Biology subjects

Park, J.

Publications and source records attributed to Park, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

Novel estimation of memory in molecular dynamics with extended and comprehensive single-molecule tracking software: FreeTrace

Single-molecule tracking (SMT) in live cells reveals how biomolecules explore crowded intracellular environments, yet most tracking software assumes Brownian motion, an approximation that fails when anomalous diffusion dominates. This leads to biased trajectory reconstruction and loss of biophysical information, particularly for the short trajectories typical of intracellular experiments. We present FreeTrace, an SMT framework that reconstructs trajectories under fractional Brownian motion (fBm), incorporating temporal correlations directly into linking with minimal input parameters. A deep neural network estimates diffusion properties (Hurst exponent H and generalised diffusion coefficient K) for individual trajectories, while an analytical ensemble estimator accurately recovers H from trajectories as short as three frames, conditions where mean-squared displacement methods fail. Benchmarking on simulated data demonstrates superior performance across motion types and densities. Applications to chromatin-bound histones, DNA repair proteins in S.c. yeast and human cells reveal biologically meaningful diffusion subpopulations, with H values consistent with polymer models and confined motion. FreeTrace bridges theoretical anomalous diffusion models and routine biological experiments.

molecular biology↗

bioRxiv2026

DelPi Learns Generalizable Peptide-Signal Correspondence for Mass Spectrometry-Based Proteomics

Peptide identification in mass spectrometry-based proteomics has traditionally relied on handcrafted features or simplified probabilistic approaches that limit the interpretation of structured peptide evidence. We present DelPi, an open-source peptide identification framework that learns generalizable peptide-signal correspondence from raw spectra through self-supervised pre-training followed by task-specific fine-tuning. With model distillation enabling practical deployment, DelPi expands the interpretation of peptide evidence across data-independent and data-dependent acquisition while maintaining robust false discovery control.

bioinformatics↗

bioRxiv2026

The Extracellular Matrix Regulates Invasion in Fusion-Negative Rhabdomyosarcoma via YAP-PIEZO1 Signaling Axis

BackgroundFusion-negative rhabdomyosarcoma (FNRMS) represents the most prevalent subtype of rhabdomyosarcoma, the most common pediatric soft tissue sarcoma. Although its invasion is a leading cause of recurrence and poor prognosis, its underlying mechanism remains unclear. We investigated how extracellular matrix (ECM) density regulates FNRMS progression via mechano-transduction. MethodsWe used three-dimensional spheroid invasion assays with RD and SMS-CTR cells embedded in varying collagen concentrations. Mechanistic insights were gained through immunofluorescence, ChIP-seq re-analysis, Fluo-4 calcium live cell imaging, and pharmacological inhibition of the YAP-PIEZO1 axis. ResultsHigh ECM density significantly enhanced invasive spreading, correlating with increased YAP nuclear localization. YAP overexpression was sufficient to promote invasion, while its inhibition attenuated the matrix-enhanced phenotype. We identified PIEZO1 as a direct transcriptional target of the YAP. High ECM density stimulated PIEZO1-dependent calcium influx, which was required for invasion. Furthermore, elevated PIEZO1 expression was significantly associated with poorer overall survival in FNRMS patients. Targeting YAP or ROCK signaling effectively suppressed both calcium flux and invasion. ConclusionsOur findings establish a YAP-PIEZO1 axis linking ECM density to FNRMS invasion. This mechanosensitive pathway represents a potential therapeutic vulnerability in aggressive FNRMS. Simple SummaryFusion-negative rhabdomyosarcoma (FNRMS) is the prevalent subtype of rhabdomyosarcoma, the most common pediatric soft tissue sarcoma. Its invasion often leads to recurrence and poor prognosis. This study investigates how the density of the extracellular matrix (ECM), surrounding cancer cells in the tissue, influences FNRMS invasion. We found that high ECM density activates the protein YAP, which directly triggers the expression of the mechanical sensor PIEZO1. This sensor allows calcium to enter the cells, providing a signal that facilitates invasion. Pharmacological inhibition of this axis successfully reduced the invasive potential, highlighting a novel therapeutic vulnerability for FNRMS patients.

cancer biology↗

bioRxiv2026

scDeepVariant: A population-informed deep learning framework for germline variant calling in scRNA-seq

