Biology subjects

Shen, Y.

Publications and source records attributed to Shen, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2024

Multi-talker speech comprehension at different temporal scales in listeners with normal and impaired hearing

Comprehending speech requires deciphering a range of linguistic representations, from phonemes to narratives. Prior research suggests that in single-talker scenarios, the neural encoding of linguistic units follows a hierarchy of increasing temporal receptive windows. Shorter temporal units like phonemes and syllables are encoded by lower-level sensory brain regions, whereas longer units such as sentences and paragraphs are processed by higher-level perceptual and cognitive areas. However, the brains representation of these linguistic units under challenging listening conditions, such as a cocktail party situation, remains unclear. In this study, we recorded electroencephalogram (EEG) responses from both normal-hearing and hearing-impaired participants as they listened to individual and dual speakers narrating different parts of a story. The inclusion of hearing-impaired listeners allowed us to examine how hierarchically organized linguistic units in competing speech streams affect comprehension abilities. We leveraged a hierarchical language model to extract linguistic information at multiple levels--phoneme, syllable, word, phrase, and sentence--and aligned these model activations with the EEG data. Our findings showed distinct neural responses to dual-speaker speech between the two groups. Specifically, compared to normal-hearing listeners, hearing-impaired listeners exhibited poorer model fits at the acoustic, phoneme, and syllable levels as well as the sentence levels, but not at the word and phrase levels. These results suggest that hearing-impaired listeners experience disruptions at both shorter and longer temporal scales, while their processing at medium temporal scales remains unaffected.

neuroscience↗

bioRxiv2024

Perfringolysin O pore-forming complexes are predominantly integral multiples of six subunits

Perfringolysin O is a well-studied bacterial cytolysin that forms large oligomeric pores with a wide range of sizes on membranes via a prepore intermediate. Here we examined the sizes of both PFO prepore and pore complexes electrophoretically using a multi-stack-gradient gel and found that, unexpectedly, there are only at most seven predominant sizes of either pores or prepores. Complexes extracted from each band exhibit contour lengths that are integral multiples of six subunits. High-resolution atomic force microscopy images of PFO pore complexes in supported bilayers also reveal a predominant hexameric-based stoichiometry. Thus, these results reveal a previously unknown structural hierarchy in PFO complexes, with larger complexes apparently built up from hexameric sub-complexes. We suggest that different inter-subunit interactions within and between the hexamers result in a likewise difference in the coordination of the prepore-to-pore transition within and between the hexamers, and is thus a critical feature of the allostery of this large multi-subunit complex.

biophysics↗

bioRxiv2024

Targeting SEZ6L2 in Colon Cancer: Efficacy of Bexarotene and Implications for Survival

BackgroundBexarotene, also recognized as Targretin, is categorized as a retinoid, a type of cancer drug. Nevertheless, the precise mechanisms of Bexarotene in relation to colon cancer remain unclear. In colon cancer, SEZ6L2 was suggested as one of the biomarkers and targets. This study presents a comprehensive exploration of the role of SEZ6L2 in colon cancer. MethodsWe utilized both TCGA data and a cohort of Chinese patients. In a meticulous analysis of 478 colon cancer cases, SEZ6L2 expression levels were examined in relation to clinical characteristics, staging parameters, and treatment outcomes. Additionally, we investigated the pharmacological impact of Bexarotene on SEZ6L2, demonstrating a significant downregulation of SEZ6L2 at both mRNA and protein levels in colon cancer patients following Bexarotene treatment. ResultsSEZ6L2 consistently overexpresses in colon cancer, serving as a potential universal biomarker with prognostic significance, validated in a diverse Chinese cohort. In vitro, SEZ6L2 promotes cell viability without affecting migration. Bexarotene treatment inhibits SEZ6L2 expression, correlating with reduced viability both in vitro and in vivo. SEZ6L2 overexpression accelerates declining survival rates in an in vivo context. Bexarotenes efficacy is context-dependent, effective in parental cells but not with SEZ6L2 overexpression. Computational predictions suggest a direct SEZ6L2-Bexarotene interaction, warranting further experimental exploration. ConclusionThe study provides valuable insights into SEZ6L2 as a prognostic biomarker in colon cancer, revealing its intricate relationship with clinical parameters, treatment outcomes, and Bexarotene effects. Context-dependent therapeutic responses emphasize the nuanced understanding required for SEZ6L2s role in colon cancer, paving the way for targeted therapeutic strategies.

