Biology subjects

Tan, Z.

Publications and source records attributed to Tan, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

OmniTCR: a foundation model unifying T cell receptor recognition prediction and conditional sequence generation

T cell receptor (TCR) recognition prediction and receptor generation are traditionally modelled separately, leaving vast TCR sequence collections disconnected from smaller TCR-peptide-MHC datasets. Here we present OmniTCR, a 113-million-parameter autoregressive foundation model pretrained on 328 million formatted human immune-sequence records. Sequence-type tokens and complementary component orders enable joint learning from individual TCR chains and partial or complete TCR-pMHC associations. On unseen epitopes, OmniTCR achieved AUPRCs of 0.7009 for peptide-TCR{beta}; recognition and 0.8235 for TCR-pMHC interaction prediction, exceeding the strongest evaluated comparators by 0.3396 and 0.3451, respectively. It distinguishes cancer from healthy repertoires across 11 independent pan-cancer cohorts (mean AUROC, 0.9436). The model achieved the highest sequence recovery on internal and external generation benchmarks. Structural modelling supported the plausibility of selected pMHC-conditioned CDR3{beta}; candidates. OmniTCR bridges heterogeneous immune sequence data, providing a foundation for computational immunology and receptor design.

bioinformatics↗

bioRxiv2026

Dynamic Nanoparticle Assembly-Based Biomedical Microrobots

Precise drug delivery within anatomically complex tissues demands systems capable of both active navigation and deep tissue access, properties that have remained difficult to reconcile in existing nanocarriers and microrobots. Here we introduce Dynabots, a dynamic microrobotic assembly constructed from multifunctional nanoparticles covalently linked by thermally cleavable molecular connectors. This nanoparticle-rich architecture enables the integration of magnetic, imaging, and therapeutic components while preserving a high content of functional material. Collective assembly imparts enhanced magnetic responsiveness and maneuverability, enabling controlled navigation through tortuous biological environments. Upon exposure to mild thermal stimuli, the assemblies undergo programmed disassembly, releasing individual nanoparticles that can diffuse through tissue for localized therapeutic action. We establish the programmable transitions, biocompatibility, and therapeutic efficacy of this process across in vitro and in vivo models, including real-time fluoroscopic guidance within anatomically realistic phantoms and live rodent and porcine systems. By integrating magnetic control, reconfigurable architecture, and stimulus-triggered disassembly, Dynabots unite navigational precision with tissue permeability, providing a versatile platform for adaptive and deep-tissue drug delivery.

bioengineering↗

bioRxiv2026

Nuclear size and physical properties of the nucleoplasm are determined by colloid osmotic pressure at the nuclear envelope

The size of the nucleus scales with cell size, suggesting a universal scaling rule. Yet the biophysical determinants of nuclear size and the significance and consequences of altered nuclear-to-cell (N/C) ratios, which are observed across diverse pathological states and cell-fate transitions, remain poorly understood. Recent theoretical models propose that nuclear size arises from a balance of colloid osmotic pressures generated by macromolecules in the nucleoplasm and cytoplasm. Here we demonstrate that altering this osmotic balance through massive overexpression of an exogenous protein targeted to either the nucleoplasm or cytoplasm produces predictable changes in the N/C ratio in S. pombe. These quantitative perturbations show that nuclear size is set primarily by the number of proteins in the nucleus and cytoplasm, providing strong support for a pure osmotic pressure mechanism. Furthermore, cells with altered N/C ratios display tunable changes in nucleoplasmic crowding, nuclear condensate formation, nucleolar scaling and heterochromatin organization, establishing a causal link between nuclear size and gene regulatory processes. These findings reveal how cells exploit osmotic forces to set organelle dimensions, with broad implications for understanding how nuclear size shapes gene expression and cell identity in health and disease.

biophysics↗

bioRxiv2026

Characterizing dynamic tissue architectures by identifying cell-type-specific spatiotemporal gene programs with stGP