Single-cell RNA sequencing (scRNA-seq) provides unprecedented resolution of cellular heterogeneity while also capturing information on germline genetic variation, but accurate variant calling remains limited by sparse coverage, allelic imbalance, and RNA-specific artifacts. Existing single-cell methods, including cellSNP, scAllele, and Monopogen, address some of these challenges, yet either suffer from low sensitivity and precision or rely on linkage disequilibrium (LD) priors that restrict performance on rare variants. Here, we introduce scDeepVariant (scDV), a deep learning-based framework adapted from DeepVariant and trained on paired whole-genome sequencing (WGS) and single-nucleus RNA sequencing (snRNA-seq) data. We show that scDV can be effectively trained on sparse single-cell data and that augmenting models with allele frequency information from gnomAD or the 1000 Genomes Project consistently improves performance. Across benchmarks, scDV with allele frequency channels achieved higher precision and recall than standard six-channel configurations, surpassing Monopogen at coverage depths above 10x and demonstrating a pronounced advantage in rare variant detection, where LD-based refinement is most limited. These results establish scDV as a robust alternative for germline variant discovery from scRNA-seq and highlight the broader value of integrating population-scale information into deep learning frameworks for transcriptomic variant calling.

bioinformatics↗

bioRxiv2025

Conserved Neuronal-like and Secretory Programs Define the Spatial Architecture of Gastroenteropancreatic Neuroendocrine Tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous malignancies whose biology and microenvironmental organization remain poorly understood. Here, we integrated single-nucleus multiomic (snRNA-seq and snATAC-seq) and spatial transcriptomic profiling across 38 well-differentiated pancreatic (pNET) and small-intestinal (siNET) tumors to define conserved malignant programs, their regulatory circuits, and spatial niches. We observed two conserved malignant cell programs spanning a continuous transcriptional spectrum: a neuronal-like program (si-cNMF1/p-cNMF1), and a secretory neuroendocrine program (si-cNMF2/p-cNMF2). Matched chromatin accessibility profiles uncovered distinct, tissue-specific regulatory networks, including MAX::MYC and MITF transcription factor binding motifs in siNETs versus ISL1 and TFAP4 in pNETs, indicating organ-specific epigenetic control. Spatial transcriptomic analyses revealed that si/p-cNMF1-high regions localized to high cell density, immune-rich tumor areas, whereas si/p-cNMF2-high regions occupied stromal and vascularized niches and co-occured with fibroblast and endothelial compartments enriched for TGFB1-ITGB1, VEGFA-FLT1, and LAMA2-ITGA1 signaling. Across both tumor types, the cNMF2 program was enriched in metastatic lesions and was enrichedfor pro-fibrotic and pro-angiogenic gene signatures. Thus, GEP-NETs are organized along a conserved neuronal-to-secretory axis defined by distinct epigenetic programs and spatially coupled to specific microenvironmental niches. This framework unifies NET heterogeneity across organ sites and identifies pathway-specific, microenvironment-linked vulnerabilities for therapeutic targeting.

cancer biology↗

bioRxiv2025

A mouse model of CHCHD10 p.R15L familial ALS presents mild, age-related motor neuron degeneration without protein instability or mitochondrial dysfunction

Mutations in the mitochondrial protein CHCHD10 (D10) cause a spectrum of hereditary neurodegenerative disorders. Among these, the p.R15L variant is linked to a slowly progressive, late-onset familial form of amyotrophic lateral sclerosis (ALS) with unclear pathogenic mechanisms. To better understand this, we investigated a knock-in (KI) mouse model carrying the p.R15L mutation in the endogenous protein. Unlike previously described mutant D10 KI models, p.R15L KI mice exhibited normal D10 protein levels, with no evidence of large protein aggregates. Mitochondrial respiration and hydrogen peroxide emission in mitochondria isolated from muscle and brain were unaltered. Similarly, fibroblasts from human p.R15L carriers exhibited normal D10 levels and unchanged oxidative phosphorylation function. Histochemical analyses of p.R15L KI muscle revealed mild increases in mitochondrial enzymatic activity in a subset of muscle fibers and muscle transcriptomics showed elevated expression of PGC-1, suggesting enhanced mitochondrial biogenesis. p.R15L KI mice developed subtle, late-onset phenotypes, including reduced body weight and motor activity and increased anxiety-like behavior. Importantly, in aged mice electrophysiological studies demonstrated decreased amplitude of the compound muscle action potential, commensurate with a moderate loss of spinal cord motor neurons and elevated serum neurofilament light levels, indicative of neurodegeneration. Together, these results indicate that the p.R15L mutation produces a mild, late-onset motor neuron phenotype in mice, partially recapitulating the human disease, without mitochondrial functional or morphological alterations. The findings indicate that p.R15L D10 selectively impairs mouse motor neurons through a gain-of-function mechanism, providing a genetically accurate yet mild in vivo model of familial ALS.

