Biology subjects

Zhai, T.

Publications and source records attributed to Zhai, T..

14 recordsLinked to original sources

bioRxiv2026

Integrating Multisource Target Evidence with Machine-Learning Potency Prediction for Alzheimer's Disease Drug Discovery

Alzheimer's disease (AD) target evidence is distributed across biological, chemical, structural, regulatory, and trial-registry sources, complicating reproducible target evaluation and modeling. We developed a traceable data-to-model platform that integrates AGORA-centered evidence through Target Explorer, Drug-Target Lookup, and Model Portfolio workspaces. The resource contains 967 targets, 452,249 compounds, and 1,430,260 measurements. On a curated PIK3CA dataset, target-specific fine-tuning of the Boltz-2 affinity head increased Pearson r from 0.248 to 0.560 and reduced mean absolute error from 0.900 to 0.706 on 469 held-out compounds. Separately, we screened 42 regression models over 50 random splits for ten moderate-sized target datasets; a random forest model for XDH achieved the highest mean R^2 (0.815). The platform connects curated evidence, model-ready datasets, reproducible evaluation, and public results while clearly separating contextual evidence from therapeutic claims and random-split performance from generalization to unseen chemical scaffolds.

bioinformatics↗

bioRxiv2026

Floss-Mediated Gingival Mucosal Immunization with HBc-E18-3 VLPs Induces Long-Lasting Intestinal IgG and Provides a Candidate Strategy for Intervention of FcRn-Related Autoimmune Injury

Echovirus 18 (E18) is a predominant pathogen causing aseptic meningitis in children, and post-E18 infection frequently triggers myasthenia gravis-like autoimmune neurological damage. This pathological process relies on neonatal Fc receptor (FcRn)-mediated IgG transcytosis across mucosal barriers, and FcRn also acts as an essential functional receptor required for E18 attachment and uncoating during host cell invasion. At present, no E18-specific prophylactic vaccine has been clinically approved, and anti-FcRn monoclonal antibodies are the available therapeutics to alleviate autoantibody-mediated tissue injury. We constructed an integrated automated phylogenetic pipeline named evolution_conservation, which enables rapid tracing of the evolutionary position and genetic relatedness of clinical isolates to identify closely related strains from previous outbreaks. Serving as an in silico alternative to animal experiments, this pipeline supports reference-guided vaccine design and longitudinal comparative assessment of vaccine safety and efficacy, facilitates identification of patient populations presenting rare post-viral sequelae, and accelerates clinical trial progression. In this study, we inserted the pre-screened linear epitope E18-3 into a truncated hepatitis B core (HBc) scaffold to generate chimeric virus-like particles (VLPs). A non-invasive floss-based gingival mucosal immunization mouse model was established, with subcutaneous Freunds adjuvant immunization set as the control group. ELISA results confirmed that gingival mucosal delivery of particulate HBc-E18-3 VLPs alone could induce sustained high levels of antigen-specific intestinal IgG in vivo. Drawing on research paradigms of therapeutic neoantigen vaccines for tumor recurrence prevention, the evolution_conservation bioinformatic pipeline and mucosal VLP platform described herein establish an innovative framework for developing antigen-competitive prophylactic and therapeutic vaccines targeting FcRn for myasthenia gravis and autoimmune encephalitis.

immunology↗

bioRxiv2026

Integrative single-nucleus multi-omics profiling identifies candidate regulators and signaling axes in Alzheimer's disease lipid-processing microglia

Lipid-processing microglia are among the microglial states most strongly associated with Alzheimers disease (AD) pathology, yet whether this association reproduces across independent cohorts, what transcriptional programs define the state, and which upstream signals and small molecules can modulate it remain unsolved. We address these questions through a cross-cohort analysis of one such substate (MG4) by integrating differential expression, transcription factor activity inference, gene set enrichment, and cell-cell communication across five independent single-nucleus RNA sequencing cohorts (ntotal = 140 donors), with paired single-nucleus ATAC sequencing in one multi-omic cohort for epigenomic corroboration. A held-out cohort (n = 150 donors) supported donor-level regression of MG4 proportion on ligand expression, and two spatial transcriptomics datasets (ntotal = 30 donors) related ligand expression to MG4 identity in neighboring spots. MG4 was reproducibly enriched in AD across all five cohorts (pooled log2 fold change = 0.90, p = 3.0 x 10-4). Expression-based inference and motif accessibility jointly nominated MITF and BACH1 as regulators of a program led by V-ATPase-driven lysosomal acidification and cholesterol efflux, a lysosomal-biogenesis signature distinct from the catabolic DAM and lipid-storage LDAM programs, with AD-specific upregulation of energy metabolism. FGF1 and TGFB2 were the most supported candidate upstream ligands, each significant in donor-level regression with further spatial evidence. Computational drug repurposing nominated ten blood-brain barrier-penetrant compounds as perturbational probes. Together, these results advance a described disease-associated microglial state into a reproducible, mechanistically framed regulatory model, providing candidate regulators, upstream ligands, and pharmacological probes for functional validation.

