Biology subjects

Tian, C.

Publications and source records attributed to Tian, C..

At least 19 recordsLinked to original sources

bioRxiv2026

A comprehensive map of the sequence basis of transcription initiation in humans

Transcription initiation is a key marker of active enhancers and promoters. Here we describe an atlas of efficient and interpretable deep learning models trained on over 200 transcription initiation profiling experiments representing all major human organs and many cancer types. We show that our models accurately predict initiation patterns from local DNA sequence and decode their sequence determinants across diverse cellular contexts.

bioinformatics↗

bioRxiv2026

Brain state locks silent memories in a trained fly connectome

Complete connectomes now exist for insect nervous systems, but whether a fixed wiring diagram can learn, and what its memories consist of, is unknown. Here, we trained a spiking model of the whole male Drosophila central nervous system, 167,106 neurons with fixed wiring, to plan moves and to remember a visual cue. Spikes write the cue into neuronal adaptation, which holds it silently until the next input reads it out. Cells that hold the trace are enriched for transcripts of a calcium-activated potassium channel in fly cell atlases. The learned readout recalls the trace only in the brain state of learning: the same trace evokes a different response at another delay, and a disease-like loss of potassium current rewrites the trace and changes how it is read. Learning in the new state is spared. Memory failure can arise from a change of state rather than a loss of storage.

neuroscience↗

bioRxiv2026

Spinal V2a neurons support locomotor propagation via long-range connectivity

The spinal cord contains a diverse set of neurons whose activity is vital for motor control. Despite the importance of these spinal interneurons in network models of locomotion, their circuitry remains poorly understood. We quantified the synaptic output of V2a (vsx2+) interneurons, a glutamatergic population implicated in control of locomotor speed, rhythm generation, and recovery from injury, using the larval zebrafish. Surprisingly, we found that the majority of monosynaptic output from V2a neurons occurs onto motor and premotor targets at long ranges, in contrast to models that posit V2a neurons as the source of recurrent local excitation. Focal loss of V2a neurons impairs long-range propagation of locomotor output, but not local rhythm generation, in accordance with their long-range connectivity. Our results position V2a neurons as major mediators of locomotor propagation and long-range coordination in the spinal cord.

neuroscience↗

bioRxiv2026

Engineering human myelin microphysiological systems for testing patient treatment response in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, demyelination, and neurodegeneration, associated with a complex interplay between the innate and adaptive immune systems. Currently, no cure is available for MS, and personalized disease-modifying treatment remains largely limited, partially due to the lack of preclinical human models that can faithfully recapitulate disease pathology and evaluate treatment responses at the individual-patient level. Here, we report a human myelin microphysiological system (myelin MPS) platform that recaptures disease phenotype and treatment response for testing patient treatment response. By culturing neural organoids on 3D-printed devices containing directional microfibers, followed by coculture with oligodendrocyte progenitor cells, 96 myelin MPS models can be generated within a conventional well plate. Using this myelin MPS platform, autologous T cells and monocytes from MS patients induced substantially greater demyelination than those from healthy donors, accompanied by expansion of proinflammatory T-cell subsets and increased myelin uptake by monocytes/macrophages after coculture with these healthy myelinating neural tissues. Integration of imaging and flow-cytometric features distinguished healthy-donor, untreated-MS, responder, and nonresponder profiles following treatment with prednisone, glatiramer acetate, interferon {beta}-1a, or dimethyl fumarate. Thus, the myelin MPS platform provides a scalable, human pathophysiology-relevant platform for functional phenotyping and individualized treatment-response evaluation in MS.

bioengineering↗

bioRxiv2026

Brain organoid computing for robotic decision-making

Biomimicry has inspired the evolution of robotics toward greater autonomy, adaptability, and symbiosis with humans and dynamic environments. However, current robotic systems still face major challenges in recapitulating the high-efficiency decision-making capabilities of the human brain under complex and dynamic conditions. Here, we present Brainobot, a biohybrid robotic system that establishes a brain organoid controller as a high-level robotic decision-making layer for closed-loop embodiment. By leveraging brain organoid reservoir computing, Brainobot interacts with dynamic environments by receiving and processing sensory inputs and generating motor actions. As a proof-of-concept demonstration, Brainobot is implemented in a humanoid robotic system to perform real-world tasks, including object grasping and laser chasing. Interestingly, Brainobot exhibits unique features, including cross-task adaptivity, high computing efficiency, and low energy consumption. Thus, our approach may provide insights for advancing robotic embodiment and understanding biological decision-making.