neuroscience↗

bioRxiv2025

Time-resolved ligand dynamics revealed in a β-lactamase using room-temperature serial crystallography

{beta}-Lactamases catalyze {beta}-lactam antibiotic hydrolysis and are important contributors to bacterial antimicrobial resistance; {beta}-lactamase inhibitors are widely used to overcome {beta}-lactamase-mediated antibiotic resistance. Nucleophilic serine {beta}-lactamases (SBLs) react with their substrates and clinically available inhibitors via a covalent reaction to give complexes which can undergo further reaction. Using room temperature drop on fixed target serial crystallography, where ligands are rapidly mixed with microcrystals, and classical single-crystal crystallography at cryogenic temperatures, we investigate the reversible covalent reaction of the SBL CTX-M-15 with the diazobicyclooctane inhibitor avibactam. We observe avibactam covalently reacted (ring-opened) with the nucleophilic Ser70, at timepoints from 80 ms to minutes (room temperature) and hours (100 K). These crystallographic data reveal time-dependent movement of the avibactam carbamoyl complex, from 1.3 s onwards, that has implications for the 5-exo-trig recyclization mechanism that determines inhibitor reformation. Combined with molecular dynamics simulations and quantum mechanics calculations at the density functional theory level, the results show that in the first seconds of the reaction the avibactam N-sulfate nitrogen is poorly positioned for recyclization. This subsequently equilibrates after 10 s to a stable endpoint that is in a conformation potentially primed to initiate recyclization through attack of the N-sulfate nitrogen on the carbamoyl carbon. These results further demonstrate the capacity of room-temperature serial crystallography to capture time-resolved changes in ligand conformation at an enzyme active site, complementing discrete classical cryo-crystallography. These data inform on ligand dynamics and the stereoelectronics of diazobicyclooctane inhibition, aiding drug discovery efforts to develop inhibitors of nucleophilic enzymes.

biochemistry↗

bioRxiv2025

Evaluating the effects of aging on biodistribution and gene silencing activity of lipid-siRNA conjugates delivered into cerebrospinal fluid

Aging is the primary risk factor for chronic neurodegenerative diseases and is associated with alterations to cerebrospinal fluid (CSF) flow and clearance. CSF delivery is currently the most clinically advanced route of administration for oligonucleotide therapeutics, but it remains poorly understood how aging, which is rarely incorporated into clinical trials, impacts biodistribution, gene silencing activity, and potential toxicity of these compounds. Here, we evaluated a lipid-siRNA conjugate (L2-siRNA) for potential age-related changes to CSF-mediated delivery, mRNA silencing, and safety. We found that L2-siRNA exhibited comparable biodistribution and on-target silencing of Huntingtin (Htt) between young and aged mice in all tested regions of the central nervous system (CNS) and across extended time points. Examining transport along CSF efflux routes revealed uptake in deep cervical lymph nodes and dura. Further, L2-siRNA did not generate detectable toxicity in the CNS or periphery of aged mice. A subset of studies benchmarked L2-siRNA against a C16 lipid-siRNA conjugate that recently entered clinical trials. Collectively, these results provide valuable insight into siRNA conjugate biodistribution and activity in the CNS in the context of aging and further establish the performance of L2-siRNA under conditions relevant to the treatment of neurodegenerative diseases.

bioengineering↗

bioRxiv2025

PKMYT1 inhibition induces DNA damage and synergizes with immune checkpoint blockade in CCNE1-amplified gastroesophageal adenocarcinoma

