Biology subjects

Wang, J.

Publications and source records attributed to Wang, J..

At least 469 records · Page 26Linked to original sources

bioRxiv2025

Incentive valence differentially engages open- and closed-loop basal ganglia circuits during movement initiation

Incentives modulate voluntary movement, yet the circuitry channeling these signals into motor output remains unclear. Classical models emphasize a closed-loop circuit (CLC) linking dorsal putamen (PUTd) with motor cortex, but this pathway is anatomically segregated from affective processing regions. Anatomical and clinical evidence point to an alternative: an open-loop circuit (OLC) from ventral putamen (PUTv) that may route affective signals to motor cortex. Here, we conducted two experiments to test whether a functional OLC exists in humans and whether it is differentially engaged by incentive conditions. First, in 7 T resting-state fMRI (multi-echo), PUTv showed robust functional connectivity with both affective and motor regions, including the cingulate motor area (CMA), even after accounting for PUTd variance. This connectivity pattern supports the plausibility of an independent pathway linking affective basal ganglia regions to the motor cortex. Second, in 3 T task fMRI (incentivized reaching), jackpot (high-reward) and robber (high-loss avoidance) incentive conditions produced distinct behavioral and neural signatures. Jackpot produced a speed-accuracy trade-off, with faster movement initiation but more false starts. Neurally, this coincided with engagement (BOLD responses relevant for initiation speed) being reduced in CLC nodes but not in OLC. Robber, in contrast, eliminated engagement in both OLC and CLC nodes, instead recruiting stopping-related regions (e.g., STN), consistent with an avoidance phenomenology. Together, these findings support a versatile architecture for movement initiation that flexibly engages distinct cortico-subcortical circuits depending on incentive phenomenology, and offer a candidate mechanism through which affective salience and valence modulate voluntary movement. Significance StatementAffective signals profoundly influence movement, yet the mechanisms linking motivationally relevant contexts with motor behavior remain unclear. Combining ultra-high field (7 T) connectomics with task-based (3 T) neuroimaging, we provide the first systems-level evidence in humans for such a mechanism: a ventral putamen-centered open-loop circuit (OLC) connecting affective and motor areas, operating alongside the canonical dorsal putamen-centered closed-loop sensorimotor circuit (CLC). Critically, the phenomenological quality of incentive (how it is construed as reward versus threat) rather than magnitude alone, likely determines which circuit dominates during movement initiation. These findings help to explain paradoxical kinesia in Parkinsons disease, where affective contexts can bypass degraded sensorimotor circuits, and establish foundations for context-based therapeutic interventions.

neuroscience↗

bioRxiv2025

An accurate phasing tool via high-quality heterozygous variations

Long-read phasing has become a widely adopted approach for reconstructing paternal and maternal haplotypes in diploid genomes. However, most existing phasing methods treat all variants equally, even though low-quality variants frequently introduce switch errors. We present a new phasing method, snpphaser, which first phases high-quality variants and then leverages them to filter out low-quality variants that are inconsistent with the high-confidence haplotypes. We benchmarked snpphaser against state-of-the-art phasing methods across nine diverse datasets. The results demonstrate that snpphaser achieves superior contiguity and accuracy compared to existing approaches.

bioinformatics↗

bioRxiv2025

AI Identifies Broadly Neutralizing Antibodies from an IGHV1-69 Public Antibody Class Exerting Continued Selection Over SARS-CoV-2

R1-32-like public antibodies, characterized by shared IGHV1-69/IGLV1-40 usage, are elicited in more than 50% of individuals with COVID-19 and have been implicated in driving recurrent mutations at L452SARS2 and F490SARS2 within their convergent epitope in the SARS-CoV-2 spike receptor-binding domain. These mutations effectively mediate escape from non-affinity-matured R1-32-like antibodies with germline-like sequences. Here, we characterize four affinity-matured R1-32-like antibodies, C092, C807, BD56-104, and BD56-597, that tolerate L452SARS2 and F490SARS2 mutations. We show that this tolerance arises from residues introduced by somatic hypermutation at convergent positions across multiple CDR loops and surrounding regions, thereby creating additional contacts that reinforce epitope binding. An unusual N354SARS2 glycosylation site, which emerged in BA.2.86 and became fixed in its descendants, is linked to escape from affinity-matured R1-32-like antibodies, implying ongoing selection by this public antibody class. Using an AI model trained on integrated structural, neutralization, and binding data, we further identified ZL525, an ultrapotent R1-32-like antibody with pan-SARS-CoV-2 variant activity, including against the highly evasive KP.3 variant carrying the N354SARS2 glycosylation, and broad sarbecovirus cross-reactivity extending to SARS-CoV-1. Together, these findings show how affinity maturation enables public antibodies to adapt to viral antigenic drift, reveal their role in shaping SARS-CoV-2 antigenic evolution, and demonstrate the potential of AI-empowered strategies for discovering broadly neutralizing antibodies.

