Biology subjects

Wang, G.

Publications and source records attributed to Wang, G..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Eco-evolutionary games in noisy environments

Cooperative and competitive interactions among individuals harvesting resources can shape environmental states, such as prey abundance. In turn, environmental conditions feed back to influence strategic interactions. Eco-evolutionary game theory studies how these feedbacks shape the co-evolution of behavior and environment. Existing models typically assume deterministic, noise-free environmental dynamics. However, real environments are inherently stochastic, for example due to finite resources, and noise can qualitatively alter social outcomes. Here, we incorporate stochastic environmental dynamics into eco-evolutionary game theory. When environmental change is slow relative to strategy updates, we show that behavior reflects a mixture of the games associated with low and high environmental states, often yielding outcomes qualitatively distinct from deterministic predictions. In particular, environmental stochasticity can eliminate bistability and enforce dominance of a single behavior. When environmental dynamics are faster, populations have less opportunity to track fluctuations, and behavior converges toward strategies that are optimal on average. Stochasticity can even causes persistent oscillations in the tragedy of commons, in regimes where classical models predict stability. Our framework provides a tractable approach for analyzing social behavior linked to environmental dynamics how noise shapes long-term eco-evolutionary outcomes.

evolutionary biology↗

bioRxiv2026

Identification of non-covalent inhibitors for the atypical peroxiredoxin PRDX5 as a therapeutic strategy in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive asbestos-linked cancer with limited therapeutic options and a dismal 5-year survival rate of [~]5%. While aberrant production of reactive oxygen and nitrogen species (ROS/RNS) is a hallmark of MPM, targeted approaches to exploit these redox vulnerabilities remain scarce. Here, using the MOSAIC multimodal cancer patient atlas, we identify Peroxiredoxin 5 (PRDX5) as being significantly upregulated in the epithelioid subtype of MPM. We show that MPM cells exhibit enhanced resistance to nitrosative and oxidative stress compared to healthy mesothelial cells, a phenotype correlated with basal PRDX5 expression. Next, utilising a machine learning guided discovery pipeline, we identified three putative allosteric pockets in PRDX5 and conducted a virtual screen of 3.6 million compounds. High-throughput biochemical validation of 452 candidates yielded 36 non-covalent hits, including sub-micromolar inhibitors. These findings establish PRDX5 as a novel, subtype specific therapeutic target in MPM and provide a chemical framework for the development of next-generation redox-modulating oncology treatments.

cancer biology↗

bioRxiv2026

The Impact of Dysregulated Lipid Metabolism on the Gut-Brain Axis in Patients with Intracerebral Hemorrhage

BACKGROUNGBisphenol A (BPA) has been linked to hypertension and disturbances in lipid metabolism; however, limited evidence is available regarding its association with hypertensive intracerebral hemorrhage (ICH). METHODSA multicenter, retrospective case-control study was conducted involving 129 participants, including individuals from an ICH group and healthy controls. Standard assays were employed to assess serum thyroid function, lipid profiles, serum fatty acid-binding [x]protein 4 (FABP4), oxidative stress markers, gap junction proteins, Wnt/{beta}-catenin signaling pathway activity, and expression changes of S100A8-mediated inflammatory cytokines involved in gut-brain interactions. Correlation analyses using Pearson and Spearman methods revealed that both BPA exposure and low T3 levels were significantly associated with elevated diastolic blood pressure, altered lipid metabolism, gut microbiota composition, and microglial activation. RESULTSGender-based disparities in lipid metabolism were identified. Changes in {beta}3-adrenergic receptor and neuromodulin-1 expression appear to influence fat regulation and attenuate oxidative stress responses. Subsequently, increased expression of gap junction proteins and activation of the Wnt/{beta}-catenin signaling pathway contribute to metabolic reprogramming and alterations in biochemical kinetics. Gut microbiota analysis demonstrated that, compared to controls, the ICH group exhibited significant dysbiosis and reduced alpha diversity. Further correlation analyses indicated that BPA levels were positively associated with FABP4 and oxidative stress markers, while S100A8 showed a strong dependence on microglial expression. CONCLUSIONThe interplay between lipid metabolism dysfunction and pro-inflammatory cytokines enhances vascular vulnerability. Collectively, BPA exposure, oxidative stress, and microglia-mediated neuroinflammation are significantly associated with an elevated risk of hypertensive ICH. China Clinical Trial Registry registration noticeFrom: China Clinical Trials Registry +To:guopingwang60a yunyanshuangfei FUNDINGThis work was supported by the Natural Science Foundation of Shanxi Province (grant no. 201701D121177) Key informationGender-specific differences were observed in lipid metabolism and oxidative stress parameters; BPA exposure was shown to induce lipid metabolic disturbances, promote excessive production of oxidative stress byproducts, and consequently elevate oxidative stress responses; BPA was associated with stress-induced alterations in thyroid hormone function, further exacerbating dysregulation of lipid metabolism and oxidative stress; Fatty acid binding protein 4 (FABP4), a key adipokine implicated in metabolic disorders and adipose tissue inflammation, exhibited a significant positive correlation with serum BPA levels, whereas low levels of triiodothyronine (T3) were negatively correlated with FABP4. These findings suggest that serum FABP4 may serve as a biochemical marker for chronic low-grade adipose tissue inflammation and metabolic dysfunction; Gap junction proteins and the Wnt/{beta}-catenin signaling pathway may contribute to microglial activation and mediate neuroinflammatory responses, nerve injury, and secondary pathological processes in obesity-related cerebral hemorrhage.