PurposeCCNE1 amplification, found in approximately 10% of gastroesophageal adenocarcinoma (GEA), drives chromosomal instability and is associated with an immune-cold tumor microenvironment. Recent studies suggest that PKMYT1 inhibition is synthetic lethal in CCNE1-amplified cancers; however, its role in GEA is largely uncharacterized. We investigated the therapeutic activity of PKMYT1 inhibition in CCNE1-amplified GEA and its potential combination with immunotherapy. Experimental DesignWe evaluated lunresertib (RP-6306), a selective first-in-class PKMYT1 inhibitor, in CCNE1-amplified and wild-type GEA cell lines to define its effects on cell viability, DNA damage, and gene expression changes. To investigate the role of PKMYT1 blockade on immune microenvironment modulation, we used a syngeneic murine model of CCNE1;Trp53-/- GEA xenografts treated with lunresertib, anti-PD-1, or the combination. ResultsLunresertib was selectively cytotoxic in CCNE1-amplified GEA cell lines in cell viability and clonogenic assays. Mechanistically, treatment with lunresertib induced DNA damage, evidence by increased {gamma}H2AX expression and DNA micronuclei formation, and activated pro-inflammatory signaling pathways by gene set enrichment analysis. In a CCNE1-amplified GEA murine model, PKMYT1 inhibition promoted T cell infiltration, reduced myeloid cells, and synergized with anti-PD-1 therapy to induce tumor regression. ConclusionsOur results suggest that CCNE1 amplification is a potentially actionable target in GEA and support the development of combination therapeutic strategies utilizing PKMYT1 inhibition and PD-1 blockade. Translational RelevanceGastroesophageal adenocarcinoma (GEA) is an aggressive malignancy with poor prognosis and few actionable molecular alterations. CCNE1 amplification is present in approximately 10% of patients with GEA and represents a potential therapeutic vulnerability through synthetic lethality with PKMYT1 inhibition. We demonstrate that targeting CCNE1-amplified GEA through PKMYT1 inhibition with lunresertib is selectively cytotoxic, induces DNA damage, and activates inflammatory signaling pathways. In a syngeneic murine model of CCNE1-amplified gastric cancer, we further identified that PKMYT1 inhibition induced T cell infiltration and tumor microenvironment remodeling, and synergized with anti-PD-1 therapy to drive tumor regression. Together, these results support further development of PKMYT1 inhibition in combination with PD-1 blockade for CCNE1-amplified GEA.

cancer biology↗

bioRxiv2025

Drop on fixed target reaction initiation approach for serial and time resolved crystallography

We describe the design and implementation of a drop on fixed target method for time-resolved serial crystallography at both synchrotron and XFEL facilities. A piezoelectric droplet dispensing pipette is employed for addition of picolitre volume (40 - 90 pL) aqueous droplets, containing (co-)substrate(s) or ligand(s), onto enzyme microcrystals immobilised on a solid support. The system was tested with various enzyme systems, including lysozyme and two -lactamases, CTX-M-15 and AmpCEC. Mitigation strategies for cross-well contamination, including the implementation of interleaved controls, are described; the overall performance of the system at synchrotron and X-ray free electron laser facilities was evaluated. This drop on fixed target method is a reliable framework for time-resolved crystallography and will improve the consistency of measurements across facilities.

biophysics↗

bioRxiv2025

Spatiotemporal Atlas of Heart Development Reveals Blood-Flow-Dependent Cellular, Structural, Metabolic, and Spatial Remodeling

Embryonic heart development depends on coordinated interactions between cellular programs, molecular signaling, and biomechanical forces, yet how mechanical cues shape cellular and molecular pathways remains incompletely understood. We perturbed cardiac blood flow by partial left or right atrial ligation (LAL/RAL) in chick embryos, generating chamber-specific hemodynamic gain- or loss-of-function states. Using single-cell and unbiased, high-resolution spatial transcriptomics, we generated a spatiotemporal atlas of flow-dependent tissue development, enabling systematic investigations of bidirectional interactions between blood-flow mechanics and tissue development. Spatially resolved analyses recapitulated key features of normal morphogenesis including regional maturation and the cellular neighborhood. We further revealed flow-specific remodeling across molecular, cellular, and architectural levels. Altered flow induced LOX-expressing cardiomyocyte and endocardial states, disrupted ventricular layer organization, and delayed maturation, alongside transient metabolic and ion-transport adaptations. Together, these findings define how redistributed blood flow reshapes developing cardiac tissues and provide a framework for studying flow-dependent remodeling in morphogenesis and malformation.

developmental biology↗

bioRxiv2025

Neuronal PARIS-STAT3 axis drives tau pathology and glial activation in Alzheimers disease

PARIS, a substrate of Parkin, accumulates in Parkinsons disease and promotes disease progression. Here, we demonstrate that PARIS also contributes to Alzheimers disease by elevating STAT3 transcriptional activity, thereby inducing tau pathology, hippocampal atrophy, and glial activation. Genetic depletion of Paris reduced tau phosphorylation and cognitive decline in tauopathy mice, whereas neuron-specific PARIS overexpression caused tau accumulation, gliosis, and memory impairment. In contrast, astrocyte-specific overexpression did not induce pathology, indicating that PARIS acts in neurons to drive tau phosphorylation and glial activation. The pathological features induced by neuronal PARIS overexpression were rescued by STAT3 inhibition, demonstrating that PARIS-STAT3 signaling underlies these effects. Moreover, Paris knockout did not alter pathology in the amyloid-driven mouse model, highlighting specificity for tau pathology. Together, these findings reveal PARIS as a neuronal regulator of STAT3 signaling that exacerbates tau-mediated neurodegeneration and identify the PARIS-STAT3 pathway as a potential therapeutic target in Alzheimers disease.