immunology↗

bioRxiv2025

Evolutionarily Conserved T-tubule-Mitochondria Contacts in Striated Muscle

The intricate architecture of skeletal muscle is essential for its contractile function, with the spatial organization of organelles such as T-tubules and mitochondria playing a crucial role in maintaining muscle performance and health1,2. T-tubules propagate electrical signals deep into muscle fibers to ensure synchronous contraction, while mitochondria provide the necessary energy for muscle contraction3-5. Previous studies have extensively documented the interactions between T-tubules and the sarcoplasmic reticulum (SR), which are essential for excitation-contraction coupling6,7. However, the detailed spatial relationship between T-tubules and mitochondria has remained relatively unexplored. In this study, we utilized zebrafish and mice as model organisms to investigate the contacts between T-tubules and mitochondria. Using array tomography, deep learning-based analysis, and advanced microscopy techniques, we discovered extensive membrane contact sites, termed T-tubule-Mitochondria (TTM) contacts. These contacts are evolutionarily conserved across vertebrates, including skeletal and cardiac muscles. Our findings reveal a previously unrecognized, intimate spatial coupling between T-tubules and mitochondria, with significant implications for muscle physiology and pathology. Understanding these TTM contacts could provide new insights into the mechanisms underlying muscle function and the development of muscle-related diseases.

cell biology↗

bioRxiv2025

AXL governs axolotl cardiac regeneration and directs mammalian cardiomyocyte dedifferentiation

Cardiac injury outcomes vary widely across species, from complete regeneration to irreversible scarring. Using single-nucleus multiomics and spatial transcriptomics, we generated a spatially resolved atlas of axolotl heart regeneration following injury, identifying a distinct border-zone cardiomyocyte population with a pro-regenerative transcriptional program. Ligand-receptor analysis of the border zone niche identified enrichment of the receptor tyrosine kinase AXL in injury-responsive cardiomyocytes and its ligand Gas6 in endothelial cells. Functional perturbation demonstrated AXL requirement for border-zone cardiomyocyte activation and axolotl heart regeneration. In murine cardiomyocytes, AXL overexpression induced sarcomere disassembly, metabolic rewiring, and immature gene expression without triggering proliferation. These findings show that AXL signaling induces cardiomyocyte dedifferentiation and uncouples dedifferentiation from cell cycle re-entry, providing mechanistic insight into cellular plasticity during heart regeneration.

cell biology↗

bioRxiv2025

Regulatable In Vivo Gene Expression via Adaptamers

Precise, reversible control of transgene expression is essential for safe and durable gene therapy, yet current inducible systems remain difficult to translate in vivo due to large size, limited induction duration, and dependence on immunogenic regulators. Here we present the adaptamer (ADAR modulatable aptamer), a compact (<120 bp) RNA switch that couples an FDA-approved small-molecule-responsive aptamer with endogenous ADAR-mediated RNA editing to regulate expression. Ligand binding stabilizes a double-stranded RNA structure that recruits ADAR to convert a stop codon into a sense codon, restoring downstream protein translation. This cleavage-free, post-transcriptional mechanism enables precise, small-molecule-dependent modulation without exogenous protein machinery. We demonstrate that adaptamers are highly functional across multiple cell lines, including human T-cells. In mice, AAV-delivered adaptamer-controlled FGF21 expression induced metabolic remodeling, significantly increasing energy expenditure and reversing obesity. This minimal, programmable system offers a clinically compatible approach for tunable genetic medicines and safe deployment of pleiotropic and dose-limited proteins.

