bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic, phenotypic and environmental correlates of speciation in the midwife toads (Alytes)
Authors: Ambu Johanna , Litvinchuk Spartak N , Caballero-Díaz Carlos , Nicieza Alfredo , Velo-Antón Guillermo , Gonçalves Helena , Martínez-Freiría Fernando , Martínez-Gil Helena , Beltrán Juan Francisco , Donaire-Barroso David , Hernandez Axel , Suchan Tomasz , Crochet Pierre-André , Martínez-Solano ĺñigo , Dufresnes Christophe 
Published: October 2024

AbstractSpeciation, i.e., the formation of new species, implies that diverging populations evolve genetic and phenotypic factors that promote reproductive isolation (RI), but the adaptive vs. neutral origin of these factors and their relative contributions across the speciation continuum remain elusive. Here we test which of genomic, bioacoustic, morphological and environmental differentiation best predicts RI across the midwife toads (genusAlytes), a diversification of Mediterranean amphibians. Hybrid zone analyses in theA. obstetricanscomplex support that without strong geographic barriers to dispersal, the extent of introgression (which should reflect the strength of RI) covaries with genomic divergence irrespective of other factors. Phenotypic divergence become important later along the continuum, namely between non-admixing species attributed to distinct subgenera. Our results suggest that by putatively causing intrinsic incompatibilities in hybrids, the genetic mutations accumulating randomly between allopatric populations act as the initial trigger of RI, while substantial ecological and behavioral differentiation is a long-term consequence of species divergence that ultimately promotes sympatry. Whereas speciation is usually claimed to be primarily adaptive, our study corroborates recent findings that new species may also be a neutral outcome of gradual phylogeographic divergence, which has practical implications for species delimitation.
Deciphering the RNA recognition by Musashi-1 to design protein and RNA mutants for in vitro and in vivo applications
Authors: Pérez-Ràfols Anna , Pérez-Ropero Guillermo , Cerofolini Linda , Sperotto Luca , Roca-Martínez Joel , Anahí Higuera-Rodríguez Rosa , Russomanno Pasquale , Kaiser Wolfgang , Vranken Wim , Danielson Helena , Provenzani Alessandro , Martelli Tommaso , Sattler Michael , Buijs Jos , Fragai Marco 
Published: October 2024

AbstractRNA Recognition Motifs (RRMs) are essential post-transcriptional regulators of gene expression in eukaryotic cells. The Human Musashi-1 (MSI-1) is an RNA-binding protein that recognizes (G/A)U1-3AGU and UAG sequences in diverse RNAs through two RRMs and regulates the fate of target RNA.Here, we combined structural biology and computational approaches to analyse the binding of the RRM domains of human MSI-1 with single-stranded and structured RNAs ligands. We used our recently developed computational tool RRMScorer to design a set of mutants of the MSI-1 protein to bind novel RNA sequences to alter the binding selectivity. Thein-silicopredictions of the designed protein-RNA interactions are assessed by NMR and SPR. These experiments also are used to study the competition of the two RRM domains of MSI-1 for the same binding site within linear and harpin RNA. Our experimental results confirm thein-silicodesigned interactions, thus opening the way for the development of new biomolecules for in vitro and in vivo studies and downstream applications.
Calcium homeostatic feedback control predicts atrial fibrillation initiation, remodeling, and progression
Authors: Moise Nicolae , Weinberg Seth H. 
Published: October 2024

