Biology subjects

Jiang, T.

Publications and source records attributed to Jiang, T..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Cross-Species Cortical Geometry Reveals Conserved Gradients Across Primates and Human-Specific Expansion

The primate cerebral cortex, characterized by its complex structural geometry, underlies advanced cognitive functions and represents a defining feature distinguishing primates from other mammals. However, cross-species patterns of cortical geometry and the links between human cortical geometry and transcriptional architecture remain poorly understood. We developed a geometry-based cross-species cortical alignment framework to systematically investigate the similarities and differences in structural connectivity and cortical expansion characteristics among macaques, chimpanzees, and humans, and additionally explored the transcriptional underpinnings of human cortical geometry. Our analysis revealed conserved spatial patterns of cortical geometric features across species, providing the foundation for constructing a cross-species structural common space to support the alignment framework. We found that primary sensory, somatomotor, and face-selective regions exhibited high structural connectivity similarity across species, whereas prefrontal and parietal association cortices displayed significant divergence. We also identified disproportionate cortical expansion in the default mode network, with a consistent expansion trend across different evolutionary lineages in primates. Furthermore, neuroimage-transcription analysis indicated that cortical geometric features were correlated with transcriptional profiles enriched in neurodevelopmental and connectivity-related pathways. These results highlight a conserved yet hierarchically differentiated organization of the cerebral cortex in primates, providing new insights into the biological basis of human brain evolution.

neuroscience↗

bioRxiv2025

Aberrant 5-Methylcytosine tRNA Modification Disrupts Proteostasis and Exacerbates Age-Related Osteoporosis

Age-related protein aggregation drives senile osteoporosis. Aberrant tRNA modifications exacerbate the progression, yet mechanisms linking these to bone loss remain unclear. In this study, we identify Nsun2 (m5C methyltransferase) as key regulator: age-dependent Nsun2 downregulation in BMSCs reduces mC levels of tRNAs, destabilizing tRNAs and impairing translation efficiency of specific transcripts. This directly disrupts the protein synthesis of molecular chaperone and pro-osteogenic factors, accelerating misfolded protein aggregates and activating unfolded protein response, inducing BMSCs senescence and impairing osteogenesis. Mice specifically depleted of Nsun2 exhibited reduced bone mass, whereas mice overexpressing Nsun2 alleviated age-associated bone loss. Notably, the exacerbated protein aggregation and bone mass loss in Nsun2-deficient mice were ameliorated following treatment with the molecular chaperone activator-ML346. Remarkably, ML346 administration proved sufficient to reverse age-related functional deficits in aged mice. Overall, our findings demonstrate that aberrant tRNA-m5C modification alters protein synthesis and induces proteostasis collapse, which constitute a novel contributor to the pathogenesis of senile osteoporosis. Additionally, reduction of protein aggregation through the activation of molecular chaperones presents a promising therapeutic strategy for this disease.

cell biology↗

bioRxiv2025

Deciphering the Antigenic Evolution of Seasonal Influenza A Viruses with PREDAC-Transformer: From Antigenic Clustering to Key Site Identification

Seasonal influenza viruses undergo continuous antigenic drift due to mutations in the hemagglutinin (HA) protein, rendering vaccines ineffective and posing a significant global public health challenge. Existing computational models can predict antigenic relationships but generally lack interpretability, making it difficult to reveal the molecular determinants driving antigenic changes. To address this, we developed PREDAC-Transformer, an end-to-end deep learning framework that integrates sequence, physicochemical, and evolutionary features, and employs a self-attention mechanism to capture long-range dependencies relevant to antigenicity. More importantly, we introduce the integrated antigenicity score, which combines attention-based attribution with information-theoretic metrics to provide continuous quantification and ranking of the antigenic contributions of individual amino acid site. Our results demonstrate that PREDAC-Transformer not only significantly improves the accuracy of antigenic relationship prediction but also successfully recapitulates major historical antigenic cluster transitions. Using integrated antigenicity score, we systematically identified two classes of key sites: global key sites with sustained impact on antigenic evolution, and cluster-transition determining sites that drive cluster transitions. These sites include most canonical epitopes and reveal additional functional residues previously overlooked, which may influence immune escape via cooperative effects or glycosylation. Collectively, these findings advance our understanding of influenza antigenic evolution and provide novel insights for refining computational models. PREDAC-Transformer achieves high-precision prediction while attributing antigenic differences to individual residues, thereby linking viral genomic variation, antigenic change, and public health decision-making. This framework has the potential to reduce experimental burdens in influenza surveillance and assist in vaccine strain recommendation, thereby supporting global influenza control efforts.

