bluuebunny/crossref_metadata_2025_split huggingface dataset:
The brain simulates actions and their consequences during REM sleep
Authors: Senzai Yuta , Scanziani Massimo 
Published: August 2024

AbstractVivid dreams mostly occur during a phase of sleep called REM1–5. During REM sleep, the brain’s internal representation of direction keeps shifting like that of an awake animal moving through its environment6–8. What causes these shifts, given the immobility of the sleeping animal? Here we show that the superior colliculus of the mouse, a motor command center involved in orienting movements9–15, issues motor commands during REM sleep, e.g. turn left, that are similar to those issued in the awake behaving animal. Strikingly, these motor commands, despite not being executed, shift the internal representation of direction as if the animal had turned. Thus, during REM sleep, the brain simulates actions by issuing motor commands that, while not executed, have consequences as if they had been. This study suggests that the sleeping brain, while disengaged from the external world, uses its internal model of the world to simulate interactions with it.
A method to increase the imaging efficiency of tiling light sheet microscopy using scanning non-coaxial beam arrays synchronized with regional virtual confocal slits
Authors: Gao Liang 
Published: August 2024

AbstractWe present a novel method to improve the imaging efficiency of tiling light sheet microscopy. In the method, scanning non-coaxial beam arrays synchronized with regional virtual confocal slits are used to illuminate imaging plane. There are two advantages. One is the imaging efficiency increases proportional to the number of excitation beams within the non-coaxial beam array. The other is the width of the regional virtual confocal slits could be very wide without admitting off-focus fluorescence generated by the non-coaxial beam array, which makes the method easy to adopt and very robust in practice. We describe the method in detail, characterize the method via numerical simulations. The results suggest that the imaging efficiency and feasibility of the tiling light sheet microscopy could be improved significantly without affecting the 3D imaging ability by using the method. In additions, we propose several configurations to implement the method in practice.
FusionESP: Improved enzyme-substrate pair prediction by fusing protein and chemical knowledge
Authors: Du Zhenjiao , Fu Weimin , Guo Xiaolong , Caragea Doina , Li Yonghui 
Published: August 2024

AbstractTo reduce the cost of experimental characterization of the potential substrates for enzymes, machine learning prediction model offers an alternative solution. Pretrained language models, as powerful approaches for protein and molecule representation, have been employed in the development of enzyme-substrate prediction models, achieving promising performance. In addition to continuing improvements in language models, effectively fusing encoders to handle multimodal prediction tasks is critical for further enhancing model performance using available representation methods. Here, we present FusionESP, a multimodal architecture that integrates protein and chemistry language models with a newly designed contrastive learning strategy for predicting enzyme-substrate pairs. Our best model achieved state-of-the-art performance with an accuracy of 94.77% on independent test data and exhibited better generalization capacity while requiring fewer computational resources and training data, compared to previous studies of finetuned encoder or employing more encoders. It also confirmed our hypothesis that embeddings of positive pairs are closer to each other in high-dimension space, while negative pairs exhibit the opposite trend. The proposed architecture is expected to be further applied to enhance performance in additional multimodality prediction tasks in biology. A user-friendly web server of FusionESP is established and freely accessible athttps://rqkjkgpsyu.us-east-1.awsapprunner.com/.
Comparative Analysis of Polysaccharide and Cell Wall Structure inAspergillus nidulansandAspergillus fumigatusby Solid-State NMR
Authors: Gautam Isha , Yarava Jayasubba Reddy , Xu Yifan , Li Reina , Scott Faith J. , Mentink-Vigier Frederic , Momany Michelle , Latgé Jean-Paul , Wang Tuo 
Published: August 2024

