bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated presentation of visual threats drives innate fear habituation and is modulated by environmental and physiological factors
Authors: Carroll Jordan N. , Myers Brent , Vaaga Christopher E. 
Published: October 2024

AbstractTo survive predation, animals must be able to detect and appropriately respond to predator threats in their environment. Such defensive behaviors are thought to utilize hard-wired neural circuits for threat detection, sensorimotor integration, and execution of ethologically relevant behaviors. Despite being hard-wired, defensive behaviors (i.e. fear responses) are not fixed, but rather show remarkable flexibility, suggesting that extrinsic factors such as threat history, environmental contexts, and physiological state may alter innate defensive behavioral responses. The goal of the present study was to examine how extrinsic and intrinsic factors influence innate defensive behaviors in response to visual threats. In the absence of a protective shelter, our results indicate that mice showed robust freezing behavior following both looming (proximal) and sweeping (distal) threats, with increased behavioral vigor in response to looming stimuli, which represent a higher threat imminence. Repeated presentation of looming or sweeping stimuli at short inter-trial intervals resulted in robust habituation of freezing, which was accelerated at longer inter-trial intervals, regardless of contextual cues. Finally, physiological factors such as acute stress further disrupted innate freezing habituation, resulting in a delayed habituation phenotype, consistent with a heightened fear state. Together, our results indicate that extrinsic factors such as threat history, environmental familiarity, and physiological stressors have robust and diverse effects on defensive behaviors, highlighting the behavioral flexibility in how mice respond to predator threats.
FBXW7 regulates MYRF levels to control myelin capacity and homeostasis in the adult CNS
Authors: Collins Hannah Y. , Doan Ryan A. , Li Jiaxing , Early Jason E. , Madden Megan E. , Simkins Tyrell , Lyons David A. , Monk Kelly R. , Emery Ben 
Published: October 2024

AbstractMyelin, along with the oligodendrocytes (OLs) that produce it, is essential for proper central nervous system (CNS) function in vertebrates. Although the accurate targeting of myelin to axons and its maintenance are critical for CNS performance, the molecular pathways that regulate these processes remain poorly understood. Through a combination of zebrafish genetics, mouse models, and primary OL cultures, we found FBXW7, a recognition subunit of an E3 ubiquitin ligase complex, is a regulator of adult myelination in the CNS. Loss ofFbxw7in myelinating OLs resulted in increased myelin sheath lengths with no change in myelin thickness. As the animals aged, they developed progressive abnormalities including myelin outfolds, disrupted paranodal organization, and ectopic ensheathment of neuronal cell bodies with myelin. Through biochemical studies we found that FBXW7 directly binds and degrades the N-terminal of Myelin Regulatory Factor (N-MYRF), to control the balance between oligodendrocyte myelin growth and homeostasis.
Epigenetic derepression of H3K9me3 mitigates Alzheimer-related pathology and improves cognition via immunomodulation and Vgf induction
Authors: Fuchs Dieu-Trang , Vit Jean-Philippe , Rentsendorj Altan , Sheyn Julia , Shi Haoshen , Koronyo Yosef , Chepurna Oksana , Davis Miyah R. , Wilson Jered W. , Schneider Lon S. , Graham Stuart L. , Gupta Vivek K. , Fahnestock Margaret , Sun Tao , Kleinman Michael T. , Horne David , Mirzaei Mehdi , Black Keith L. , Koronyo-Hamaoui Maya 
Published: October 2024

