Biology subjects

Yang, S.

Publications and source records attributed to Yang, S..

At least 19 recordsLinked to original sources

bioRxiv2026

NicheCorr: Identifying Niche-Specific Differential Gene Co-Expression in Spatial Transcriptomics

Cell-cell communication is central to biological processes such as immune responses and tumor progression, yet the role of spatial proximity between distinct cell types in shaping gene co-expression remains poorly understood. Existing approaches primarily identify differences in average gene expression across tissue regions, often overlooking how local cellular microenvironments reshape gene-gene interactions within cells. To address this gap, we introduce NicheCorr, a statistical procedure that identifies cell type-specific niche-associated gene co-expression changes within distinct spatial niches. In simulations, NicheCorr attained the highest power for detecting niche-dependent co-expression. It was also the only method evaluated that maintained Type I error control when mean expression varied nonlinearly with the niche, a setting in which CS-CORE, scHOT without mean adjustment, and the Pearson test all exhibited inflated false positive rates. Furthermore, NicheCorr integrates ligand-receptor (LR) inference, enabling a comprehensive view of spatially structured signaling interactions. We applied the framework to the CosMx SMI Human Liver FFPE Dataset and the Xenium Human Pancreatic Cancer Dataset, identifying 52 gene pairs in liver tumor cells whose co-expression changes with T-cell niche composition and 48 gene pairs in pancreatic cancer whose fibroblast niche-dependent co-expression differs between tumor and CFTR- tumor cells, and uncovering potential LR interactions that may underlie these differential co-expression patterns.

genomics↗

bioRxiv2026

Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis

Clonal Hematopoiesis (CH) affects the aging population and is associated with increased risk of hematological malignancy, cardiovascular disease, and all-cause mortality. Therapeutic options for CH remain limited. Using hematopoietic stem and progenitor cell (HSPC) color barcoding and mosaic mutagenesis in zebrafish, we identified perturbed choline metabolism and increased phosphatidylcholine (PC) biosynthesis via choline kinase alpha (CHKA) in asxl1-mutant HSPCs. Suppressing CHKA-dependent choline flux reduced ASXL1-driven clonal expansion. This effect was conserved in a murine DNMT3A and human TET2 model. Mechanistically, CHKA- dependent choline flux controls phosphatidylcholine production that supports platelet activating factor (PAF) production. Exogenous PAF overcomes the suppressive effect of CHKA inhibition in ASXL1 and TET2 models. We isolated primary, human HSPCs from the peripheral blood of patients with endogenous ASXL1 mutations and demonstrated that perturbing PAF signaling reduces their competitive potential in an ex vivo clonal competition assay. This CHKA/PAF axis is conserved in TET2-mutant HSPCs. Together, these findings identify a mutation agnostic metabolic dependency across the three most common CH genotypes and demonstrate that targeting the CHKA-dependent choline flux suppresses clonal expansion.

cancer biology↗

bioRxiv2026

Denoising single-cell ATAC-seq data with Shannon entropy

Single-cell Assay for Transposase Accessible Chromatin with sequencing (scATAC-seq) is widely used to investigate chromatin accessibility but experiments often contain empty droplets, droplets containing damaged nuclei or cellular-debris. Accurately filtering high-quality nuclei is important as noisy droplets contribute reads that can distort downstream analysis and obscure rare cell population. Current approaches often rely on read depth and or predefined genomic features that are not exactly the same as chromatin accessibility landscape. Here, we present a Shannon entropy-based method that filters high-quality nuclei more robustly by quantifying genome-wide accessibility complexity. This approach improves signal-to-noise ratio, increases sensitivity for accessible-region detection, and enables more reliable downstream inference in scATAC-seq studies.

bioinformatics↗

bioRxiv2026

Tamoxifen and Doxorubicin Synergistically Target Estrogen Receptor beta-Mutant p53-p73 Axis, a Therapeutically Actionable Vulnerability in Triple Negative Breast Cancer

