bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative chromatin protein dynamics during replication origin firing in human cells
Authors: Gadi Sampath Amitash , Hendriks Ivo Alexander , Nielsen Christian Friberg , Popova Petya , Hickson Ian D. , Nielsen Michael Lund , Toledo Luis 
Published: April 2024

AbstractAccurate genome duplication requires a tightly regulated DNA replication program, which relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyse protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronised wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3,269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.
Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes
Authors: Nelson Victoria L. , Eadie Ashley L. , Madhu Malav , Platt Mathew , Mercer Angella , Pulinilkunnil Thomas , Kienesberger Petra , Simpson Jeremy A. , Brunt Keith R. 
Published: April 2024

AbstractMyocardial infarction and reperfusion is a complex injury consisting of many distinct molecular stress patterns that influence cardiomyocyte survival and adaptation. Cell signalling that is essential to cardiac development also presents potential disease-modifying opportunities to recover and limit myocardial injury or maladaptive remodelling. Here we hypothesized that Yap signalling could be sensitive to one or more molecular stress patterns associated with early acute ischemia. Yap, not Taz, patterns of expression differ in post-myocardial infarct compared to peri-infarct tissue suggesting cell-specificity that would be challenging to resolve for causation in vivo. Using H9c2 ventricular myotubes in vitro as a model, Yap levels were most sensitive to nutrient deprivation compared to other stress patterns typified by ischemia within the first hour of stress. Moreover, this is mediated by amino acid availability, dominantly L-isoleucine, and influences the expression of Ctgf—a major determinant of myocardial adaptation after injury. These findings present novel opportunities for future therapeutic development and risk assessment for myocardial injury and adaptation.
Bayesian estimation of trunk-leg coordination during walking using phase oscillator models
Authors: Furukawa Haruma , Arai Takahiro , Funato Tetsuro , Aoi Shinya , Aoyagi Toshio 
Published: April 2024

ABSTRACTIn human walking, the legs and other body parts coordinate to produce a rhythm with appropriate phase relationships. From the point of view for rehabilitating gait disorders, such as Parkinson Disorders, it is important to understand the control mechanism of the gait rhythm. A previous study showed that the antiphase relationship of the two legs during walking is not strictly controlled using the reduction of the motion of the legs during walking to coupled phase oscillators. However, the control mechanisms other than those of the legs remains unknown. In particular, the trunk moves in tandem with the legs and must play an important role in stabilizing walking because it is above the legs and accounts for more than half of the mass of the human body. This study aims to uncover the control mechanism of the leg-trunk coordination in the sagittal plane using the coupled phase oscillators model and Bayesian estimation. We demonstrate that the leg-trunk coordination is not strictly controlled, as well as the interleg coordination.
Systematic identification of exercise-induced anti-aging processes involving intron retention
Authors: Kodama Hayata , Ijima Hirotaka , Matsui Yusuke 
Published: April 2024

AbstractExercise is one of the most promising anti-aging interventions for maintaining skeletal muscle health in older adults. Nine “Aging Hallmarks”, proposed by López-Otín, offer insights into the aging process; however, the link between these hallmarks and exercise is not fully elucidated. In this study, we conducted a systematic multi-omics analysis of skeletal muscles, focusing on aging and exercise, based on gene signatures for aging hallmarks. It is posited that mRNA splicing activity, linked to genomic instability, constitutes a fundamental hallmark of aging, and it exhibits divergent expression patterns in response to aging and exercise. Additionally, we analysed splicing events and discovered that intron retention (IR) is significantly impacted by aging, exhibiting contrasting changes to those induced by resistance training in the older cohort. The isoforms characterised by IR are notably enriched in mitochondrial functions. Conclusively, our results underscore the significance of splicing mechanisms as a novel aspect of aging hallmarks in skeletal muscles and propose a new mechanism by which exercise exerts its anti-aging effects on skeletal muscles through intron retention.Key points summarySkeletal muscle aging involves significant structural and functional changes, including loss of muscle mass, decline in strength, and mitochondrial dysfunction, all influenced by genomic instability.Exercise has been identified as a key intervention that counters genomic instability and modulates mRNA splicing patterns, particularly through the regulation of Intron Retention, to mitigate aging effects in skeletal muscle.We reveal the novel role of IR, especially in principal isoforms, where it is linked to critical cellular processes like mitochondrial function, suggesting a targeted pathway through which exercise exerts its anti-aging effects.The findings provide new insights into the molecular mechanisms underlying the beneficial effects of exercise on aging skeletal muscle.This study lays the groundwork for future research on exercise-induced modulation of mRNA splicing as a therapeutic strategy for aging and potentially age-related diseases, pointing towards a significant shift in how we approach aging intervention strategies.
SCREP: Towards Single-Cell Drug Response Prediction by Pharmacogenomic Embedding Enhanced Meta-Pretraining and Few-Shot Transfer Learning
Authors: Ge Shuang , Sun Shuqing , Ren Yiming , Xu Huan , Cheng Qiang , Ren Zhixiang 
Published: April 2024