bioinformatics↗

bioRxiv2025

Engineering auxin degradation into root-associated bacteria promotes plant growth

Overproduction of indole-3-acetic acid (IAA) by rhizosphere bacteria disrupts plant auxin homeostasis and induces root growth inhibition (RGI). Variovorax reverses this effect by degrading IAA, but the underlying pathway remains incompletely resolved. Here, using genetics, metabolomics, and isotope tracing, we define a nine-gene region (iadCDEFGHIJK2) required for IAA catabolism in Variovorax paradoxus CL014, identify a previously uncharacterized intermediate (CHNO), and revise the early oxidative steps of the pathway. Although IadDE adopts a Rieske-type oxygenase architecture, our data are consistent with the IadCDE complex functioning as a monooxygenase during IAA degradation. Using these insights, we introduce iad genes into two rhizobacterial chassis, Polaromonas MF047 and Paraburkholderia MF376. These engineered strains degrade IAA and alleviate RGI induced by exogenous IAA, an auxin-producing strain, and a synthetic bacterial community. Engineered Paraburkholderia MF376 delivers the strongest performance, improving plant growth in natural soil. Together, these results establish a framework for engineering auxin-balancing root commensals.

microbiology↗

bioRxiv2025

A spatially-resolved human brain proteome atlas for understanding function and disease

While the brain performs specialized functions across distinct regions, the spatial organization of the human brain proteome remains largely uncharted. Here we present a comprehensive spatially-resolved proteome atlas of the human brain, analyzing over two thousand MRI- guided locations across four individuals. Proteome analysis integrated with transcriptomics reveals extensive post-transcriptional regulation, with cortical regions showing markedly higher protein diversity than transcript. Unsupervised molecular clustering defines distinct brain territories that transcend anatomical boundaries, instead reflecting metabolic demands and functional specialization patterns. Application to epilepsy brain tissue uncovered disrupted astrocyte metabolism, protein homeostasis and therapeutic targets including the seizure-associated purinergic receptor P2RX7. This resource bridges molecular and systems neuroscience to accelerate neurological drug discovery.

neuroscience↗

bioRxiv2025

Within-subject rhythmicity and stability of hunger, satiety, and physiological markers: insights from a five-day laboratory study in time-isolation conditions

Hunger and satiety are interoceptions involved in the control of food intake. How they change across the day and from one day to the next, as well as their relationships with physiological parameters, remain poorly understood. In a five-day laboratory study, twenty healthy male participants (24.2 {+/-} 3.3 years) were given three meals per day (breakfast, lunch, dinner), at times based on each individuals internal time. Subjects had an 8-h sleep opportunity at night recorded by polysomnography, during which time they were exposed to 4 different light intensities (0, 3, 8, or 20 lux). Hunger and satiety were assessed before and after each meal. Heart rate was measured continuously and glucose levels were sampled every 15 minutes. We found that: 1) Hunger and satiety varied dynamically with the lowest levels at breakfast and the highest at lunch and dinner (p < 0.01); 2) the intensity of hunger and satiety remained stable across the five experimental days, and were subject-dependent; 3) Heart rate was higher after than before meals (p < 0.0001), and higher around breakfast than dinner; 4) Glycemia before and after meals was respectively stable throughout the day and over the study period; 5) Interoception was correlated with fluctuations in heart rate, glucose levels and sleep duration. Overall, our results reveal that hunger and satiety perception are individual characteristics. To better understand the role of interoception in food intake control, both hunger and satiety should be measured, but separately in their respective states.

physiology↗

bioRxiv2025

Dual Modes of Gene Regulation by CDK12

The process of transcription is driven forward by the activity of kinases including CDK7, CDK9 and CDK12. Accordingly, acute inhibition of any of these kinases results in profound downregulation of gene expression. Here, we discover that loss or inhibition of CDK12 also significantly upregulates a set of coding and non-coding loci, whose activation could contribute to the anti-proliferative effects of CDK12 inhibitors. Mechanistically, CDK12 inhibition impairs transcription elongation, leading to increased RNA polymerase II termination or arrest in long genes. However, short genes such as MYC and enhancer RNAs are highly transcribed in the absence of CDK12 activity. Indeed, in HER2+ breast cancer, a malignancy where CDK12 is co-amplified with HER2 and its expression correlates with disease status, CDK12 inhibition markedly elevates MYC expression to induce lethality. The dual effects of CDK12 inhibition elucidated herein clarify its role in transcriptional control and have significant translational implications.