Current therapeutic regimens for triple negative breast cancer (TNBC) are not very effective in majority of patients and have serious adverse effects. Tamoxifen (Tam), a selective estrogen receptor modulator (SERM), routinely used to treat estrogen receptor alpha-positive breast cancer, has traditionally not been considered for TNBC therapy because it lacks expression of ER alpha, the canonical target of Tam. Challenging this conventional clinical paradigm, we have demonstrated, using genetic and pharmacological approaches, that Tam synergizes with DNA-damaging agent doxorubicin (Doxo) to increase cell death by both apoptosis and ferroptosis leading to growth inhibition of TNBC CDXs and PDXs expressing mutant p53. Mechanistically, these responses are dependent on ER beta-mutant p53 interaction enhanced by Tam, thereby disrupting p73-mutant p53 complex resulting in reactivation of p73 and transcriptomic reprogramming converging on apoptosis and ferroptosis. These studies demonstrate the potential for repurposing Tam with Doxo as an effective and safe therapeutic strategy to treat molecularly stratified TNBC.

cancer biology↗

bioRxiv2026

Pan-cancer nucleosome landscapes reveal tumor heterogeneity and inform cell-free DNA-based detection

Background: Nucleosome positioning and occupancy are fundamental features of chromatin organization, yet their variation across human cancers and potential utility for noninvasive cancer detection remain poorly characterized. Methods: We systematically characterized nucleosome organization across 410 primary tumors spanning 23 cancer types using ATAC-seq, establishing a high-confidence pan-cancer nucleosome atlas validated by independent MNase-seq data. We characterized shared and cancer-type-enriched nucleosome patterns, investigated their associations with tumor heterogeneity and regulatory alterations, and evaluated tissue-derived nucleosome signatures for cancer classification and detection using circulating cell-free DNA (cfDNA). Results: The atlas identified shared and cancer-type-enriched nucleosomes associated with distinct regulatory programs. Notably, nucleosome occupancy provided information complementary to chromatin accessibility for tumor stratification and revealed molecular heterogeneity within individual cancers, including subgroups associated with Basal-like breast cancer. In hepatocellular carcinoma, differential nucleosome analysis revealed cancer-associated chromatin remodeling involving regulatory pathways, transcription factor motifs, and candidate genes. Importantly, tissue-derived nucleosome signatures were detectable in cfDNA, enabling classification among three cancer types (AUROC = 0.877) and colorectal cancer detection (AUROC = 0.930), with an AUROC of 0.773 in an independent validation cohort. We also developed OncoNucAtlas, a publicly accessible database facilitating exploration of these nucleosome landscapes. Conclusions: Our study cancer-associated nucleosome organization as a complementary source of epigenomic information and demonstrates the potential of tissue-derived nucleosome signatures for cfDNA-based cancer detection. The pan-cancer atlas provides a resource for investigating tumor heterogeneity and developing noninvasive cancer detection approaches.

bioinformatics↗

bioRxiv2026

Towards Robust Automated Mouse Scratching Behavior Detection for Itch Research

Automated detection of mouse scratching behavior could reduce manual annotation and is essential for preclinical itch research. However, robust performance across laboratories remains a challenge for current methods. We present Scratch-AID+, a framework dedicated to automated mouse scratching detection, including a diverse and progressive set of approaches: classic ResNet-based detectors, task-adaptive fine-tuning of video foundation models, and in-context learning with advanced multimodal large language models. To simulate real-world use cases, we benchmark on a public dataset and utilize additional cross-laboratory video recordings for independent testing. We find that classic baselines suffered severe performance degradation on external data under the realistic setting with sparse scratching events. In contrast, fine-tuned video foundation models successfully bridged this generalizability gap, achieving significantly better detection performance. Furthermore, frozen multimodal large language models demonstrated promising out-of-the-box ability using only few-shot demonstrations. We also examined the effects of different video preprocessing strategies. Our findings highlight the improved performance and generalizability of the adapted foundation models for automated scratching behavior analysis and shed light on the real-world deployment of such detectors. Our code is publicly available at https://anonymous.4open.science/r/scratch aid-plus/.