synthetic biology↗

bioRxiv2025

CyTOF-based profiling of circulating tumor cells predicts aggressiveness and therapy response in SCLC liquid biopsies at a personalized level

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma characterized by high numbers of circulating tumor cells (CTCs). We applied CyTOF and a 20-marker antibody panel to detect and phenotype CTCs directly in liquid biopsies of 51 SCLC patients (treatment-naive, chemotherapy and immunotherapy-treated, and tarlatamab-treated), of which a subset were longitudinally tracked. Unsupervised clustering revealed distinct cell populations enriched in patient liquid biopsies compared to those from healthy donors. Further analysis identified CTC populations of the three established SCLC subtypes driven by the high expression of ASCL1, NeuroD1, and POU2F3 transcription factors respectively. Significant differences in CTC EMT markers, established therapeutic targets (e.g. DLL3), and subtype heterogeneity were observed between naive versus treated samples. Changes in subtype proportions were observed in longitudinally tracked samples in both treatment modalities. Our study demonstrates the utility of CyTOF for high-resolution CTC profiling, offering dynamic insights into CTC heterogeneity, treatment response, and resistance mechanisms. HighlightsO_LICTCs can be detected, subtyped and phenotyped in SCLC liquid biopsies using CyTOF C_LIO_LICTC subtypes and EMT states are differentially associated with treatment modality C_LIO_LICTC DLL3 levels and epithelial features increase following anti-DLL3 BiTE therapy C_LIO_LICyTOF CTC subtyping can predict disease aggressiveness C_LIO_LILongitudinal tracking reveals CTC plasticity and therapy response correlations C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/694669v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@384cbcorg.highwire.dtl.DTLVardef@35dd37org.highwire.dtl.DTLVardef@4e7d61org.highwire.dtl.DTLVardef@1098e4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A novel, fig-associated microbe promotes reproductive success via variable life history mechanisms in C. elegans and C. inopinata

Variation in life history strategies is among the most striking features of animal diversity. Simultaneously, the microbes an animal interacts with are a critical and dynamic aspect of the host environment that can have profound impacts on their life history traits. As microbial environments diverge across animal lineages, life histories and their responses to such microbial contexts are expected to evolve as a consequence. Caenorhabditis nematodes are bacterivores that exhibit a diversity of life history strategies and fill diverse ecological niches. C. elegans thrives on rotting plants and grows rapidly with high fecundity; C. inopinata thrives in fresh figs and grows more slowly with lower fecundity. To understand how hosts with divergent life histories and ecologies respond to the microbes they interact with, we isolated over forty bacterial species from the natural fig environment of C. inopinata. This microbial survey revealed an isolate, Klebsiella sp. WOUb2, that doubles the population growth rate of C. inopinata. While this isolate also increases the population growth rate of C. elegans, Klebsiella sp. WOUb2 increases individual fecundity and developmental rate in C. elegans, whereas it only increases developmental rate of C. inopinata. Thus, fitness is modulated by variable life history mechanisms in the two species. Comparisons with nucleotide databases reveal Klebsiella sp. WOUb2 is closely related to other Klebsiella isolates known to influence Caenorhabditis nematode fitness. Additionally, the similarity of Klebsiella sp. WOUb2 to microbes associated with fig wasps and figs suggests C. inopinata frequently encounters this microbe in its natural context. Taken together, this shows that different physiological responses can underlie conserved, beneficial interspecific interactions.

evolutionary biology↗

bioRxiv2025

Ectopic engraftment of nociceptive neurons derived from hPSCs for pain relief and joint homeostasis

