Biology subjects

Tong, X.

Publications and source records attributed to Tong, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Structure-resolved fold annotation of the medicinal-leech salivary-EV cargo: a Ly-6/uPAR three-finger scaffold and a structurally dark fraction

Many proteins that medicinal leeches package into salivary extracellular vesicles (EVs) carry no interpretable sequence annotation, so the least-characterised part of a pharmacologically important secretome lacks even a fold assignment. A companion Astral-DIA study of Hirudinaria manillensis nominated 17 ultra-enriched candidate EV cargo proteins. Here we ask whether structure prediction and structural search can assign folds where sequence methods fail, and which candidates remain unresolved under prespecified criteria. With an offline pipeline (ESMFold, TM-align, Foldseek against AFDB-SwissProt and PDB100, UniRef90 search, protein-to-genome alignment), the candidates separate into intracellular/membrane machinery and a secreted, cysteine-dense fraction of three proteins with no Pfam domain. The predicted structure of the leech Protein-sleepless homolog g21166 supports its assignment to the Ly-6/uPAR three-finger fold (TM 0.58 vs CD59; best significant PDB match Lynx1); no function is inferred. g436 and g20791 returned no match meeting the criterion (alnTM [≥] 0.5, E [≤] 0.05) in either database, g436 even after homolog-informed modelling. Gene structure and splice junctions support a conserved locus for the two-Trypsin-segment model g8114 (catalytic unit not established). A Boltz-2 thrombin pilot did not support target engagement, and a pre-registered nicotinic test was terminated as undecidable. The results yield a structure-informed shortlist for experimental follow-up.

bioinformatics↗

bioRxiv2026

Desmoglein-1 coordinates cell proliferation and actin dynamics to promote epidermal morphogenesis.

Skin development depends on coordinated biochemical and mechanical signaling to form a multilayered epidermal barrier. Our previous work demonstrated that the stratified tissue-specific desmosomal cadherin Desmoglein-1 (Dsg1) promotes epidermal differentiation in human in vitro models. Dsg1 first appears in the developing mouse epidermis around E14, coinciding with a developmental transition in stratification and the onset of terminal differentiation, raising the question of how Dsg1 contributes to epidermal morphogenesis in vivo. We generated a wild-type (WT) single-cell RNA sequencing (scRNA-seq) atlas of murine skin and integrated scRNA-seq data from Dsg1 knockout (Dsg1 KO) embryos spanning E14.5, E15.5, E16.5, and E18.5. Six keratinocyte subpopulations were annotated, including a Transitional subpopulation co-expressing basal and suprabasal markers, positioned between basal and differentiated states. Dsg1 KO epidermis exhibited reduced thickness at E14.5-E15.5, but recovered by E16.5-E18.5, suggesting compensatory adaptation. Differential gene expression analysis revealed enrichment of cell-cycle and actin-associated programs in Dsg1 KO during late development. EdU incorporation and PCNA staining confirmed increased proliferation in superficial layers accompanied by altered actin organization and changed cell morphology. Notably, actin and the Arp2/3 actin nucleation-promoting factor N-WASP exhibited marked changes in distribution during early and late development, respectively. Mechanistically, Dsg1 associates with Nck1, an adaptor linking N-WASP to Arp2/3-dependent actin polymerization. Silencing Nck1 or N-WASP reduced Dsg1-mediated stratification significantly, while a Nck1-binding-deficient Dsg1 mutant failed to rescue stratification in Dsg1-deficient keratinocytes in vitro. Together, these findings identify a Dsg1-Nck1-N-WASP axis linking desmosomal adhesion to cytoskeletal remodeling and support a model in which Dsg1 coordinates cell-cycle, cell morphology, and actin dynamics to drive epidermal morphogenesis.

cell biology↗

bioRxiv2026

Port of Protein-Protein Interactomes: An experiment-based protein-protein interactome database for rice