bioengineering↗

bioRxiv2026

Information processing-like phenotype of human brain organoids

Human brain organoids recapitulate key physiological features and functions of the human brain and hold remarkable potential for studying neurological diseases. Despite clinical evidence suggesting that neurodegenerative diseases impair the information-processing ability of the human brain, the capacity of brain organoids for information processing and its relationship to neural network function remain largely unexplored. Here, we test and quantify information-processing-like properties of human cortical organoids using a task-based functional phenotyping framework (Brainopheno). We demonstrate the pattern-processing-like phenotype of cortical organoids through the representation and classification of evoked neural activities in response to distinct spatial input stimulation patterns via a microelectrode array (MEA) system. Moreover, this functional phenotype emerges with network maturation and is disrupted by pharmacological perturbations, linking classification performance to the functional integrity of organoid neural networks (ONNs). Importantly, this functional phenotype also reveals functional deficits in ONNs altered by a familial Alzheimer's disease (AD)-associated gene mutation (APP) and by monocytes from patients with sporadic AD. This work may establish a new quantifiable functional phenotype of neural organoids and provide a framework to bridge molecular and cellular profiles with neural circuit function for basic neurology, disease phenotyping, and therapeutic development.

bioengineering↗

bioRxiv2026

MEGA-ODE: Learning Biologically Structured and Navigable Continuous Perturbation Dynamics from Sparse Omics

Perturbation-omics experiments usually measure only a subset of molecular feature, intervention and time space, leaving many response trajectories, perturbation effects and disease- or differentiation-associated transitions unobserved. Here we present MEGA-ODE, a graph-constrained continuous-time framework for reconstructing sparse dynamic omics landscapes, predicting unmeasured molecular states and prioritizing virtual perturbations toward defined biological endpoints. MEGA-ODE integrates molecular-network priors, graph neural ordinary differential equations and context-adaptive mixture-of-experts routing. In L1000 transcriptomic perturbations and CPPA proteomic drug-response data, MEGA-ODE improved held-out-feature and unseen-perturbation prediction over baseline methods, and in SARS-CoV-2 infection time-series data it remained competitive for future-time-point forecasting. In a COVID-19 patient cohort, predicted intermediate profiles improved retrospective disease-stage stratification relative to observed profiles alone, while expert programs highlighted immune and inflammatory signals associated with severity. Across the MAPK drug-response and stem-cell differentiation case studies, graph- and expert-level attributions prioritized perturbation-associated MAPK edges, developmental regulators and TF-target relationships supported by independent promoter-proximal ChIP-seq overlap. In hESC-to-definitive-endoderm differentiation, MEGA-ODE prioritized candidate transcription-factor perturbations predicted to shift 12-36 h profiles toward 96 h definitive-endoderm marker signatures, framing trajectory navigation as a concrete hypothesis-generation task. Together, these results support biologically structured continuous-time modeling for prediction, interpretation and virtual-perturbation prioritization from sparse temporal omics data.

bioinformatics↗

bioRxiv2026

Novel mouse models for perianal fistulizing Crohns disease reveal therapeutic value of interferon-gamma antagonists