bioinformatics↗

bioRxiv2026

The Onset of Breathing at Birth Switches Off Regenerative Capacity

Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO2 exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO2 exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK), which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO2 inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO2 inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO2/pH signaling shapes the regenerative capacity across life and pointing to a potential CO2-based strategy for promoting tissue regeneration.

neuroscience↗

bioRxiv2026

Contrasting gene gain and loss shape metabolic diversification in the Ralstonia solanacearum species complex

Metabolic repertoires are continually remodeled by gene acquisition and loss, but how these contrasting processes jointly generate phenotypic diversity within bacterial species complexes remains poorly understood. Here, we elucidated the genetic and evolutionary basis of the classical biovar phenotypes of the Ralstonia solanacearum species complex (RSSC), which are defined by differential utilization of three hexitols (sorbitol, mannitol, and dulcitol) and three disaccharides (lactose, maltose, and cellobiose). Although this classification has been used for over half a century, the genetic determinants and evolutionary origins of these phenotypes have not been systematically resolved. Machine-learning analysis of genomic data from 250 RSSC strains with documented biovar phenotypes, combined with genome-wide association analysis and gene deletion, identified the smoEFGK gene cluster and flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenase (FADGDH) as the major determinants of hexitol and disaccharide utilization, respectively. Comparative phylogenomics revealed fundamentally different evolutionary histories of these loci. An ancestral smoEFGK system was lost early in RSSC evolution and subsequently reacquired by the ancestor of phylotype I through horizontal transfer from a Burkholderia-related lineage, whereas vertically inherited FADGDH underwent recurrent, independent losses across multiple RSSC lineages. Extending the analysis to 1,082 RSSC strains further showed that disaccharide-utilization capacity was significantly depleted among monocot-associated strains after accounting for phylogenetic relatedness and geographic origin. Together, these findings reveal how contrasting trajectories of gene gain and loss can reshape bacterial metabolic repertoires, generate lineage-associated phenotypic diversity, and potentially contribute to ecological differentiation.

genomics↗

bioRxiv2026

Tractable and Thermodynamically Consistent pKa Prediction via First-Dissociation Aggregation

Ionization governs molecular behavior, yet predicting aqueous pKa accurately and tractably remains a fundamental challenge. Rigorous ensemble methods require enumerating a protonation-state space that grows exponentially with the number of ionizable sites, while fast graph predictors return numbers without thermodynamic consistency. Here we derive an exact thermodynamic identity showing that the macroscopic first-dissociation constant is fully determined by protonated-microstate populations and unique first-deprotonation events, eliminating the deprotonated ensemble algebraically and reducing aggregation to O(n+E) operations. We implement this identity in DTi-pKa, a dual-head graph neural network whose free-energy and dissociation heads are coupled by thermodynamic constraints. On four external benchmarks (355 molecules), DTi-pKa achieves a pooled MAE of 0.5665 pKa units, with 0.6285 on the 169 records lacking training-cache matches, while providing site-resolved micro-pKa values and protonation-state populations. Controlled ablations show that constraint placement at the level of the reported macroscopic equilibrium matters more than microscopic label precision--a design principle transferable to physics-informed machine learning beyond chemistry. Closure diagnostics expose numerical self-consistency as an open frontier, which we report transparently. By replacing an intractable computation with a physical identity, DTi-pKa unifies macroscopic accuracy and microscopic interpretability in a single framework.

bioinformatics↗

bioRxiv2026

Structural streamlining of axonemal doublet microtubules in Plasmodium male gametes