AbstractObjectiveSingle-cell pharmacogenomic data is crucial for identifying biomarkers and understanding resistance mechanisms. However, the limited availability of those data poses significant challenges for efficient pre-training and thus hinders the generalization capability of the model. This paper aims to develop an efficient predictive model for single-cell drug response inference by leveraging knowledge from a bulk dataset.MethodsTo translate knowledge from bulk cell lines to single-cell analysis, this paper proposes a meta-pretraining and few-shot transfer learning frame-work based on pharmacogenomic embeddings. To enhance feature representation and alignment, genomic information is processed by a position-based feature extraction network to extract contextual features. Simultaneously, a graph-aware Transformer is developed to capture interatomic relations for drug information representation. Underlying this framework, key drug action pathways can be identified at the cellular level through the proposed gene gradient attribution algorithm.ResultsThis model integrates drug response data from 223 drugs across 14 tissues for meta pre-training, followed by transfer and testing on seven single-cell datasets. In comparison to other models, the proposed framework achieves an average accuracy increase of 4.58% for pre-trained drugs and demonstrates a 20% improvement in generalization performance for previously unseen drugs. Case studies further illustrate its capability to differentiate between resistance genes.ConclusionThe proposed framework exhibits enhanced generalization capabilities in predicting cellular responses across multiple drugs, including unseen drugs. This model serves as an effective tool for investigating drug action pathways and elucidating resistance mechanisms from single-cell insights, with significant implications for guiding clinical medication practices.
Spatial neglect after subcortical stroke: sometimes a cortico-cortical disconnection syndrome
Authors: Sperber Christoph , Rosenzopf Hannah , Wawrzyniak Max , Klingbeil Julian , Saur Dorothee , Karnath Hans-Otto 
Published: April 2024

AbstractBackground and ObjectivesSpatial neglect is commonly attributed to lesions of a predominantly right-hemispheric cortical network. Although spatial neglect was also repeatedly observed after lesions to the basal ganglia and the thalamus, many anatomical network models omit these structures. We investigated if disruption of functional or structural connectivity can explain spatial neglect in subcortical stroke.MethodsWe retrospectively investigated data of first-ever, acute stroke patients with right-sided lesions of the basal ganglia (n = 27) or the thalamus (n = 16). Based on lesion location, we estimated i) functional connectivity via lesion-network mapping with normative resting state fMRI data, ii) structural white matter disconnection and iii) tract-wise disconnection of association fibres based on normative tractography data to investigate the association of spatial neglect and disconnection measures.ResultsApart from very small clusters of functional disconnection observed in inferior/middle frontal regions in lesion-network symptom mapping for basal ganglia lesions, our analyses found no evidence of functional or structural subcortico-cortical disconnection. Instead, the multivariate consideration of lesion load to several association fibres predicted the occurrence of spatial neglect (p = 0.0048; AUC = 0.76), which were the superior longitudinal fasciculus, inferior occipitofrontal fasciculus, superior occipitofrontal fasciculus, and the uncinate fasciculus.ConclusionDisconnection of long (cortico-cortical) association fibres can explain spatial neglect in subcortical stroke. Like the competing theory of remote cortical hypoperfusion, this mechanism does not require the assumption of a genuine role for subcortical grey matter structures in spatial neglect.
Correlating Protein Aggregate Structure with Cellular Function in Differentiated Muscle Cells: Discriminating Pathogenic from Non-Pathogenic Forms
Authors: Mallon Sander D. , Bos Erik , Sheikhhassani Vahid , Shademan Milad , Rocca Dino , Voortman Lenard M. , Mashaghi Alireza , Sharp Thomas H. , Raz Vered 
Published: April 2024

AbstractAgeing has a major adverse impact on maintaining cellular proteostasis and age-related dysregulation leads to an increase in protein aggregation. Equivalently, the accumulation of aggregated proteins accelerates proteostasis impairment. Accumulation of protein aggregates and impaired proteostasis are hallmarks of ageing-associated neuromuscular disorders and tissue degeneration is predominantly in post-mitotic muscle and neuronal cells. A short alanine expansion mutation in the Poly(A) binding protein nuclear 1 (PABPN1) causes Oculopharyngeal muscular dystrophy (OPMD), a rare age-associated protein aggregation myopathy. PABPN1 is a vital RNA-binding protein but OPMD pathology is limited to skeletal muscles connected to nuclear aggregates. In contrast to the mutant PABPN1, the wild-type PABPN1 forms age-associated non-pathogenic aggregates.We generated an inducible muscle cell models for mutant and wild-type PABPN1 protein aggregation. By combining four different, but complementary, imaging modalities, covering micro- to nanoscale resolutions, we were able to characterise differences in structure and dynamics between pathogenic and non-pathogenic PABPN1 aggregates in differentiated muscle cells. These data allowed us to correlate the structure of aggregates to cellular function, providing important insights into how aggregates lead to cell dysfunction in post-mitotic cells.Graphical summary
Group social dynamics in a semi-natural setup reveal an adaptive value for aggression in male mice
Authors: Anpilov Sergey , Shemesh Yair , Benjamin Asaf , Biagini Tommaso , Sztainberg Yehezkel , Richter-Levin Alon , Forkosh Oren , Chen Alon 
Published: April 2024