AbstractAtrial fibrillation (AF) is a progressive disorder, with arrhythmia episodes becoming increasingly longer and ultimately permanent. The chaotic electrical activity by itself is well-known to drive progression, a process classically summarized as “AF begets AF.” However, the mechanisms underlying this progression are not yet well defined. We hypothesize that calcium homeostatic feedback regulating ion channel expression is a critical mechanistic component of this pathological process. We propose a modeling framework that tracks both short-term beat-to-beat electrical and calcium activity and long-term tissue substrate remodeling as a single coupled dynamical system. Importantly, the full AF progression from healthy to pathological remodeled tissue is reproduced, in contrast with prior studies that consider “snapshots” of various AF stages. Simulations predict that single cells respond to fast pacing by maintaining intracellular calcium concentrations through dynamic ion channel expression and electrical phenotype changes. In two-dimensional (2D) homogeneous tissue, spontaneous spiral waves stabilize into permanent re-entry. In 2D heterogeneous tissue, we observe the initiation of re-entrant activity in response to fast pacing, followed by increasingly longer intermittent, and then permanent, arrhythmic activity. Simulations predict critical properties of re-entrant wave locations, leading to a novel hypothesis: spiral wave activity itself drives underlying substrate remodeling and the emergence of remodeled tissue “niches” that support the stabilization of fast re-entrant activity. Thus, the model joins multiple lines of inquiry (i.e., long-term calcium regulation, ion channel co-expression and remodeling, and tissue-scale arrhythmia spatiotemporal organization) into a single coherent framework, and for the first time, captures the dynamics of the long-term natural history of AF.
A new discrete-geometry approach for integrative docking of proteins using chemical crosslinks
Authors: Zhang Yichi , Jindal Muskaan , Viswanath Shruthi , Sitharam Meera 
Published: October 2024

AbstractThe structures of protein complexes allow us to understand and modulate the biological functions of the proteins. Integrative docking is a computational method to obtain the structures of a protein complex, given the atomic structures of the constituent proteins along with other experimental data on the complex, such as chemical crosslinks or SAXS profiles. Here, we develop a new discrete geometry-based method, wall-EASAL, for integrative rigid docking of protein pairs given the structures of the constituent proteins and chemical crosslinks. The method is an adaptation of EASAL (Efficient Atlasing and Search of Assembly Landscapes), a state-of-the-art discrete geometry method for efficient and exhaustive sampling of macromolecular configurations under pairwise inter-molecular distance constraints. We provide a mathematical proof that the method finds a structure satisfying the crosslink constraints under a natural condition satisfied by energy landscapes. We compare wall-EASAL with IMP (Integrative Modeling Platform), a commonly used integrative modeling method, on a benchmark, varying the numbers, types, and sources of input crosslinks, and sources of monomer structures. The wall-EASAL method performs better than IMP in terms of the average satisfaction of the configurations to the input crosslinks and the average similarity of the configurations to their corresponding native structures. The ensembles from IMP exhibit greater variability in these two measures. Further, wall-EASAL is more efficient than IMP. Although the current study uses crosslinks, the method is general and any source of distance constraints can be used for integrative docking with wall-EASAL. However, the current implementation only supports binary rigid protein docking,i.e., assumes that the monomer structures are known and remain rigid. Additionally, the current implementation is deterministic,i.e., it does not account for uncertainties in the crosslinking data beyond using distance bounds. Neither of these appears to be a theoretical or algorithmic limitation of the EASAL methodology. Structures from wall-EASAL can be incorporated in methods for modeling large macromolecular assemblies, for example by suggesting rigid bodies or restraints for use in these methods. This will facilitate the characterization of assemblies and cellular neighborhoods at increased efficiency, accuracy, and precision. The wall-EASAL method is available athttps://bitbucket.org/geoplexity/easal-dev/src/Crosslinkand the benchmark is available athttps://github.com/isblab/Integrative_docking_benchmark.
DeepRNA-Twist : Language Model guided RNA Torsion Angle Prediction with Attention-Inception Network
Authors: Abir Abrar Rahman , Tahmid Md Toki , Rayan Rafiqul Islam , Rahman M Saifur 
Published: October 2024