Protein-protein interactions (PPIs) play a crucial role in enabling proteins to carry out their functions within various biological processes (Hui et al., 2003). Since the introduction of the yeast two-hybrid (Y2H) method for PPI detection in 1989 (Fields and Song, 1989), the identification of PPIs has become a significant focus in modern biological research. PPI goes beyond examining individual proteins, allowing researchers to establish a comprehensive network that regulates biological processes. Rice, as a key model organism in plant biological studies, has been at the forefront of PPI research. In 2008, prominent rice scientists in China called for concerted efforts to define a comprehensive protein-protein interaction network experimentally, which aimed to facilitate the prediction of the functional mechanisms operating throughout a plants lifecycle (Zhang et al., 2008). With efforts for 2 decades, the experimentally identified rice PPIs have reached over ten thousand. Several public databases have been established to systematically collate and store PPIs, including STRING (Szklarczyk et al., 2019), BioGRID (Oughtred et al., 2020), IntAct (del Toro et al., 2022), PRIN (Gu et al., 2011), RicePPINet (Liu et al., 2017) and RiceNet v2 (Lee et al., 2015). However, most PPI datasets in rice stem from computational predictions, while experiment-based rice PPI datasets are fragmented due to the lack of systematic profiling at the rice PPIome level, which largely hinders information sharing in the rice research community. To bridge this gap, we constructed the Port of Protein-Protein Interactomes (POPPIN; https://riceome.hzau.edu.cn/poppin/), an integrated database dedicated to sharing experimentally verified PPIs and functional clues in rice. Empowered by high-throughput PPIome profiling technologies and text mining assisted by a large language model (Huang et al., 2025; Liu et al., 2025), POPPIN currently has deposited over 150,451 pieces of rice PPI-related information. Additionally, POPPIN provides detailed protein information, including GO annotations, subcellular localizations, domains, trait ontology (TO) information, and hyperlinks to external biological databases. Through offering a user-friendly web interface for search and dynamic network visualization, POPPIN serves as the first large-scale, experiment-based database for searchable PPIs in rice, and has the potential to be extended to other species under this structural framework.

systems biology↗

bioRxiv2026

MAFB is essential for the maintenance of adult human α-cell identity and glucagon secretion

Dysregulated hormone secretion and erosion of endocrine cell identity are features of type 1 and type 2 diabetes, but the transcriptional programs maintaining adult human islet identity and function remain poorly defined. The large MAF transcription factor MAFB is expressed in human - and {beta}-cells, marks their most functionally mature subpopulations, and is downregulated in diabetes, but its role in adult human islets has not been tested directly. Using shRNA-mediated MAFB knockdown (KD) in whole and CD26+ -cell-enriched human pseudoislets, we found that whole pseudoislet MAFB KD impaired glucagon synthesis and secretion while only modestly reducing insulin content and cAMP-potentiated insulin release. Single-cell profiling detected no {beta}-cell transcriptional response beyond MAFB KD itself, consistent with buffering by the related {beta}-cell-enriched MAFA transcription factor. In contrast, -cell-restricted MAFB KD unmasked a cell-autonomous requirement for MAFB in stimulus-secretion coupling. MAFB deficiency also destabilized -cell identity, downregulating canonical -cell and neuroendocrine secretory genes while ectopically inducing mesenchymal and extracellular matrix remodeling programs. In addition, MAFB-dependent downregulation of electron transport chain genes was confined to a large -cell subcluster, manifesting as impaired islet-wide mitochondrial respiration within the broader -cell population. Together, these findings identify MAFB as an essential adult human -cell maintenance factor that links diabetes-associated downregulation to impaired glucagon secretion, -cell identity erosion, and mitochondrial dysfunction. RESEARCH IN CONTEXTO_LIWhat is already known about this subject? O_LIMAFB is expressed in adult human - and {beta}-cells, marks their most functionally mature subpopulations, and is downregulated in type 1 and type 2 diabetes C_LIO_LIIn human stem cell models, MAFB is essential for generating insulin-producing {beta}-like cells, whereas glucagon-producing -like cells are reduced but still formed C_LIO_LINeither model addresses adult human islets: rodent MafB becomes -cell restricted after birth, and stem cell models capture differentiation, not maintenance C_LI C_LIO_LIWhat is the key question? O_LIIs MAFB required to maintain identity and secretory function in adult human islet cells? C_LI C_LIO_LIWhat are the new findings? O_LIMAFB knockdown in primary human pseudoislets impaired glucagon synthesis and secretion but minimally affected {beta}-cells, consistent with buffering by MAFA C_LIO_LIKnockdown in CD26+ -cell-enriched pseudoislets revealed a cell-autonomous requirement for MAFB in stimulus-secretion coupling, and destabilized -cell identity by inducing mesenchymal and extracellular matrix programs C_LIO_LIMAFB loss downregulated electron transport chain genes in the largest -cell subcluster and reduced mitochondrial respiration C_LI C_LIO_LIHow might this impact on clinical practice in the foreseeable future? O_LIPreserving MAFB activity in adult human -cells may represent a strategy to limit -cell dysfunction in diabetes C_LI C_LI

