify that Store-Operated Calcium Entry (SOCE) plays a critical role in synaptic gene regulation. SOCE components show differential enrichment in sub- and non-synaptic muscle regions. Especially, STIM1 accumulation at rough endoplasmic reticulum associates with functional SOCE at the endplate. Denervation increases SOCE in non- and sub-synaptic regions, together with reticulum remodeling.Stim1knockdown hampers denervation-induced synaptic gene up-regulation, while STIM1 overexpression increases synaptic gene expression in innervated muscle. Finally, mTORC1 activation mimics the effect of denervation on SOCE capacity, STIM1 localization and reticulum remodeling. Together, our results reveal a decisive role of SOCE in sensing innervation and regulating muscle response to denervation. They further suggest that SOCE perturbation may contribute to neuromuscular integrity loss in pathological conditions associated with mTORC1 dysregulation.