cancer biology↗

bioRxiv2025

Single-cell transcriptome sequencing for opening the blood-brain barrier through specific mode electroacupuncture stimulation

BackgroundThe blood-brain barrier (BBB) interferes with the treatment of central nervous system disorders owing to the complexity of its structure and restrictive function. Thus, it is challenging to develop central nervous system drug delivery strategies. Specific mode electroacupuncture (EA) stimulation can effectively open the BBB in rats. MethodsHere, we used single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell population in the Sprague-Dawley rat cerebral cortex. ResultsWe identified 23 cell subsets and eight types of cells in the brain by cell annotation. scRNA-seq revealed transcriptional changes in the cerebral cortex under EA. ConclusionsOur findings offer valuable insights into the molecular and cellular modifications in the brain resulting from EA intervention and serve as a resource for drug delivery across healthy and diseased states. Innovative approaches to enhance BBB opening will lead to more effective therapeutic plans and enhanced drug delivery.

neuroscience↗

bioRxiv2025

ProteinReasoner: A Multi-Modal Protein Language Model with Chain-of-Thought Reasoning for Efficient Protein Design

Reasoning has emerged as a central capability of large language models, yet how it should be formulated for scientific foundation models remains unclear because scientific knowledge is distributed across interdependent, domain-specific representations. Here we introduce modality-chain reasoning, which organizes representations into ordered computational chains, each conditioning prediction or generation of the next. Based on this principle, we develop ProteinReasoner, a multimodal generative protein foundation model that sequentially connects amino acid sequence, evolutionary constraints and three-dimensional structure within a shared autoregressive architecture. Across zero-shot structure prediction, inverse folding and fitness prediction, ProteinReasoner outperformed two multimodal protein foundation models, while controlled comparisons supported the functional contribution of the modality chain. We further extended this principle beyond pretraining: reorganizing the chain across successive structural states enabled multiple-conformation prediction, while introducing experimental feedback as an additional modality enabled an in-context learning paradigm for protein optimization without target-specific parameter updates. In particular, across thermostability and affinity-maturation evaluations, this paradigm improved over matched fine-tuned models and showed stronger mean performance than target-specific active-learning baselines. These results establish modality-chain reasoning as a unified and effective foundation-modelling strategy in protein science. More broadly, they suggest a general route towards reasoning across interdependent representations in other scientific domains.

bioinformatics↗

bioRxiv2025

SVPG: A pangenome-based structural variant detection approach and rapid augmentation of pangenome graphs with new samples

Breakthrough advances in long-read sequencing technologies have opened unprecedented opportunities to study genetic variations through comprehensive pangenome analysis. However, the availability of structural variant (SV) calling tools that can effectively leverage pangenome information is limited. In addition, efficient construction of pangenome graphs becomes increasingly challenging with acquisition of larger number of samples. In this study, we present SVPG, an approach that leverages haplotype-resolved pangenome reference for accurate SV detection and rapid pangenome graph augmentation from long-read sequencing data. Compared to state-of-the-art SV callers, SVPG maintained superior overall performance across different sequencing technologies and coverages. SVPG also achieved notable improvements in calling rare and individual-specific SVs on both simulated and real somatic datasets. Furthermore, in a benchmark involving 20 samples, SVPG accelerated pangenome graph augmentation by nearly 10-fold compared to traditional augmentation strategies. We believe that this novel SVPG method, has the potential to revolutionize SV detection and serve as an effective and essential tool, offering new possibilities for advancing pangenomic research.

bioinformatics↗

bioRxiv2025

Immunomodulatory effect of HLA-G Overexpressed Mesenchymal Stromal Cell in Cell-based Therapy for Myocardial Infarction