AbstractRNA torsion and pseudo-torsion angles are critical in determining the three-dimensional conformation of RNA molecules, which in turn governs their biological functions. However, current methods are limited by RNA’s structural complexity and flexibility, as it can adopt multiple conformations, with experimental techniques being costly and computational approaches struggling to capture the intricate sequence dependencies needed for accurate predictions. To address these challenges, we introduce DeepRNA-Twist, a novel deep learning framework designed to predict RNA torsion and pseudo-torsion angles directly from sequence. DeepRNA-Twist utilizes RNA language model embeddings, which provides rich, context-aware feature representations of RNA sequences. Additionally, it introduces 2A3IDC module (AttentionAugmentedInceptionInsideInception withDilatedCNN), combining inception networks with dilated convolutions and multi-head attention mechanism. The dilated convolutions capture long-range dependencies in the sequence without requiring a large number of parameters, while the multi-head attention mechanism enhances the model’s ability to focus on both local and global structural features simultaneously. DeepRNA-Twist was rigorously evaluated on benchmark datasets, including RNA-Puzzles, CASP-RNA, and SPOT-RNA-1D, and demonstrated significant improvements over existing methods, achieving state-of-the-art accuracy. Source code is available athttps://github.com/abrarrahmanabir/DeepRNA-Twist
Altered systemic bioenergetic reserve in chronic kidney disease predisposes hearts to worse functional outcomes
Authors: Young Megan , Aastrup Malene , Patel Nikayla , Cullen Fenn , Hansen Esben S.S. , Clark James E. , Eykyn Thomas R. , Vaeggemose Michael , Vujic Ana , Karatzia Loucia , Valkovič Ladislav , Miller Jack J.J.J. , Buus Niels H. , Laustsen Christoffer , Yaqoob Magdi M. , Aksentijevic Dunja 
Published: October 2024

AbstractChronic kidney disease (CKD) is the tenth biggest killer worldwide and is projected to be the fifth leading cause of mortality by 2040. CKD is an inherently systemic disease with progressive deterioration of kidney, muscle, and liver function creating a vicious cycle of comorbidity. However, whether systemic energetic deficiency in CKD contributes to cardiac dysfunction of the uraemic cardiomyopathy remains unknown. Using two pre-clinical renal failure models of different aetiology in rats (4-week 0.75% adenine diet and 12-week post-partial nephrectomy) we investigated both cardiac and systemic metabolic remodelling in CKD. In addition to significant uraemia, anaemia and alterations in exogenous plasma substrate homeostasis, non-targeted1H NMR spectroscopy metabolomic profiling of peripheral tissues (skeletal muscle, liver, kidneys) revealed extensive metabolic alterations and changes in bioenergetic reserve in both experimental CKD models. Similarly,31P magnetic resonance spectroscopy assessment of the exercising lower leg muscle of CKD human patients identified systemic bioenergetic deficiency. During exercise CKD patients were unable to utilise the energetic capacity to the same extent as healthy controls. Both experimental CKD models developed mild cardiac dysfunction, however metabolic remodelling was less severe than that of systemic organs. Upon challenge with 25-minute total global ischemia, CKD hearts from both experimental models had poorer functional outcome. Thus, in CKD perturbation of systemic metabolism precedes and exceeds severity of cardiac metabolic changes. Prevention of systemic metabolic derangement in CKD may be a new therapeutic approach to improve cardiac functional outcomes in CKD.One Sentence SummaryPerturbations of systemic metabolism precede and exceed severity of cardiac metabolic changes in chronic kidney disease.
The metabolic costs of meiotic drive
Authors: Bradshaw Sasha L , Rodriguez Enrique , Wang Hanting , Yu Cyn Thea , De La Noue Cyril De Villiers , Hafezjee Aadil , Pomiankowski Andrew , Camus M. Florencia 
Published: October 2024

