Biology subjects

Wu, Y.

Publications and source records attributed to Wu, Y..

At least 505 records · Page 28Linked to original sources

bioRxiv2024

Ectopic Reconstitution of a Spine-Apparatus Like Structure Provides Insight into Mechanisms Underlying Its Formation

The endoplasmic reticulum (ER) is a continuous cellular endomembrane network that displays focal specializations. Most notable examples of such specializations include the spine apparatus of neuronal dendrites, and the cisternal organelle of axonal initial segments. Both organelles exhibit stacks of smooth ER sheets with a narrow lumen and interconnected by a dense protein matrix. The actin-binding protein synaptopodin is required for their formation. Here, we report that expression in non-neuronal cells of a synaptopodin construct targeted to the ER is sufficient to generate stacked ER cisterns resembling the spine apparatus with molecular properties distinct from the surrounding ER. Cisterns within these stacks are connected to each other by an actin-based matrix that contains proteins also found at the spine apparatus of neuronal spines. These findings reveal a critical role of a synaptopodin-dependent actin matrix in generating cis-ternal stacks. These ectopically generated structures provide insight into spine apparatus morphogenesis.

cell biology↗

bioRxiv2024

Association of 10 VEGF Family Genes with Alzheimer's Disease Pathology at Single Cell Resolution

The cell-type specific role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimers disease (AD) is not well characterized. In this study, we utilized a single-nucleus RNA sequencing dataset from Dorsolateral Prefrontal Cortex (DLFPC) of 424 donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP) to investigate the effect of 10 VEGF genes (VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1, and NRP2) on AD endophenotypes. Mean age of death was 89 years, among which 68% were females, and 52% has AD dementia. Negative binomial mixed models were used for differential expression analysis and for association analysis with {beta}-amyloid load, PHF tau tangle density, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated signaling was profiled using CellChat. We discovered prefrontal cortical FLT1 expression was upregulated in AD brains in both endothelial and microglial cells. Higher FLT1 expression was also associated with worse cross-sectional global cognitive function, longitudinal cognitive trajectories, and {beta}-amyloid load. Similarly, higher endothelial FLT4 expression was associated with more {beta}-amyloid load. In contrast to the receptors, VEGFB showed opposing effects on {beta}-amyloid load whereby higher levels in oligodendrocytes was associated with high amyloid burden, while higher levels in inhibitory neurons was associated with lower amyloid burden. Finally, AD cells showed significant reduction in overall VEGF signaling comparing to those from cognitive normal participants. Our results highlight key changes in VEGF receptor expression in endothelial and microglial cells during AD, and the potential protective role of VEGFB in neurons.

neuroscience↗

bioRxiv2024

Unlocking TAS2R14 activation through intricate multi-ligand binding networks

Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents1-3. In addition, TAS2R14 has broad expression in non-gustatory tissues, suggesting its important roles in selective physiological processes and therapeutic potential4. Here, we present cryo-electron microcopy structures of TAS2R14 in complex with flufenamic acid and aristolochic acid, coupling with G protein subtypes gustducin and Gi. Distinct from most known GPCRs, agonists of TAS2R14 bind to multiple intracellular pockets. We highlight the cholesterol molecules occupying an upper transmembrane site, typically the orthosteric pocket in other GPCRs, also binding in the entrance to an intracellular agonist binding pocket, suggesting an endogenous modulatory function5. The structural and mutagenesis analysis illuminate the receptors broad-spectrum ligand recognition and activation via intricate multiple ligand-binding sites. Furthermore, we unveil the structural configuration of gustducin and its interaction with TAS2R14, as well as the coupling mode of Gi1. This investigation should be instrumental in advancing our knowledge of the mechanisms underlying bitter taste recognition and response, with broader relevance to sensory biology and pharmacology.

biophysics↗

bioRxiv2024

Reduction of Cystatin B results in increased cathepsin B activity in disomic but not Trisomy21 human cellular and mouse models