neuroscience↗

bioRxiv2025

The MTL200: a surface-based, probabilistic atlas of the medial temporal lobe

The human medial temporal lobe (MTL) includes a number of cortical regions surrounding the hippocampus implicated in long-term memory and high-level perception, including temporopolar cortex (TPC), entorhinal cortex (ERC), perirhinal cortex (PRC), and parahippocampal cortex (PHC). A critical prerequisite to studying the function of these areas is to define their anatomical boundaries. While several atlases or segmentations methods for automated boundary definition exist, they have limitations: 1) they are derived from small sample sizes; 2) most do not include TPC; and 3) they are volumetric rather than surface-based and are therefore not straightforward to use for surface-based analysis of MRI data. Here we present the MTL200: a surface-based, probabilistic atlas of MTL regions TPC, ERC, PRC, and PHC. The atlas is derived from hand drawings of regions based on gross anatomical features corresponding to cytoarchitectonic boundaries, using anatomical MRI data from 200 human participants. This work provides a valuable tool for researchers studying the anatomy and function of MTL regions, particularly the poorly characterized area TPC.

neuroscience↗

bioRxiv2025

AAV-mediated neuronal expression of FOXG1 restores oligodendrocyte maturation, myelination, and hippocampal structure in mouse models of FOXG1 Syndrome

FOXG1 syndrome is a devastating neurodevelopmental disorder caused by haploinsufficiency of the transcription factor FOXG1, leading to intellectual disability, epilepsy, and white-matter deficits. Although FOXG1 is well known for its neuronal functions, its role in glial pathology remains poorly understood. Here, we show that reducing FOXG1 selectively in neurons impairs oligodendrocyte lineage progression and myelination, establishing a critical non-cell-autonomous role for neuronal FOXG1 in glial maturation. To restore FOXG1 in neurons, we developed AAV vectors expressing human FOXG1 under neuron-specific promoters. Neonatal administration of these vectors normalized oligodendrocyte precursor cell (OPC) accumulation, enhanced myelination, and corrected hippocampal structural abnormalities in Foxg1 conditional heterozygous mice. To test therapeutic robustness under stringent conditions, we used the patient-specific W300X heterozygous model, which combines FOXG1 loss-of-function with a toxic truncated protein and represents one of the most severe FOXG1 syndrome genotypes. Remarkably, neuron-restricted AAV-FOXG1 delivery produced substantial rescue even in this high-bar model, suppressing OPC overaccumulation, restoring myelination, and progressively improving dentate gyrus morphology, with benefits persisting into adulthood. Moreover, adolescent administration remained highly effective, rescuing myelination, axonal bundle thickness, and microglial activation. These findings identify neuronal FOXG1 as a master regulator of neuron-glia interactions and establish neuron-targeted AAV-FOXG1 as a potent and clinically translatable therapeutic strategy across diverse severities of FOXG1 syndrome.

developmental biology↗

bioRxiv2025

Evaluation of single-cell RNA profiling technologies using FFPE, fresh, and frozen ccRCC tumor specimens

The application of single-cell transcriptomic approaches has deepened our understanding of tumor heterogeneity, immune dynamics, and molecular programs underlying therapy response. The recent development of fixation-compatible single-cell platforms, such as 10x Genomics Flex, offers the opportunity to profile archived formalin-fixed, paraffin-embedded (FFPE) specimens, expanding access to clinically valuable samples. However, most benchmarking studies of recent single-cell RNA sequencing (scRNA-seq) technologies have relied on peripheral blood mononuclear cells, limiting their relevance to human tissues. Here, we compared three 10x single-cell RNA profiling methods, fresh tumor scRNA-seq, flash-frozen single-nucleus Multiome, and FFPE single-nucleus Flex (snFlex), using clear cell renal cell carcinoma (ccRCC) biopsies. Across methods, we observed broadly consistent cell type-specific transcriptional profiles among major ccRCC cell populations. Despite lower gene and UMI counts, snFlex reliably identified fine-grained states within CD8+ T cells, tumor-associated macrophages, and tumor compartments, comparable to those detected by scRNA-seq. Together, these findings highlight the distinct advantages of each technology depending on sample preservation type and study design, providing practical guidance for single-cell RNA profiling technology selection in translational studies using human tumor biopsies.