AbstractBackgroundMaladaptive aggression in humans is associated with several psychiatric conditions and lacks effective treatment. Nevertheless, aggression constitutes an essential behavior throughout the animal kingdom as long as it is tightly regulated. Studying how social dominance hierarchies (SDH) regulate aggression and access to resources in an enriched environment (EE) can narrow the translational gap between aggression in animal models and humans normal and pathological behavior.MethodsThe ‘social box’ (SB) is a semi-natural setup for automatic and prolonged monitoring of mouse group dynamics. We utilized the SB to decipher complex tradeoffs between aggression, social avoidance, resource allocation, and dominance in two mouse models of increased aggression: (i) a model of early exposure to EE and (ii) a model of oxytocin receptor deficiency (OxtR-/-). While EE increases aggression as an adaptive response to external stimuli, hyper-aggression in OxtR-/-mice is accompanied by marked abnormalities in social behavior.ResultsEE groups exhibited significant social avoidance, and an increased proportion of their encounters developed into aggressive interactions, resulting in lower levels of exploratory activity and overall aggression. The hierarchy in EE was more stable than in control groups, and dominance was correlated with access to resources. In OxtR-/-groups, mice engaged in excessive social encounters and aggressive chasing, accompanied by increased overall activity. In OxtR-/-groups, dominance hierarchies existed but were not correlated with access to resources.ConclusionMeasuring aggression and social dominance hierarchies in a semi-natural setup reveals the adaptive value of aggression in EE and OxtR-/-mice, respectively. This approach can enhance translational research of pathological aggression.
One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients
Authors: Bénit Paule , Rak Malgorzata , Rustin Pierre 
Published: April 2024

ABSTRACTWith the hope of better understanding and characterizing the dramatic differences in antioxidant response of human cells carrying mutations in the frataxin gene responsible for Friedreich ataxia (FRDA), we studied primary cultures of skin fibroblasts derived from five FRDA patients harboring different large expansion sizes in the frataxin gene. Because oxidative stress was previously established to be instrumental in FRDA, among the many enzymes likely to modulate sensitivity to oxidative stress, we selected some previously shown to play a critical role in this stress. However, we failed to identify a consistent clue to order individual cultures based on these measurements. We therefore focused our study on cell death of FRDA fibroblasts and its modulation by different antioxidants under culture conditions exacerbating sensitivity to oxidative stress. Under conditions that force the cells to rely on mitochondrial activity, we observed significant yet variable FRDA cell proliferation. These conditions were thereafter used to screen the effectiveness of a set of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA,i.e.Uridine, Pyruvate, and Pioglitazone, to prevent or slow down cell mortality. We observed a surprising variability of response to antioxidant molecules even under the similar, controlled conditions used to culture patient’s fibroblasts. We conclude that the specific response of each individual already discernable at cellular level may well play an important role in the frequent difficulties encounter to reach firm conclusions when testing the capacity of antioxidants to counteract the consequences of frataxin depletion, including in clinical trials.
Screening great ape museum specimens for DNA viruses
Authors: Hämmerle Michelle , Guellil Meriam , Trgovec-Greif Lovro , Cheronet Olivia , Sawyer Susanna , Ruiz-Gartzia Irune , Lizano Esther , Rymbekova Aigerim , Gelabert Pere , Bernardi Paolo , Han Sojung , Rattei Thomas , Schuenemann Verena J. , Marques-Bonet Tomas , Guschanski Katerina , Calvignac-Spencer Sebastien , Pinhasi Ron , Kuhlwilm Martin 
Published: April 2024

AbstractNatural history museum collections harbour a record of wild species from the past centuries, providing a unique opportunity to study animals as well as their infectious agents. Thousands of great ape specimens are kept in these collections, and could become an important resource for studying the evolution of DNA viruses. Their genetic material is likely to be preserved in dry museum specimens, as reported previously for monkeypox virus genomes from historical orangutan specimens. Here, we screened 209 great ape museum specimens for 99 different DNA viruses, using hybridization capture coupled with short-read high-throughput sequencing. We determined the presence of multiple viruses within this dataset from historical specimens and obtained several near-complete viral genomes. In particular, we report high-coverage (>18-fold) hepatitis B virus genomes from one gorilla and two chimpanzee individuals, which are phylogenetically placed within clades infecting the respective host species.
Urbanization Affects Nest Material Composition and Use of Anthropogenic Materials in Blue Tit Nests (Cyanistes caeruleus)
Authors: Roy Joseph , Dominoni Davide M. 
Published: April 2024