biochemistry↗

bioRxiv2024

Synthetic genomes unveil the effects of synonymous recoding

Engineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information flow into and out of genetically modified organisms while (iii) allowing the biosynthesis of genetically encoded unnatural polymers1-4. Achieving these three goals requires the reassignment of multiple of the 64 codons nature uses to encode proteins. However, synonymous codon replacement--recoding--is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using whole-genome synthesis, multiplexed directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple recoded genomes. Using this information, we assemble a synthetic Escherichia coli genome in seven sections using only 57 codons to encode proteins. By discovering the rules responsible for the lethality of synonymous recoding and developing a data-driven multi-omics-based genome construction workflow that troubleshoots synthetic genomes, we overcome the lethal effects of 62,007 synonymous codon swaps and 11,108 additional genomic edits. We show that synonymous recoding induces transcriptional noise including new antisense RNAs, leading to drastic transcriptome and proteome perturbation. As the elimination of select codons from an organisms genetic code results in the widespread appearance of cryptic promoters, we show that synonymous codon choice may naturally evolve to minimize transcriptional noise. Our work provides the first genome-scale description of how synonymous codon changes influence organismal fitness and paves the way for the construction of functional genomes that provide genetic firewalls from natural ecosystems and safely produce biopolymers, drugs, and enzymes with an expanded chemistry.

synthetic biology↗

bioRxiv2024

Inactivation of PRMT1 inhibits cardiac fibrosis via transcriptional regulation and perturbation of FBL activity in fibroblast-to-myofibroblast transition

Cardiac fibrosis is a recognized cause of morbidity and mortality, yet effective pharmacological therapy that directly targets the fibrotic process remains lacking. Here we surveyed a group of methyltransferases known as protein arginine methyltransferases (PRMT) and demonstrated that PRMT1, which is the most highly expressed PRMT in the heart, was upregulated in activated cardiac fibroblasts, or myofibroblasts, in failing hearts. Deleting Prmt1 specifically in myofibroblasts or treating systemically with the PRMT1 inhibitor MS023 blocked myofibroblast formation, leading to a significant reduction in cardiac fibrosis and improvement in cardiac function in both acute and chronic heart injury models that manifest pervasive cardiac fibrosis. PRMT1 promoted the transition of cardiac fibroblasts to myofibroblasts by regulating transcription and epigenetic status. Additionally, PRMT1 methylated a key nucleolar protein fibrillarin 1 (FBL) and regulated nucleoli morphology and function during fibroblast fate transition. We further demonstrated a previously unrecognized requirement for FBL in myofibroblasts formation, by regulating myofibroblast gene induction and contractile force generation.

cell biology↗

bioRxiv2024

Cell-type specific inference from bulk RNA-sequencing data by integrating single cell reference profiles via EPIC-unmix

Cell type specific (CTS) analysis is essential to reveal biological insights obscured in bulk tissue data. However, single-cell (sc) or single-nuclei (sn) resolution data are still cost-prohibitive for large-scale samples. Thus, computational methods to perform deconvolution from bulk tissue data are highly valuable. We here present EPIC-unmix, a novel two-step empirical Bayesian method integrating reference sc/sn RNA-seq data and bulk RNA-seq data from target samples to enhance the accuracy of CTS inference. We demonstrate through comprehensive simulations across three tissues that EPIC-unmix achieved 4.6% - 109.8% higher accuracy compared to alternative methods. By applying EPIC-unmix to human bulk brain RNA-seq data from the ROSMAP and MSBB cohorts, we identified multiple genes differentially expressed between Alzheimers disease (AD) cases versus controls in a CTS manner, including 57.4% novel genes not identified using similar sample size sc/snRNA-seq data, indicating the power of our in-silico approach. Among the 6-69% overlapping, 83%-100% are in consistent direction with those from sc/snRNA-seq data, supporting the reliability of our findings. EPIC-unmix inferred CTS expression profiles similarly empowers CTS eQTL analysis. Among the novel eQTLs, we highlight a microglia eQTL for AD risk gene AP3B2, obscured in bulk and missed by sc/snRNA-seq based eQTL analysis. The variant resides in a microglia-specific cCRE, forming chromatin loop with AP3B2 promoter region in microglia. Taken together, we believe EPIC-unmix will be a valuable tool to enable more powerful CTS analysis.