Down syndrome, resulting from trisomy of human chromosome 21, is a common form of chromosomal disorder that results in intellectual disability and altered risk of several medical conditions. Individuals with Down syndrome have a greatly increased risk of Alzheimers disease (DSAD), due to the presence of the APP gene on chromosome 21 that encodes the amyloid-{beta} precursor protein (APP). APP can be processed to generate amyloid-{beta}, which accumulates in plaques in the brains of people who have Alzheimers disease and is the upstream trigger of disease. Cathepsin B has potential roles in both APP processing and amyloid-{beta} degradation and has been suggested to contribute to amyloid-{beta} accumulation. An endogenous inhibitor of Cathepsin B, Cystatin B (CSTB), is encoded on chromosome 21. The abundance of this protein is increased in the brains of individuals with DSAD, which may be associated with a decrease in Cathepsin B activity compared to individuals who have Alzheimers disease in the general population. Whether targeting CSTB can modulate Cathepsin B activity in the context of trisomy of chromosome 21 is unclear. Here we test if reducing CSTB can alter Cathepsin B activity in a mouse and a cellular model of trisomy of chromosome 21. We find that reducing CSTB abundance increases Cathepsin B activity in disomic controls but not in the presence of trisomy of chromosome 21. These findings offer new insights into the role of CSTB in regulating Cathepsin B activity.

neuroscience↗

bioRxiv2024

STARDUST: a pipeline for the unbiased analysis of astrocyte regional calcium dynamics

Calcium imaging has become a popular way to probe astrocyte activity, but few analysis methods holistically capture discrete calcium signals that occur across the astrocyte domain. Here, we introduce STARDUST, a pipeline for the Spatio-Temporal Analysis of Regional Dynamics & Unbiased Sorting of Transients from fluorescence recordings of astrocytes, and provide step-by-step guidelines. STARDUST yields fluorescence time- series from data-defined regions of activity and performs systematic signal detection and feature extraction, enabling the in-depth and unbiased study of astrocyte calcium signals. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/588196v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@c6a97aorg.highwire.dtl.DTLVardef@a0b0fdorg.highwire.dtl.DTLVardef@1c3dd73org.highwire.dtl.DTLVardef@1ffa9ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Spatiotemporal transcriptomic profiling reveals the dynamic immunological landscape of alveolar echinococcosis

Alveolar echinococcosis (AE) is caused by the invasive growth of the metacestodes of Echinococcus multilocularis (E. multilocularis). The early diagnosis, management, and treatment of AE remains challenging. Herein, we integrated bulk RNA-seq, scRNA-seq, and ST technologies to reveal the immune characteristics both spatially and chronologically in E. multilocularis infected mouse liver. An unprecedented high-resolution spatial atlas of the E. multilocularis infection foci was obtained, revealing the pivotal role of neutrophils, Spp1+ monocyte-derived macrophages (MoMFs), and fibroblasts in AE progression. We observed continuous recruitment of neutrophils and macrophages into the infected tissues, indicating prolonged immune stimulation by the growing metacestodes. However, their spatial distribution patterns and functions changed during the infection cause. At the early infection stage, Il1bhi neutrophils aggregated in the lesion displayed the highest pattern-recognition receptor activity and may kill the metacestodes through NETosis, but their death in the infection foci might also trigger immune suppression. Meanwhile, Spp1+ MoMFs attached to the protoscoleces to clear the infection. At the late infection stage, the neutrophils failed to infiltrate into the lesion although their continuous recruitment into the infected liver. Even though the Spp1+ MoMFs enclosing the microcysts of E. multilocularis may retain their pathogen-killing ability, they may also promote fibrosis and angiogenesis through interaction with fibroblasts. The pro- and anti-inflammatory phenotype balance of these immune cells may be associated with the transition of parasite control strategy from "active killing" to "negative segregation" by the host. Our findings identify key molecular traits involved in AE development, which may benefit the treatment of echinococcosis.

immunology↗

bioRxiv2024

Age-dependent regulation of axoglial interactions and behavior by oligodendrocyte AnkyrinG