Cellular gene programs unfold over biological time within spatially organized tissues. The same cell type can activate distinct programs in different spatial domains or multicellular niches. Spatiotemporal transcriptomics enables in situ measurement of these processes; however, the interplay between temporal progression and spatial organization complicates the identification of whether a gene program is influenced by temporal changes, spatial structure, or both. To overcome this challenge, we present spatiotemporal Gene Programs (stGP), a statistical framework for identifying interpretable cell-type-specific gene programs across multi-sample spatiotemporal transcriptomic studies. stGP preserves the molecular identity of each program through shared gene loadings, and decomposes individual cell activity into a temporal component that captures gene program responses over biological time, and a spatial component that characterizes variations within tissue sections. We quantify their relative contributions by estimating their variance components. Through comprehensive simulations and analyses of three spatiotemporal transcriptomic datasets across different tissues and technologies, stGP reveals spatiotemporal gene programs that distinguish preserved tissue architecture from dynamic remodeling. Our framework delineates age-associated cellular responses and uncovers localized program deployment within anatomical regions, aging hotspots, and multicellular niches. Our results establish stGP as an effective and robust framework for dissecting dynamic tissue architecture, providing insights into how cell-type-specific gene programs are coordinated across biological time and spatial microenvironments.

bioinformatics↗

bioRxiv2026

Vegetation change and functional composition shifts in southwestern China during late MIS 3 to LGM

The climatic transition from Marine Isotope Stage 3 (MIS3) to the Last Glacial Maximum (LGM) had caused widespread vegetation change. Despite the dynamic equilibrium between vegetation and climate, the specific role of functional composition in vegetations response to climate change was inadequately understood. Here, we analyzed the long-term trajectories of palynological diversity, vegetation coverage and community-weighted-mean (CWM) functional traits based on EH22 pollen record (35-18 cal ka BP) from Erhai Lake, southwestern China. The results disclosed a vegetation transition from temperate deciduous broadleaf forest dominance in late MIS3 to cold coniferous and mixed broadleaved/coniferous forests in LGM. This vegetation dynamic involved functional composition shifts from competitive-driven functional convergence to partial recovery via niche differentiation during the late MIS3, and finally to a low-diversity but functional differentiation state through trait complementarity and diversification strategies during the cold LGM. Our results likely support a function-mediated climate filtering process whereby climate change regulated long-term vegetation dynamics during the MIS3-LGM transition primarily through shifts in CWM functional composition. These findings underscore the potential of pollen-based trait approaches to reconstruct ecosystem properties and advance our understanding of ecosystem change over decadal to millennial time-scales.

ecology↗

bioRxiv2026

Visual uncertainty and task demands shape active sensing strategies in mice

In natural environments, animals actively sample visual information to guide behavior. Sensory feedback is dynamic and often requires active movements, whether saccading across the lines of this page or walking through a park. From high-acuity vision in hawks to low-acuity mice, many animals actively navigate to seek information, which can be called infotaxis. Although mice have relatively low-acuity vision, they still rely on sight for critical behaviors including navigation and prey capture. Yet, how sensitive they are to visual information and performing infotaxis has not been established. Here, we develop a virtual reality object discrimination task to investigate visual decision-making under naturalistic conditions. We show that mice perform infotaxis by actively seeking out informative views to guide their choices. Stimulus manipulations confirm that this strategy is modulated by the amount of available visual information. These results reveal that mice use principled active strategies to resolve visual uncertainty, highlighting a key role for information-seeking in natural vision. HighlightsO_LIMice perform active visual sensing in a free-range VR object discrimination task. C_LIO_LIThey perform infotaxis and select the correct object under variable visibility. C_LIO_LIDecisions decoded from head-body movements and speed reflect occlusion sensitivity. C_LI

neuroscience↗

bioRxiv2026

Killer-cell dominance dichotomy governs tumor immune networks and stratifies inflamed cancers