genomics↗

bioRxiv2024

BioInformatics Agent (BIA): Unleashing the Power of Large Language Models to Reshape Bioinformatics Workflow

Bioinformatics plays a crucial role in understanding biological phenomena, yet the exponential growth of biological data and rapid technological advancements have heightened the barriers to in-depth exploration of this domain. Thereby, we propose Bio-Informatics Agent (BIA), an intelligent agent leveraging Large Language Models (LLMs) technology, to facilitate autonomous bioinformatic analysis through natural language. The primary functionalities of BIA encompass extraction and processing of raw data and metadata, querying both locally deployed and public databases for information. It further undertakes the formulation of workflow designs, generates executable code, and delivers comprehensive reports. Focused on the single-cell RNA sequencing (scRNA-seq) data, this paper demonstrates BIAs remarkable proficiency in information processing and analysis, as well as executing sophisticated tasks and interactions. Additionally, we analyzed failed executions from the agent and demonstrate prospective enhancement strategies including selfrefinement and domain adaptation. The future outlook includes expanding BIAs practical implementations across multi-omics data, to alleviating the workload burden for the bioinformatics community and empowering more profound investigations into the mysteries of life sciences. BIA is available at: https://github.com/biagent-dev/biagent.

bioinformatics↗

bioRxiv2024

Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the Arylsulfa-tase A (ARSA) gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models. Notably, a model developed by participants of a genetics and coding bootcamp, trained with standard machine-learning tools in Python, demonstrated superior performance among sub-missions. Furthermore, the study observed that state-of-the-art deep learning methods provided small but statistically significant improvement in predictive performance compared to less elaborate techniques. These findings underscore the utility of variant effect prediction, and the potential for models trained with modest resources to accurately classify VUS in genetic and clinical research.

genetics↗

bioRxiv2024

Deconvolution of polygenic risk score in single cells unravels cellular and molecular heterogeneity of complex human diseases

Polygenic risk scores (PRSs) are commonly used for predicting an individuals genetic risk of complex diseases. Yet, their implication for disease pathogenesis remains largely limited. Here, we introduce scPRS, a geometric deep learning model that constructs single-cell-resolved PRS leveraging reference single-cell chromatin accessibility profiling data to enhance biological discovery as well as disease prediction. Real-world applications across multiple complex diseases, including type 2 diabetes (T2D), hypertrophic cardiomyopathy (HCM), and Alzheimers disease (AD), showcase the superior prediction power of scPRS compared to traditional PRS methods. Importantly, scPRS not only predicts disease risk but also uncovers disease-relevant cells, such as hormone-high alpha and beta cells for T2D, cardiomyocytes and pericytes for HCM, and astrocytes, microglia and oligodendrocyte progenitor cells for AD. Facilitated by a layered multi-omic analysis, scPRS further identifies cell-type-specific genetic underpinnings, linking disease-associated genetic variants to gene regulation within corresponding cell types. We substantiate the disease relevance of scPRS-prioritized HCM genes and demonstrate that the suppression of these genes in HCM cardiomyocytes is rescued by Mavacamten treatment. Additionally, we establish a novel microglia-specific regulatory relationship between the AD risk variant rs7922621 and its target genes ANXA11 and TSPAN14. We further illustrate the detrimental effects of suppressing these two genes on microglia phagocytosis. Our work provides a multi-tasking, interpretable framework for precise disease prediction and systematic investigation of the genetic, cellular, and molecular basis of complex diseases, laying the methodological foundation for single-cell genetics.

genetics↗

bioRxiv2024

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ER) and exhibit active ER signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ER expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ER+ macrophages in the metastatic niche and functionally tied ER signaling in macrophages to T cell exclusion during metastatic colonization. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/593016v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1cd65b6org.highwire.dtl.DTLVardef@1d099e2org.highwire.dtl.DTLVardef@26cd91org.highwire.dtl.DTLVardef@181f5f3_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics. C_LIO_LIMetastatic niches are typically enriched with macrophages and depleted of T cells. C_LIO_LIDirect interaction with cancer cells induces ER expression in niche macrophages. C_LIO_LIKnockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization. C_LI

cancer biology↗

bioRxiv2024

Single cell profiling of bone metastasis ecosystems from multiple cancer types reveals convergent and divergent mechanisms of bone colonization.