The bipolar disorder (BD) risk gene ANK3 encodes the scaffolding protein AnkyrinG (AnkG). In neurons, AnkG regulates polarity and ion channel clustering at axon initial segments and nodes of Ranvier. Disruption of neuronal AnkG causes BD-like phenotypes in mice. During development, AnkG is also expressed at comparable levels in oligodendrocytes and facilitates the efficient assembly of paranodal junctions. However, the physiological roles of glial AnkG in the mature nervous system, and its contributions to BD-like phenotypes, remain unexplored. Here, we generated oligodendroglia-specific AnkG conditional knockout mice and observed the destabilization of axoglial interactions in aged but not young adult mice. In addition, these mice exhibited profound histological, electrophysiological, and behavioral pathophysiologies. Unbiased translatomic profiling revealed potential compensatory machineries. These results highlight the critical functions of glial AnkG in maintaining proper axoglial interactions throughout aging and suggests a previously unrecognized contribution of oligodendroglial AnkG to neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Redefining the Game: MVAE-DFDPnet's Low-Dimensional Embeddings for Superior Drug-Protein Interaction Predictions

Precisely predicting drug-protein interactions (DPIs) is pivotal for drug discovery and advancing precision medicine. A significant challenge in this domain is the high-dimensional and heterogeneous data characterizing drug and protein attributes, along with their intricate interactions. In our study, we introduce a novel deep learning architecture: the Multi-view Variational Auto-Encoder embedded within a cascade Deep Forest (MVAE-DFDPnet). This framework adeptly learns ultra-low-dimensional embedding for drugs and proteins. Notably, our t-SNE analysis reveals that two-dimensional embedding can clearly define clusters corresponding to diverse drug classes and protein families. These ultra-low-dimensional embedding likely contribute to the enhanced robustness and generalizability of our MVAE-DFDPnet. Impressively, our model surpasses current leading methods on benchmark datasets, functioning in significantly reduced dimensional spaces. The models resilience is further evidenced by its sustained accuracy in predicting interactions involving novel drugs, proteins, and drug classes. Additionally, we have corroborated several newly identified DPIs with experimental evidence from the scientific literature. The code used to generate and analyze these results can be accessed from https://github.com/Macau-LYXia/MVAE-DFDPnet-V2.

bioinformatics↗

bioRxiv2024

One signal activated TIL enable potent anti-tumor activity across diverse solid tumor types

Adoptive T cell therapy (ACT) is a promising therapeutic option that enhances the anti-cancer immune response to recognize and eliminate tumor burden. Recently, ACT modalities with autologous tumor-infiltrating lymphocytes (TILs) have shown robust anti-tumor efficacy in solid tumors. However, this therapeutic strategys application remains suboptimal in stability and faces critical challenges, primarily due to the lack of costimulatory signals. Here, we unveil a novel engineering strategy one-signal-activated TIL (OSAT), which integrates CD3{zeta} with secondary signaling domains, to bypass the classical dual-signal requirement for T cell activation. We demonstrate that OSAT molecules 2 (CD3{zeta}-CD28, M2) and 7 (CD3{zeta}-CD137-CD28, M7) mediate efficient mono-signal activation, and recapitulate both the activation signatures and functional markers of mock T cells stimulated with dual signals. Notably, OSAT exhibited enhanced cytotoxicity and in vivo anti-tumor activity across syngeneic tumor models, especially when combined with PD-1 blockade therapy. Mechanistically, OSAT can be fully activated by first signal stimulation, leading to upregulation of activation and metabolic reprogramming genes, production of IL-2/IFN-{gamma}/TNF-, initiation of cytotoxicity, and enhanced TIL antitumor efficacy. These findings unveil integrating CD3{zeta} with secondary signaling domains as a higher efficacy modification for TILs with therapeutic potential for clinical cancer immunotherapy.

immunology↗

bioRxiv2024

Multi-omics Identify Serotonin Transporter as a Promising Therapeutic Target for Essential Tremor