Chronic pain arises from the interplay of inflammatory signals that activate and sensitize nociceptors within injured tissues. Most analgesics fail clinically due to their mono-targeted mechanisms. Here, we apply human pluripotent stem cell-derived nociceptive neurons (hPSC-NNs) as therapeutic agents for osteoarthritis, targeting both pain and joint degeneration. We generated sensory neurons from hPSCs and identified CD200 as a nociceptor marker. Transcriptomic and functional profiling revealed that CD200highhPSC-NNs closely resemble human nociceptors, expressing pain-relevant receptors and ion channels. Strikingly, ectopic transplantation of CD200highhPSC-NNs into the knee joint of osteoarthritic mice reduced pain and promoted bone and cartilage repair, whereas CD200low cells exhibited no benefit. Mechanistically, human and mouse proteomics suggest that CD200highhPSC-NNs act as decoys by sequestering inflammatory ligands while secreting reparative factors in joint tissues. These findings uncover a fundamental role of nociceptors in tissue repair, providing a multi-targeted, disease-modifying strategy for OA and chronic pain. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/694733v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@15f0948org.highwire.dtl.DTLVardef@5a59bforg.highwire.dtl.DTLVardef@1ba4439org.highwire.dtl.DTLVardef@1d518d1_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIhPSC-derived nociceptors (hPSC-NNs) as Decoy Engraftment for Cellular Interception and Repair (DECIR) when transplanted into the knee joint, extending beyond conventional regenerative strategies C_LIO_LICD200 serves as a clinically actionable surface marker for the purification of hPSC-NNs C_LIO_LIEctopic grafting of CD200high hPSC-NNs delivers dual benefits, alleviating pain and modulating the neuro-immune environment within joint tissues C_LIO_LIProteomic analyses reveal that CD200highhPSC-NNs sequester inflammatory mediators and secrete reparative factors to support joint homeostasis C_LI

neuroscience↗

bioRxiv2025

IGHV3-53 antibody abundance drives divergent SARS-CoV-2 immune imprinting

The mechanisms driving divergent SARS-CoV-2 immune imprinting in populations with distinct SARS-CoV-2 exposure histories remain unclear. However, conventional wild-type mouse models fail to recapitulate severe imprinting, even after potent ancestral-strain mRNA immunization, hindering imprinting-related mechanistic investigation and vaccine evaluation. Here, we surprisingly found that V(D)J-humanized mice could faithfully recapitulate human severe imprinting phenotypes. Comprehensive antibody repertoire analysis and deep mutational scanning-based epitope mapping of 583 monoclonal antibodies from these models revealed that the pre-existing IGHV3-53/66 antibody abundance determine imprinting severity through antibody-mediated masking of Omicron-specific epitopes. Both passive IGHV3-53/66 antibody transfer and IGHV3-53 knock-in were sufficient to induce severe imprinting in wild-type mice. Together, these findings demonstrate that the V(D)J germline repertoire--even a single germline-encoded antibody response--can profoundly shape humoral imprinting severity. Accordingly, we established an IGHV3-53 knock-in mouse model that accurately recapitulates the human antibody landscape, providing a valuable tool for guiding future COVID-19 vaccine updates.

immunology↗

bioRxiv2025

A Multi-Modal Transfer Learning Framework to Reduce Health Disparities in Prostate Adenocarcinoma

Prostate cancer is the second most common cancer in men across the United States, of which prostate adenocarcinoma (PRAD) is the most common subtype. Despite remarkable progress has been made in PRAD diagnosis and prognosis, Black American men have been found to have disproportionately high incidence and mortality rate in PRAD compared with non-Hispanic White men in the United States. While machine learning (ML) methods like transfer learning (TL) have shown promise in reducing racial disparities in PRAD, its effectiveness is often compromised by the requirement for large-scale training datasets, which are challenging to obtain in clinical settings. In addition, existing ML approaches only leverage single-omics data without integrating multi-omics information. To address these concerns, we propose a novel approach called MOTLPRAD that develops a Multi-Omics integration Transfer Learning framework to reduce health disparities in PRAD. Specifically, we first investigated two multi-modal ensemble methods, Pearson correlation coefficient (PCC) based patient-pairwise similarity and variational autoencoder (VAE), to integrate different types of omics data. Then, we adopted a transfer learning model based on domain adaptation to pre-train the model on the majority group (e.g., non-Hispanic White Americans) and fine-tune the model using the minority group (e.g., Black Americans). To mitigate data imbalance across different ethnic groups, we leveraged the Synthetic Minority Oversampling Technique (SMOTE) to augment the sample size of minority groups, which could further improve the performance of reducing health disparities in PRAD. Results based on a series of multi-omics data (mRNA, miRNA, and methylation) from The Cancer Genome Atlas (TCGA) database suggested that our proposed model significantly outperformed conventional transfer learning models and other computational models for reducing racial disparities when predicting progression-free interval (PFI) prognosis for PRAD patients. In addition, our model also demonstrated that integrating multi-omics data could remarkably boost the performance of mitigating health disparities compared to using single-omics data. We believe our proposed framework could provide a new way to systematically mitigate health disparities towards underrepresented groups for PRAD diagnosis, prognosis, and treatment.