AbstractWe investigated the role of histone 3 lysine 9 trimethylation (H3K9me3), an epigenetic mechanism involved in the repression of synaptic plasticity and memory-related genes, within aging and Alzheimer’s disease (AD). Our study reveals that elevated cortical H3K9me3 strongly correlates with cognitive dysfunction in individuals with mild cognitive impairment (MCI) and AD. In old (18 months) and younger (14 months) APPSWE/PS1ΔE9 and 3xTg AD mouse models, inhibiting SUV39H1 methyltransferase with ETP69, substantially reduces cerebral H3K9me3 levels and attenuates amyloid-β burden, tau pathology, and gliosis. Administration of ETP69 further promotes dendritic spine formation, leading to rapid and sustained improvements in cognitive function. Proteomics analysis indicates that a significant proportion of dysregulated proteins in the brains of AD-model mice are reversed by ETP69. These proteins are enriched for synaptic plasticity and learning-related pathways. ETP69 exerts its effects through multiple neuroprotective mechanisms, including regulation of neuroinflammation, induction of both blood and cerebral-infiltrating monocytes involved in cerebral Aβ clearance. Moreover, ETP69 activates brain-derived neurotrophic factor (Bdnf) network, and particularly its downstream effector neurosecretory protein Vgf. These findings support the pharmacological inhibition of H3K9me3-mediated gene silencing to reverse AD-related pathology and cognitive decline.
a2iHelper: a Python toolkit for a differential editing site analysis of RNA-Seq data
Authors: Ribas Guilherme T. , Guizelini Dieval , Riella Leonardo V. , Riella Cristian V. 
Published: October 2024

AbstractBackgroundA-to-I RNA editing, mediated byADARenzymes, plays a crucial role in cancer and autoimmune disorders but lacks standardized tools for differential analysis. After reviewing 55 studies, it highlights significant methodological heterogeneity, hindering result comparability and reproducibility. To address this, we developed a2iHelper, a Python package that streamlines RNA editing analysis by filtering noise, performing statistical analyses, and generating visualizations. a2iHelper integrates seamlessly with Python machine learning tools, aiming to standardize and simplify RNA editing research.ResultsWe applied our methods to analyze A-to-I editing in a public dataset comparing wild-type andADARknockout. The source code is open, freely available on GitHub, and organized in a well-documented Python package. Using Snakemake for preprocessing, we conducted differential editing analysis on the top 104 most edited genes. The results include p-values from statistical tests, Odds ratios for Manhattan plots, and correlations between editing frequencies and gene expression, visualized in various plots.ConclusionsWe developed a2iHelper, a Python-based package for analyzing and visualizing A-to-I RNA editing data. It allows researchers with minimal programming experience to perform organized, reproducible editing analyses. Novice users can easily detect editing sites, filter noise, and generate figures, while advanced users can integrate functionalities into their workflows. a2iHelper runs on personal computers without needing High-Performance Computing resources.
From Simulations to Inference: Using Machine Learning to Tune Patient-Specific Finite-Element Models of the Middle Ear Towards Objective Diagnosis
Authors: Motallebzadeh Hamid , Deistler Michael , Schönleitner Florian M. , Macke Jakob H. , Puria Sunil 
Published: October 2024

AbstractComputational models, particularly finite-element (FE) models, are essential for interpreting experimental data and predicting system behavior, especially when direct measurements are limited. A major challenge in tuning these models is the large number of parameters involved. Traditional methods, such as one-by-one sensitivity analyses, are time-consuming, subjective, and often return only a single set of parameter values, focusing on reproducing averaged data rather than capturing the full variability of experimental measurements.In this study, we applied simulation-based inference (SBI) using neural posterior estimation (NPE) to tune an FE model of the human middle ear. The training dataset consisted of 10,000 FE simulations of stapes velocity, ear-canal (EC) input impedance, and absorbance, paired with seven FE parameter values randomly sampled within plausible ranges. The neural network learned the association between parameters and simulation outcomes, returning the probability distribution of parameter values that can reproduce experimental data.Our approach successfully identified parameter sets that reproduced three experimental datasets simultaneously. By accounting for experimental noise and variability during training, the method provided a probability distribution of parameters, representing all valid combinations that could fit the data, rather than tuning to averaged values. The network demonstrated robustness to noise and exhibited an efficient learning curve due to the large training dataset.SBI offers an objective alternative to laborious sensitivity analyses, providing probability distributions for each parameter and uncovering interactions between them. This method can be applied to any biological FE model, and we demonstrated its effectiveness using a middle-ear model. Importantly, it holds promise for objective differential diagnosis of conductive hearing loss by providing insight into the mechanical properties of the middle ear.
Virion-associated influenza hemagglutinin clusters upon sialic acid binding visualized by cryo-electron tomography
Authors: Huang Qiuyu J. , Kim Ryan , Song Kangkang , Grigorieff Nikolaus , Munro James B. , Schiffer Celia A. , Somasundaran Mohan 
Published: October 2024