Cancer immunotherapy benefits remain limited, even among "hot" tumors with high killer lymphocyte infiltration. Here, we investigated the population-level architecture of killer cells based on nearly 5,000 pan-cancer scRNA-seq samples, together with orthogonal validation by spectral cytometry and spatial transcriptomics. Unlike the prevailing "hot-cold" paradigm, which assumes coordinated infiltration of multiple cytotoxic lineages, we uncovered a conserved framework wherein terminal cytotoxic immunity in individuals or malignancies diverges into states dominated by either exhausted CD8+ T cells (Tex) or CD56dimCD16hi NK (NK1) cells. Despite the complexity of the tumor microenvironment, Tex-NK1 divergence governs the primary axis of tumor-intrinsic and tumor-extrinsic variance. Distinct from the conventional view that NK cells positively contribute to immunotherapy efficacy, NK1-skewed tumors, although highly cytolytic, are refractory to current immune checkpoint blockade regimens. This killer divergence defines a foundational axis of cancer immunity and provides a resource for prioritizing next-generation targets for NK-directed immunotherapy.

immunology↗

bioRxiv2026

Efficient and accurate near telomere-to-telomere haplotype reconstruction of diploid genomes

Telomere-to-telomere (T2T) and haplotype-resolved assembly are crucial for understanding eukaryotic genomes. For diploid species, this resolution is critical to uncover allelic variations, inheritance patterns, and functional genomic traits. Current scaffolding methods typically employ either sequence-based or graph-based strategies. Sequence-based approaches rely on proximity signals to yield high contiguity, but underutilize assembly graph information, resulting in more structural errors and chromosomal misassignments. Graph-based methods leverage graph topology for higher accuracy but frequently struggle to achieve chromosome-scale contiguity. However, neither strategy alone can overcome its inherent limitations to simultaneously achieve high contiguity and accuracy. To address these challenges, we introduce HapFold, the first hybrid scaffolding framework that synergistically leverages the complementary strengths of both graph-based and sequence-based approaches. By integrating the topological accuracy of assembly graphs with the proximity-guided contiguity of sequence models, HapFold achieves highly accurate, chromosome-scale or near-T2T haplotype reconstructions for diploid genomes. Compared to existing methods, HapFold achieves superior assembly quality while accelerating computation by an order of magnitude. Furthermore, in the haplotype reconstruction of diploid genomes using standard Oxford Nanopore Technologies simplex reads, HapFold enables the reconstruction of a greater number of near-T2T assemblies. Our approach provides a robust and scalable solution for the high-fidelity reconstruction of haplotype-resolved diploid genomes.

bioinformatics↗

bioRxiv2026

Nmur1 and Cckar fail to support functional genetic access in adult dopamine neurons and challenge GPCR atlas assignments

Apuschkin et al. (2024) proposed a GPCR-based transcriptomic atlas for midbrain dopamine (DA) neuron subpopulations, including candidates such as Nmur1, Cckar, and Ffar4. To guide genetic targeting, these markers must reflect functional expression in adult DA neurons. Using in situ hybridization, Cre-dependent reporter lines, and both intracranial and systemic viral approaches, we find no evidence of adult Nmur1-mediated recombination in DA neurons, while Cckar-driven recombination is consistent with developmental expression only. Notably, Ffar4 expression overlaps extensively with Ntsr1 midbrain populations, indicating that it does not define a distinct DA neuron class. Furthermore, analysis of independent spatial transcriptomic datasets together with our MERFISH data shows that many proposed GPCR markers are not detectably expressed in adult DA neurons. These findings demonstrate that transcriptomic enrichment does not always yield reliable adult markers and highlight the need for functional validation prior to use in circuit targeting.

neuroscience↗

bioRxiv2026

Chemoproteomic Characterization of GPX4 Covalent Ligands and Targeted Degradation

Despite intensive efforts, the ferroptosis gatekeeper glutathione peroxidase 4 (GPX4) remains difficult to selectively target due to stringent structural constraints surrounding its catalytic selenocysteine, which impose tight requirements on warhead reactivity and geometry. Here, leveraging a chemoproteomic approach, we characterize a potent and selective covalent GPX4 inhibitor featuring a pyrimidinylmethyl isourea warhead and define the chemical features underlying its proteome-wide selectivity. This chemotype enables tunable electrophile reactivity through steric and electronic modulation of leaving group ability, suggesting potential broader utility for targeting other recalcitrant proteins. Building on this scaffold, we further develop two selective GPX4 degraders - one CRBN-dependent and the other CRBN-independent - enabling complementary modulation of GPX4 through both inhibition and degradation. Together, these molecules expand the GPX4 chemical toolbox for more nuanced interrogation of GPX4 biology.