AbstractAvian nests are complex structures that protect eggs and nestlings. Nest-building behaviour varies between species and habitats, and recent work has highlighted that in areas with high human activity and low availability of natural nest material, birds may use anthropogenic material to construct nests. However, we still know relatively little about how nest composition is affected by human presence, including along urban gradients. Here we present the results of a study where we examined how nest composition differed between an urban and a forest population of blue tits, and the impact that variation in nest composition had on reproductive success. We found a significant decrease in the amount of natural materials and an increase in anthropogenic materials in urban compared to forest nests. Earlier urban nests showed a higher amount of anthropogenic materials compared to late urban nests. The amount of moss incorporated in a nest was the strongest predictor of fledgling success, suggesting that the use of anthropogenic material by urban birds might be a maladaptation, and/or that urban birds are constrained in the amount of moss they can use to build their nests. Future studies should aim at quantifying the availability of natural materials to distinguish between these two hypotheses.
LSD flattens the hierarchy of directed information flow in fast whole-brain dynamics
Authors: Shinozuka Kenneth , Tewarie Prejaas K.B. , Luppi Andrea , Lynn Christopher , Roseman Leor , Muthukumaraswamy Suresh , Nutt David J. , Carhart-Harris Robin , Deco Gustavo , Kringelbach Morten L. 
Published: April 2024

AbstractPsychedelics are serotonergic drugs that profoundly alter consciousness, yet their neural mechanisms are not fully understood. A popular theory, RElaxed Beliefs Under pSychedelics (REBUS), posits that psychedelics flatten the hierarchy of information flow in the brain. Here, we investigate hierarchy based on the imbalance between sending and receiving brain signals, as determined by directed functional connectivity. We measure directed functional hierarchy in a magnetoencephalography (MEG) dataset of 16 healthy human participants who were administered a psychedelic dose (75 micrograms, intravenous) of lysergic acid diethylamide (LSD) under four different conditions. LSD diminishes the asymmetry of directed connectivity when averaged across time. Additionally, we demonstrate that machine learning classifiers distinguish between LSD and placebo more accurately when trained on one of our hierarchy metrics than when trained on traditional measures of functional connectivity. Taken together, these results indicate that LSD weakens the hierarchy of directed connectivity in the brain by increasing the balance between senders and receivers of neural signals.
Self-Assembled Origami Neural Probes for Scalable, Multifunctional, Three-Dimensional Neural Interface
Authors: Yan Dongxiao , Ruiz Jose Roberto Lopez , Hsieh Meng-Lin , Jeong Daeho , Vöröslakos Mihály , Lanzio Vittorino , Warner Elisa V. , Ko Eunah , Tian Yi , Patel Paras R. , ElBidweihy Hatem , Smith Connor S. , Lee Jae-Hyun , Cheon Jinwoo , Buzsáki György , Yoon Euisik 
Published: April 2024

AbstractFlexible intracortical neural probes have drawn attention for their enhanced longevity in high-resolution neural recordings due to reduced tissue reaction. However, the conventional monolithic fabrication approach has met significant challenges in: (i) scaling the number of recording sites for electrophysiology; (ii) integrating of other physiological sensing and modulation; and (iii) configuring into three-dimensional (3D) shapes for multi-sided electrode arrays. We report an innovative self-assembly technology that allows for implementing flexible origami neural probes as an effective alternative to overcome these challenges. By using magnetic-field-assisted hybrid self-assembly, multiple probes with various modalities can be stacked on top of each other with precise alignment. Using this approach, we demonstrated a multifunctional device with scalable high-density recording sites, dopamine sensors and a temperature sensor integrated on a single flexible probe. Simultaneous large-scale, high-spatial-resolution electrophysiology was demonstrated along with local temperature sensing and dopamine concentration monitoring. A high-density 3D origami probe was assembled by wrapping planar probes around a thin fiber in a diameter of 80∼105 μm using optimal foldable design and capillary force. Directional optogenetic modulation could be achieved with illumination from the neuron-sized micro-LEDs (μLEDs) integrated on the surface of 3D origami probes. We could identify angular heterogeneous single-unit signals and neural connectivity 360° surrounding the probe. The probe longevity was validated by chronic recordings of 64-channel stacked probes in behaving mice for up to 140 days. With the modular, customizable assembly technologies presented, we demonstrated a novel and highly flexible solution to accommodate multifunctional integration, channel scaling, and 3D array configuration.