Background and AimsPerianal fistulizing Crohns disease (PFCD) is a challenging complication with poorly understood pathogenesis and limited treatment options, largely due to the lack of clinically relevant animal models. Interferon-gamma (IFN-{gamma}) signaling is hyperactivated in human PFCD. We aimed to establish mouse models recapitulating human PFCD and to evaluate IFN-{gamma} as a new therapeutic target. MethodsPerianal fistulas were established in three mouse models with concurrent Crohns disease-like intestinal inflammation: wild-type (WT) mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced proctocolitis, Il10-/-mice, and TNF{Delta}69AU/+ mice. A modified MAGNIFI-CD index was developed for longitudinal fistula assessment in mice. Transcriptomic analysis and flow cytometry were conducted on mouse fistula tissue. Re-analysis of single-cell and spatial transcriptomics of human PFCD tissues was performed. Therapeutic benefits of anti-TNF-, upadacitinib, and IFN-{gamma} pathway antagonists were evaluated in the PFCD models. ResultsAll three PFCD models sustained chronic perianal fistula tracts for at least 5 weeks after wire removal. All three models closely recapitulate the pathological and molecular features of PFCD in patients, as confirmed by clinical examination, MRI, histopathology, immunostaining, flow cytometry, and transcriptomics. IFN-{gamma} signaling emerged as a central and conserved pathway across all three mouse models and human PFCD. Targeting of the IFN-{gamma} pathway promptly improved fistula healing with mitigation of IFN-{gamma} signaling, inflammation, and epithelial-to-mesenchymal transition (EMT). Moreover, combining IFN-{gamma} and TNF- blockade demonstrated augmented therapeutic efficacy compared to anti-TNF- monotherapy. ConclusionsThese PFCD mouse models and imaging tools provide first reliable and clinically relevant platforms for mechanistic studies and therapeutic evaluation. IFN-{gamma} signaling represents a potential therapeutic target warranting clinical investigation.

immunology↗

bioRxiv2026

Targeting THOC2-Mediated mRNA Export Induces PARP Inhibitor Vulnerability in DNA Repair-Competent Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in tumors with DNA repair defects, their clinical utility in HCC is hindered by the low prevalence of canonical repair gene mutations and the enhancing DNA repair capacity. Through proteomic analysis of two independent cohorts (n=260), we identified the THO complex component THOC2 as a master regulator of DNA damage response (DDR) via mRNA nuclear export control. Clinically, THOC2 overexpression predicted poor survival (HR=2.68-6.84, P<0.001) and correlated with enhanced DDR gene expression. Mechanistically, THOC2 chaperones mRNA nuclear export of DDR effectors (MDC1, PRKDC, MSH6) and proliferation drivers (TOP2A), thereby establishing a dual pro-repair/pro-growth program. Targeting this vulnerability, THOC2 knockdown induced synthetic lethality with PARPi, reducing Olaparib IC50 by up to 61% and suppressing tumor growth by 76% (P<0.001). Our study illuminates mRNA transport as a druggable DDR modulator and establishes THOC2 as both a prognostic biomarker and a therapeutic target to overcome PARPi resistance in HCC. This work pioneers a strategy to expand synthetic lethality beyond genetic defects by targeting post-transcriptional regulation.

cancer biology↗

bioRxiv2026

Receptor-Anchored Olfaction Representation through Perception-Consistent Metric Learning

Olfactory perception arises from distributed activation across hundreds of olfactory receptors (ORs), yet our understanding of this landscape remains constrained by the scarcity of OR affinity measurements. Here, we present Receptor-Anchored Metric Supervision (RAMS), a transfer learning framework using perceptual consistency as weak supervision to predict OR activation spectra. RAMS fine-tunes a pretrained drug-target affinity model by imposing constraints derived from olfactory perception, where similar odorants are encouraged to exhibit similar OR activations. It transfers protein-ligand interaction knowledge learned from large-scale pharmacological data into the olfactory domain and reshapes it toward OR activation prediction. Evaluations against experimental measurements show that RAMS improves the accuracy of receptor-spectrum prediction and yields biologically plausible activation patterns. The predicted spectra show concordance between receptor discriminative capacity and expression level, and highlight the understudied OR52 family as a potential contributor to primary odor recognition. Together, RAMS provides a scalable framework for reconstructing receptor-anchored olfactory representations.

bioinformatics↗

bioRxiv2026

IEKB: a comprehensive knowledge base for inner ear genetics integrating curated associations, cochlear interactions, Bayesian candidate prioritisation, explainable dark-gene support relations, and a scientific entity network