cancer biology↗

bioRxiv2026

A phosphorylation switch in PAGE4 drives MED12-mutant fibroid pathogenesis

Recurrent somatic mutations in MED12, found in [~]70% of uterine leiomyomas (ULs), define the dominant molecular subtype of these highly prevalent tumors, yet the downstream effector mechanisms remain poorly understood. Using an integrated multi-omics workflow, encompassing discovery-phase DDA proteomics of matched leiomyoma-myometrium pairs, validation-phase DIA proteomics across genetically stratified cohorts (MED12 p.G44D, RAD51B-HMGA2, IRS4/FH subtypes), phosphoproteomics, immunohistochemistry, and AP-MS interactomics, we identify prostate-associated gene 4 (PAGE4) as a central effector of MED12-mutant UL pathogenesis. PAGE4 emerged as one of the most significantly upregulated proteins in MED12-mutant ULs and harbored the highest-occupancy hyperphosphorylation sites (T51, T85) in the tumor phosphoproteome, a pattern confirmed by immunohistochemistry and orthogonal phosphoproteomics. Kinase-substrate enrichment nominated HIPK2 as the primary upstream kinase, with supporting evidence from the broader CMGC family. Subsequent analysis revealed that phosphorylation acts as a molecular switch, fundamentally restructuring the PAGE4 interactome to favor the Mediator complex and RNA Pol II transcriptional machinery. This rewiring was functionally validated by ChIP-seq and luciferase reporter assays, which demonstrated corresponding shifts in transcription factor occupancy and downstream pathway activity. Collectively, these data establish phospho-PAGE4 as a critical mechanistic node downstream of MED12 mutation, expand PAGE4 biology from prostate cancer to female reproductive tumors, and nominate it as a mechanistic biomarker and candidate therapeutic vulnerability in the most prevalent molecular subtype of uterine leiomyomas.

systems biology↗

bioRxiv2026

Systems-level longitudinal immune profiling reveals individualized immunotypes and genetic associations

The human immune system exhibits substantial inter-individual variation, yet how this variability is coordinated across the system and persists over time remains incompletely defined. Here, we integrated whole-genome sequencing with longitudinal multi-omics immune profiling in 101 healthy individuals followed over two years, combining mass cytometry-based immune cell profiling, PBMC transcriptomics, plasma proteomics, and clinical measurements. Coordinated variation across cellular composition, gene expression, and circulating proteins revealed reproducible immune patterns within individuals across visits. Integrative analyses identified three major immunotypes: adaptive lymphoid (CD4 T cell and B cell enriched), myeloid-inflammation (monocyte and dendritic cell-driven), and cytotoxic (CD8 T cell-dominated), each associated with distinct metabolic and inflammatory profiles. Genome-wide association analyses identified cell-type-specific quantitative trait loci primarily affecting memory lymphocytes, and a polygenic score for memory B cells correlated with both cellular abundance and transcriptional activity. Together, these findings provide a systems-level view for understanding baseline immune heterogeneity in human populations. TeaserLongitudinally stable immune individuality reflects coordinated modules shaped by systemic physiology and genetics

systems biology↗

bioRxiv2026

Clarified an rDNA Gene Unit Pattern with (CTTT)n and (CT)n Microsatellites Aggregation Ahead of and Behind the Gene in Human Genome