bioinformatics↗

bioRxiv2026

Plasma proteomics reveals divergent sex-specific senescence and bone biology signatures across neurodegenerative diseases

Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimers disease(AD), Lewbody dementia(LB) and Parkinsons disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

neuroscience↗

bioRxiv2026

Quantification of domain-specific intrinsic capacity using mortality data

Functional health is centered on five domains of Intrinsic Capacity (IC): locomotion, cognition, vitality, psychological and sensory capacity. Therefore, measuring IC at the domain-specific level is the cornerstone for developing preventive interventions to help individuals preserve their independence. In this study, we used 63 clinical features from the UK Biobank to develop IC age, an 18-year mortality risk estimator that approximates an individuals biological age associated with the decline of each IC domain. By establishing proteomic surrogates of IC age, we find immune system activation across domains and provide a proteomic framework that may facilitate scalable monitoring of functional health decline.

systems biology↗

bioRxiv2026

Brain morphological pattern is associated with the presence, severity, and transition of transdiagnostic psychiatric disorders in preadolescents

Cognitive function, psychological processes, mental states, and behaviors are key dimensions of human subjective experience that separately relate to mental disorders across diagnostic categories. However, whether these dimensions are linked to common or distinct brain morphological patterns that convey risk or resilience for psychiatric disorders remains unclear. The current study is a longitudinal investigation on 11,875 youths from the Adolescent Brain Cognitive Development (ABCD) Study aged 9-10 years at baseline. A machine learning approach based on canonical correlation analysis was used to identify latent dimensional associations of cortical morphology (4 metrics: surface area, cortical and subcortical volume, cortical thickness, and sulcal/gyral depth) with multidomain behavioral assessments including cognitive scores and psychological measures indexing motivation, impulse control, mental states, and behaviors across a normative continuum from healthy to pathological. Across morphological measures, we identified a robust latent brain structural variate that correlated positively with cognitive performance and negatively with psychological measures indexing greater psychology. Notably, higher scores on this brain variate reflected larger cortical surface area and cortical volume--especially in the temporal gyri--together with a posterior-anterior gradient in cortical thickness, showing relatively greater thickness in occipital, parietal, and temporal cortices and lower thickness in cingulate and frontal regions. This brain variate and the related cognitive-psychological-behavioral variate remained stable at the 2-year follow-up, demonstrating temporal consistency. Importantly, the brain variate showed a dose-dependent relationship with the cumulative number of psychiatric diagnoses assessed concurrently and at 2-year follow-up, with lower brain variate scores being associated with higher numbers of comorbid diagnoses. In addition, the brain scores were associated with longitudinal transitions between healthy and diagnosed states over the 2-year study period, in which lower scores at baseline were associated with persistent psychiatric diagnoses whereas higher scores at baseline were associated with persistent healthy states, suggesting that the brain scores capture a vulnerability- resilience continuum for psychopathology. By revealing shared brain structural substrates across conventional diagnostic boundaries, these findings advance the neurodevelopmental understanding of psychiatric disorders and highlight the potential utility of morphology-informed approaches for early screening and intervention in youth.

developmental biology↗

bioRxiv2025

Physiological Arousal as a Predominant Source of Individual Differences in Functional Brain Networks

Individual differences in brain network function and organization are promising targets for fMRI-based biomarkers in precision psychiatry, yet the sources of individual variability remain poorly understood. We show that arousal, assessed by systemic low-frequency oscillation (sLFO) amplitude in the fMRI signal, accounts for a substantial portion of variance in brain network properties (e.g.: R= 0.70 for default mode network (DMN)-dorsal attention connectivity; R= -0.63 for DMN dynamics). These relationships replicated across sessions, across independent samples, and when assessed with traditional arousal indices. Critically, associations persisted after sLFO denoising, indicating a genuine brain-physiology relationship rather than hemodynamic artifact. Pharmacological manipulation showed that drug-induced sLFO-assessed arousal changes were accompanied by corresponding shifts in network connectivity and dynamics. This work identifies arousal as a prominent determinant of variability in functional brain networks, providing a new perspective on brain-based individual differences while offering an approach to measure arousal directly from fMRI data.