biochemistry↗

bioRxiv2026

conMItion: an R package adjusting confounding factors for associations in multi-omics

SummaryAssociation measurements, such as mutual information (MI), are fundamental in the analysis of cancer multi-omics data for identifying cancer-related genes, gene signatures, and gene regulatory networks, thereby shedding light on tumor development, progression, and treatment. Confounding factors, including tumor purity and mutation burden, can bias association measurements in MI, potentially leading to the misclassification of passenger events as drivers. Conditional mutual information (CMI) provides a robust framework for assessing both linear and non-linear associations while effectively accounting for different confounding factors. An R package called conMItion is introduced to estimate CMI and its statistical significance for multi-omics data, with flexibility to adjust for one or two confounding factors. We demonstrated the utilization of conMItion through two use cases. First, we identified co-occurring somatic alterations in bladder cancer genomic data. Second, we applied conMItion to a single-cell RNA sequencing dataset of lung cancer patients and identified positively or negatively associated cell types within the lung cancer tumor microenvironment. Availability and ImplementationThe conMItion package is freely available on CRAN at https://CRAN.R-project.org/package=conMItion. The two use cases described in the paper can be accessed at https://github.com/GJYWang/conMItion. A supplementary document is available online.

bioinformatics↗

bioRxiv2026

Tripeptidyl peptidase II is essential for maintaining cerebrovascular homeostasis of female mice and represents a novel therapeutic target for vascular dementia

Although cerebrovascular impairment is a known common driver of both Vascular dementia (VaD) and Alzheimers disease (AD), the underlying mechanisms remain poorly defined. Substantial evidence has demonstrated that brain-derived estrogen is essential for cerebrovascular health and neuroprotection. Consequently, therapeutic strategies that can replicate the beneficial effects of estrogen replacement therapy (ERT) in the brain while avoiding its peripheral risks are being actively pursued. Here, we demonstrate that tripeptidyl peptidase II (TPP2) is essential for cerebrovascular homeostasis in adult female mice by orchestrating intracellular Ca{superscript 2} distribution and local estrogen biosynthesis. Specifically, TPP2 deficiency triggers a vicious cycle of Ca{superscript 2} imbalance and estrogen deficiency, thereby disrupting the anticipatory unfolded protein response (UPR). This disruption consequently drives aberrant pexophagic flux and ultimately depletes ether-linked phosphatidylcholine (PC-O)--the essential building block of endothelial cell (EC) membranes. In addition, we identified PC-O as a key facilitator of choline uptake through FLVCR2 and therefore its deficiency causes subsequent choline depletion as well as significantly decreased acetylcholine (ACh). Consistent with the fact that choline is a building block of PC and that ACh is a primary driver of vascular dilation, TPP2 depletion leads to significant cerebrovascular degeneration characterized by narrowed lumens, decreased EC number, and abnormal aggregation of ECs within the blood vessel. Additionally, AAV-mediated specific expression of Far1 in ECs to promote ether-PC biosynthesis significantly increases cerebrovascular volume and diameter in hippocampi of adult female TPP2 knockout (T2KO) mice. Importantly, ectopic expression of Far1 in ECs not only significantly ameliorates memory impairment in global and conditional TPP2-depleted female mice, but also significantly improves memory performance of naturally aged female mice. In total, our findings establish TPP2 as a key determinant of cerebrovascular homeostasis in adult female mice, positioning it as a novel therapeutic candidate for the treatment of VaD and AD.