BackgroundConventional models of human ribosomal DNA (rDNA) array organization have historically depended on transcription-centric boundaries, partitioning the unit into a [~]13 kb rDNA transcription region and a monolithic [~]31 kb intergenic spacer (IGS). While our previous identification of Duplication Segment Units (DSUs) mapped these arrays based on an intuitive analysis of the microsatellite density landscape of the complete reference human genome, our present deep mining of this landscape has revealed a more accurate rDNA Gene Unit Pattern. Methods & ResultsIn this study, we conducted a deep mining analysis of our previously established microsatellite density landscape of the T2T-CHM13 assembly, focusing specifically on nucleolar organizing regions (NORs). We suggest a more accurate rDNA Gene Unit Pattern containing a (CTTT)n microsatellite aggregation ahead of the rDNA gene and a (CT)n microsatellite aggregation behind the gene, rather than a pattern featuring an IGS region inserted between two rDNA genes. ConclusionsA correct rDNA gene pattern of the human genome probably includes a (CTTT)n microsatellite aggregation ahead of the gene and a (CT)n microsatellite aggregation behind it, which possibly constitute cis- and trans-regulating regions; the (CTTT)n and (CT)n microsatellite aggregations may provide two different local stable DNA structures for regulatory protein binding.

genetics↗

bioRxiv2025

UC Irvine Brain Initiative Cell Atlas Network (BICAN) Brain Procurement Program for the Center for Multiomic Human Brain Cell Atlas Project

High-quality neurotypical postmortem human brain tissue is essential but difficult to obtain for constructing comprehensive human brain cell atlases. Here we describe the establishment of UC Irvines Brain Procurement Program, a coordinated initiative to collect and process neurotypical donor brains for multiomic mapping studies within the NIH BRAIN Initiative Cell Atlas Network (BICAN) consortium. Through partnerships with the Orange County Coroners Office, the UC Irvine Willed Body Program, UCI Medical Center, and the Childrens Hospital of Orange County, we have developed standardized workflows encompassing donor identification, postmortem brain recovery and processing, region-of-interest dissection, neurotypical donor selection, and data management. Our experience demonstrates the feasibility of a community-based, multi-institutional procurement framework while highlighting challenges in recruiting neurotypical donors and ensuring demographic representation reflective of Southern California. We further identify opportunities to strengthen outreach and donation pathways. This program provides a scalable model for advancing population-reflective, high-quality human brain cell atlas efforts. HighlightsO_LIEstablish a multi-site pipeline for procuring high-quality neurotypical human brains. C_LIO_LIDemonstrate feasibility of donor collection across childhood to adulthood. C_LIO_LIIdentify barriers and propose strategies to improve broad donor recruitment. C_LI

neuroscience↗

bioRxiv2025

Multiscale Spatial Transcriptomic Atlas of Human Basal Ganglia Cell-Type and Cellular Community Organization

We generated a multi-region, subcellular-resolution spatial transcriptomic atlas of the human basal ganglia by integrating MERFISH+ and Stereo-seq across four neurotypical donors. These datasets profiled [~]7 million cells spanning the caudate, putamen, nucleus accumbens, and globus pallidus, resolving 60 transcriptionally distinct cell types. We show region-selective, molecular and spatial diversification of medium-spiny-neuron cell types and multiple non-neuronal populations with distinct molecular identities and spatial localizations. Subcellular RNA localization captures somatic size and projection-inferred signatures that reflect direct and indirect pathway topology. Cellular community analyses reveal the enrichment of sub-clusters of astrocytes and oligodendrocytes at striosome-matrix borders, while primate-expanded interneurons are confined to matrix territories. Cross-species mapping uncovers orthologous striosome-matrix organization and conserved dorsolateral-ventromedial gene expression gradients. This atlas provides a foundational molecular and spatial framework for studying human basal ganglia architecture, offering a multi-centimeter scale resource that links cell types, spatial architecture, and subcellular transcript topography across multiple nuclei. HighlightsO_LIOur multi-centimeter scale spatial taxonomy identifies the precise locations of 60 neuronal and glial cell types of human basal ganglia. C_LIO_LIMERFISH+ and Stereo-seq platforms map consistent spatial modules that align with classical neuroanatomical nuclei. C_LIO_LID1D2 hybrid MSNs and primate-expanded interneurons show regional and domain specific organization C_LIO_LISubcellular RNA localization reports soma morphology and projection-inferred signatures. C_LI

