bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using AlphaFold2 to Predict the Conformations of Side Chains in Folded Proteins
Authors: Maisuradze Gia G. , Thakur Abhishek , Khatri Kisan , Haldane Allan , Levy Ronald M. 
Published: February 2025

AbstractAlphaFold has revolutionized protein structure prediction by accurately creating 3D structures from just the amino acid sequence. However, even with extensive research validating its overall accuracy, a key question remains: Can AlphaFold predict the conformation of individual amino acid residue side chains within a folded protein? This is important for the field of molecular modeling, particularly when predicting the effects of mutations on protein stability and ligand binding. AlphaFold generates a set of atomic coordinates not just for the mutated side chain but also for potential rearrangements across the entire protein structure. In this study we investigate the ability of ColabFold, an online implementation of AlphaFold2 (AF2), to predict the conformations of residue side chains in folded proteins. We find that over a set of 10 benchmark proteins, the side chain conformation prediction error of ColabFold is on average ∼14% for χ1dihedral angles, and increases to ∼48% for χ3dihedral angles. The prediction error is smaller for non-polar side chains and is somewhat improved using structural templates. ColabFold demonstrates a bias towards the most prevalent rotamer states in the protein data bank (PDB), potentially limiting its ability to capture rare side chain conformations effectively. As an application of AlphaFold to explore the structural consequences of strongly cooperative mutations on side chain rearrangements, we employ a Potts sequence-based statistical energy model to perform large scale mutational scans of two proteins ABL1 and PIM1 kinase, searching for the most strongly cooperative mutational pairs, and then use ColabFold to predict the structural signatures of this cooperativity on the interacting side chains. Our results demonstrate that integration of the sequence-based Potts model with AlphaFold into a single pipeline provides a new tool that can be used to explore the fundamental relationship between protein mutations, cooperative changes in structure, and fitness.
Targeting lysosomal damage is a new therapeutic perspective for Duchenne Muscular Dystrophy
Authors: Jaber Abbass , Palmieri Laura , Bakour Rania , Lachiver Elise , Hong Ai Vu , Bourg Nathalie , Poupiot Jérôme , Albini Sonia , Stockholm Daniel , Van Wittenberghe Laetitia , Miranda Adeline , Daniele Nathalie , Barthélèmy Inés , Blot Stephan , Bui Mai Thao , Evangelista Teresinha , Richard Isabelle , Israeli David 
Published: February 2025

AbstractDuchenne Muscular Dystrophy (DMD), a muscle degenerative disease affecting young boys, arises from the loss of dystrophin. Current gene therapy approaches aim to restore a shortened form of dystrophin (microdystrophin) via Adeno-Associated Vector (AAV) delivery, but clinical studies show limited efficacy, emphasizing the need for improved strategies such as combined therapies. In this study, we identified lysosomal perturbations in the myofibers of DMD patients and animal models, an overlooked mechanism of cellular damage in muscular dystrophies. These were notably marked by the upregulation and recruitment of Galectin-3, a known biomarker of lysosomal membrane permeabilization, to damaged lysosomes, alongside alterations in lysosome number, morphology, and activation of endolysosomal damage response. Importantly, microdystrophin therapy inDmdmdxmice fails to fully correct these damages. However, combining it with trehalose, a lysosome-protective disaccharide, significantly improves outcome, enhancing muscle function, histology and transcriptome. These findings highlight lysosomal damage as a novel mechanism in DMD pathogenesis and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy.TeaserLysosomal damage contributes to DMD pathology and is an interesting therapeutic target worth considering for current and future approaches.
Mixed Selectivity of Subthalamic Nucleus Neurons in Encoding Motor and Reward Behaviors
Authors: Wu Bing-Shiuan , Ming Min-Yuan , Wu Yu-Wei 
Published: February 2025