AbstractSelfish genetic elements, such as meiotic drive genes, disrupt Mendel’s law of equal segregation by biasing their own transmission, often at a detriment to the rest of the genome. The Malaysian stalk-eyed fly (Teleopsis dalmanni)sex-ratio (SR) meiotic drive system is located within a series of large inversions on the X chromosome subject to low recombination and is associated with deleterious effects on fitness. Here we examine the metabolic effects of meiotic drive across male and female stalk-eyed flies. High-resolution O2k respirometry coupled with whole-organism respirometry were used to obtain mitochondrial function and metabolic rates. Complimentary assays on food consumption established downstream effects of metabolism on nutrient acquisition. The experiments demonstrate that individuals with SR meiotic drive elements have impaired mitochondrial function and reduced capacity for ATP synthesis, as shown by a lower respiratory control ratio and weaker contribution of Complex I to respiration. Drive individuals also exhibited an increased basal metabolic rate and consumed a greater amount of food than wild-type individuals. These findings show that the drive genotype imposes metabolic costs in both male and female hosts. The disruption in mitochondrial function likely leads to compensation via an increase in both basal metabolic rate and nutrient acquisition. A potential cause lies in the accumulation of deleterious mutations in the inversions on the X chromosome that house the meiotic drive, which are subject to weak natural selection. In females, the drive chromosome has a dominant effect, with a single copy causing substantial metabolic compromise. There was little evidence of male-specific metabolic costs, nor evidence of an accumulation of sexually antagonistic effects of drive chromosomes on female metabolism. These results suggest that direct metabolic costs from meiotic drive on spermatogenesis and from sexually antagonistic selection are relatively weak. This research provides new insight into the interplay between meiotic drive and metabolism, drawing attention to the broader physiological repercussions selfish genetic elements may have on their hosts.
RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress
Authors: Jernigan Janna E. , Staley Hannah A. , Baty Zachary , Bolen MacKenzie L. , Gomes Beatriz Nuñes , Holt Jenny , Cole Cassandra L. , Neighbarger Noelle K. , Dheeravath Kruthika , Merchak Andrea R. , Menees Kelly B. , Coombes Stephen A. , Tansey Malú Gámez 
Published: October 2024

AbstractRegulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson’s Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether CSF-resident peripheral immune cells in individuals with PD also exhibit decreased levels of RGS10. Therefore, we performed an analysis of RGS10 levels in the proteomic database of the CSF from the Michael J. Fox Foundation Parkinson’s Progression Markers Initiative (PPMI) study. We found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. Moreover, we find that RGS10 levels decrease with age but not PD progression and that males have less RGS10 than females in PD. Importantly, studies have established an association between chronic systemic inflammation (CSI) and neurodegenerative diseases, such as PD, and known sources of CSI have been identified as risk factors for developing PD; however, the role of peripheral immune cell dysregulation in this process has been underexplored. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to CSI prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated peripheral immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.
Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting
Authors: Ponte Michael E. , Prom John C. , Newcomb Mallory A. , Jordan Annabelle B. , Comfort Lucas L. , Hu Jiayin , Puchalska Patrycja , Geisler Caroline E. , Hayes Matthew R. , Morris E. Matthew 
Published: October 2024

AbstractObjectiveThe capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within-meal food intake inhibition is impaired in human subjects with obesity and obese pre-clinical models. Previously, we have shown decreased hepatic mitochondrial energy metabolism (i.e., oxidative metabolism & ADP-dependent respiration) in male liver-specific, heterozygous PGC1a mice results in increased short-term diet-induced weight gain with increased within meal food intake. Herein, we tested the hypothesis that decreased liver mitochondrial energy metabolism impairs meal termination following nutrient oral pre-loads.MethodsLiver mitochondrial respiratory response to changes in ΔGATPand adenine nucleotide concentration following fasting were examined in male liver-specific, heterozygous PGC1a mice. Further, food intake and feeding behavior during basal conditions, following nutrient oral pre-loads, and following fasting were investigated.ResultsWe observed male liver-specific, heterozygous PGC1a mice have reduced mitochondrial response to changes in ΔGATPand tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake.ConclusionThese data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.
Gene-Excessive Sleepiness Interactions Suggest Treatment Targets for Obstructive Sleep Apnea Subtype
Authors: Nagarajan Pavithra , Kurniansyah Nuzulul , Lee Jiwon , Gharib Sina A. , Xu Yushan , Zhang Yiyan , Spitzer Brian , Faquih Tariq , Zhou Hufeng , Boerwinkle Eric , Chen Han , Gottlieb Daniel J. , Guo Xiuqing , Heard-Costa Nancy L. , Hidalgo Bertha A. , Levy Daniel , Liu Peter Y. , Mei Hao , Montalvan Rebecca , Mukherjee Sutapa , North Kari E. , O’Conner George T. , Palmer Lyle J. , Patel Sanjay R. , Psaty Bruce M. , Purcell Shaun M. , Raffield Laura M. , Rich Stephen S. , Rotter Jerome I. , Saxena Richa , Smith Albert V , Stone Katie L. , Zhu Xiaofeng ,   TOPMed Sleep Trait WG, Cade Brian E. , Sofer Tamar , Redline Susan , Wang Heming 
Published: October 2024