physiology↗

bioRxiv2026

Architectural Confinement and Seasonal Forcing Shape Cross-Domain Pathogen Assemblages in Complex Built Environments

Airborne microbial pathogens in built environments (BEs) may pose potential health threats, yet the ecological mechanisms governing their assembly and persistence across interconnected architectural spaces are less studied. Here, we conducted a year-long, multi-spatial investigation across a university campus complex, sampling the exhaust outlets of three indoor environments and the adjacent outdoor inlets. By integrating the 16S rRNA gene and ITS sequencing from 437 paired bacterial-fungal samples, we characterized the spatiotemporal dynamics of airborne opportunistic pathogen-containing genera. Our study showed that spatial filtering emerged as the dominant determinant of pathogen community structure, with confined elevator environments serving as reservoirs of pathogens with limited but continuous microbial influx from surrounding spaces. Superimposed on this spatial baseline, bacterial and fungal pathogens displayed distinct seasonal dynamics. Opportunistic fungal pathogens such as Fusarium peaked during autumn and winter, possibly driven by enhanced aerosol persistence and dispersal under cooler, drier conditions. In contrast, bacterial pathogens exhibited greater temporal resilience, with key taxa such as Listeria transcribed actively during winter, predisposing them to increased relative abundance during spring. Cross-domain ecological networks further revealed the dynamic interactions among pathogens, centered on the skeletal structure mediated by the keystone fungal pathogen Aspergillus, suggesting that coordinated microbial interactions reinforced pathogen persistence across seasons. Together, our findings support a unified ecological framework in which pathogen dynamics within BEs arise from the coupled effects of spatial filtering, climatic modulation, and biotic interactions. These results provide a foundation for transitioning from static environmental control toward predictive pathogen management in BEs. ImportanceBEs are the primary settings of human microbial exposure, yet the ecological principles governing the persistence of airborne pathogens across interconnected indoor spaces remain poorly resolved. Most previous indoor studies have focused on isolated environments or single microbial groups, limiting our understanding of how pathogens are maintained and redistributed within complex architectural systems. By integrating bacterial and fungal community dynamics across spatial environments over four seasons, this year-long study demonstrates that the ecology of airborne pathogens is not static, but is instead dictated by a complex interplay of spatial, climatic, and biological forces. Our findings identify enclosed, high-transit elevator spaces as critical hotspots for pathogen accumulation and highlight the role of seasonal ecological reorganization in driving airborne health risks. More broadly, this work establishes a systems-level ecological framework for understanding airborne pathogen dynamics in BEs and provides a conceptual basis for developing more adaptive strategies for indoor microbial risk management.

microbiology↗

bioRxiv2026

Integrated optimization of experimental and computational workflows improves genome recovery in long-read gut metagenomics