SUMMARYInfluenza viruses are enveloped, negative sense single-stranded RNA viruses covered in a dense layer of glycoproteins. Hemagglutinin (HA) accounts for 80-90% of influenza glycoprotein and plays a role in host cell binding and membrane fusion. While previous studies have characterized structures of receptor-free and receptor-bound HA in vitro, the effect of receptor binding on HA organization and structure on virions remains unknown. Here, we used cryo-electron tomography (cryoET) to visualize influenza virions bound to a sialic acid receptor mimic. Overall, receptor binding did not result in significant changes in viral morphology; however, we observed rearrangements of HA trimer organization and orientation. Compared to the even inter-glycoprotein spacing of unliganded HA trimers, receptor binding promotes HA trimer clustering and formation of a triplet of trimers. Subtomogram averaging and refinement yielded 8-10 Å reconstructions that allowed us to visualize specific contacts between HAs from neighboring trimers and identify molecular features that mediate clustering. Taken together, we present new structural evidence that receptor binding triggers clustering of HA trimers, revealing an additional layer of HA dynamics and plasticity.
A resource for extracellular vesicles from activated CD4 T cells that relay pro-inflammatory signals
Authors: Jainarayanan Ashwin K. , Mahla Ranjeet Singh , Capera Jesusa , Elanchezhian Mirudula , Gupta Dhanu , Anand Nithishwer Mouroug , Thomas Tom , Beckers Daniel , Leithner Alexander , Achar Sooraj R , Valvo Salvatore , Conceição Mariana , Kurz Elke , Devaprasad Abhinandan , Amin Sakina , Berridge Georgina , Hester Svenja , Fischer Roman , Céspedes Pablo F. , Dustin Lynn B. , Wood Matthew J. A. , Dustin Michael L. 
Published: October 2024

AbstractCD4 T helper cells (TH cells) play a vital role in coordinating and amplifying the immune response to specific pathogens. They constitutively produce different kinds of extracellular vesicles (EVs), which mediate cell-to cell communication and play diverse roles in immune regulation and inflammatory processes. Here we provide a resource documenting the composition of activated TH cell EVs and demonstrating their ability to instigate pro-inflammatory response in antigen-presenting cells (APCs). EVs were characterized by lipidomics, proteomics, and NanoFCM. The activated TH cells derived EVs (act-EVs) were found to be enriched in TH cell-specific proteins, transmembrane and cytosolic EV marker proteins, and HLA proteins relative to resting CD4 T cells EVs (rest-EVs). The pro-inflammatory effect of act-EVs vs rest-EVs on donor matched APCs were characterized by chemokine and cytokine profiling and flow cytometry analysis. There was no discernible contrast in endotoxin levels between act-EVs and rest-EVs. Functional distinctions were seen to arise from variations in the content and composition of these EVs. Moreover, we validated our findings with an in-vivo investigation in mice, demonstrating the recruitment of monocytes, dendritic cells (DCs), neutrophils, and NK cells in the spleen, accompanied by the release of pro-inflammatory cytokines in the serum after administering act-EVs. In summary, this study sheds light on the role of TH cell released EVs in modulating the immune response during pro-inflammatory responses and this resource provides a foundation for development of novel therapeutics on EV based scaffolds.
Widespread Prevalence of CD19 Exon 5-6 Skipping In Indian Pediatric B-cell Acute Lymphoblastic Leukemia Patients
Authors: Srivastava Devesh , Gupta Anurag , Verma Nishant , Misra Ashish 
Published: October 2024