Male gametogenesis in malaria parasites produces up to eight flagellated gametes within approximately 15 min, requiring de novo construction of motile axonemes on an unusually short timescale. Here we combine cellular cryo-electron tomography, high-resolution cryo-EM, proteomics, and parasite genetics to define the molecular architecture and assembly states of the Plasmodium male gamete axoneme. The doublet microtubules retain the principal surface-associated motility modules but contain a markedly reduced luminal microtubule inner protein network. Their inner junction lacks PACRG and is instead organized by CFAP20 and CFAP52, whose combined loss disrupts doublet integrity and exflagellation. We further identify a calmodulin protein at the outer dynein arm docking region and show that outer dynein arms accumulate progressively during gametogenesis. These findings establish distinct form of axonemal remodeling in Plasmodium and reveal the ordered assembly of structural and motor modules during rapid male gamete formation.

cell biology↗

bioRxiv2026

Beyond RMSD: Deterministic Dlow Matching for Ultrafast and Physically Validated Transition-State Generation

Transition state (TS) generation is typically evaluated by geometric similarity, yet low root-mean-square deviation (RMSD) does not establish first-order saddle-point character or reaction-path connectivity. Here we introduce Kairos-GFM, a deterministic equivariant flow-matching model that combines a two-dimensional reaction graph with the Kabsch-aligned mean of three-dimensional reactant and product geometries. Using 881 Transition1x reactions whose reference TSs passed strict saddle-point and bidirectional intrinsic reaction coordinate validation, Kairos-GFM generates one candidate in 0.0118 s with a median RMSD of 0.14 [A]. A hierarchical physical-validation framework--spanning reaction-center geometry, raw single-point energy, DFT saddle-point optimization, harmonic frequency analysis, and IRC endpoint matching reveals that low RMSD and saddle-point convergence do not guarantee the intended reaction channel. Kairos-GFM recovers the target channel in 75.94% of reactions, outperforming diffusion-based baselines but remaining below transport-based methods. These results position Kairos-GFM as a rapid initial-geometry generator for quantum-chemical refinement and provide a transferable validation standard that distinguishes geometric similarity from physical fidelity.

biochemistry↗

bioRxiv2026

Olfactory-mediated host tracking and rapid local adaptation in a seed-feeding wasp

Understanding how specialized herbivores track divergence among their hosts is central to evolutionary biology. Congruent genetic structure between hosts and herbivores is often interpreted as evidence of long-term codivergence, but similar patterns may also arise when herbivores rapidly adapt to pre-existing host differentiation. Here, we integrate population genomics, host volatile profiling, and behavioral assays to examine host-associated divergence in the obligate seed-feeding wasp Megastigmus daduheensis and its conifer host Cupressus chengiana across three river valleys on the eastern Qinghai-Tibet Plateau. Despite strong phylogeographic congruence between each of the three wasp and host lineages, calibrated demographic analyses indicate that wasp divergence occurred during the early Holocene, substantially later than the Pliocene-Pleistocene divergence of host lineages. This temporal mismatch is inconsistent with strict long-term codivergence and instead supports rapid host tracking in a topographic complex region. Host lineages differed in volatile organic compound profiles, and behavioral assays showed that wasps were preferentially attracted to volatiles from their local host lineages. These results identify olfactory-mediated host recognition as a plausible mechanism promoting host fidelity and reinforcing host-associated genomic and behavioral differentiation. Our findings show that apparently concordant host-herbivore divergence can emerge over compressed evolutionary timescales through rapid local adaptation, highlighting how ecological differentiation can accumulate within species through host tracking.

evolutionary biology↗

bioRxiv2026

Pair-complete structural gating enables Pareto optimization of de novo cyclic peptides with preserved binding geometry and improved developability