Essential tremor (ET) stands as one of the most prevalent cerebellar movement disorders. However, effective treatment remains elusive, largely due to a limited understanding of its molecular pathology. Harmaline-induced tremor in mouse is a well-established animal model for ET, while with enigmatic mechanism. The aim of this study was to get insight into the molecular intricacies underlying cerebellar dysfunction in harmaline-induced tremor. Combining LC-MS/MS and RNA-Seq analysis, we delved into the variation of the cerebellum between harmaline-induced tremor and the control ones. This comprehensive investigation revealed a profile of this mouse model from mRNA and protein level, highlighting 5194 correlated coding molecules, with 19 proving to be significant. Further KEGG enrichment analysis identified cerebellar serotonin transporter (SERT) as the key molecule in harmaline-induced tremor. The implications of this transcriptomic and proteomic exploration underscore the potential therapeutic value of targeting SERT as a novel treatment approach for ET. In general, our study unveils crucial insights that could pave the way for molecular target identification and effective therapeutic interventions for ET.

neuroscience↗

bioRxiv2024

Detection of spatial chromatin accessibility patterns with inter-cellular correlations

Recent advances in spatial sequencing technologies enable simultaneous capture of spatial location and chromatin accessibility of cells within intact tissue slices. Identifying peaks that display spatial variation and cellular heterogeneity is the first and key analytic task for characterizing the spatial chromatin accessibility landscape of complex tissues. Here we propose an efficient and iterative model, Descartes, for spatially variable peaks identification based on the graph of inter-cellular correlations. Through the comprehensive benchmarking for spatially variable peaks identification, we demonstrate the superiority of Descartes in revealing cellular heterogeneity and capturing tissue structure. In terms of computational efficiency, Descartes also outperforms existing methods with spatial assumptions. Utilizing the graph of inter-cellular correlations, Descartes denoises and imputes data via the neighboring relationships, enhancing the precision of downstream analysis. We further demonstrate the ability of Descartes for peak module identification by using peak-peak correlations within the graph. When applied to spatial multi-omics data, Descartes show its potential to detect gene-peak interactions, offering valuable insights into the construction of gene regulatory networks.

bioinformatics↗

bioRxiv2024

Three-dimensional spatio-angular fluorescence microscopy with a polarized dual-view inverted selective-plane illumination microscope (pol-diSPIM)

Polarized fluorescence microscopy is a valuable tool for measuring molecular orientations, but techniques for recovering three-dimensional orientations and positions of fluorescent ensembles are limited. We report a polarized dual-view light-sheet system for determining the three-dimensional orientations and diffraction-limited positions of ensembles of fluorescent dipoles that label biological structures, and we share a set of visualization, histogram, and profiling tools for interpreting these positions and orientations. We model our samples, their excitation, and their detection using coarse-grained representations we call orientation distribution functions (ODFs). We apply ODFs to create physics-informed models of image formation with spatio-angular point-spread and transfer functions. We use theory and experiment to conclude that light-sheet tilting is a necessary part of our design for recovering all three-dimensional orientations. We use our system to extend known two-dimensional results to three dimensions in FM1-43-labelled giant unilamellar vesicles, fast-scarlet-labelled cellulose in xylem cells, and phalloidin-labelled actin in U2OS cells. Additionally, we observe phalloidin-labelled actin in mouse fibroblasts grown on grids of labelled nanowires and identify correlations between local actin alignment and global cell-scale orientation, indicating cellular coordination across length scales.

biophysics↗

bioRxiv2024

High Frequency Terahertz Stimulation Alleviates Neuropathic Pain by Inhibiting the Pyramidal Neuron Activity in the Anterior Cingulate Cortex of mice

Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system and is characterized by abnormal hypersensitivity to stimuli and nociceptive responses to non-noxious stimuli, affecting approximately 7-10% of the general population. However, current first-line drugs like non-steroidal anti-inflammatory agents and opioids have limitations, including dose-limiting side effects, dependence, and tolerability issues. Therefore, developing new interventions for the management of NP is urgent. In this study, we discovered that the high-frequency terahertz stimulation (HFTS) at approximate 36 THz effectively alleviates NP symptoms in mice with spared nerve injury. Computational simulation suggests that the frequency resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating the translocation of potassium ions. In vivo and in vitro results demonstrate that HFTS reduces the excitability of pyramidal neurons in the anterior cingulate cortex through enhancing the voltage-gated K+ and also the leak K+ conductance. This research presents a novel optical intervention strategy with terahertz waves for the treatment of NP and holds promising application in other nervous system diseases.