neuroscience↗

bioRxiv2025

IRF2 degradation tunes the innate immune response

The transcription factor IRF2 protects against skin inflammation in mice and humans but, paradoxically, promotes pyroptosis by inducing Gsdmd. How IRF2 activates some proinflammatory genes, but suppresses others is unclear. We show that skin inflammation in Irf2-deficient mice is driven by IRF1 activation of interferon-stimulated genes (ISGs). Chromatin profiling revealed that IRF1 and IRF2 occupy the same ISG regulatory sites, but as a weaker transcriptional activator, IRF2 limited ISG transcription by IRF1. Toll-like receptor signaling favored IRF1-driven transcription by inducing Irf1. In addition, IRF1 recruited the ubiquitin ligase SPOP to ISG sites, resulting in proteasomal degradation of IRF2. This shift from IRF2 to IRF1 occupancy enhanced ISG transcription. Collectively, these findings define a hierarchical transcriptional circuit in which IRF2 limits IRF1 activity under homeostatic conditions but is displaced during an immune response, allowing IRF1-dependent gene programs central to innate immunity and autoinflammation.

immunology↗

bioRxiv2025

Establishing a continuum of cell types in the visual cortex

The mammalian cerebral cortex is composed of neurons whose properties vary in a continuous fashion rather than falling into discrete cell types. In the mouse visual cortex, excitatory neurons in layer 2 and 3 (L2/3) form such a continuum along cortical depth, patterned by the graded expression of hundreds of genes. Here we sought to understand how this continuum develops and contributes to cortical wiring. Using single-nucleus multiomics (RNA- and ATAC-Seq) and spatial transcriptomics, we show that the L2/3 continuum is established in two phases. During the first postnatal week, a genetically hardwired program establishes a primitive continuum of cell identities spanning the depth of L2/3. The second program, promoted by visual experience, is later superimposed upon the preexisting continuum. This second phase is driven by activity-regulated transcription factors that drive the L2/3 depth-dependent expression of genes linked to synaptic function and plasticity. We show that neurons at different positions along the L2/3 continuum project preferentially to distinct higher visual areas and that visual deprivation disrupts targeting to some higher visual areas while sparing others. Thus, cortical continua emerge through a stepwise process in which genetic programs and sensory experience specify neuronal identity and sculpt intracortical wiring specificity.

neuroscience↗

bioRxiv2025

KDM5A enhances MHC-I antigen presentation and potentiates antitumor immunity unleashed by immune checkpoint blockade

While some studies have implicated the histone 3 lysine 4 demethylase KDM5A in tumorigenesis and promotion of metastasis, KDM5A has also been shown to boost immunotherapy responses in melanoma. The distinct functional role of KDM5A in the context of immunotherapy and the underlying mechanisms remain largely unknown. Here, we report that higher KDM5A expression strongly correlates with higher MHC-I expression, CD8+ T cell infiltration, and prolonged survival in colorectal cancer and gastric cancer patients receiving anti- PD-1 therapy. KDM5A promotes MHC-I-mediated antigen presentation and CD8+ T cell-mediated tumor killing across multiple murine cancer models. Mechanistically, KDM5A upregulates MHC-I expression through the SOCS1/IFN-{gamma}/STAT1 signaling and improves tumor cell-intrinsic antigen presentation capacity by inhibiting lysosomal proteases in a demethylase-dependent manner. Moreover, KDM5A directly represses lysosomal cathepsins in dendritic cells and promotes the cross-priming activity. Through a high-throughput chemical compound library-based screen, we identified Clomiphene, an FDA-approved small molecule, which significantly elevates KDM5A expression, and enhances antitumor immunity during anti-PD-1 immunotherapy in mouse models of melanoma and colon cancer. Our findings that KDM5A functions in MHC-I-mediated immune activation during anti-PD-1 therapy present an opportunity for developing KDM5A-enhancing therapies to increase tumor immunogenicity, sensitize solid tumors to immunotherapy and exclude immune evasion.

immunology↗