neuroscience↗

bioRxiv2025

Dynamic alterations of DNA methylation and transcriptome in adaptation to and recovery from the space environment

Space exploration presents tremendous health challenges. Here, we report time series of multi-omic and phenotypic profiles of seventeen astronauts from six China Manned Space missions with continuous spaceflight durations ranging from 13 to 180 days. We revealed a key role of DNA methylation regulation in reshaping gene expression patterns to adapt to the space environment. Long-duration spaceflight showed more alterations in epigenetic modifications correlated with alternative splicing and protein acetylation. During recovery, an "overrange rebound" phenomenon was observed, furthermore, a mathematical model was established to describe this implying important phenomenon. Moreover, we revealed the correlations between molecular alterations and phenotypic changes such as coagulation activation and bone intensity loss. Additionally, we performed ground-based simulation experiments to estimate the impacts of individual stressors in the space environment on DNA methylation. In summary, our study highlights the importance and complexity of epigenetic regulation in adaptation to and recovery from the space environment.

genomics↗

bioRxiv2025

From rest to focus: Pharmacological modulation of the relationship between resting state dynamics and task-based brain activation

Dynamic resting-state brain activity provides insight into intrinsic neural function and holds promise for predicting individual responses to cognitive demands and pharmacological interventions. This research could ultimately guide medication selection, yet links between network dynamics and medication effects on cognitive function require further validation. Here, we examined whether dynamic activity of an attentional network at rest relates to task-evoked brain activation on the Multi Source Interference Task (MSIT) following administration of methylphenidate (20mg) and haloperidol (2mg), which have opposing effects on attention and catecholaminergic function. Fifty-nine healthy adults completed resting-state and task-based fMRI on three separate days on which they received methylphenidate, haloperidol, or placebo in a double-blind placebo-controlled design. Coactivation pattern analysis determined time spent in the dorsal attention network (DAN) under placebo at rest. Linear mixed-effects modelling assessing the relationship between MSIT task activation under drug and time spent in DAN at rest under placebo and MSIT task activation under drug identified a significant interaction in the dorsolateral prefrontal cortex (dlPFC; p<0.001). Post-hoc analyses indicated that more time in the DAN at rest under placebo was associated with decreased MSIT dlPFC activation under methylphenidate and increased dlPFC activation under haloperidol. Findings demonstrate that resting dynamics of an attentional network are linked to task-related brain responses under different drug conditions within a region implicated in attentional control and sensitive to catecholaminergic variance. Resting-state dynamics may predict pharmacological modulation of goal-directed cognition, highlighting the potential clinical utility of resting-state dynamics in predicting medication response and supporting individualized treatment.

neuroscience↗

bioRxiv2025

Maturation of Dorsal Association Tracts during Preadolescence Links to Concurrent and Future Cognitive Performance and Transdiagnostic Psychopathology

Many psychiatric disorders begin during adolescence, coinciding with the rapid development of brain white matter (WM). However, it remains unclear whether deviations from normal WM maturation during this age period contribute to the development of psychopathology. In this study, we developed and validated normative models of brain age based on specific WM tracts using three large-scale developmental datasets (a total of [~]10,000 subjects). We found that tract-specific deviations in WM development of association and limbic/subcortical systems were linked to concurrent cognition and psychopathology. The spatial pattern of the association system aligned closely with distributions of high-order brain networks, and with mitochondrial content and respiratory capacity. The maturation of the association system contributed significantly to better cognitive performance assessed two or three years later. Importantly, delayed WM development especially in dorsal association tracts predicted psychiatric disorders across diagnoses and disorder onset over a 2-year follow-up. By identifying tract-specific WM development during preadolescence as a predictor of cognitive capacity and psychiatric disorder risks, this study provides a valuable framework for tracking individualized brain maturation and understanding the neurobiological underpinnings of cognitive performance and transdiagnostic psychopathology.

neuroscience↗

bioRxiv2025

MSIanalyzer: Targeted Nanopore Sequencing Enables Single Nucleotide Resolution Analysis of Microsatellite Instability Diversity