Short-read metagenomic sequencing has been widely applied in microbial research due to its high quality and decreasing cost. However, short reads are inherently fragmented, which limits assembly contiguity and the recovery of complete microbial genomes. In contrast, long-read sequencing, with significantly longer read lengths, helps overcome these limitations. Achieving complete and accurate genome recovery is the core goal of metagenomics. To address this challenge, we systematically evaluated and optimized the long-read metagenomic workflow, from sample processing to computational assembly, using the CycloneSEQ platform.

bioinformatics↗

bioRxiv2026

Comprehensive Complete-Genome Analysis of Lactobacillaceae and Bifidobacteriaceae Reveals Strain-Specific Metabolic Interactions in Chinese Gut Microbiota

Bifidobacteriaceae and Lactobacillaceae are key probiotic families and widely used in food production, yet a comprehensive understanding of strain functions and their gut microbial interactions based on complete genomes remain understudied. Here we constructed a complete-genome dataset of 3,300 strains from these two families, including 1,151 newly isolated from China. Compared with draft assemblies, complete genomes substantially recovered a gene functional landscape encompassing stress tolerance, surface exopolysaccharide synthesis, nutrient utilization, and mobile genetic elements. Major species from both families exhibited a prevalence >60% in the Chinese population, far higher than that in US/Dutch cohorts. Notably, as a core probiotic species with remarkable genomic plasticity and gut-adaptive potential, Lactiplantibacillus plantarum stood out in our dataset for its enriched functional profile and was particularly abundant in the Chinese population. Moreover, compared with non-Chinese genomes, our isolates of key species displayed less metabolic complementarity and stronger competition with potentially pathogenic keystone species in the gut, thereby linking strain origin to enhanced probiotic potential and ecological fitness to benefit human gut health.

microbiology↗

bioRxiv2026

Identification of a neural circuit that enables safe, long-term torpor in mice

Torpor, a state of regulated hypothermia and hypometabolism, is a critical survival strategy in certain mammals. Previous studies established the primacy of neuron control in initiating acute torpor. However, whether neuromodulation can safely sustain torpor over the long term, and the specific governing pathways, remain unanswered challenges limiting its translational potential. Here we identify a distinct preoptic neuronal population expressing General control nonderepressible 2 ( G neurons) in mice that is essential and sufficient for torpor induction. Strikingly, sustained and selective activation of G neurons induces a stable, weeks-long torpid state (G neuron-driven long-term torpor, GLT), from which animals arouse without obvious behavioral deficits or tissue pathology. In contrast, long-term torpor driven by pan-neuronal activation of the same brain region (PLT) causes multiple post-recovery damages, underscoring the unique safety profile of selective pathway of G neurons. In a mouse cancer model, GLT directly suppressed tumor proliferation and markedly sensitized tumors to chemotherapy, achieving profound therapeutic outcomes. Together, we delineate a distinct neuronal population safely enabling prolonged torpor. This establishes a specific paradigm for inducing a stable and sustained hypometabolic state, providing a transformative platform for fundamental physiological research and pioneering clinical strategies against chronic pathologies such as cancer.

neuroscience↗

bioRxiv2026

Hierarchical Assembly of Native Cytoplasmic Lattices Revealed by Cryo-EM

Oocytes depend on maternal factors for maturation and early embryogenesis. Cytoplasmic lattices (CPLs) are distinctive fibrillar structures in mammalian oocyte cytoplasm implicated in maternal factor storage and developmental competence, yet their molecular composition and architecture remain elusive. Here, we use cryo-electron microscopy to resolve the high-resolution structure of native mouse oocyte CPLs. We identify 14 intrinsic components of multiple copies that assemble into filaments in which PADI6-mediated self-assembly and two subtypes of subcortical maternal complexes (SCMCs) form the core scaffold. Unexpectedly, we discover that /{beta}-tubulin dimers and two autoinhibited ubiquitination modules (UHRF1-UBE2D3, SKP1-FBXW18) are internal components of CPLs. We also uncover multivalent interactions that organize adjacent CPL filaments into higher-order helical bundles. By integrating CPL structure with biochemical and proteomic data, we propose a hierarchical assembly mechanism of CPLs, from subcomplexes to filaments to supramolecular lattices. Our study offers mechanistic insights into how maternal proteins are spatially organized to ensure successful early embryonic development and provides a structural foundation for understanding female infertility related to CPL-associated gene mutations.