SummaryThe subthalamic nucleus (STN) plays a critical role in modulating motor and cognitive functions within the basal ganglia, with its dysfunction being implicated in movement disorders such as Parkinson’s disease. However, the behavioral representations of individual STN neurons remain incompletely understood. Usingin vivotwo-photon calcium imaging in behaving mice, we systematically mapped the activity of single STN neurons across diverse behavioral contexts, including locomotion, licking, and reward-driven actions. Our findings reveal that STN neurons exhibit mixed selectivity, encoding multiple behaviors with distinct temporal dynamics and excitatory or inhibitory response patterns. This mixed selectivity allows the STN to robustly encode motor parameters such as locomotion speed and licking intensity while integrating contextual information from different behavioral states. Comparisons with the adjacent zona incerta (ZI) revealed distinct encoding properties: while both regions represent locomotion, STN neurons more faithfully track motor states, whereas ZI neurons exhibit prolonged calcium events with weaker movement correlations. Population-level analysis showed STN activity in a low-dimensional neural manifold, with components linked to movement velocity and licking intensity. Notably, locomotion encoding in STN was context-dependent, diverging when movements were internally generated versus reward-modulated. Together, these findings highlight the specialized yet flexible role of the STN in integrating motor and reward-related signals, supporting a framework in which STN neurons contribute to motor control through multiplexed and context-dependent encoding. This work provides new insights into the functional organization of basal ganglia circuits and has implications for understanding STN’s role in both physiological and pathological conditions.
Phylogenetic clustering of microbial communities as a biomarker for chemical pollution
Authors: Smith Thomas P. , Hope Rachel , Bell Thomas 
Published: February 2025

AbstractMicrobial communities play a critical role in ecosystem functioning and offer promising potential as bioindicators of chemical pollution in aquatic environments. Here we examine the responses of both bacterial isolates and microbial communities to a range of pollutants, focusing on the phylogenetic predictability of their responses. We found that bacterial isolates exhibited a strong phylogenetic signal in their growth responses, with closely related taxa responding similarly to chemical stress. In microbial communities, pollutants that significantly impacted isolates also reduced community diversity and growth, causing shifts in community structure toward increased phylogenetic clustering, suggesting environmental filtering. The net relatedness index (NRI) effectively captured these shifts, indicating its potential as a simple metric for monitoring pollution. Our findings highlight the predictability of microbial responses to pollution and suggest that microbial-based bioindicators, coupled with rapid sequencing technologies, could transform environmental monitoring.
Integrated Cross-Disease Atlas of Human And Mouse Astrocytes Reveals Heterogeneity and Conservation of Astrocyte Subtypes in Neurodegeneration
Authors: Lucas Tawaun A. , Novikova Gloriia , Rao Sadhna , Wang Yuanyuan , Laufer Benjamin I. , Pandey Shristi. , Webb Michelle. G. , Jorstad Nikolas. , Friedman Brad A. , Hanson Jesse E. , Kaminker Joshua S. 
Published: February 2025

AbstractAstrocytes play a pivotal role in central nervous system homeostasis and neuroinflammation. Despite advancements in single-cell analyses, the heterogeneity of reactive astrocytes in neurodegenerative diseases, particularly across species, remains understudied. Here, we present an integrated atlas of 187,000 astrocytes from mouse models of Alzheimer’s (AD) and multiple sclerosis (MS) alongside 438,000 astrocytes from AD, MS, and Parkinson’s (PD) patients. Our analysis identified four distinct mouse astrocyte clusters, including two disease-associated astrocyte (DAA) clusters, DAA1 and DAA2. DAA1 displayed reactivity resembling responses to acute stimuli, including endotoxemia, while DAA2 expressed well-known AD risk genes. In an AD model, DAA1 and DAA2 exhibited distinct spatial relationships to amyloid plaques. In humans, we identified eight distinct astrocyte clusters, encompassing homeostatic and disease-associated subtypes. Cross-species analysis linked disease-associated clusters while also highlighting divergent expression in others. Our astrocyte atlas is available through a user-friendly, searchable website:http://research-pub.gene.com/AstroAtlas/.
Associations between gut microbiota and personality traits: insights from a captive common marmoset (Callithrix jacchus) colony
Authors: Ye Huimin , Šlipogor Vedrana , Hanson Buck T. , Séneca Joana , Hausmann Bela , Herbold Craig W. , Pjevac Petra , Bugnyar Thomas , Loy Alexander 
Published: February 2025