Bone represents congenial soil for metastatic seeds and is frequently affected by metastasis of multiple cancer types. The histological and molecular characteristics of bone metastases (BMs) are diverse but poorly understood. Herein, we performed single-cell RNA-seq on 34 BMs from 6 cancer types and identified 3 ecosystem archetypes characterized by enrichment of macrophages/osteoclasts (M{varphi}-OC), regulatory/exhausted T cells (Treg-Tex), and monocytes (Mono), respectively. Breast cancer BMs are mostly the M{varphi}-OC archetype driven by the osteolytic vicious cycle, whereas kidney cancers BMs mainly belong to the Treg-Tex archetype that lacks osteoclasts. Lung cancers BMs evenly distributed across all archetypes. Further analyses revealed parallel mechanisms of immunosuppression and bone remodeling. Elevated estrogen signaling distinguishes macrophages in the M{varphi}-OC subtype, which was investigated in a companion study. Together, we elucidated that divergent mechanisms toward bone colonization and that BMs of different origins can adopt the same mechanism through convergent evolution or adaptation. HIGHLIGHTSO_LIAnalyses of bone metastases from 6 cancer types revealed three immune archetypes. C_LIO_LIArchetypes diverge on immune trajectories, and features of tumor and stromal cells. C_LIO_LIDominant cell type in each archetype undergoes convergent evolution. C_LIO_LIRegulatory networks converge on osteoclasts and Tregs to drive archetype formation. C_LI Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/593027v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@82cef6org.highwire.dtl.DTLVardef@1e1b021org.highwire.dtl.DTLVardef@1f2881eorg.highwire.dtl.DTLVardef@1c6874a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

CD74+ fibroblasts proliferate upon mechanical stretching to promote angiogenesis in keloid

The healing of human skin wounds is susceptible to perturbation caused by excessive mechanical stretching, resulting in enlarged scars, hypertrophic scars, or even keloids in predisposed individuals. Keloids are fibro-proliferative scar tissues that extend beyond the initial wound boundary, consisting of the actively progressing leading edge and the quiescent center. The stretch-associated outgrowth and enhanced angiogenesis are two features of the leading edge of keloids. However, which cell population is responsible for transducing the mechanical stimulation to the pathological alterations of keloid tissues remains unclear. Herein, through joint analysis of single-cell RNA sequencing of keloid specimens and RNA sequencing of stretched keloid fibroblasts, we identified CD74+ fibroblasts, a previously unappreciated subset of fibroblasts, as a key player in stretch-induced keloid progression. Examination of macrophage markers suggested a possible myeloid origin of the CD74+ fibroblasts. Immunostaining of keloid cryosections depicted a predominant distribution of CD74+ fibroblasts in the leading edge, interacting with vasculature. CD74+ fibroblasts possessed pro-angiogenic and migratory capacities, as revealed by in vitro transwell and tube formation assays on purified CD74+ fibroblasts. Additionally, these cells underwent proliferation upon stretching, through PIEZO1-mediated calcium influx and the downstream ERK and AKT signaling. Collectively, our findings propose a model wherein CD74+ fibroblasts serve as pivotal drivers of stretch-induced keloid progression, fueled by their proliferative, pro-angiogenic, and migratory capacities. Targeting the attributes of CD74+ fibroblasts hold promise as a therapeutic strategy for keloid management. Significance statementKeloids are fibro-proliferative scars resulting from aberrant skin wound healing processes, consisting of the actively progressing leading edge and the quiescent center. Mechanical stretching and neo-vascularization have both been implicated in keloid progression, yet little is known about whether they are interconnected. Herein, we demonstrated that CD74+ fibroblasts, a previously undiscovered fibroblast subset, possessed heightened pro-angiogenic and migratory capacities, and underwent proliferation upon mechanical stretching, thereby facilitating the progression of the leading edge of keloids. Examination of macrophage markers suggested a possible myeloid origin of CD74+ fibroblasts. Our findings uncover the connection between stretch-induced keloid progression and neo-vascularization through CD74+ fibroblasts and provide valuable insights into potential therapeutic interventions.