Cyclic peptides can engage extended protein interfaces, but sequence changes that improve developability often disrupt the selected target-bound geometry. Existing property-guided design methods lack a principled way to preserve this geometry during local multiproperty optimization. Here we present RF-PepTune, which separates structural eligibility from property prioritization. Before any property score is queried, RF-PepTune evaluates single substitutions and all position-distinct pairs induced by admitted substitutions to build a parent-specific, pair-complete admission graph. Pareto Monte Carlo tree search then optimizes predicted permeability, solubility, non-fouling, and low-haemolysis scores exclusively within this graph, and selected sequences undergo full structural re-evaluation. In a matched three-arm comparison of 334 parents across MDM2, GABARAP, and MCL1, joint property-structure success rose from 10.2% without admission to 51.5% with single-substitution admission and 77.5% with pair-complete admission; pair-complete gating improved success by 26.0 percentage points over single-substitution gating (95% CI, 20.7-31.4). Property-positive but structure-failing endpoints fell from 88.3% to 9.3%. In a separate target-balanced set, all 90 prioritized outputs improved all four model-native scores while satisfying prespecified structural criteria. This work establishes pairwise structural gating as a general strategy for constrained multi-objective molecular optimization.

bioinformatics↗

bioRxiv2026

Common viral infections seed regionally distinct resident memory T cells in the human CNS

T cells persist in the central nervous system (CNS) and can drive both protection and neurological disease. How these cells are organized in humans and what they recognize is largely unknown. Here, we profiled CD8 T cells across anatomically distinct CNS regions, obtained through on-site autopsies and temporal lobe resection surgeries, using single-cell RNA sequencing, paired T cell receptor sequencing, and DNA-barcoded tetramers. Resident memory T cells (TRM) specific for Epstein-Barr virus, cytomegalovirus, influenza A, and SARS-CoV-2 were identified across CNS compartments. Anatomical location was the strongest correlate of TRM cell state, with leptomeningeal cells adopting a cytokine-poised TRM program, whereas brain TRM cells were transcriptionally restrained. Cells of the same clonotype spanned tissues yet adopted local transcriptional states. Viral specificity added another layer of TRM heterogeneity with GZMK/GZMA-expressing EBV-specific populations and interferon-stimulated gene signatures in SARS-CoV-2 and Influenza A-specific cells. The human CNS thus harbors regionally distinct CD8+ TRM shaped by common viral exposures.

immunology↗

bioRxiv2026

Collateral Immune Cell Signaling Compromises the Efficacy of T-cell Engaging Therapies for Cardiac Fibrosis

Cardiac fibrosis is causally linked to heart failure progression and survival. Currently, there are no approved treatments that directly target cardiac fibrosis. Recent studies have identified a subset of activated cardiac fibroblasts distinct from myofibroblasts that are marked by fibroblast activation protein (FAP) expression, emerge in the injured and diseased heart through inflammatory signaling, and contribute to fibrosis. Using a genetic mouse model, we demonstrate the potential benefits of FAP+ fibroblast depletion following myocardial infarction. Unexpectedly, while FAP targeted bispecific T-cell engaging antibodies (BiTE(R) molecules) effectively eliminate FAP+ fibroblasts from the heart, they surprisingly lead to accelerated deterioration of cardiac function, enhanced remodeling, and increased scar size. FAP BiTE(R) molecules elicit a robust cytokine response within the heart with prominent activation of interferon gamma (IFNg) and CD40 ligand pathways. Target cell killing was independent of IFNg; and CD40L signaling and blockade of these pathways was sufficient to unmask the protective therapeutic effects of FAP+ fibroblast depletion. Mechanistically, we reveal that IFNg; signaling to fibroblasts drives the differentiation of an independent lineage of activated fibroblasts not typically found in the infarcted heart, which are responsible for the harmful effects of FAP BiTE(R) molecules. Collectively, these findings highlight a previously unrecognized cardiac liability of BiTE(R) molecules and inform the design of the next generation of therapeutics.