AbstractRecent studies have suggested the link between inter-individual behavioural variation (i.e., animal personality) and gut microbiota. Non-human primates living under controlled conditions are valuable models to investigate diet-independent microbiome-host interactions. In this study, we investigated links between specific gut microbiota members and personality traits, as well as group membership, sex, age class, breeding status and relatedness of 26 captive common marmosets (Callithrix jacchus), maintained under the same diet and housing conditions. Personality was assessed using an established testing battery in repeated tests. Then, we collected a total of 225 fecal samples during the summers of 2017 and 2019 from five marmoset social groups for 16S rRNA gene amplicon sequencing. Within-individual microbiota variance was smaller than that between group members. Group members also exhibited more similar gut microbiota than individuals from different groups in each sampling year. Beta diversity of the gut microbiota was linked with personality traits, age class, sex, and breeding status, but not with genetic relatedness. We identified specific bacterial taxa associated with personality traits. In particular, members of the sulfite-reducing generaDesulfovibriowere enriched in more avoidant marmosets. Amplicon sequencing of the dissimilatory sulfite reductase genedsrBconfirmed this pattern, yet additionally revealed an unknown uncultured bacterium that was the predominant sulfite-reducing bacterium in the fecal samples and was linked to more explorative individuals. These findings highlight specific association patterns between selected microbial taxa and personality traits in captive common marmosets.ImportanceThis study provides valuable insights into the intricate relationship between gut microbiota and host personality traits, using captive common marmosets as a model. By controlling for diet and housing conditions, it probes key host factors such as personality, age, sex, and social group membership, offering a robust framework for understanding microbiome-host interactions. The discovery of specific microbial taxa associated with personality traits, particularly the enrichment of sulfite-reducing genera in more avoidant individuals, underscores the potential role of the gut microbiome in shaping or reflecting personality. These findings advance our understanding of microbiome-host dynamics and pave the way for future research on the mechanistic links between behavior and gut microbiota in other animal models and across broader ecological contexts.
Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions
Authors: Flores Jonathan A. , O’Neill Susan E. , Jarodsky Joshua M. , Reichow Steve L. 
Published: February 2025

ABSTRACTGap junctions facilitate electrical and metabolic coupling essential for tissue function. Under ischemic conditions (e.g.,heart attack or stroke), elevated intracellular calcium (Ca2+) levels uncouple these cell-to-cell communication pathways to protect healthy cells from cytotoxic signals. Using single-particle cryo-EM, we elucidate details of the Ca2+-induced gating mechanism of native connexin-46/50 (Cx46/50) gap junctions. The resolved structures reveal Ca2+binding sites within the channel pore that alter the chemical environment of the permeation pathway and induce diverse occluded and gated states through N-terminal domain remodeling. Moreover, subunit rearrangements lead to pore collapse, enabling steric blockade by the N-terminal domains, reminiscent of the “iris model” of gating proposed over four decades ago. These findings unify and expand key elements of previous gating models, providing mechanistic insights into how Ca2+signaling regulates gap junction uncoupling and broader implications for understanding cell stress responses and tissue protection.
Comorbidity analysis and clustering of endometriosis patients using electronic health records
Authors: Khan Umair , Oskotsky Tomiko T. , Yilmaz Bahar D. , Roger Jacquelyn , Gjoni Ketrin , Irwin Juan C. , Opoku-Anane Jessica , Elhadad Noémie , Giudice Linda C. , Sirota Marina 
Published: February 2025

