bluuebunny/crossref_metadata_2025_split huggingface dataset:
The methyl-CpG-binding protein 2 inhibits cGAS-associated signaling
Authors: Chamma Hanane , Guha Soumyabrata , Schüssler Moritz , Messaoud-Nacer Yasmine , Le Hars Pierre , Salma Mohammad , McKellar Joe , Re Joanna , Chemarin Morgane , Carrier Arnaud , Disyak Michael A. , Taffoni Clara , Charpentier Robin , Husson Zoé , Valjent Emmanuel , Andrieu-Soler Charlotte , Soler Eric , Majzoub Karim , Vila Isabelle K. , Laguette Nadine 
Published: February 2025

AbstractThe detection of cytosolic dsDNA is tightly regulated to avoid pathological inflammatory responses. A major pathway involved in their detection relies on the cyclic GMP-AMP synthase (cGAS) that triggers activation of the Stimulator of interferon genes (STING) which subsequently drives the expression of inflammatory genes and type I Interferons (IFNs). Here, we show that the methyl-CpG-binding protein 2 (MECP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. We show that the presence of cytosolic dsDNA promotes MECP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening cGAS activation. Our data also indicate that MECP2 export from the nucleus partially phenocopies MECP2 deficiency, leading to the expression of inflammatory and interferon stimulated genes, enforcing an antiviral state. Finally, we also show that MECP2 displacement from the nucleus following dsDNA stimulation is sufficient to disrupt its canonical function, leading to the reactivation of otherwise repressed genes, such endogenous retroelements of the Long interspersed nuclear element-1 (LINE-1) family. Re-expression of the latter led to the accumulation of DNA species feeding cGAS-dependent signaling and can be dampened by reverse transcriptase inhibitors. We thus establish a previously unforeseen direct role of MECP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses. Furthermore, our results suggest that targeting dsDNA-associated pathways or pharmacological inhibition of LINE-1 may bear therapeutic hopes for Rett syndrome (RTT) patients that present with MECP2 deficiency.
NoisyFlow: Differentially Private Optimal Transport Using Neural Networks for Secure Biomedical Data Sharing
Authors: Li Yunyang , Khandekar Nikhil , Wang Skylar , Khanna Varada , Sanker Julian , Gerstein Mark B. 
Published: February 2025

AbstractMotivationAdvancing data sharing in biomedical research, particularly for sensitive genomic and clinical datasets, is crucial for improving model performance across diverse patient populations. However, stringent privacy concerns hinder collaboration and limit insights derived from multi-institutional datasets. Current approaches to privacy-preserving data sharing fail to address gaps between data distributions.ResultsWe introduce NoisyFlow, a differentially private neural network-based optimal transport framework designed to enable secure and unbiased biomedical data sharing. By integrating optimal transport theory with neural networks and differential privacy mechanisms, our framework aligns data distributions across institutions while preserving individual privacy. NoisyFlow eliminates the need for direct data sharing and reduces distribution shifts caused by covariate and batch effects. Empirical evaluations demonstrate the framework’s effectiveness in handling high-dimensional single-cell genomic data and histopathology images, achieving superior privacy guarantees while maintaining high utility in downstream tasks such as disease classification.Availability and implementationThe implementation of NoisyFlow is available athttps://github.com/liyy2/NoisyFlow.Contactmark@gersteinlab.org.Supplementary informationSupplementary data are available online.
adabmDCA 2.0 – a flexible but easy-to-use package for Direct Coupling Analysis
Authors: Rosset Lorenzo , Netti Roberto , Muntoni Anna Paola , Weigt Martin , Zamponi Francesco 
Published: February 2025

AbstractIn this methods article, we provide a flexible but easy-to-use implementation of Direct Coupling Analysis (DCA) based on Boltzmann machine learning, together with a tutorial on how to use it. The packageadabmDCA 2.0is available in different programming languages (C++, Julia, Python) usable on different architectures (single-core and multi-core CPU, GPU) using a common front-end interface. In addition to several learning protocols for dense and sparse generative DCA models, it allows to directly address common downstream tasks like residue-residue contact prediction, mutational-effect prediction, scoring of sequence libraries and generation of artificial sequences for sequence design. It is readily applicable to protein and RNA sequence data.
Viral-mediated fluorescent labeling of hyaluronan reveals extracellular matrix dynamics in the mouse brain in vivo
Authors: Fernández-Ballester Mario , Ardaya María , Dutheil Nathalie , Largitte Leslie-Ann , Martín Abraham , Soria Federico N. 
Published: February 2025