AbstractInvasive aspergillosis poses a significant threat to immunocompromised patients, leading to high mortality rates associated with these infections. Targeting the biosynthesis of cell wall carbohydrates is a promising strategy for antifungal drug development and will be advanced by a molecular-level understanding of the native structures of polysaccharides within their cellular context. Solid-state NMR spectroscopy has recently provided detailed insights into the cell wall organization ofAspergillus fumigatus, but genetic and biochemical evidence highlights species-specific differences amongAspergillusspecies. In this study, we employed a combination of13C,15N, and1H-detection solid-state NMR, supplemented by Dynamic Nuclear Polarization (DNP), to compare the structural organization of cell wall polymers and their assembly in the cell walls ofA. fumigatusandA. nidulans, both of which are key model organisms and human pathogens. The two species exhibited a similar rigid core architecture, consisting of chitin, α-glucan, and β-glucan, which contributed to comparable cell wall properties, including polymer dynamics, water retention, and supramolecular organization. However, differences were observed in the chitin, galactosaminogalactan, protein, and lipid content, as well as in the dynamics of galactomannan and the structure of the glucan matrix.
Mapping eye, arm, and reward information in frontal motor cortices using electrocorticography in non-human primates
Authors: Ouchi Tomohiro , Scholl Leo R. , Rajeswaran Pavithra , Canfield Ryan A. , Smith Lydia I. , Orsborn Amy L. 
Published: August 2024

AbstractGoal-directed reaches give rise to dynamic neural activity across the brain as we move our eyes and arms, and process outcomes. High spatiotemporal resolution mapping of multiple cortical areas will improve our understanding of how these neural computations are spatially and temporally distributed across the brain. In this study, we used micro-electrocorticography (µECoG) recordings in two male monkeys performing visually guided reaches to map information related to eye movements, arm movements, and receiving rewards over a 1.37 cm2area of frontal motor cortices (primary motor cortex, premotor cortex, frontal eye field, and dorsolateral pre-frontal cortex). Time-frequency and decoding analyses revealed that eye and arm movement information shifts across brain regions during a reach, likely reflecting shifts from planning to execution. We then used phase-based analyses to reveal potential overlaps of eye and arm information. We found that arm movement decoding performance was impacted by task-irrelevant eye movements, consistent with the presence of intermixed eye and arm information across much of motor cortices. Phase-based analyses also identified reward-related activity primarily around the principal sulcus in the pre-frontal cortex as well as near the arcuate sulcus in the premotor cortex. Our results demonstrate µECoG’s strengths for functional mapping and provide further detail on the spatial distribution of eye, arm, and reward information processing distributed across frontal cortices during reaching. These insights advance our understanding of the overlapping neural computations underlying coordinated movements and reveal opportunities to leverage these signals to enhance future brain-computer interfaces.Significance statementPicking up your coffee mug requires coordinating movements of your eyes and hand and processing the outcomes of those movements. Mapping how neural activity relates to different functions helps us understand how the brain performs these computations. Many mapping techniques have limited spatial or temporal resolution, restricting our ability to dissect computations that overlap closely in space and time. We used micro-electrocorticography recordings to map neural activity across multiple cortical areas while monkeys made goal-directed reaches. These measurements revealed high spatial and temporal resolution maps of neural activity related to eye, arm, and reward information processing. These maps reveal overlapping neural computations underlying movement and open opportunities to use eye and reward information to improve therapies to restore motor function.
Early atrial remodelling drives arrhythmia in Fabry Disease
Authors: Roy Ashwin , O’Shea Christopher , Dasi I Martinez Albert , Patel Leena , Cumberland Max , Nieves Daniel , Canagarajah Hansel , Thompson Sophie , Azad Amar , Price Anna , Hall Caitlin , Alvior Amor Mia , Rath Phalguni , Davies Ben , Rodriguez Blanca , Holmes Andrew P , Pavlovic Davor , Townend Jonathan N , Geberhiwot Tarekegn , Gehmlich Katja , Steeds Richard P 
Published: August 2024

ABSTRACTBackgroundFabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency, resulting in multi-organ accumulation of sphingolipid, namely globotriaosylceramide (Gb3). This triggers ventricular myocardial hypertrophy, fibrosis, and inflammation, driving arrhythmia and sudden death, a common cause of FD mortality. Atrial fibrillation (AF) is common in FD, yet the cellular mechanisms accounting for this are unknown. To address this, we conducted electrocardiography (ECG) analysis from a large cohort of adults with FD at varying stages of cardiomyopathy. Cellular contractile and electrophysiological function were examined in an atrial FD model, developed using gene-edited atrial cardiomyocytes and imputed intoin-silicoatrial models to provide insight into arrhythmia mechanisms.MethodsIn 115 adults with FD, ECG P-wave characteristics were compared with non-FD controls. Induced pluripotent stem cells (iPSCs) were genome-edited using CRISPR-Cas9 to introduce theGLAp.N215Svariant and differentiated into atrial cardiomyocytes (iPSC-CMs). Contraction, calcium handling and electrophysiology experiments were conducted to explore proarrhythmic mechanisms. A bi-atrialin-silicomodel was developed with the cellular changes induced byGLAp.N215SiPSC-CMs.ResultsECG analysis demonstrated P-wave duration and PQ interval shortening in FD adults before onset of cardiomyopathy on imaging and biochemical criteria. FD patients exhibited a higher incidence of premature atrial contractions and increased risk of developing AF. In our cellular model,GLAp.N215SiPSC-CMs were deficient in α-Gal A and exhibited Gb3 accumulation. AtrialGLAp.N215SiPSC-CMs demonstrated a more positive diastolic membrane potential, faster action potential upstroke velocity, greater burden of delayed afterdepolarizations, greater contraction force, slower beat rate and dysfunction in calcium handling compared to wildtype iPSC-CMs. Inputting these changes into thein-silicomodel resulted in similar P-wave morphology changes to those seen in early FD cardiomyopathy and increased the action potential duration (APD) restitution slope, causing APD alternans and inducing AF.ConclusionsThese findings enhance our understanding of atrial myopathy in FD by providing novel insights into underpinning mechanisms for atrial arrhythmia and a rationale for early P-wave changes. These may be targeted in future research to develop therapeutic strategies to reduce the arrhythmic burden in FD and other atrial cardiomyopathies.
Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis
Authors: Promila Lakra , Sarkar Kabita , Guleria Shivika , Rathore Manisha , Singh Nishakumari C , Khan Shazia , Tomar Manendra Singh , Ammanathan Veena , Barthwal Manoj Kumar , Kumaravelu Jagavelu , Shrivastava Ashutosh , Mitra Kalyan , Guha Rajdeep , Aggarwal Amita , Lahiri Amit 
Published: August 2024

AbstractRheumatoid arthritis (RA) is characterized by the aggressive migration and invasion of fibroblast-like synoviocytes (FLS) into cartilage and bone, a process that is significantly influenced by mitochondrial calcium uptake. This study highlights the critical role of mitochondrial calcium uniporter (MCU) in regulating FLS migration and mitochondrial dynamics, and its potential as a therapeutic target in RA. Notably, RA-FLS exhibited increased MCU expression and mitochondrial dysfunction compared to controls. Treatment with Ru360, a potent MCU inhibitor significantly reduced RA-FLS migration, calcium influx, and mitochondrial reactive oxygen species (ROS) levels, while restoring mitochondrial morphology and enhancing ATP production. Further analysis of MCU complex expression revealed elevated levels of MCU and other regulatory subunits (EMRE, MICU1, MICU2) in RA-FLS compared to controls, indicating mitochondrial dysfunction in RA. Mechanistically, MCU inhibition altered gene expression related to cytoskeletal dynamics, focal adhesion, and metabolic pathways. In human RA-FLS, MCU inhibition suppressed migration and invasion both in vitro and in vivo. The interaction between MCU and Miro1, essential for mitochondrial transport, was validated, and its disruption impaired FLS migration. Our findings highlight MCU as a promising therapeutic target to inhibit FLS migration and ameliorate RA progression.
Behavior- and circuit-specific cortico-striatal decoupling during the early development of Parkinson’s disease-like syndrome
Authors: Yao Xu-Ran , Liu Yang , Zheng Wei-Tong , He Kai-Wen 
Published: August 2024