cell biology↗

bioRxiv2024

Mechano-metabolism of adherent cells in 2D and 3D microenvironments

Cells dynamically regulate their morphology, contractility, and metabolism in response to the mechano-chemical properties of their microenvironment. Here, we show matrix stiffness and ligand density jointly govern the bioenergetics of contractile cells through a nonequilibrium active chemo-mechanical model built around a newly introduced cellular metabolic potential. This concept links ATP hydrolysis to mechanosensitive signaling, quantifies the energetic cost of stress fiber assembly, and determines mechanically stable states. The metabolic potential enables quantitative prediction of cell contractility, morphology, and ATP consumption in different stiffness 2D and 3D environments, and we find quantitative agreement with experimental measurements in MDA-MB-231 breast cancer cells. The model further predicts activation of AMPK accompanies increased energetic demands in stiffer microenvironments which we experimentally validate and correlate with increased mitochondrial membrane potential, glucose uptake, and intracellular ATP levels. Together, these findings establish a predictive quantitative framework unifying mechanosensitive control of cell shape and contractility with the metabolic pathways sustaining cellular function across diverse mechanical environments. TeaserMatrix stiffness reshapes the cellular energy budget, driving metabolic adaptation to mechanical demand.

biophysics↗

bioRxiv2024

Site saturation mutagenesis of 500 human protein domains reveals the contribution of protein destabilization to genetic disease

Missense variants that change the amino acid sequences of proteins cause one third of human genetic diseases1. Tens of millions of missense variants exist in the current human population, with the vast majority having unknown functional consequences. Here we present the first large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the impact of >500,000 variants on the abundance of >500 human protein domains. This dataset, Human Domainome 1, reveals that >60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases, and is particularly important in recessive disorders. Combining stability measurements with protein language models annotates functional sites across proteins. Mutational effects on stability are largely conserved in homologous domains, allowing accurate stability prediction across entire protein families using energy models. Domainome 1 demonstrates the feasibility of assaying human protein variants at scale and provides a large consistent reference dataset for clinical variant interpretation and the training and benchmarking of computational methods.

genomics↗

bioRxiv2024

Matrix Vesicles from Osteoblasts Promote Atherosclerotic Calcification

BackgroundsVascular calcification often occurs with osteoporosis, a contradictory association known as "the calcification paradox". Osteoblast-derived matrix vesicles (Ost-MVs) have been implicated in bone mineralization, and also have a potential role in ectopic vascular calcification. Herein, we aim to investigate the contributions that Ost-MVs make to the bone-vascular calcification paradox and the underlying mechanisms. Methods and ResultsHyperlipidemia-induced atherosclerotic calcification in mice was accompanied with bone mineral loss, as evidenced by reduced deposition of Ost-MVs in the bone matrix and increased release of Ost-MVs into the circulation. Intravenous injection of fluorescent DiI-labeled Ost-MVs revealed a marked fluorescence accumulation in the aorta of atherogenic mice, whereas no fluorescence signals were observed in normal controls. Using proteomics to analyze proteins in non-matrix bound Ost-MVs and mineralized SMC-derived MVs (SMC-MVs), we found Lamp1 was specifically expressed in SMC-MVs, and Nid2 was exclusively expressed in Ost-MVs. We further demonstrated that both Lamp1 and Nid2 were co-localized with Collagen I within calcific plaques, indicating the involvement of both Ost-MVs and SMC-MVs in atherosclerotic calcification. Mechanistically, LPS-induced vascular injury facilitated the transendothelial transport of Ost-MVs. The recruitment of circulating Ost-MVs was regulated by remodeled Collagen I during calcification progression. Furthermore, the phenotypic transition of SMCs determined the endocytosis of Ost-MVs. Finally, we demonstrated that either recruited Ost-MVs or resident SMC-MVs accelerated atherosclerotic calcification, depending on the Ras-Raf-ERK signaling. ConclusionAtherosclerotic calcification-induced Ost-MVs are released into circulation, facilitating the transport from bone to plaque lesions and exacerbating artery calcification progression. The mechanisms of Ost-MVs recruitment include vascular injury allowing transendothelial transport of Ost-MVs, collagen I remodeling promoting Ost-MVs aggregation, and SMC phenotypic switch to facilitate Ost-MVs uptake. Our results further revealed that both recruited Ost-MVs and calcifying SMC-MVs aggravate calcification through the Ras-Raf-ERK pathway.