bioinformatics↗

bioRxiv2025

Polus: a Transformer-based Soft-decision Codec Enhancement Platform for DNA Storage

DNA storage offers exceptional information density and archival longevity, but is constrained by the complex, heterogeneous errors inherent to synthesis, storage, and sequencing. Conventional error-correction schemes often rely on excessive logical redundancy to mitigate these biochemical imperfections, thereby compromising storage efficiency. Here, we introduce Polus, a deep-learning-enabled platform that bridges the gap between biochemical constraints and digital reliability through soft-decision decoding. At its core is SeqFormer, a Transformer-based channel model that synergizes sequence context with quality signals to characterize platform-specific error profiles, generating calibrated per-base confidence scores. This mechanism transforms uncertain biochemical noise into informative "soft" erasures. In in silico benchmarks, Polus significantly enhances mainstream codecs: it reduces the sequencing coverage required for DNA Fountain by 38.9% --increasing effective physical density by [~]80%--and eliminates persistent indel-induced errors in the Yin-Yang codec. Furthermore, it enables a targeted resequencing strategy that achieves full recovery with 99.9% less overhead than brute-force deepening. To formalize these gains and address the lack of systematic benchmarking in the field, Polus establishes a standardized nine-metric evaluation framework that rigorously quantifies the trade-offs between reliability, density, and cost. This work provides a reproducible, quantitative foundation for next-generation, context-aware DNA storage systems.

bioinformatics↗

bioRxiv2025

Leaf microbiome assembly is linked to plant phylogeny

Background and AimsThe plant microbiome is considered as an extended part of the plant genome, and it provides key functions in regulating plant fitness, and stress tolerance. Plants and associated microbiomes have co-evolved over millennia, yet evidence for a strong influence of plant phylogeny in influencing their microbiomes is largely lacking. Our main aims was to identify key drivers of plant microbiome assembly. MethodsHere, we conducted a full factorial experiment that included three levels of soil microbial diversity, five plant species from three functional groups (C3, C4, and C3 nitrogen-fixing), and two moisture availability levels. ResultsOur results showed that host identity and plant functional group exerted the strongest effect on leaf microbial assembly, while root and soil microbiomes showed less sensitivity to host selection. The initial soil microbial diversity and community structure significantly impacted soil and root microbial composition, but not leaf microbiomes. Importantly, we observed significant positive linkage between host phylogeny distance and Bray-Curtis dissimilarity index in leaf microbiomes. This finding was further validated through analysis of microbiome data from seven plant species grown across different field and environmental conditions. Interestingly, there was no significant impact of short-term water stress on plant microbial communities. ConclusionsBy providing empirical evidence for important role of host selection in shaping plant microbiomes, this study advances our fundamental knowledge of plant-microbe interactions and their co-evolutionary relationships, and enhances our ability to develop future tools harnessing plant microbiome to improve plant health and productivity.