ABSTRACTThe extracellular matrix (ECM) of the brain is primarily composed of the glycan polymer hyaluronan (HA), a core scaffold that nucleates proteoglycans forming a self-assembled matrix that acts as structural framework and signaling hub. Since most of the neural matrix is composed of sugars, development of genetically encoded tags has been limited. Therefore, although several staining protocols exist for ECM in fixed tissue, there are no reliable matrix labels for live imaging. Here we report a viral-mediated fluorescent probe that binds to HA and labels the mouse brain ECM. The vector encodes the HA binding domain from neurocan fused to GFP and an externalization tag (AAV-Ncan-GFP), enabling transduced cells to secrete the fluorescent hyalectan into the extracellular space, thereby labeling HA. We demonstrate stable probe expression in organotypic brain slices, as well as in vivo in the mouse cortex, where it labels both perineuronal nets and interstitial matrix. We validate HA labeling through colocalization with HABP and sensitivity to hyaluronidase, and confirm the probe’s extracellular localization by shadow imaging. As a proof of concept, we combine AAV-Ncan-GFP with dendritic spine imagingex vivoand calcium transient imagingin vivo, providing a real-time map of local ECM alongside neural function. The probe enables time-lapse imaging of ECM dynamics in live mice, facilitating longitudinal studies across a wide range of timescales, from minutes to days. The results establish AAV-Ncan-GFP as a valuable tool for real-time observation of brain ECM and a promising resource to explore ECM dynamics and brain function in vivo.
Subjective sleep quality in healthy young adults moderates associations of sensitivity to punishment and reward with functional connectivity of regions relevant for insomnia disorder
Authors: Zareba Michal Rafal , Davydova Tatiana , Palomar-García María-Ángeles , Adrián-Ventura Jesús , Costumero Victor , Visser Maya 
Published: February 2025

AbstractChronic unhealthy sleeping behaviours are a major risk factor for the emergence of mood and anxiety disorders. Nevertheless, we are still lacking understanding why some individuals are more prone than others to affective dysregulation caused by sleep disruption. With preliminary evidence suggesting that brain activity during positive and negative emotional processing might play an important modulating role, we conducted whole-brain resting-state functional connectivity analyses in a large cohort of healthy young adults (N = 155). Using regions consistently affected in insomnia disorder as seeds, we investigated sleep quality-related neural connectivity patterns that were both insensitive and sensitive to the interactions with individual measures of reward and punishment processing, additionally assessing the links with indices of emotional health. Majority of the findings reflected interactions between sleep quality and reinforcement sensitivity, with the opposite associations reported in the good and poor sleepers. One of such connections, the coupling between precentral gyrus and posterior insula, was additionally negatively linked to trait anxiety, with the lowest connectivity values observed in poor sleepers with higher sensitivity to punishment. In turn, the only finding associated solely with sleep quality, i.e. coupling between subgenual anterior cingulate cortex and thalamus, was also related to the habitual use of emotion suppression strategies. As such, the present study provides evidence that affective functioning plays an essential role in determining the effects of poor sleep quality on brain connectivity and emotional health, providing a plausible mechanism for why certain individuals are more susceptible to sleep-related affective dysregulation than others.Highlights●Functional connectivity of insomnia-related brain regions is altered in poor sleepers●Sleep quality interacts with reinforcement sensitivity for most of such effects●Distinct sleep-related mechanisms are linked to trait anxiety and emotion suppression●Poor sleep and high punishment sensitivity increase the risk of affect dysregulation.
Genetic diversity and conservation insights for the baobabAdansonia suarezensisin northern Madagascar: a whole genome SNP analysis
Authors: Razanamaro Onja Hariveloniaina Morilline , La Montagna Dario , Attorre Fabio , Rondoni Elisa , Buttarazzi Francesco , Andriaharimalala Tahiana , Ishikawa Naoko , Suyama Yoshihisa , Parducci Laura 
Published: February 2025