neuroscience↗

bioRxiv2024

Enhancing Gastrodin Production in Yarrowia lipolytica by Metabolic Engineering

Gastrodin, 4-hydroxybenzyl alcohol-4-O-{beta}-D-glucopyranoside, has been widely used in the treatment of neurogenic and cardiovascular diseases. Currently, gastrodin biosynthesis has been achieved in model microorganisms. However, the production levels are insufficient for industrial applications. In this study, we successfully engineered a Yarrowia lipolytica strain to overproduce gastrodin through metabolic engineering. Initially, the engineered strain expressing the heterologous gastrodin biosynthetic pathway, which comprises chorismate lyase, carboxylic acid reductase, phosphopantetheinyl transferase, endogenous alcohol dehydrogenases, and a UDP-glucose dependent glucosyltransferase, produced 1.05 g/L of gastrodin from glucose in a shaking flask. Then, the production was further enhanced to 6.68 g/L with a productivity of 2.23 g/L/day by over-expressing the key node DAHP synthases of the shikimate pathway and alleviating the native tryptophan and phenylalanine biosynthetic pathways. Finally, the best strain, Gd07, produced 13.22 g/L of gastrodin in a 5-L fermenter. This represents the highest reported production of gastrodin in an engineered microorganism to date, marking the first successful de novo production of gastrodin using Y. lipolytica. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/584284v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1eddb6corg.highwire.dtl.DTLVardef@e0bd94org.highwire.dtl.DTLVardef@be472dorg.highwire.dtl.DTLVardef@32fe9d_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

CoupleVAE: coupled variational autoencoders for predicting perturbational single-cell RNA sequencing data

With the rapid advances in single-cell sequencing technology, it is now feasible to conduct in-depth genetic analysis in individual cells. Study on the dynamics of single cells in response to perturbations is of great significance for understanding the functions and behaviours of living organisms. However, the acquisition of post-perturbation cellular states via biological experiments is frequently cost-prohibitive. Predicting the single-cell perturbation responses poses a critical challenge in the field of computational biology. In this work, we propose a novel deep learning method called coupled variational autoencoders (CoupleVAE), devised to predict the post-perturbation single-cell RNA-Seq data. CoupleVAE is composed of two coupled VAEs connected by a coupler, initially extracting latent features for both controlled and perturbed cells via two encoders, subsequently engaging in mutual translation within the latent space through two nonlinear mappings via a coupler, and ultimately generating controlled and perturbed data by two separate decoders to process the encoded and translated features. CoupleVAE facilitates a more intricate state transformation of single cells within the latent space. Experiments in three real datasets on infection, stimulation and cross-species prediction show that CoupleVAE surpasses the existing comparative models in effectively predicting single-cell RNA-seq data for perturbed cells, achieving superior accuracy.

bioinformatics↗

bioRxiv2024

Intrinsically linked lineage-specificity of transposable elements and lncRNAs reshapes transcriptional regulation species- and tissue-specifically

Unlike protein-coding genes, many mammalian lncRNAs are lineage-specific (LS), but which human and mouse reference lncRNAs are lineage-specific, how they are generated, and whether their regulatory elements are lineage-specific remain unclear. To resolve their origins, properties, and impacts, we systematically classified primate-, simian-, rodent-, human-, and mouse-specific lncRNAs in GENCODE-annotated human and mouse genomes using structure-aware covariance modeling. We predicted their DNA-binding domains (DBDs) and genomic binding sites (DBSs) and traced the origins of embedded transposable elements (TEs). LS TEs contribute to over 84% (human) and 98% (mouse) of LS lncRNAs, 61% and 95% of their DBDs, and 46% and 73% of their DBSs. Analyses of multi-omics data and a developmental process suggest that LS TE-linked lineage-specificity substantially rewires transcriptional regulation and that many evolutionary novelties may be structurally predisposed. These findings bridge the gap between human diseases and mouse models, providing valuable resources for identifying human-specific therapeutic lncRNA targets.