microbiology↗

bioRxiv2025

Motility Functions as an Essential Defense in the Bacterial Persister Lifecycle

Bacterial persisters are phenotypically antibiotic-tolerant variants driving recurrent infections. While motility is a key trait for bacterial survival and virulence, its function throughout the persister lifecycle remains poorly understood. Here, we unveil a stage-specific trajectory for motility that underlies sophisticated survival strategies in rifampin-induced Escherichia coli persistence. During persister formation, intact motility functions as an immediate behavioral defense that decreases intracellular bactericidal antibiotic concentrations to ensure survival. This initial behavioral defense provides critical time for transcriptional reprogramming in persisters, which, by downregulating the major outer membrane porins (OmpC & OmpF) that facilitate antibiotic influx, supplants the preceding motility-based strategy. Subsequently, in structurally fortified persisters, motility becomes dispensable and gradually diminishes- a process independent of cell bioenergetic profile-yet re-emerges as essential for timely resuscitation upon antibiotic removal. Collectively, these findings establish the significance of motility in bacterial survival, redefine persister defense against antibiotics as a transition from behavioral to architectural strategies, and identify motility as a potential adjuvant therapeutic target. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/694804v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@afdee5org.highwire.dtl.DTLVardef@52b4beorg.highwire.dtl.DTLVardef@1d865b6org.highwire.dtl.DTLVardef@1fd9cfb_HPS_FORMAT_FIGEXP M_FIG C_FIG The dynamic roles and underlying mechanisms of bacterial motility throughout the rifampin-induced persister lifecycle: motility initially serves as a behavioral defense mechanism essential for persister formation, then becoming dispensable in the persister state which implements a structural defense via membrane porin downregulation, and ultimately re-emerges as a critical requirement for timely resuscitation.

microbiology↗

bioRxiv2025

Mechanical Ventilation Suppresses Glymphatic Function in Parallel with Delirium-Like Symptoms in Mice

Delirium is a common and serious complication in critically ill patients, arising from multiple overlapping risk factors. Its pathogenesis remains poorly understood because it reflects the combined effects of interacting clinical insults, and because appropriate experimental models for mechanistic studies have been lacking. Delirium most commonly develops in patients undergoing major surgery or requiring intensive care, where inhalational anesthesia, opioid sedation, and mechanical ventilation are common clinical exposures. Here, we tested the hypothesis that these clinically relevant interventions are sufficient to induce delirium-like behavior in healthy young wild-type mice by disrupting cerebrospinal fluid (CSF) glymphatic transport. The analysis showed that inhalational anesthesia combined with mechanical ventilation increased intracranial pressure (ICP) and induced a sustained suppression and rerouting of glymphatic waste clearance, resulting in impaired waste clearance, and acute cytokine accumulation. These findings identify disruption of brain fluid dynamics as a potential mechanism contributing to delirium in perioperative and intensive care settings. Equally important, this model represents a distinct experimental platform that combines clinically relevant mechanical ventilation, inhalational anesthesia, and opioid analgesia to produce delirium-like behavioral abnormalities in otherwise healthy mice. It therefore provides a powerful tool for future mechanistic studies of delirium pathogenesis.

neuroscience↗

bioRxiv2025

RPRM (Reprimo) triggers SCF(FBXW11)-mediated DNA-PKcs degradation to block non-homologous end joining and radiosensitize tumors

Targeting DNA damage repair pathways represents a promising strategy in cancer radiotherapy, however, the limited insight into the regulation of the non-homologous end joining (NHEJ) repair pathway in cancer cells severely restricts the development of precise radiosensitization approaches. Here, we identify Reprimo (RPRM), a p53-inducible tumor suppressor, is a potent inhibitor of NHEJ in which RPRM promotes proteasomal degradation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylated at the T2609 site. Upon irradiation, RPRM quickly translocates into the nucleus to enhance the transcription of FBXW11, a F-box protein gene that encodes the substrate recognition component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. In the nucleus, RPRM is also able to scaffold the assembly of the SCFFBXW11 E3 ligase complex by binding to both CUL1 and FBXW11. This complex can specifically ubiquitylate phosphorylated DNA-PKcs (T2609), leading to reduced levels of both phosphorylated DNA-PKcs (T2609) and total DNA-PKcs, thereby suppressing NHEJ-driven repair and enhancing tumor radiosensitivity. In consistence, inhibiting the SCFFBXW11 E3 ligase complex eliminates RPRM-mediated radiosensitization by protecting DNA-PKcs. Clinically, high RPRM expression in non-small cell lung cancer (NSCLC) predicts better patient prognosis. Moreover, RPRM expression correlates positively with FBXW11 and PRKDC (DNA-PKcs) in the tumor tissues of the NSCLC patient cohort. Significantly, high expression of RPRM protein is linked to enhanced radiosensitivity of patient-derived organoids (PDOs) from these NSCLC patients. These results establish RPRM as a key negative regulator in NHEJ repair pathway and the RPRM-SCFFBXW11-DNA-PKcs axis as a potential target to enhance cancer radiosensitivity.