developmental biology↗

bioRxiv2026

Optimization of Retinoid Detection in Cerebrospinal Fluid Using Liquid Chromatography Mass Spectrometry

IntroductionRetinoids are bioactive vitamin A derivatives that regulate cellular differentiation and gene expression, yet their reliable quantification remains challenging due to low abundance, structural isomerism, and sensitivity to ionization conditions while handling. ObjectivesIn this study, we performed a systematic optimization of liquid chromatography-mass spectrometry (LC-MS)-based detection of retinoids across tissues and biofluids. MethodsChromatographic separation, adduct formation, ionization parameters, fragmentation behavior, and extraction procedures were evaluated in an integrated workflow. ResultsChromatographic conditions influenced not only retention time but also the ionic species detected, affecting precursor selection for MS{superscript 2} analysis. Retinoids exhibited compound-dependent responses to electrospray ionization and collision energy, requiring tailored acquisition parameters. Extraction experiments demonstrated differential recovery among retinoid classes and revealed matrix-dependent behavior, indicating that protocols used for tissues cannot be directly transferred to low-abundance biofluids. Using optimized conditions, retinoids were detected in mouse cerebrospinal fluid (CSF) at concentrations approaching the analytical detection limit, where MS{superscript 2} confirmation was necessary for reliable identification. ConclusionTogether, our results provide a framework for reproducible retinoid profiling across biological matrices and enables comparative studies of retinoid biology in low-volume and low-abundance biofluids.

biochemistry↗

bioRxiv2026

Complete genome-derived metabolic interactions reveal impact of gut ecology on human health

Metabolic interactions govern gut microbiome assembly, yet functional rules remain obscured by genomic incompleteness and fragmentation. Here, we leverage 1,150 complete genomes to construct genome-scale metabolic models, demonstrating that draft genomes introduce systemic artifacts missing critical transport functions. We observe that metabolic interactions are intrinsically driven by genomic traits and niche specialization rather than random association. We stratifies strains into four ecological groups, including active players, resource predators, utilizers, and contributors, each of which exhibits distinct metabolite exchange/competition signatures. This functional architecture is strongly coupled to secondary metabolism. Applying this framework to inflammatory bowel disease revealed distinct temporal dynamics of ecological groups across disease subtypes, where group-specific dysbiosis predicted clinical phenotypes better than whole community profiles. Furthermore, integrating metabolic and co-occurrence networks to identify keystone for classifiers as features significantly improved disease diagnosis. Our study provides novel insights into gut metabolic interaction landscape, bridging the gap between genomic potential and clinical utility for precision microbiome therapeutics.

microbiology↗

bioRxiv2026

Complete Genomes of Cultivated Gut Bacteria Reveal Mobile Genetic Element-Driven Functional Diversity with Therapeutic Implications

Cultivated bacterial isolates are essential for elucidating gut microbiota functions, yet reliance on fragmented draft genomes and limited mobile genetic element (MGE) annotation has constrained high-resolution analyses. Here, we present the Cultivated Complete Genome Reference (CCGR), a comprehensive compendium of 1,150 fully circularized human gut bacterial genomes. Overcoming draft limitations, CCGR achieves chromosome-scale resolution and reveals distinct evolutionary strategies shaping gene topological organization in response to bacterial growth. Furthermore, we decode the dynamic landscape of MGEs, demonstrating that broad-host-range phages follow strict positional patterns by integrating at conserved chromosomal hotspots flanked by nutrient transporter loci. Importantly, we provide mechanistic in vivo evidence that accessory genomic elements drive strain-level functional heterogeneity. Specifically, the plasmid-encoded scrK gene in Levilactobacillus brevis involved in fructose catabolism is required to mitigate fructose-diet-exacerbated colitis. Collectively, CCGR establishes a framework linking chromosomal architecture and MGEs to bacterial evolution and host health, enabling precise, strain-resolved functional investigations.