ABSTRACTDespite that cortico-striatal decoupling has been widely reported in individuals diagnosed with Parkinson’s Disease (PD), its onset, circuit specificity and underlying mechanism remain largely unclear. To investigate these questions, dual fiber photometry is established for the first time to evaluate cortico-striatal coupling during varied motor behaviors, whose cell-type resolution was provided by the usage of Cre transgenic mouse lines. Contralateral turning, digging and licking show distinct coupling patterns, among which digging induces the strongest coupling. Striatal D1R-expressed medium spiny neurons (dMSNs) and D2R-expressed MSNs (iMSNs) similarly contribute to the cortical-striatal coupling during turning and licking but not digging, with much tighter coupling between the dMSNs and the M1 cortex. In PD-like mouse model induced via intra-striatal injection of synthetic mouse wildtype α-synuclein preformed fibril (PFF), digging-associated cortical-striatal decoupling emerges as early as 1-month post induction (Mpi), which becomes significant since 2 Mpi and correlates with later-onset behavioral deficit. Notably, impaired dMSNs but not iMSNs mediate this decoupling, which can be rescued by activation of D1 but not D2 receptor. Mechanistically, we found an inverted U-shape decline in striatal dopamine level along the disease development in PFF-injected mice. Supplement with L-DOPA alleviates the decoupling and motor deficit, suggesting that early dopamine deficiency directly contributes to the cortical-striatal decoupling and the associated motor deficit. These findings provide new insights into the temporal profile and mechanisms underlying the PD-associated cortico-striatal decoupling, which has been implicated as functional biomarker for early diagnosis of PD.
Chronic and Acute Mediators of Passive Viscoelasticity in Human Skeletal Muscle Fibers
Authors: Privett Grace E. , Ricci Austin W. , Needham Karen Wiedenfeld , Callahan Damien M. 
Published: August 2024

AbstractCellular viscoelastic modulus in skeletal muscle tissue responds dynamically to chronic stressors, such as age and exercise. Passive tissue mechanics may also be sensitive to acute stimuli such as mechanical loading and/or activation-induced muscle fatigue. These insights are largely derived from preclinical studies of age and acute muscle activation. Therefore, we sought to understand the relative responsiveness of muscle cellular passive mechanics to chronic (resistance training) and acute (muscle fatigue) stressors in healthy young males and females categorized as “resistance trained” or “untrained”. We measured passive mechanics to test the hypothesis that Young’s Modulus and stress would be greater in fibers from trained versus untrained participants and both would be reduced following fatigue. We further assessed the translation of these findings to composite tissue in a sub-set of volunteers where muscle tissue bundles, containing both fibers and extracellular matrix, were analyzed in addition to single fibers. We report a main effect of training such that cellular passive mechanical measures were increased in single fibers from trained versus untrained participants. We likewise report reductions in passive mechanical measures following fatiguing exercise. Surprisingly, both training and acute fatigue only impacted muscle fiber passive measures in males, whereas females showed a more variable response across conditions. Last, we provide preliminary evidence supporting the translation of per-individual cellular differences to the tissue level. Together, these data suggest males respond more dynamically to acute and chronic stressors of muscle tissue mechanics, potentially linking cellular response and sex-dependent differences in musculotendinous injury risk.New and noteworthyWe report that passive stress and modulus in single muscle fibers was higher in resistance trained healthy adults and fatiguing exercise reduced passive stress and modulus. In each case, dynamic responsiveness of muscle fibers to chronic and acute stressors was observed consistently in males, whereas responses in females varied considerably. We provide further evidence that cellular mechanisms may contribute to multicellular muscle tissue samples, suggesting these findings have relevance to in vivo tissue mechanics.
Anomalies in regional and chronological distributions of Omicron BA.1.1 lineage in the United States
Authors: Kakeya Hideki 
Published: August 2024