AbstractMadagascar is home to seven unique baobab species in the genusAdansonia, all threatened by climate change, habitat destruction, and deforestation. Previous studies have highlighted the vulnerability of baobabs, particularlyA. suarezensis, without delving into the specific genetic structure of its populations. In this paper we examine the genetic structure, diversity, and connectivity of seven populations ofA. suarezensis, using genome-wide Single Nucleotide Polymorphism (SNP) data. The results revealed significant genetic differentiation between inland and coastal populations, with the Mahory population forming a distinct genetic cluster characterized by high heterozygosity but low polymorphism, indicative of historical bottlenecks. In contrast, northern populations showed greater admixture and gene flow but higher inbreeding coefficients in coastal regions, such as Ambilo and Cap d’Ambre, suggesting localized inbreeding depression. Additionally, historical climatic shifts and potential anthropogenic dispersal are explored as contributing factors to the current genetic patterns. This study highlights the importance of understanding genetic dynamics for conservation, emphasizing habitat restoration and targeted management strategies to preserve the evolutionary potential ofA. suarezensisand ensure its long-term survival.
Identification of Viral Variants from Functional Genomics Data
Authors: Röckl Florian , Friedel Caroline C. 
Published: February 2025

The analysis of virus knockout mutants is a common approach for studying the role of individual viral genes in viral infections and is increasingly performed using functional genomics sequencing experiments, e.g. RNA-seq or ATAC-seq, of infected cells. Identifying viral variants directly in these experiments avoids additional genome sequencing and allows confirming the presence of particular mutations directly in the experiment of interest. Here, we present a pipeline to directly identify viral variants from these functional genomics data. This combines existing SNP callers with novel methods for identifying deletions, insertions, and corresponding inserted sequences. The latter address the problem that existing structural variant callers performed poorly on functional genomics data with large variations in coverage. We evaluated the pipeline on RNA-seq data for infection with wild-type Herpes simplex virus 1 (HSV-1) and null mutants of important HSV-1 proteins. Comparison of variants identified by our pipeline with the descriptions of the original publications showed that we could correctly recover the introduced mutations. Thus, our pipeline offers researchers a fast and easy way to verify the existence of variants in the viral genome without additional genome sequencing experiments.AvailabilityThe pipeline is implemented as a workflow for the workflow management system Watchdog and is available athttps://github.com/watchdog-wms/watchdog-wms-workflows/(Variant-CallerPipeline).
Generalizable Prediction of Alzheimer Disease Pathologies with a Scalable Annotation Tool and an High-Accuracy Model
Authors: Gopal Ramaswamy Vivek , Ahirwar Monika , Ryan Gennadi , Dugger Brittany N. , Al Dalahmah Osama , Signaevsky Maxim , Purohit Dushyant P. , Haroutunian Vahram , Finkbeiner Steven 
Published: February 2025

AbstractCharacterizing the cardinal neuropathologies in Alzheimer disease (AD) can be laborious, time consuming, and susceptible to intra- and inter-observer variability. The lack of high throughput unbiased approaches to reliably assess neuropathology hampers efforts to use pathology as a means to link clinical features of AD to molecular pathogenesis in the ever-growing datasets of persons with AD. To remove this roadblock, we designed an annotation tool in addition to a computational pipeline to analyze digital microscopic images of postmortem tissue from persons with AD in a fully automated and unbiased manner in only a fraction of the time taken with conventional approaches and allows neuropathological analyses and lesion quantification at multiple scales. The pipeline includes a Mask Regional-Convolutional Neural Network (Mask R-CNN) we trained to detect, classify, and segment different types of amyloid. To establish ground truth for training and validation, we utilized an existing open source platform, QuPath, and developed a tool to collect consensus annotations of neuropathology experts. The Mask R-CNN identified amyloid pathology in samples (with accuracy: 94.6%, F1: 87.7%, Dice: 81.8%) unrelated to the training dataset, indicating that it detects generalizable pathology features. Its quantitative measurements of amyloid pathology on 298 samples correlated with the severity of AD neuropathology assessed by experts and neuropathologists (CERAD ratings) and estimates of cognitive compromise (Clinical Dementia Ratings (CDR)). Our computational pipeline should enable rapid, unbiased, inexpensive, quantitative, and comprehensive neuropathological analysis of large tissue collections and integration with orthogonal clinical and multi-omic measurements.
Epithelial miR-149-5p up-regulation is associated with immune evasion in progressive bronchial premalignant lesions
Authors: Ning B , Chiu DJ , Pfefferkorn RM , Kefella Y , Kane E , Reyes-Ortiz V , Liu G , Zhang S , Liu H , Sultan L , Green E , Constant M , Spira AE , Campbell JD , Reid ME , Varelas X , Burks EJ , Lenburg ME , Mazzilli SA , Beane JE 
Published: February 2025