Inner-ear genetics has expanded rapidly, yet the supporting evidence remains dispersed across a vast literature and across resources that typically emphasise loci, variants, or expression data rather than integrated biological interpretation. Here we present the Inner Ear Knowledge Base (IEKB; https://earkb.org), an open database that unifies curated associations, cochlear interaction evidence, candidate prioritisation, explainable support relations, and network exploration for inner-ear research. IEKB was built with an automated agent-assisted curation workflow that combines schema-constrained literature extraction, continuous human monitoring, and final expert review by inner-ear genetics researchers. By systematically analysing 250,696 PubMed-indexed records retrieved across 16,563 screened genes, IEKB curates 6,051 gene-phenotype-disease associations from 2,494 genes across 43 phenotype categories and 4,102 cochlear gene-gene interactions with pathway, cell-type, and experimental context. IEKB further includes a Bayesian "dark matter" module that prioritises 243,071 candidate gene-phenotype associations for 13,229 genes across all 43 phenotypes (global AUC-ROC = 0.8603; global AUC-PR = 0.1674), together with a supervised dark-relation layer that ranks phenotype-specific known-gene support for each candidate and a multi-entity scientific network containing nearly 4,000 entities, 28,616 deterministic edges, and 83,712 literature-derived relational links. The web resource supports interactive search, multi-parameter filtering, gene-detail pages, bibliometric exploration, domain-specific enrichment against IEKB phenotype and disease gene sets, network visualisation, bulk download in CSV, JSON, SQLite, and XLSX formats, and natural-language evidence-grounded question answering through a companion conversational interface (IEKB QA). To our knowledge, IEKB is the first openly accessible inner-ear resource that integrates curated associations, cochlear interactions, probabilistic candidate prioritisation, auditable known-gene support relations for novel candidates, and a multi-entity scientific network within a single database. All data are released without registration under the CC BY 4.0 license.

bioinformatics↗

bioRxiv2026

A Conserved Metabolic Oxidative Axis Underlies Immune Cell Cryo-vulnerability

Immunotherapy has emerged as a transformative approach for treating cancer and other diseases, yet its widespread deployment requires effective cryopreservation strategies to enable scalable global distribution. However, many immune cell types remain acutely vulnerable to freeze-thaw stress, and the underlying mechanisms of this cryo-vulnerability are not well defined. In this study, we combined metabolic flux analysis, ROS quantification, lipidomics, and preclinical xenograft models to investigate how metabolic state influences cryopreservation outcomes. We found that immune cell activation induces a metabolic shift characterized by elevated glucose utilization and excessive ROS production, leading to profound post-thaw loss of viability and function, as demonstrated by a [~]25% survival rate in natural killer (NK) cells. Targeted pretreatments--including inhibitors of glucose metabolism, antioxidants, and suppression of lipid peroxidation--restored post-thaw recovery to nearly 90% while preserving effector activity and antitumor efficacy. Similar protective effects were observed across {beta} T cells, {gamma}{delta} T cells, and macrophages, defining a conserved metabolic-oxidative pathway of cryo-vulnerability and offering applicable strategies to enhance immune cell preservation.

immunology↗

bioRxiv2026

Hierarchical Gating of Cortical Population Dynamics Drives Pain

The prefrontal cortex and anterior cingulate cortex are key cortical hubs for pain regulation, yet the functional hierarchy between them remains unclear. We examined how the prelimbic cortex (PL) to ACC pathway regulates nociceptive processing and pain behavior in freely moving rats across synaptic, cellular, and network levels. Activation of the PL to ACC pathway reduced aversion to both evoked and spontaneous pain, whereas inhibition increased pain aversion, indicating that this circuit exerts tonic modulatory control. Meanwhile, ex vivo electrophysiology revealed that PL inputs recruit local ACC interneurons to produce feedforward inhibition of ACC pyramidal neurons. At the cellular level, in vivo microendoscopic calcium imaging showed that optogenetic activation of PL axon terminals suppresses nociceptive-evoked activity of ACC pyramidal neurons. At the network level, PL activation reduced pain-induced excitability while centralizing nociceptive information flow within the ACC, resulting in a gated, low output population state. Overall, these findings identify a hierarchically organized cortical circuit that tonically controls pain related sensory and affective experience.

neuroscience↗

bioRxiv2025

The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit.