cell biology↗

bioRxiv2024

Mitigation of Stress-induced Structural Remodeling and Functional Deficiency in iPSC-CMs with PLN R9C Mutation by Promoting Autophagy

BackgroundPhospholamban (PLN) is a key regulator of cardiac function connecting adrenergic signaling and calcium homeostasis. The R9C mutation of PLN is known to cause early onset dilated cardiomyopathy (DCM) and premature death, yet the detailed mechanisms underlie the pathologic remodeling process are not well defined in human cardiomyocytes. The aim of this study is to unravel the role of PLN R9C in DCM and identify potential therapeutic targets. MethodsPLN R9C knock-in (KI) and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated and comprehensively examined for their expression profile, contractile function, and cellular signaling under both baseline conditions and following functional challenges. ResultsPLN R9C KI iPSC-CMs exhibited near-normal morphology and calcium handling, slightly increased contractility, and an attenuated response to {beta}-adrenergic activation compared to wild-type (WT) cells. However, treatment with a maturation medium (MM) has induced fundamentally different remodeling in the two groups: while it improved the structural integrity and functional performance of WT cells, the same treatment result in sarcomere disarrangement, calcium handling deficiency, and further disrupted adrenergic signaling in PLN R9C KI cells. To understand the mechanism, transcriptomic analysis showed the enrichment of protein homeostasis signaling pathways specifically in PLN R9C KI cells in response to the MM treatment and increased contractile demands. Further studies also indicated elevated ROS levels, interrupted autophagic flux, and increased pentamer PLN aggregation in functionally challenged KI cells. These results were further confirmed in patient-specific iPSC-CM models, suggesting that functional stresses exacerbate the deficiencies in PLN R9C cells through disrupting protein homeostasis. Indeed, treating stressed patient cells with autophagy-accelerating reagents, such as metformin and rapamycin, has restored autophagic flux, mitigated sarcomere disarrangement, and partially rescued {beta}-adrenergic signaling and cardiac function. ConclusionsPLN R9C leads to a mild increase of calcium recycling and contractility. Functional challenges further enhanced contractile and proteostasis stress, leading to autophagic overload, structural remodeling, and functional deficiencies in PLN R9C cardiomyocytes. Activation of autophagy signaling partially rescues these effects, revealing a potential therapeutic target for DCM patients with the PLN R9C mutation. Graphic abstractsA graphic abstract is available for this article.

molecular biology↗

bioRxiv2024

Early hippocampal high-amplitude rhythmic spikes predict post-traumatic epilepsy in mice

Oscillations, a highly conserved brain function across mammalian species, are pivotal in brain physiology and pathology. Traumatic brain injury (TBI) often leads to subacute and chronic brain oscillatory alterations associated with complications like post-traumatic epilepsy (PTE) in patients and animal models. Our recent work longitudinally recorded local field potential from the contralateral hippocampus of 12 strains of recombinant inbred Collaborative Cross (CC) mice alongside classical laboratory inbred C57BL/6J mice after lateral fluid percussion injury. In this study, we profiled the acute (<12 hr post-injury) and subacute (12-48 hr post-injury) hippocampal oscillatory responses to TBI and evaluated their predictive value for PTE. We found dynamic high-amplitude rhythmic spikes with elevated power density and reduced entropy that prevailed during the acute phase in CC031 mice who later developed PTE. This characteristic early brain oscillatory alteration is absent in CC031 sham controls or other CC and reference C57BL/6J strains that did not develop PTE after TBI. Our work provides quantitative measures linking early brain oscillation to PTE at a population level in mice under controlled experimental conditions. These findings will offer insights into circuit mechanisms and potential targets for neuromodulatory intervention.

neuroscience↗

bioRxiv2024

Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair

Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.

neuroscience↗