immunology↗

bioRxiv2026

Hygrochastic Seedpods: Engineering Microclimates for Forest Restoration

Forest restoration at scale depends on sowing seeds directly onto the land, yet seedling establishment is often poor and inconsistent. Seed enhancement technologies, such as priming, coating, and pelleting, improve germination under water, temperature, and salinity stress by supplying polymers, nutrients, or microorganisms at the seed surface. Being mainly conformal films, they act continuously once wetted and cannot gate when a seed is exposed to the soil. They also enclose no air volume, so the microenvironment they create is inseparable from the surrounding soil and has been inferred from plant performance rather than measured directly. Whether an engineered carrier can instead set both the state and the duration of the post-dispersal microenvironment, and how such an effect can be directly quantified, remains unexplored. Here we show that hygrochastic seedpods hold seeds in a timed, directly measurable microclimate and accelerate seedling emergence. The pods are programmable, responsive conical shells enclosing an air cavity around the seed. Two design solutions were investigated in parallel: wooden seedpods that crack open upon hydration, and poly(vinyl alcohol)/boric acid seedpods that gradually disintegrate after sustained wetting. In both, wax coatings act as a programmable diffusion-limited timer that sets activation from hours to days. The pod cavity permits direct sensing and monitoring, which no coating geometries allow. As directly measured during the initial phase after deployment, seedpod interiors ran 2 - 3 C warmer and drier than the surrounding soil, and these differences persisted after opening. Across indoor and field trials in several tree species, pods accelerated early seedling emergence without penalizing subsequent growth. These results identify artificial hygrochastic seedpods as a transient ecological mediator that regulates both the timing of seed exposure and the microclimate around the seed, offering a strategy for improving forest restoration under variable environmental conditions.

bioengineering↗

bioRxiv2026

PAXIP1-PAGR1 directs cohesin recruitment during break-induced telomere repair

Cohesin is a conserved multiprotein complex (SMC1, SMC3, RAD21, and either STAG1 or STAG2) that organizes three-dimensional genome architecture and regulates chromosome segregation, gene expression, and DNA damage repair (1-4). Following double-strand breaks (DSBs), cohesin is recruited to sites of DNA damage - a process considered essential for efficient homologous recombination (5-15). Yet how DSB signaling elicits cohesin recruitment and subsequent cohesion establishment remains poorly understood. Here we show that telomere replication stress activates de novo STAG2-cohesin loading, thereby promoting break-induced telomeric DNA repair. We demonstrate that this DNA break-elicited cohesin recruitment is strictly controlled by the BRCT domain-containing DNA damage recognition factor PAXIP1 and its functional partner PAGR1. Cryo-electron microscopy structure reveals that PAGR1, together with PAXIP1, physically binds to a composite interface formed by the STAG2-RAD21 cohesin subcomplex. Complementary mutational and biochemical analyses define the molecular basis of this interaction and establish its essential role in break-induced cohesion establishment. Furthermore, we show that PAXIP1-PAGR1-enacted STAG2-cohesin recruitment complements with the PML body-associated pathway in orchestrating break-induced alternative lengthening of telomeres (ALT). Concurrent depletion of PML together with PAXIP1, PAGR1 or STAG2 disrupts ALT-mediated telomere maintenance, leading to end-to-end chromosomal fusion and mitotic cell death. Collectively, these findings uncover a distinctive molecular mechanism through which DSB signaling directs de novo cohesion establishment, and highlight its critical importance in break-induced telomere repair.

molecular biology↗

bioRxiv2026

Precision cooling assists electrical stimulation: Breaking selectivity barriers in nerve control

Peripheral neuromodulation can relieve pain through sensory activation or conduction block. However, electrical stimulation of mixed nerves couples these intended effects to unwanted neural activity. Here we demonstrate local cooling can separate targeted from off-target neural activity. In the rat sciatic nerve, precooling reduced the onset response to kilohertz-frequency stimulation by about 90% and maintained block in the target pathway during rewarming. During low-frequency stimulation, spatially graded cooling suppressed A{delta} enriched activity and blocked nontarget propagation. This produced a directional, A{beta} biased afferent output. A cooling-electrical neural digital twin predicted both responses and linked them to field-edge transition dynamics and spatially separated control of recruitment and conduction. These findings provide a mechanistically grounded route beyond the targeting limits of electrical stimulation alone.

bioengineering↗