ABSTRACTThe molecular drivers bronchial premalignant lesion progression to invasive lung squamous cell carcinoma are not well defined. Prior work profiling longitudinally collected bronchial premalignant lesion biopsies by RNA sequencing defined a proliferative subtype, enriched with bronchial dysplasia. We found that a gene co-expression module associated with interferon gamma signaling and antigen processing/presentation was down-regulated in progressive/persistent versus regressive lesions within the proliferative subtype, suggesting a functional impact of these genes on immune evasion. RNA from these same premalignant lesions was profiled by microRNA (miRNA) sequencing and a miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of this antigen presentation gene co-expression module associated with lesion progression. hsa-miR-149-5p was found to be predominantly expressed in the epithelium and up-regulated in progressive/persistent versus regressive proliferative lesions while targets of this miRNA, the transcriptional coactivator of MHC-I gene expression,NLRC5, and the genes it regulates were down-regulated. MicroRNA in situ hybridization of hsa-miR-149-5p in tissue from adjacent fixed biopsies showed that hsa-miR-149-5p was increased in areas of bronchial dysplasia in progressive/persistent versus regressive lesions. Imaging mass cytometry showed that NLRC5 protein expression was decreased in progressive/persistent versus regressive lesions within areas of hyperplasia, metaplasia, and dysplasia. Additionally, basal cells with high versus low levels of NLRC5 were found to be in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in lesions with low hsa-miR-149-5p expression. Collectively, our data suggests a functional role for hsa-miR-149-5p in bronchial premalignant lesions and may serve as a therapeutic target for PML immunomodulation.STATEMENT OF SIGNIFICANCEIntegrative analysis across bronchial premalignant lesions has identified and localized a potential regulator of immune evasion in progressive/persistent lesions that could be a novel therapeutic target.
Transcription start sites experience a high influx of heritable variants fuelled by early development
Authors: Guzmán Miguel Cortés , Castellano David , Colomé Clàudia Serrano , Seplyarskiy Vladimir , Weghorn Donate 
Published: February 2025

AbstractMutations drive evolution and genetic diversity, but the impact of transcription on germline mutagenesis remains poorly understood. Here, we identify a hypermutation phenomenon at transcription start sites in the human germline, spanning several hundred base pairs in both directions. We link this TSS mutational hotspot to divergent transcription, RNA polymerase II stalling, R-loops, and mitotic—but not meiotic—double-strand breaks, revealing a recombination-independent mechanism distinct from known processes. Notably, the hotspot is absent inde novomutation data. We reconcile this by showing that TSS mutations are significantly enriched with early mosaic variants often filtered out inde novomutation calls, indicating that the hotspot arises during early embryogenesis. Mutational signature analysis reinforces these findings and implicates alternative non-homologous end joining and maternal mutation clusters. Our study provides the first detailed description of a germline TSS mutation hotspot, with broad evolutionary and biomedical implications.
Dynamic Proximal Interactomics and Chemical Genetic Screening Reveal CCR4-NOT Sequestration in Stress Granules as a Mechanism for Transcript Stabilization
Authors: Tsai Yi-Cheng , Uechi Hiroyuki , Millar Sean R. , Kadijk Eileigh , Schreiber Karl J. , Minkovich Alon , Huang Jie Qi , Kasmaeifar Vesal , Zhang Zhixin , Barsacchi Rico , Möbius Claudia , Janosch Antje , Savage Jonathan C. , Röst Hannes , Hyman Anthony A. , Youn Ji-Young 
Published: February 2025