cancer biology↗

bioRxiv2025

Antiviral and anti-inflammatory effects of Tabamide A derivative, TA25, against human rhinovirus and multiple zoonotic viruses in vitro and in silico

Human rhinovirus (HRV), first isolated in 1956, belongs to the family Piconaviridae containing a positive-sense, single-stranded RNA genome. HRV causes mild cold and severe respiratory disease, such as asthma, COPD, and pneumonia. To date, no Food and Drug Administration-approved antiviral or anti-inflammatory drugs are available for HRV. TA25 is a phenolic amide derivative extracted from the leaves of Nicotiana tabacum. To investigate the potential candidate for antiviral therapeutics against zoonotic viruses, we evaluated the antiviral potency of TA25 for HRV and multiple zoonotic viruses. The antiviral and anti-inflammatory effects of TA25 were evaluated using RT-qPCR and RNA-seq. Strand-specific RT-qPCR was performed to measure genomic and anti-genomic RNA expression after TA25 treatment. In addition, an AI-based docking test was conducted to investigate the binding affinity of TA25 with viral target proteins. TA25 induced a significant reduction in viral replication and suppressed the expression of pro-inflammatory genes. Inhibition of viral replication by TA25 treatment was confirmed by strand-specific RT-qPCR. TA25 showed broad-spectrum antiviral activity against multiple viruses, including HRV-1A, Zika virus, Dengue virus, Vaccinia virus, and Influenza B virus Victoria. Using an AI-driven structure-based docking analysis, TA25 showed the strongest binding affinity with the HRV 2B protein. This study demonstrates that TA25 confers the broad antiviral and anti-inflammatory activity against HRV and multiple zoonotic viruses. These findings provide valuable insights into antiviral strategies of TA25 for a promising therapeutic candidate in response to emerging RNA and DNA viruses.

microbiology↗

bioRxiv2025

Simulation and empirical evaluation of biologically-informed neural network performance

Biologically-informed neural networks (BiNNs) offer interpretable deep learning models for biological data, but the dataset characteristics required for strong performance remain poorly understood. For instance, we previously developed P-NET, a BiNN with an architecture based on the Reactome pathway database, and applied this model to predict metastatic status of patients with prostate cancer using somatic mutation and copy number information. It seems likely that including additional relevant signal - e.g., germline variation in this context - should improve model performance, but we currently lack a principled approach to assess whether BiNNs will successfully detect this signal. Here, we developed two simulation frameworks to evaluate the factors that influence BiNN performance - including signal type, signal strength, feature sparsity, and sample size - and empirically tested how integrating germline and somatic data affects the models ability to predict prostate cancer metastatic status. Simulations revealed that small sample size, weak signal strength, and especially extreme feature sparsity limit BiNN performance, and that the model preferentially uses linear over nonlinear signal. Empirically, P-NET performed poorly on sparse germline data, and while adding germline to somatic data did not improve prediction, it improved gene prioritization and model interpretation. Broadly, our simulation frameworks enable systematic evaluation of how dataset-level characteristics affect BiNN performance and provide a principled framework for benchmarking novel methods.

bioinformatics↗

bioRxiv2025

T-Cell Synaptosomes Orchestrate Long-Term Anti-Tumor Immunity via Proliferative and Metabolic Reprogramming

A defining feature of T-cell activation is its dependence on physical contact with antigen-presenting cells (APCs). During this interaction, activated T cells release microvesicles, known as T-cell immunological synaptosomes (TIS), onto the surface of APCs. While TIS are known to activate APCs, their broader in vivo functions remain largely unexplored. Here, we show that TIS are primarily phagocytosed by macrophages and dendritic cells, persist intracellularly for several days, and reprogram these cells in a manner distinct from LPS. TIS upregulate genes involved in metabolism, proliferation, and anti-inflammatory responses, and promote immune cell recruitment, including eosinophils. Notably, TIS induce minimal immune activation upon initial exposure but trigger a rapid and robust response upon secondary administration, indicating a priming effect reminiscent of adaptive immunity. In an MC38 colon cancer model, TIS treatment resulted in near-complete tumor suppression and durable protection upon rechallenge, highlighting their potential as a potent and long-lasting immunotherapeutic platform.

immunology↗