genomics↗

bioRxiv2024

MYT1L deficiency impairs excitatory neuron trajectory during cortical development

Mutations that reduce the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. Furthermore, MYT1L is routinely used as a proneural factor in fibroblast-to-neuron transdifferentiation. MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss. In this study, we profiled 313,335 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete, to examine the role of MYT1L levels in the trajectory of neuronal development. We found that MYT1L deficiency significantly disrupted the relative proportion of cortical excitatory neurons at E14 and P21. Significant changes in gene expression were largely concentrated in excitatory neurons, suggesting that transcriptional effects of MYT1L deficiency are largely due to disruption of neuronal maturation programs. Most effects on gene expression were cell autonomous and persistent through development. In addition, while MYT1L can both activate and repress gene expression, the repressive effects were most sensitive to haploinsufficiency, and thus more likely mediate MYT1L syndrome. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.

neuroscience↗

bioRxiv2024

Enhanced Ca2+-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

Background and AimsSubstantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca2+ dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca2+-driven instabilities compared to male cardiomyocytes. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs females and establish their responses to Ca2+-targeted interventions. Methods and ResultsWe incorporated known sex differences and AF-associated changes in the expression and phosphorylation of key Ca2+-handling proteins and in ultrastructural properties and dimensions of atrial cardiomyocytes into our recently developed 3D atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca2+-handling processes. Our simulations of quiescent cardiomyocytes show increased incidence of Ca2+ sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca2+ releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca2+ transients compared with the male model. Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation in female AF cardiomyocytes emerged as the major SCR contributor, while reduced L-type Ca2+ current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulations of tentative Ca2+-targeted interventions identified potential strategies to attenuate Ca2+-driven arrhythmogenic events in female atria (e.g., t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca{superscript 2}-ATPase), and revealed enhanced efficacy when applied in combination. ConclusionsOur sex-specific computational models of human atrial cardiomyocytes uncover increased propensity to Ca2+-driven arrhythmogenic events in female compared to male atrial cardiomyocytes in AF, and point to combined Ca2+-targeted interventions as promising approaches to treat AF in female patients. Our study establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms. Translational perspectiveAccumulating evidence demonstrates substantial sex-related differences in atrial fibrillation (AF), which is the most common arrhythmia, with female patients faring worse with the condition. By integrating known sex-differential components into our computational atrial cardiomyocyte model we found that female atrial cardiomyocytes in AF exhibit greater propensity to develop Ca2+-driven arrhythmia than male cardiomyocytes. Model analyses provided novel mechanistic insights and suggested strategies such as t-tubule restoration, correction of Ca2+-handling disturbances, and the combination of both, as promising approaches to treat AF in female patients. Our study uncovers and validate sex-specific AF mechanisms and inform the development of targeted anti-AF strategies. O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/583217v2_figa1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@d3ec3borg.highwire.dtl.DTLVardef@13a2c7borg.highwire.dtl.DTLVardef@3e4605org.highwire.dtl.DTLVardef@6726b4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO Sex-specific 3D spatiotemporal models of human atrial cardiomyocyte Ca2+ signaling reveal a greater propensity to develop Ca2+-driven arrhythmic events in female vs male atrial cardiomyocytes in AF. Model analysis links sex-specific AF remodeling to arrhythmogenic mechanisms. AF, atrial fibrillation; SCR, spontaneous Ca2+ release; CaT, cytosolic Ca2+ transient; RyR2-P, phosphorylated ryanodine receptor type 2 (RyR2); CSQ, calsequestrin; LTCC, L-type Ca2+ channel; PLB, phospholamban; SERCA, sarcoendoplasmic reticulum Ca2+ ATPase; SR, sarcoplasmic reticulum. C_FIG

physiology↗