BackgroundOur previous study demonstrated that intravenous administration of mesenchymal stromal cells (MSCs) significantly increased local cell engraftment and improved heart function. We sought to investigate whether HLA-G1 overexpressed MSCs could further increase local transplanted cells engraftment and improve heart function. Methods and ResultsMice were randomized to receive intravenous administration of saline, human umbilical cord blood derived MSCs (hUCB-MSCs) 7 days prior to acute myocardial infarction (AMI), induced by ligation of the left anterior descending coronary artery. Then, intramyocardial transplantation of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) was performed 30 minutes following AMI. Echocardiographic assessment was performed to assess heart function. In-vivo fluorescent imaging analysis were used to analyze cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was conducted to evaluate the immunomodulatory effect. Our result showed that systemic intravenous administration of hUCB-MSCs significantly increased systemic Tregs, decreased systemic NK cells, increased cell engraftment of intramyocardial transplanted hiPSC-CMs, culminating in improvement of heart function. Our in-vitro study showed that HLA-G1 overexpressed hUCB-MSCs modulated immune response by decreasing pro-inflammatory cytokines. ConclusionsSystemic intravenous administration of HLA-G1 overexpressed hUCB-MSCs modulated immune response and enhanced the survival of local transplanted hiPSC-CMs to improve heart function following AMI.

cell biology↗

bioRxiv2025

Epithelial tumor cells utilize mast cell-derived histamine to regulate perineural invasion

Cancer dissemination by perineural invasion (PNI) is associated with poor outcomes in epithelial malignancies, yet the cellular interactions critical to this process are not fully defined. Single-cell transcriptomic analysis of cutaneous squamous cell carcinoma (cSCC) with PNI highlighted KITLG-KIT signaling activation between keratinocytes and mast cells. Additionally, we observed increased expression of HRH1 on tumor cells, which encodes the H1 histamine receptor. We confirmed these changes in other cancers, including PNI-positive hepatobiliary and oral mucosal tumors. Histamine enhanced tumor invasion into nerve in organoids that recapitulate key features of PNI, an effect rescued by H1-antihistamines. Mechanistically, broad upregulation of matrix metalloproteinases (MMPs) through P38 activation underscored histamine-mediated PNI by enabling collagen degradation in the nerve sheath. Examination of multiple cancer types with PNI showed co-expression of HRH1 and MMP2 on tumor cells as well as type IV collagen loss in involved nerves. Retrospective analysis of >15,000 patient health records in two independent databases demonstrated that H1-antihistamine use improved overall survival and immunotherapy response in cancers that spread by PNI. Together, these data reveal a critical role for mast cells in PNI and present a new therapeutic strategy for targeting this process in epithelial cancers.

cancer biology↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Prime assembly with linear DNA donors enables large genomic insertions

Targeted insertion of large DNA fragments has promising applications for genome engineering and gene therapy1,2. Twin prime editing (PE) guide RNAs (pegRNAs) have enabled relatively large insertions, but the efficiency remains low for insertions greater than 400 base pairs3-6. Here we describe a Prime Assembly (PA) approach for the insertion of large DNA donor fragments, whose ends are designed to overlap with the flaps generated by twinPE. We used PA to insert one, two, or three overlapping DNA fragments, with total insertion sizes ranging from 0.1 to 11 kilobase pairs. An inhibitor of non-homologous end joining (NHEJ) enhanced both the efficiency and precision of insertions. PA relies on DNA templates that are easily produced and does not require co-delivery of exogenous DNA-dependent DNA polymerases. Our study demonstrates that PA can initiate "Gibson-like" assembly in cells to generate gene insertions without double-stranded DNA breaks or recombinases.

biochemistry↗

bioRxiv2025

Digital Twin Brain Predicts rTMS Effects on Brain State Dynamics in Chronic Tinnitus

Predicting repetitive transcranial magnetic stimulation (rTMS) effects on whole-brain dynamics in clinical populations is crucial for developing personalized therapies and advancing precision medicine in brain disorders. This study provides the first proof-of-concept demonstrating that the Digital Twin Brain (DTB) can forecast rTMS effects on brain state dynamics in individuals with brain disorders (chronic tinnitus). First, we identified two aberrant brain states that predominantly overlapped with the somatomotor and default mode networks, respectively. Subsequently, we developed DTB for patients and derived regional responses for each brain region, revealing distinct roles of the parieto-occipital and frontal regions. Mechanistically, we examined the biological plausibility using tinnitus-specific risk genes and investigated the multi-scale neurobiological relevance. Clinically, we found that DTB can predict rTMS effects in an independent, longitudinal dataset (all r > 0.78). Particularly, the predictive capacity exhibits a state-specific nature. Overall, this work proposes a novel DTB-based framework for predicting rTMS effects in clinical populations and provides the first empirical evidence supporting its clinical utility. This approach may be generalizable to other brain disorders and neuromodulation techniques, promoting broader advancements in brain health.