AbstractEndometriosis is a prevalent, complex, inflammatory condition associated with a diverse range of symptoms and comorbidities. Despite its substantial burden on patients, population-level studies that explore its comorbid patterns and heterogeneity are limited. In this retrospective case-control study, we analyzed comorbidities from over forty thousand endometriosis patients across six University of California medical centers using de-identified electronic health record (EHR) data. We found hundreds of conditions significantly associated with endometriosis, including genitourinary disorders, neoplasms, and autoimmune diseases, with strong replication across datasets. Clustering analyses identified patient subpopulations with distinct comorbidity patterns, including psychiatric and autoimmune conditions. This study provides a comprehensive analysis of endometriosis comorbidities and highlights the heterogeneity within the patient population. Our findings demonstrate the utility of EHR data in uncovering clinically meaningful patterns and suggest pathways for personalized disease management and future research on biological mechanisms underlying endometriosis.
Land-use history causes differences in park nighttime cooling capacity and forest structure
Authors: Richmond Isabella C. , Paulauskas Michael A. , Padvaiskas Erica , Sinisterra Laura Carolina Gonzàlez , Hutt-Taylor Kayleigh , Robitaille Alec L. , Ziter Carly D. 
Published: February 2025

AbstractCities are temporally dynamic ecosystems that experience continuous redevelopment over time. Urban parks, which provide critical benefits to resident wellbeing, are developed on different land-use types and contain natural elements that are susceptible to the effects of historical decision making. Thus, understanding the current day functioning of our city’s ecosystems and planning for the equitable distribution of park benefits in the future requires incorporation and understanding of the impacts of historical decision-making. We measured neighbourhood socio-demographic composition, forest structure, and the cooling effect of 33 sites in parks across Montreal, each with a past land-use in one of three classes: agricultural, forested, or industrial. We asked: 1) what are the effects of historical land-use on current park forest structure, diversity, and consequently the capacity to provide cooling? 2) how do surrounding communities differ around parks of each historical land-use type, and what are the implications for equitable access to cooling? We found that forest structure and cooling capacity differed across past land-use type, and forest structure has complex relationships with park cooling capacity. Our results provide evidence of historical environmental injustice impacting current day cooling capacity for marginalized groups. Previously industrial parks had less cooling capacity at night, while simultaneously being surrounded by communities with higher proportions of immigrants, and lower median incomes than Montreal’s average. However, daytime cooling capacity was similar across past land-use type, highlighting the importance of current management decisions to provide a critical ecosystem service, temperature mitigation, regardless of a site’s history. Planting areas of small, dense forest stands with trees >= 5 cm DBH within urban parks can help augment daytime cooling benefits in the city but may hinder nighttime cooling. To provide both nighttime and daytime cooling, a mixed management strategy of park trees is required, where small and large trees are incorporated at different densities. Finally, we find evidence of gentrification surrounding all park sites, emphasizing the complex socioecological dynamics of green infrastructure and the need for community-led greening projects paired with social housing policies.
Nano-organization of synapses defines synaptic release properties at cortical neuron dendritic spines
Authors: Jafri Haani , Thomas Samantha J. , Yang Sung Hoon , Cain Rachel E. , Dalva Matthew B 
Published: February 2025

AbstractVisualization of the submicron organization of excitatory synapses has revealed an unexpectedly ordered architecture consisting of nanocolumns of synaptic proteins that group into nanomodules which scale in number as spine size increases. How these features are related to synaptic function has remained unclear. Here, using super-resolution followed by live-cell line-scan imaging, we find that the size of the smallest miniature calcium and glutamate events are the same, regardless of whether spines have one or two nanopuncta of PSD-95, and that miniature synaptic response in all spines are best fit by a three term Poisson. Two nanomodule spines exhibit more large events without a significant change in event frequency, with the number of the largest events increasing disproportionately. These data support a model where nanomodules define sites of synaptic release and where the nanoarchitecture of synaptic proteins specifies subtypes of excitatory synapses, with increasing numbers of nanomodules increasing coordinated multivesicular release.
Long-term evaluation of the association between dominance, bib size, sex and age
Authors: Silva Nicolas J. , Silva Liliana R. , D’Amelio Pietro B. , Ferreira André C. , Lucas Annick , Covas Rita , Doutrelant Claire 
Published: February 2025