We present a targeted sequencing-based pipeline that profiles microsatellite instability (MSI) at single-nucleotide resolution. Targeted amplicons from the five widely studied Bethesda panel microsatellite loci were sequenced using Oxford Nanopore Technology in two microsatellite unstable colorectal cancer cell lines (HCT15, HCT116), two microsatellite stable cancer cell lines (TK6, U2OS), and two peripheral blood mononuclear cell samples from healthy donors. An anchor-extension algorithm was developed to capture repeat motifs while allowing interruptions, using a threshold informed by platform-specific error. Cluster-aware Dirichlet-multinomial and beta-binomial tests were applied for between-sample comparisons while accounting for read-level clustering within samples. The algorithm revealed distinct repeat profiles in HCT15 and HCT116 compared to other cell types and uncovered allelic diversity across samples at different MSI loci. Our approach complements existing short tandem repeat callers by preserving read-level diversity and delivering targeted, quantitative MSI calls with potential applications in mechanistic research and clinical assay development.

molecular biology↗

bioRxiv2021

Brain functional connectome defines a transdiagnostic dimension associated with cognition and psychopathology in youth

BackgroundCognitive dysfunction and high-order psychopathologic dimensions are two main classes of transdiagnostic factors related to psychiatric disorders. They may link to common or distinct core brain networks underlying developmental risk of psychiatric disorders. MethodThe current study is a longitudinal investigation with 11,875 youths aged 9-to 10-years-old at study onset, from the Adolescent Brain Cognitive Development study. A machine-learning approach based on canonical correlation analysis was used to identify latent dimensional associations of the resting-state functional connectome with multi-domain behavioral assessments of cognitive functions and psychopathological problems. For the latent rsFC factor showing a robust behavioral association, its ability to predict psychiatric disorders was assessed using two-year follow-up data and its genetic association was evaluated using twin data from the same cohort. ResultA latent functional connectome pattern was identified that showed a strong and generalizable association with the multi-domain behavioral assessments (5-fold cross validation: {rho} = 0.68~0.73, for the training set (N = 5096); {rho} = 0.56 ~ 0.58, for the test set (N = 1476)). This functional connectome pattern was highly heritable (h2 = 74.42%, 95% CI: 56.76%-85.42%), exhibited a dose-response relationship with cumulative number of psychiatric disorders assessed concurrently and 2-years post-MRI-scan, and predicted the transition of diagnosis across disorders over the 2-year follow-up period. ConclusionThese findings provide preliminary evidence for a transdiagnostic connectome-based measure that underlies individual differences in developing psychiatric disorders in early adolescence.

neuroscience↗

bioRxiv2020

Identification and validation of a ferroptosis-related genes based prognostic signature for prostate cancer

Ferroptosis, an iron-dependent form of selective cell death, involves in the development of many cancers. However, systematic analysis of ferroptosis related genes (FRGs) in prostate cancer (PCa) remains to be clarified. In our research, we collected the mRNA expression profiles and clinical information of PCa patients from TCGA and MSKCC databases. The univariate, LASSO and multivariate Cox regression method were performed to construct prognostic signature in TCGA cohort. Seven FRGs, AKR1C3, ALOXE3, ATP5MC3, CARS1, MT1G, PTGS2, TFRC, were included to establish the risk model, which was validated in MSKCC dataset. Subsequently, we found that high risk group was strongly correlated with copy number alteration load, tumor burden mutation, immune cell infiltration, mRNAsi, immuetherapy and bicalutamide response. Finally, it was identified that overexpression of TFRC could induce proliferation and invasion in PCa cell lines in vitro. These results demonstrated that this risk model based on recurrence free survival (RFS) could accurately predict prognosis in PCa patients, suggesting that FRGs are promising prognostic biomarkers and drug target genes for PCa patients.

cancer biology↗

bioRxiv2019

Clinical diagnosis of single-gene disorders and chromosomal abnormalities based on BGISEQ-500 platform

Most of the variation in the human genome is a single nucleotide variation (SNV) based on a single base or small fragment insertions and deletions and genomic copy number variation (CNV). Both types of mutations are involved in many human diseases. Such diseases often have complex clinical symptoms and difficult clinical diagnosis, so an effective detection method is needed to help clinical diagnosis and prevent birth defects. With the development of sequencing technology, the method of chip capture combined with high-throughput sequencing has been extensively used because of its high throughput, high accuracy, high speed and low cost. This study designed a chip that captures the coding region of 3043 genes associated with 4013 monogenic diseases. In addition, 148 chromosomal abnormalities can be identified by setting targets in specific regions. Compared with the whole exon chip, the chip can detect 4013 monogenic diseases and 148 chromosomal abnormalities at a lower cost, including SNV, intra-gene CNV and genomic copy number variation. This study utilized a strategy of combining the BGISEQ500 sequencing platform with the chip to identify 102 disease-associated mutations in 63 patients, 69 of which were new mutations. The evaluation test results also show that this combination complies with the requirements of clinical testing and has good clinical application value.

genomics↗