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in C. elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights develop a circuit for how genetic induction of the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.

physiology↗

bioRxiv2025

Understanding monocyte-driven neuroinflammation in Alzheimers disease using human brain organoid microphysiological systems

Increasing evidence suggests that Alzheimers disease (AD) pathogenesis strongly correlates with neuroinflammation. Peripheral monocytes are crucial components of the human immune system that may play a role in neuroinflammation, but their contribution to AD pathogenesis is largely understudied partially due to the lack of appropriate human models. Here, we present human cortical organoid microphysiological systems (hCO-MPSs) for modeling dynamic AD neuroinflammation mediated by monocytes. By incorporating 3D printed devices into an existing cortical organoid protocol, 96 hCO-MPSs can be established with significantly reduced necrosis and hypoxia as well as enhanced viability within a commonly used 96 well plate, and each hCO-MPS consists of a doughnut-shaped hCO and a 3D printed device per well. Using this approach, monocytes from AD patients exhibit higher infiltration, decreased amyloid-beta (A{beta}) clearance, and stronger inflammatory responses compared to monocytes from age-matched control donors. Moreover, pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis were observed to be induced by AD monocytes. Furthermore, the significant increase in the expression of IL1B and CCL3, both at the transcriptional and protein levels, indicated the pivotal role of these cytokine and chemokine in monocyte-mediated AD neuroinflammation. Our findings provide insight for understanding monocytes role in AD pathogenesis, and the user-friendly MPS models we present are compatible with existing laboratory settings, highlighting their potential for modeling neuroinflammation and developing new therapeutics for various neuroinflammatory diseases.

bioengineering↗

bioRxiv2024

Simple One-step Vial-based Pretreatment for Deep Single-cell Proteomics and Its Application to Oocyte Aging

Single-cell proteomics is a pivotal technology for studying cellular phenotypes, offering unparalleled insights into cellular heterogeneity and dynamic functions. Technical improvement in mass spectrometry instrument and sample preparation has made single-cell proteomics feasible in recent years. Yet, developing a simple and robust sample preparation method to enable deep proteomics profiling of single cells remains a significant challenge. Herein, we developed a simple one-step vial-based pretreatment (SOViP) for deep label-free single-cell proteomics. SOViP integrates all sample preparation procedures into a single step in autosampler vials, yet it is highly efficient and high-throughput. SOViP can be finished within [~]2 h, with hands-on time limited to merely a few minutes. We show that on average over 6,500 can be quantified from a single mouse oocyte using SOViP. In total 6,983 protein groups were identified from single mouse oocytes across an entire reproductive lifespan, offering a valuable proteomics resource for oocyte aging. Unique molecular characteristics of oocytes at different ages were revealed, and a classifier consisting of ten proteins demonstrated accurate age-group classification and fertility-level prediction. Although demonstrated using mouse oocytes in this study, SOViP is adaptable to rare cell samples and other large cells, including follicles and preimplantation embryo cells, among others.

biochemistry↗

bioRxiv2024

Metabolic mapping of the human solute carrier superfamily

Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked to cellular function and identity. Despite their key role, individual functions of the members of the SLC superfamily were not evaluated systematically. We determined the metabolic and transcriptional profiles upon SLC overexpression in knock-out or wild-type isogenic cell backgrounds. Targeted metabolomics provided a fingerprint of 189 intracellular metabolites, while transcriptomics offered insights into cellular programs modulated by SLC expression. Beyond the metabolic profiles of 102 SLCs directly related to their known substrates, we also identified putative substrates or metabolic pathway connections for 71 SLCs without previously annotated bona fide substrates, including SLC45A4 as a new polyamine transporter. By comparing the molecular profiles, we identified functionally related SLC groups, including some with distinct impacts on osmolyte balancing and glycosylation. The assessment of functionally related human genes presented here may serve as a blueprint for other systematic studies of human gene function and supports future investigations into the functional roles of SLCs.

systems biology↗

bioRxiv2024

Vascular network-inspired diffusible scaffolds for engineering functional neural organoids

Organoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present Vascular network-Inspired Diffusible (VID) scaffolds to fully recapture the benefits of physiological diffusion physics for generating functional organoids and phenotyping their drug response. In a proof-of-concept application, the VID scaffolds, 3D-printed meshed tubular channel networks, support the successful generation of engineered human midbrain organoids almost without necrosis and hypoxia in commonly used well-plates. Compared to conventional organoids, these engineered organoids develop with more physiologically relevant features and functions including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared to conventional organoids with significant diffusion limits. Combining these unique scaffolds and engineered organoids may provide insights for organoid development and therapeutic innovation.

bioengineering↗