AbstractB-cell acute lymphoblastic leukemia (B-ALL) is characterized by the malignant burgeoning of abnormal B-cell lymphoblasts. In recent years, the use of CART therapy which targets CD19 antigen present on the surface of B-cells, has gained significant attention as a treatment option against aggressive and refractory forms of B-ALL. However, the loss of CD19 antigen on B-cell surface due to aberrant splicing under therapy pressure has been suggested as one of the main factors for the emerging CART therapy resistance. Herein, using RT-PCR based splice assays we examined CD19 splicing patterns in 43 primary pediatric B-ALL patient samples spread across various subtypes. We observed that CD19 isoform lacking exon 5-6 exists in ∼ 55% of pediatric patients at the initial diagnosis stage itself. Using in-silico analysis, we identified RNA binding proteins, RC3H1 and MBNL1, as potential regulators of exon 5-6 skipping. Furthermore, qRT-PCR analysis in patient samples revealed that RC3H1 and MBNL1 are significantly upregulated in samples exhibiting exon 5-6 skipping. Taken together, we for the first time report the existence of aberrantly splicedCD19isoform lacking exon 5-6 in primary pediatric patients, and this occurrence could potentially result from RC3H1 and MBNL1 dysregulation.
Cardiopulmonary Exercise Tests in People with Chronic Stroke: Interpretation and Clinical Application
Authors: McCartney Kiersten M. , Edwards David , Pohlig Ryan , Boyne Pierce , Wright Tamara , Wright Henry , Overstreet Matthew , Reisman Darcy S. 
Published: October 2024

AbstractObjectiveTo understand in people with stroke: 1) reasons for cardiopulmonary exercise test termination, 2) how frequently secondary criteria indicating a maximal test are met, and 3) how additional clinical measures provide context to interpreting test data.DesignA secondary analysis from the Promoting Recovery Optimization of Walking Activity in Stroke (NCT02835313) clinical trial.SettingFour outpatient rehabilitation clinics.ParticipantsPeople with chronic stroke able to walk without assistance of another person.InterventionParticipants (n= 250) were randomized into a high-intensity treadmill or a step activity monitoring group. Cardiopulmonary exercise tests were conducted pre- (n= 247) and post-intervention (n= 185).Main MeasuresThe primary measure was reason for cardiopulmonary exercise test termination. Secondary measures included: oxygen consumption, ventilatory threshold, peak heart rate, respiratory exchange ratio, six-minute walk test, and fastest walking speed. General Linear Mixed Methods were used to determine the fixed main effects of group and time, and their interaction for outcome variables.ResultsThere were 4 categories of test termination. Only 1.9% of tests achieved the threshold to confirm a maximal aerobic effort. Despite one group receiving a high-intensity walking intervention, there were no between group differences in oxygen consumption or ventilatory threshold. There were significant differences between groups in measures of walking capacity.ConclusionsAnalyses indicate few with chronic stroke demonstrate a maximal aerobic effort on a cardiopulmonary exercise test. If the cardiorespiratory system is not thoroughly taxed during these tests in people with chronic stroke, interpreting results as their cardiorespiratory fitness should be done cautiously.Clinical MessagesPeople with stroke rarely (< 2%) attain an aerobic maximum on cardiopulmonary exercise tests.People with chronic stroke, frequently stop these tests due to biomechanical reasons which could reflect neuromuscular impairments, not cardiorespiratory impairments.Interpretation of test results as a measure of solely cardiorespiratory fitness or to prescribe exercise should be done cautiously in people with chronic stroke.
Voluntary Exercise Attenuates Tumor Growth in a Preclinical Model of Castration-Resistant Prostate Cancer
Authors: Berger Nicolas , Kugler Benjamin , Han Dong , Li Muqing , Nguyen Paul , Anderson Meaghan , Zhang Songqi , Cai Changmeng , Zou Kai 
Published: October 2024

ABSTRACTPurposeTo examine the effects of voluntary exercise training on tumor growth and explore the underlying intratumoral molecular pathways and processes responsible for the beneficial effects of VWR on tumor initiation and progression in a mouse model of Castration-Resistant Prostate Cancer (CRPC).MethodsMale immunodeficient mice (SCID) were castrated and subcutaneously inoculated with human CWR-22RV1 cancer cells to construct CRPC xenograft model before randomly assigned to either voluntary wheel running (VWR) or sedentary (SED) group (n=6/group). After three weeks, tumor tissues were collected. Tumor size was measured and calculated. mRNA expression of markers of DNA replication, Androgen Receptor (AR) signaling, and mitochondrial dynamics was determined by RT-PCR. Protein expression of mitochondrial content and dynamics was determined by western blotting. Finally, RNA-sequencing analysis was performed in the tumor tissues.ResultsVoluntary wheel running resulted in smaller tumor volume at the initial stage and attenuated tumor progression throughout the time course (P < 0.05). The reduction of tumor volume in VWR group was coincided with lower mRNA expression of DNA replication markers (MCM2,MCM6, andMCM7), AR signaling (ELOVL5andFKBP5) and regulatory proteins of mitochondrial fission (Drp1 and Fis1) and fusion (MFN1 and OPA1) when compared to the SED group (P<0.05). More importantly, RNA sequencing data further revealed that pathways related to pathways related to angiogenesis, extracellular matrix formation and endothelial cell proliferation were downregulated.ConclusionsThree weeks of VWR was effective in delaying tumor initiation and progression, which coincided with reduced transcription of DNA replication, AR signaling targets and mitochondrial dynamics. We further identified reduced molecular pathways/processes related to angiogenesis that may be responsible for the delayed tumor initiation and progression by VWR.
Experiments and modelling of pulmonary surfactant disruption by aerosolised compounds
Authors: Barlow Hugh , Sengupta Sreyoshee , Baltazar Maria Teresa , Sørli Jorid B. 
Published: October 2024