microbiology↗

bioRxiv2026

Structural basis of underwound DNA topology bearing PAM-mutant recognition by AtCas9

The CRISPR-Cas9 system locates genomic targets through gRNA pairing and recognition a protospacer-adjacent motif (PAM). While PAM specificity is typically sequence-determined, we previously found that DNA topology can regulate PAM specificity, relaxing PAMs of various Cas9 effectors and allowing near-PAMless cleavage activity of a type II-C Alicyclobacillus tengchongensis Cas9 (AtCas9). However, the structural mechanism underlying this regulation remains unknown. Here, we report cryo-EM structures of AtCas9 bound to B-form DNA or a 340-bp underwound minicircle DNA bearing WT or mutant PAMs. Despite differences in PAM sequences, all three underwound complexes adopt an almost identical architecture that is distinct from the B-form DNA-bound state. On B-form DNA, AtCas9 recognizes the PAM via base-specific hydrogen bonds and steric exclusion, conferring preference for N4CNNN and N4RNNA (R = A/G). In contrast, underwound minicircle DNA widens the PAM major groove, reduces steric clashes, and enables a compensatory mode involving sequence-independent backbone contacts, explaining near-PAMless cleavage under underwound conformation. These findings uncover a topology-dependent mechanism of PAM recognition and establish a cryo-EM platform using underwound minicircle DNA for structural studies under native-like topological states.

biochemistry↗

bioRxiv2026

Soluble DLK1 secreted by telomere-shortening-induced senescent microglia impairs oligodendrocyte functions and alters neuronal activity

Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. Because telomere erosion is a hallmark of aging, we examined its impact on glial and neuronal physiology. Telomere shortened mice showed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single nuclei RNA-seq revealed accelerated glial aging, elevated microglial senescence pathways, and impaired oligodendrocyte functions. Inducing senescence in human iPSC derived microglia with shortened telomeres identified soluble DLK1 as a novel senescence associated ligand. sDLK1 was increased in the cerebrospinal fluid of telomere shortened and naturally aged mice, and this increase was eliminated by microglial depletion. AAV delivery of sDLK1 in vivo caused hypomyelination and blocked oligodendrocyte lineage progression, demonstrating the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.

neuroscience↗

bioRxiv2026

A targeted mutational strategy aiding generating antisense RNA to knockdown the Ehrlichia chaffeensis p28-outer membrane protein 19 expression

Obligate intracellular pathogenic bacteria belonging to the order Rickettsiales include several important emerging pathogens causing major health and economic impact to people, companion animals, and agricultural animals. Despite some recent progress, the lack of well-established genetic manipulation methods for diverse research applications remains a challenge. We recently reported the establishment of targeted mutagenesis methods to disrupt genes in Ehrlichia and Anaplasma species. Many essential genes in Ehrlichia chaffeensis are likely refractory to targeted mutagenesis, thus we developed a novel targeted mutational approach leading to the expression of antisense RNA to facilitate the knockdown of p28-Omp19 protein expression from ECH_1143. This gene was selected as its encoded protein is among the highly immunogenic proteins of E. chaffeensis and is likely essential for the pathogen. This method involved introducing a mutation at a distal genomic location within the E. chaffeensis genome to allow for generation of a 209 nucleotide-long antisense RNA segment complementary to ECH_1143 coding mRNA from the same gene promoter which was duplicated as part of the mutagenesis. The mutational strategy was designed to retain the surrounding genomic regions unaltered. The antisense knockdown version of E. chaffeensis resulted in a reduction of p28-Omp19 expression when compared to wild-type E. chaffeensis during its replication in a macrophage cell line, where the gene expression is known to occur. We anticipate that the antisense mutational strategy will be broadly applicable to facilitate investigating essential genes of obligate intracellular bacterial pathogens.