cancer biology↗

bioRxiv2025

Gasdermin E couples mitochondrial damage to pyroptotic neurodegeneration in Parkinson disease

Parkinsons disease (PD) features progressive loss of nigrostriatal dopamine neurons, but how mitochondrial damage engages programmed cell death pathways remains unresolved. Here, we identify gasdermin E (GSDME), the caspase-3-activated executor of pyroptosis, as a critical mediator of neurodegeneration in toxin-based PD models. In primary neurons and SH-SY5Y cells, the mitochondrial complex I inhibitor MPTP/MPP triggered caspase-3 activation, GSDME cleavage, and lytic membrane rupture. Genetic silencing of Gsdme or its transcriptional regulator SP1 reduced neuronal death. In vivo, Gsdme deficiency preserved substantia nigra pars compacta dopaminergic neurons, improved motor performance, and mitigated anxiety- and depression-like behaviors after MPTP administration. Loss of Gsdme also dampened microglial and astrocytic activation and lowered proinflammatory cytokines in striatum and substantia nigra. Mechanistically, cleaved GSDME localized to mitochondria, disrupted membrane potential, increased reactive oxygen species, and precipitated organelle injury, thereby coupling mitochondrial dysfunction to pyroptotic cell death. These findings identify GSDME-mediated pyroptosis as a mechanistic link between mitochondrial toxicity and neuroinflammation in PD and nominate GSDME as a therapeutic entry point to slow disease progression. SignificanceHow mitochondrial injury kills dopamine neurons in Parkinsons disease is a central unresolved question. We show that the pyroptosis executor GSDME is required for neurodegeneration and neuroinflammation in MPTP models, mechanistically linking caspase-3 activation and mitochondrial damage to lytic cell death. Targeting GSDME may provide a strategy to protect vulnerable neurons in PD. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/694264v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@15364e7org.highwire.dtl.DTLVardef@57b65org.highwire.dtl.DTLVardef@1e85108org.highwire.dtl.DTLVardef@1200d34_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsGSDME drives PD-linked neuronal loss. Silencing GSDME (or its transcriptional factor Sp1) ameliorates MPTP-triggered neuronal cell death. Genetic ablation of Gsdme is protective in the MPTP-induced PD mouse model. Gsdme-/-mice retain nigrostriatal DA neurons, show improved motor and affective behaviors, and exhibit reduced microglial and astrocytic activation and cytokines release upon MPTP treatment. Cleaved GSDME accumulates on mitochondria, collapses {Delta}{Psi}m, raises ROS, and links mitochondrial toxicity to pyroptosis, thus positioning GSDME as a tractable target to slow PD progression.

neuroscience↗

bioRxiv2025

Functional rescue of critical-size bone defect using molecular network analysis of axolotl limb regeneration.

The salamander limb has served as a canonical model for successful regeneration that has yielded numerous molecular insights on its basic mechanism. Harnessing such information to induce regeneration in a non-regenerative setting has been a long-sought goal. The amputated salamander limb efficiently regenerates all of its missing bones, but paradoxically, a large bone gap without amputation - commonly called a Critical Size Defect (CSD) - is not regenerated, similarly to other vertebrates1. This non-regenerating injury provides a human-relevant setting to understand how to rescue lack-of-regeneration. Satoh and colleagues demonstrated in axolotl that transplantation of blastema cells from an amputated limb into a CSD yields cartilage bridging of the CSD2. This work provided a roadmap for rescuing the CSD. Here we asked, what are the crucial molecular differences in cells populating a regenerating blastema versus the CSD and can they be used to elicit CSD bridging? Previous genetic fate mapping and single cell transcriptomics showed that limb regeneration occurs via migration and dedifferentiation of fibroblastic, soft connective tissue (CT) cells that form a multipotent, skeletal stem cell 3, 4. Here using single cell transcriptomics and genetic fate mapping we found that the CSD is populated by CT cells that undergo a divergent molecular transition compared to the blastema. Using gene regulatory network (GRN) modeling, and lipid nanoparticle (LNP) delivery of mRNA we could express a single molecular factor, Wnt3a, to induce cartilage bridging of the CSD. Our results demonstrate the power of using molecular information from successful regeneration to rescue a non-regenerating injury.

cell biology↗