AbstractWithin the deep lung, pulmonary surfactant coats the air-liquid interface at the surface of the alveoli. This complex mixture of amphiphilic molecules and proteins modifies the surface tension and mechanical properties of this interface to assist with breathing. In this study, we examine the effects on pulmonary surfactant function by two industrially used compounds composing surfactants and polymers. Using an experimental method previously developed to imitate the in vivo exposure in the alveoli[1], we quantify the change in the dilational rheology of the pulmonary surfactant due to the introduction of two widely used chemicals; Benzalkonium Chloride (BAC) and Polyhexamethylene Biguanide (PHMB). We observe that these chemicals alter the dilational rheology of the surfactant monolayer. Using a mechanistic theory, we are able to semi-quantitatively model the changes induced by the introduction of these compounds to the pulmonary surfactant.
Critical-Size Defect Tibialis Anterior (TA) Muscle Regeneration using Ex-Vivo Mice Hindlimbs Culturing under Dynamic Mechanical Loading
Authors: Jacho Diego , Huynh James , Crowe Emily , Rabino Agustin , Yildirim Mine , Czernik Piotr J. , Lecka-Czernik Beata , Garcia-Mata Rafael , Yildirim-Ayan Eda 
Published: October 2024

AbstractIn this study, we introduced an innovative computer-controlled ex vivo mice hindlimb culturing platform operating under dynamic loading, coupled with injectable cell-laden nanofibrous matrix (PNCOL), to investigate tissue response and therapeutic outcomes in critical size defect tibialis anterior (TA) muscle regeneration. The combination of mechanical stimulation and cell therapy offers a distinctive opportunity to delve into the regenerative rehabilitation field and create sustainable solutions in musculoskeletal (MSK) tissue regeneration. The application of mechanical loading on the whole mice hindlimbs increased total bone area and marrow area suggesting an increase in periosteal bone formation and resorption on the endosteal surface. Viability assessments confirmed the sustained culturing of the samples throughout the study. Then, the effect of mechanical loading and PNCOL injection on muscle regeneration at the TA defect site was evaluated. Histological analyses revealed enhanced muscle regeneration in PNCOL-treated hindlimbs. Structural analysis of the defect area through scanning electron microscopy (SEM) showed regeneration of ECM fibers at the defect site in PNCOL-treated groups. An analysis of cytokine levels in conditioned media at the end experiment showed changes in the number of proteins with the role in wound healing, muscle regeneration WNT, and IGF-1 signaling suggesting an anabolic effect of mechanical stimulation on muscle and bone. Similarly, gene expression analysis showed a significant upregulation of PAX7, Mrf4, MYF5, and TGFβ1 mRNA levels, indicating enhanced muscle regeneration after coupled mechanical loading and PNCOL treatments. Lastly, immunostaining showed an increase in tissue regeneration and anti-inflammatory response (CD206) in PNCOL-treated groups. Overall, the ex vivo hindlimb organ culturing platform– maintained tissue functions under mechanical loading, while PNCOL treatment promoted muscle tissue regeneration and reduced inflammation. These findings demonstrated the potential of multidimensional approaches for enhancing therapeutic outcomes in MSK disorders. In addition, this study aligns with the growing emphasis on minimizing the number of animals used in research and developing a robust sense of responsible animal experimentation through introducing dynamic ex-vivo muscle organ culturing platform.