AbstractIndividual-based long-term datasets are needed to investigate the relationships between drivers of labile individual traits. A case in point is dominance structures, which has been shown to vary greatly across years and populations. Using an eight-year dataset, encompassing more than 700 individuals, we studied the association between the size of a melanin-based plumage trait (a black patch under the beak or ‘bib’), individual attributes (age and sex) and dominance. Our study model, the sociable weaver (Philetairus socius), is a small passerine, which lives year-round in colonies of varying size. Bib sizes were obtained from pictures and automatically pre-processed with an object segmentation deep learning network based on YOLO. We recorded 36,346 dominance-related interactions to estimate dominance hierarchies. We then investigated the effect of sex and age on bib size, and the overall and between-year association of bib size and age with dominance for each sex. We found that bib size increased with age within individuals of both sexes. Age was a strong and consistent predictor of dominance in males, but not in females. Nevertheless, dominance was not correlated with bib size in males and not in females. Finally, these relationships did not strongly vary between years. Our results suggest that males and females may use different factors to regulate dominance interactions. Furthermore, our longitudinal dataset allowed us to show that bib size is not a badge of status under our population conditions even though its growth encodes age information, highlighting the importance of considering multiple traits over time when studying morphological signalling of hierarchy positions.
Informational Complexity as a Neural Marker of Cognitive Reserve
Authors: Stolp Laura , Mandke Kanad N , Mediano Pedro AM , Gellersen Helena M , Swartz Alex , Rudzka Katarzyna , Simons Jon , Bekinschtein Tristan A , Bor Daniel 
Published: February 2025

ABSTRACTIn Alzheimer’s disease (AD), a mismatch between neurological damage and cognitive functioning often is attributed to individual differences in cognitive reserve. Understanding the neural mechanism of cognitive reserve could help assessing the therapeutic effectiveness of interventions in AD. To address this, here, 38 elderly participants performed a sustained attention task during high-density EEG while awake and during drowsiness. Operationally, the degree to which performance was impaired under drowsiness signalled the extent of cognitive reserve, with less impairment indicating a higher level of cognitive reserve. Investigating performance variations during the active management of neural challenges offers a novel approach to studying cognitive reserve, capturing dynamics that mirror everyday cognitive demand. We related cognitive reserve to various measures, including informational complexity using the Lempel-Ziv (LZSUM) algorithm. We found a significant interaction effect between arousal and performance, where LZSUM values increased in high performers when drowsy but decreased in low performers. This effect was most pronounced in the frontal and central areas. Our findings suggest LZSUM to be indicative of a compensatory mechanism and thus show potential for LZSUM as a neural marker in assessing cognitive reserve. However, we found no consistent relationship between performance and structural brain measures, and proxies of cognitive reserve. Critically, our findings present a counterexample to the prevailing view that informational complexity purely reflects conscious level. Further research, such as a study with the same paradigm in patients with mild cognitive impairment (MCI) and AD, may lead to additional insights of whether we are truly measuring cognitive reserve.
The Evolving Landscape of Neuroscience
Authors: Senden Mario 
Published: February 2025

AbstractNeuroscience emerged as a distinct academic discipline during the 20th century and has undergone rapid expansion since then. However, a comprehensive analysis of its evolving landscape remains lacking. The present study provides a large-scale, data-driven, mapping of neuroscience research. Leveraging large language models and clustering techniques to analyze 461,316 articles published between 1999 and 2023, this study reveals the field’s structural organization and highlights dominant themes. Citation network analysis uncovers a surprisingly integrated picture and key intellectual hubs that shape the broader research landscape. An analysis of how research clusters align with pre-defined dimensions demonstrates a strong experimental focus, widespread reliance on micro theories, and a growing emphasis on applied and translational research. At the same time, fundamental research is at the risk of decline while theoretical work and cross-scale integration remain limited. This study provides a framework for understanding neuroscience’s trajectory and identifies potential avenues for strengthening the field.