ABSTRACTLiving cells adapt to stress by protecting essential resources, such as stabilizing transcripts. Stress granules, which form during stress through the coalescence of polyadenylated transcripts released from polysomes and RNA-binding proteins, are implicated in post-transcriptional regulation, although their precise roles remain contested. To address this, we generated dynamic proteomic landscapes of stress granules during assembly and disassembly under oxidative and hyperosmotic stress using multi-bait BioID profiling combined with quantitative mass spectrometry. Our analysis reveals dynamic rewiring of stress granule proximal interaction networks, identifying RNA-binding proteins involved in translation repression and mRNA decay, including the CCR4-NOT deadenylase complex, as universal molecular signatures of condensed stress granules. Using the CCR4-NOT deadenylase complex as a model, we demonstrate the function of dynamic components associated with stress granules. Complementary genome-wide chemical genetic screening identified CCR4-NOT components as regulators of stress granule formation. Reduced CCR4-NOT activity, which lengthens poly(A) tails, enhanced stress granule assembly, while shortened poly(A) tails inhibited it. Furthermore, stress-induced sequestration of the CCR4-NOT complex to stress granules coincided with known global poly(A) tail lengthening. These findings suggest that stress granule condensation promotes transcriptome stabilization by regulating CCR4-NOT localization as part of an adaptive stress response. This work underscores the power of integrating quantitative proteomics with chemical genetics to advance our understanding of biomolecular condensates in diverse biological processes.
Evolution of developmental bias explains divergent patterns of phenotypic evolution
Authors: Picao-Osorio Joao , Bouleau Charlotte , Gonzalez de la Rosa Pablo M. , Stevens Lewis , Fekonja Nina , Blaxter Mark , Braendle Christian , Félix Marie-Anne 
Published: February 2025

AbstractRates of phenotypic evolution vary across traits, and these evolutionary patterns themselves evolve. Understanding how development contributes—or biases—such patterns remains a challenge because it requires large-scale measurement of phenotypic variation resulting from random mutations across multiple species. Using the experimentally tractable system of nematode vulval development, we quantified the mutational sensitivity of six cell fates across two nematode clades. The results show that within each clade, mutational sensitivity is sufficient to explain the observed phenotypic evolution. The difference between clades can be explained by a simple spatial shift across cells of the sensitive region of a Wnt signaling dose-response curve. These findings underscore the importance of integrating the evolving genotype-phenotype map into the understanding of phenotypic change at both micro- and macroevolutionary scales.
Continuum architecture dynamics of vesicle tethering in exocytosis
Authors: Puig-Tintó Marta , Ortiz Sebastian , Meek Sasha , Coray Raffaele , Hernández Altair C. , Castellet Anna , Kramer Eric , Betancur Laura I. , Hoess Philipp , Mund Markus , Izquierdo-Serra Mercè , Oliva Baldo , de Marco Alex , Ries Jonas , Castaño-Díez Daniel , Manzo Carlo , Gallego Oriol 
Published: February 2025

SUMMARYEssential for eukaryotic organisms, multiple copies of the exocyst complex tether each secretory vesicle to the plasma membrane (PM) in constitutive exocytosis. The exocyst higher-order structure (ExHOS) that coordinates the action of these multiple exocysts remains unexplored. We integrated particle-tracking, super-resolution microscopy and cryo-electron tomography in a model that time-resolves the continuum conformational landscape of the ExHOS and functionally annotates its different conformations. We found that 7 exocysts form flexible ring-shaped ExHOS that tether vesicles at <45 nm from the PM. The ExHOS, initially 19 nm in radius, rapidly expands while it pulls the vesicle towards the PM. Subsequently, the ExHOS stabilizes, securing the vesicle at ∼4 nm from the PM. After fusion, Sec18 mediates the ExHOS disassembly when its radius is 38 nm. By resolving the fundamental biophysical principles of tethering we bridged the gap between static isolated structures and the dynamic and multimeric nature of exocytosis.