ABSTRACTObstructive sleep apnea (OSA) is a multifactorial sleep disorder characterized by a strong genetic basis. Excessive daytime sleepiness (EDS) is a symptom that is reported by a subset of OSA patients, persisting even after treatment with continuous positive airway pressure (CPAP). It is recognized as a clinical subtype underlying OSA carrying alarming heightened cardiovascular risk. Thus, conceptualizing EDS as an exposure variable, we sought to investigate EDS’s influence on genetic variation linked to apnea-hypopnea index (AHI), a diagnostic measure of OSA severity. This study serves as the first large-scale genome-wide gene x environment interaction analysis for AHI, investigating the interplay between its genetic markers and EDS across and within specific sex. Our work pools together whole genome sequencing data from seven cohorts, enabling a diverse dataset (four population backgrounds) of over 11,500 samples. Among the total 16 discovered genetic targets with interaction evidence with EDS, eight are previously unreported for OSA, includingCCDC3,MARCHF1, andMED31identified in all sexes;TMEM26,CPSF4L, andPI4K2Bidentified in males; andRAP1GAPandYY1identified in females. We discuss connections to insulin resistance, thiamine deficiency, and resveratrol use that may be worthy of therapeutic consideration for excessively sleepy OSA patients.
Sequence-based TCR-Peptide Representations Using Cross-Epitope Contrastive Fine-tuning of Protein Language Models
Authors: Im Chiho , Zhao Ryan , Boyd Scott D. , Kundaje Anshul 
Published: October 2024

AbstractUnderstanding T-Cell receptor (TCR) and epitope interactions is critical for advancing our knowledge of the human immune system. Traditional approaches that use sequence similarity or structure data often struggle to scale and generalize across diverse TCR/epitope interactions. To address these limitations, we introduce ImmuneCLIP, a contrastive fine-tuning method that leverages pre-trained protein language models to align TCR and epitope embeddings in a shared latent space. ImmuneCLIP is evaluated on epitope ranking and binding prediction tasks, where it consistently outperforms sequence-similarity based methods and existing deep learning models. Furthermore, ImmuneCLIP shows strong generalization capabilities even with limited training data, highlighting its potential for studying diverse immune interactions and uncovering patterns that improve our understanding of human immune recognition systems.
Single-molecule analysis reveals the mechanism of chromatin ubiquitylation by variant PRC1 complexes
Authors: Teslenko Alexandra , Fierz Beat 
Published: October 2024

AbstractChromatin regulation relies on ‘writer’ enzymes that add post-translational modifications (PTMs) to histone proteins. Variant Polycomb repressive complex 1 (PRC1) exists as several subtypes, which are key ‘writers’ of ubiquitylation on histone H2A lysine 119 (H2AK119ub), crucial for transcriptional repression during development and cell identity determination. The mechanism by which dynamic chromatin exploration by varia nt PRC1 complexes is coupled to ubiquitin writing is unknown. Here, we developed a single-molecule approach to directly observe chromatin interactions and ubiquitylation by PRC1. We find that variant PRC1 transiently samples chromatin until reaching a catalytically competent nucleosome-bound state, resulting in E2 recruitment and ubiquitin transfer. Variant PRC1 is weakly processive in ubiquitylating neighboring nucleosomes. Moreover, activity differences between PRC1 subtypes, containing either a PCGF1 or PCGF4 subunit, result from distinct probabilities of achieving a catalytically competent state. Our results thus demonstrate that the dynamic formation of an active complex between variant PRC1, E2 and chromatin is the critical determinant of subtype-specific variant PRC1 activity.