AbstractThis study compares the collection dates and locations of the Omicron BA.1 lineage and other major SARS-CoV- 2 mutants registered in NCBI GenBank and provides a detailed analysis of the emergence patterns of pure reverse mutants, which contain only reverse mutations and no other mutations in the surface glycoprotein. The results indicate that Omicron BA.1.1 and its pure reverse mutants were widely distributed throughout the United States from the early days of their emergence, showing a statistically significant difference compared to other major variants, which spread from a small number of sources. The peak emergence of BA.1.1 and BA.1.1.18 pure reverse mutants occurred a few weeks before the peak of all collected samples, whereas the peak of pure reverse mutants in major BA.1 variants and BA.2 coincides with the overall sampling peak. Although the peaks of BA.1.x collections are not all synchronous, the peaks of pure reverse mutants in the BA.1 lineage completely overlap, with the number of such mutants declining abruptly after the peak. These regional and temporal anomalies in the Omicron BA.1 lineage, especially in the BA.1.1 lineage, are virtually impossible to explain by current theories of natural mutation and spread by human-to-human infection.
Optogenetic quantification of source sink relationship in intact hearts to explain cardiac arrhythmia initiation and protection
Authors: Langen Judith S. , Boyle Patrick M. , Malan Daniela , Sasse Philipp 
Published: August 2024

AbstractIncreased cardiac excitability and reduced electrical coupling promote cardiac arrhythmia and can be quantified by input resistance (Rm), pacing threshold (Ithr), and cardiac length constant (λ). However, measurement of these parameters in the heart was not feasible, because the required homogenous current injection cannot be performed with electrical stimulation. Here, we overcame this problem by optogenetic current injection into all illuminated cardiomyocytes of mouse hearts in different action potential phases. Precisely triggered and patterned illumination enabled measuring Rmand λ, which both were smallest at diastole and larger during plateau and repolarization. Pharmacological and depolarization-induced reduction of inward rectifying K+currents (IK1), gap junction block and cardiac infarction reduced Ithrshowing the importance of high IK1density and intact cardiomyocyte coupling for preventing arrhythmia initiation. Simulations in a calibrated cardiomyocyte model were used to classify pro- and anti-arrhythmic mechanisms based on their effects on Rmand Ithr. Finally, combining experiments with simulations allowed for quantification of IK1inward rectification in the intact heart, identifying strong rectification as a new pro-arrhythmic concept.
Genomic analyses identify 15 susceptibility loci and revealHDAC2,SOX2-OT, andIGF2BP2in a naturally-occurring canine model of gastric cancer
Authors: Cook Shawna R. , Hugen Sanne , Hayward Jessica J. , Famula Thomas R. , Belanger Janelle M. , McNiel Elizabeth , Fieten Hille , Oberbauer Anita M. , Leegwater Peter A.J. , Ostrander Elaine A. , Mandigers Paul J.J. , Evans Jacquelyn M. 
Published: August 2024

SUMMARYGastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for theEPAS1(HIF2A) andPTENgenes and a coding variant inCD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois atSOX2-OTandIGF2BP2. Among Tervuren and Sheepdogs,HDAC2putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such asPDZRN3, that have not been associated with human GC.
S-RNase Evolution in Self-Incompatibility: Phylogenomic Insights into Synteny with S-Like Genes
Authors: Liu Yunxiao , Zhang Yangxin , Han Songxue , Guo Bocheng , Liang Jiakai , Yu Ze , Yang Fan , Sun Yaqiang , Xue Jiayu , Lin Zongcheng , Schranz M. Eric , Guan Changfei , Ma Fengwang , Zhao Tao 
Published: August 2024

AbstractS-RNases are essential in the gametophytic self-incompatibility (GSI) system of many flowering plants, where they act as stylar-S determinants. Despite their significance, the syntenic genomic origin and evolutionary trajectory of S-RNase genes in eudicots have remained largely unclear. Here, we performed large-scale phylogenetic and microsynteny network analyses of RNase T2 genes across 130 angiosperm genomes, encompassing 35 orders and 56 families. Based on the connections observed in the synteny network, particularly the persisting synteny block in none-SI Cucurbitaceae species, we infer that well-characterized S-RNase genes (Class III-A RNase genes) were duplicated and evolved from Class I S-like RNase genes, possibly as a result of the gamma triplication event shared by core eudicots. Additionally, we identified frequent lineage-specific gene transpositions of S-RNase genes across diverse angiosperm lineages, including Rosaceae, Solanaceae, and Rutaceae families, accompanied by a significant increase in transposable element (TE) activity near these genes. Our findings delineate the precise genomic origin and evolutionary path of eudicot S-RNase genes, enhancing our understanding of the evolution of the S-RNase-based GSI system.