neuroscience↗

bioRxiv2025

Development a computational framework for risk evaluation of emerging flu viruses based on genomic sequences and AI

The recent resurgence of highly pathogenic avian influenza H5N1 viruses in North America and Europe has heightened global concerns regarding potential influenza pandemics. Despite significant progress in the surveillance and prevention of emerging influenza viruses, effective tools for rapid and accurate risk assessment remain limited. Here, we present FluRisk, an innovative computational framework that integrates viral genomic data with artificial intelligence (AI) to enable rapid and comprehensive risk evaluation of emerging influenza strains. FluRisk incorporates a curated database of over 1,000 experimentally validated molecular markers linked to key viral phenotypes, including mammalian adaptation, mammalian virulence, mammalian transmission, human receptor-binding preference, and antiviral drug resistance. Leveraging these markers, we developed three state-of-the-art machine learning models to predict human adaptation, mammalian virulence, and human receptor-binding potential, all of which demonstrated superior performance compared to traditional approaches such as BLAST, prior models, and baseline classifiers. In addition, a reference-based method was implemented to provide preliminary estimates of human transmissibility and resistance to six commonly used antiviral drugs. To facilitate broad accessibility and practical application, we developed a user-friendly web server that integrates both the molecular marker atlas and predictive tools for influenza virus phenotyping (available at: http://www.computationalbiology.cn/FluRisk/#/). This computational platform offers a valuable resource for the timely risk assessment of emerging influenza viruses and supports global influenza surveillance efforts.

bioinformatics↗

bioRxiv2025

Arcuate Fasciculus: Evolutionary Convergence in Marmosets and Humans

The marmoset is a highly vocal platyrrhine monkey that shares key anatomical and functional features with humans, offering insights into the evolution of brain connectivity. Although similarities in vocalization features with humans have been reported, it remains unclear whether marmosets possess an arcuate fasciculus (af) homolog. This study delineated white matter tracts in marmosets, establishing homologies with those observed in other primates, including macaques, chimpanzees, and humans. The presence of an af homolog in marmosets was confirmed by tracer and ultra-high-resolution diffusion magnetic resonance imaging datasets. We compared cortical connectivity patterns across these species and found the af in marmosets terminates in the ventral frontal cortex, with greater similarity to humans than macaques. Furthermore, we linked af connectivity with vocalization-related brain activation in both marmosets and humans. Collectively, our findings suggest that a dorsal pathway, which emerged early in marmoset evolution, has evolved convergently with humans, despite their distant phylogenetic kinship.

neuroscience↗

bioRxiv2025

Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity

Commensals shape host physiology through molecular crosstalk with host receptors. Identifying specific microbial factors that causally influence host immunity is key to understanding homeostasis at the host-microbe interface and advancing microbial-based therapeutics. Here, we identify trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis (C. mast) as a potent stimulator of IL-17 production by {gamma}{delta} T cells at the ocular surface. Mechanistically, TMCM-driven IL-17 responses require both IL-1 signals and {gamma}{delta} TCR signaling, which also supports endogenous {gamma}{delta} T cell IL-1R1 expression. Notably, synthetic TMCM alone is sufficient to mimic the effect of C. mast in inducing {gamma}{delta} T cell immunity and protect against pathogenic corneal infection. Our findings establish TMCM as a key mediator of commensal-driven immune defense, highlighting its potential as a {gamma}{delta} T cell adjuvant and a microbiome-informed therapeutic to enhance IL-17-driven protection at barrier sites such as the ocular surface. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@63139forg.highwire.dtl.DTLVardef@9d6978org.highwire.dtl.DTLVardef@775e37org.highwire.dtl.DTLVardef@ca84b6_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LICorynomycolates enable ocular C. mast colonization and protective IL-17 immunity C_LIO_LITMCM drives IL-17 from {gamma}{delta} T cells through TCR and IL-1R signaling C_LIO_LI{gamma}{delta} TCR signaling maintains the expression of endogenous IL-1R1 C_LIO_LISynthetic TMCM mimics the ability of C. mast to induce {gamma}{delta} T cell immunity in the eye C_LIO_LITMCM protects against P. aeruginosa keratitis, highlighting its therapeutic potential C_LI

immunology↗