molecular biology↗

bioRxiv2025

Structural guidance in 3D microgel-in-hydrogel systems to improve chondrogenesis

Anisotropic biomaterials are broadly studied in regenerative medicine as they aim to mimic the hierarchical structures of native tissue. The Anisogel, an anisotropic microgel-in-hydrogel system, involves two key factors for tissue engineering: guidance cues - magnetically aligned rod-shape structures - and a surrounding matrix - polyethylene glycol-vinylsulfone (PEG-VS) with a degradable peptide crosslinker. This research shows the potential of using a PEG-VS-based Anisogel to allow for guided ingrowth and chondrogenic differentiation of human mesenchymal stromal cells (hMSCs) modulated by the alignment and size of anisometric microgels. The properties of the surrounding matrix are optimized for the availability of anchoring peptides (RGD concentration) and matrix density (hydrogel precursor concentration). The microgels of highest tested dimensions (10x10x100 {micro}m3) lead to a donor-independent significant upregulation of chondrogenic markers (SOX 9, ACAN and COL2AI) and a decrease of hypertrophic chondrogenic markers (RUNX 2), compared to unaligned and smaller microgel sizes. As a proof of concept, the Anisogel is tested in a semi-orthotopic mouse model where the effect of microgel alignment on cell infiltration and osteochondral tissue formation is evaluated.

bioengineering↗

bioRxiv2025

Cross-species etiologically informed stratification enables T cell receptor-based diagnosis of Parkinson's Disease

BackgroundDeveloping peripheral blood-based diagnostic models for idiopathic Parkinsons disease (iPD), particularly those leveraging the T-cell receptor (TCR) repertoire, has long been considered infeasible because patient-derived TCRs appear to lack convergent sequence motifs. We reasoned that this apparent absence of shared TCR features likely reflects both insufficient sample sizes and unaccounted immune heterogeneity within the iPD population. MethodsWe reconstructed TCR repertoires from the two largest iPD cohorts currently available, anchoring them with three mechanistically distinct mouse models to stratify patients into model-anchored informed subtypes. Within these data-driven subtypes, we trained subtype-specific, multimodal multi-instance classifiers. ResultsWe demonstrated that iPD patients can be successfully stratified into model-anchored informed subtypes. Furthermore, the trained subtype-specific, multimodal multi-instance classifiers achieved an Area Under Curve (AUC) exceeding 0.8 for both subtypes. ConclusionsOur findings underscore the critical role of disease stratification in enabling TCR repertoire-based modeling in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Deep Learning of Brain-Behavior Dimensions Identifies Transdiagnostic Biotypes in Youth with ADHD and Anxiety Disorders

Attention-deficit/hyperactivity disorder and anxiety disorders are highly prevalent in youth and are characterized by substantial heterogeneity and frequent co-occurrence. This transdiagnostic complexity challenges conventional diagnostic frameworks that rely on symptom-based categories, which often obscure underlying dimensional and neurobiological mechanisms and offer limited neurobiological specificity. To address these issues, we developed a deep learning-based brain-behavior modeling framework that integrates clinically salient functional connectivity with cognitive and behavioral measures to identify interpretable dimensions and biologically grounded subtypes (biotypes). We applied our model to the Adolescent Brain Cognitive Development (ABCD) dataset comprising 3,508 children aged 9-11 years and revealed two reproducible brain-behavior dimensions that captured variation in cognitive control and emotion-attention regulation. These dimensions further yielded three distinct biotypes, each exhibiting unique symptom profiles and distinct brain development. We tested the robustness and generalizability of the dimensions and corresponding biotypes in an independent cohort of 224 age-matched participants from the Healthy Brain Network (HBN) and documented their early expression before symptom onset during adolescence. These findings highlight the utility of brain-behavior dimensions for elucidating heterogeneous psychiatric presentations and advance a biologically grounded framework for early classification and potential clinical translation in youth mental health.

neuroscience↗