neuroscience↗

bioRxiv2026

Lymphatic egress recycles tumor-experienced effector CD8 T cells to sustain immune surveillance

Successful anti-tumor immune surveillance depends on stem-like CD8+ T cells that are enriched in tumor-draining lymph nodes (LN), but how they are maintained over time remains poorly understood. Here, we identify a continuous lymphatic circuit that sustains stem-like CD8+ T cells. Using photoconversion to fate-map intratumoral T cells we demonstrate that effector cells exit the tumor microenvironment and migrate back to the draining LN. These tumor-specific, migratory effector T cells avoid chronic antigen stimulation, re-express the transcription factor associated with self-renewal, TCF1, and enter a stem-like state in the LN. Antigen presentation in LNs by dendritic cells drives their proliferation thereby inflating the LN stem-like population. Consequently, maintenance of stem-like T cells and ICB response depends on constitutive lymphatic transport, while LN metastasis compromises the stem-like niche, diminishing ICB response. We, therefore, define a continuous, peripheral lymphatic circuit that recycles tumor-experienced effector T cells to fuel durable, systemic immune surveillance.

immunology↗

bioRxiv2026

A Long-lived Avatar for Modeling Age-Related Vascular Disease

BackgroundCurrent microphysiological models do not support long-term investigations into the chronic effects of vascular risk factors and the development of vascular diseases. Prolonged culture frequently leads to cellular senescence and loss of functional integrity, resulting in variability and inconsistency in modeling chronic vascular responses. Here we aimed to develop and sustain a long-term multicellular human vascular avatar, addressing the critical need for long-term disease modeling and drug testing. MethodsTo identify the optimal media for longevity, cell identity and function were assessed by morphology, qPCR, beta-gal staining, ELISA, bulk RNA-seq and single cell RNA-seq analysis. After optimizing the culture media, iPSCs-derived ECs and VSMCs from unaffected and Hutchinson-Gilford Progeria Syndrome (HGPS) donors were grown in Gravitational Lumen Patterning (GLP) Vessel- Chips for 1-6 months to generate a long-lived vascular avatar for the study of vascular aging. ResultsGuided by quantitative morphological analyses and bulk RNAseq profiling, we generated a novel optimized culture media VSL (VEGF, SB431542 as a TGF-{beta} inhibitor, low fetal bovine serum) that enhances the long-term health of vascular endothelial cells (ECs). Furthermore, we modified the VSL formulation (mVSL) by modulating 8Br-cAMP, FGF, PDGF, and a cell viability enhancer HMH1015 levels to enhance EC-VSMC (vascular smooth muscle cell) crosstalk and support long-term cellular viability. Subsequently, we maintained and characterized a human vascular avatar with a three-dimensional extracellular matrix environment and 3D vascular architecture for over 180 days. Finally, we demonstrated that this long-lived human vascular avatar enabled modeling vascular aging using iPSC-derived vascular cells from patients with Hutchinson-Gilford Progeria Syndrome (HGPS). ConclusionsWe have successfully engineered and maintained a human vascular avatar for over 180 days. The vascular avatar provides a robust platform for modeling disease-associated vascular aging and for evaluating therapeutic strategies targeting chronic vascular disorders.

bioengineering↗

bioRxiv2026

Behavior-Driven Marine Larval Dispersal and Settlement with AI Agent-Based Modeling

Larval dispersal models are central to mapping and predicting ichthyoplankton dynamics in the ocean, yet despite decades of refinement they remain fundamentally limited by their ability to represent adaptive behaviors, relying instead on static trait parameterizations. This deficiency constrains our capacity to design effective restoration and mitigation strategies in an increasingly stressed ocean. SWARM (Simulating Waterborne Agent Routes for Marine connectivity) overcomes this barrier by integrating Large Language Model (LLM)-based behavioral agents with a standard biophysical model to simulate active decision-making during the pelagic larval stage. In both idealized and realistic conditions focusing on Red Snapper larvae in the Gulf of Mexico, agents develop adaptive behaviors that improve settlement and generate explainable vertical distribution patterns. SWARM demonstrates that LLMs can overcome long-standing limitations in dispersal modelling by explicitly representing behavioral drivers of movement, opening new pathways for predicting connectivity and designing effective marine-ecosystem restoration.

ecology↗

bioRxiv2026

Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling

Chronic skin inflammation frequently recurs at the same anatomical sites after therapy withdrawal, implying stromal cells may encode local inflammatory memory. Here, we identified nicotinamide N-methyltransferase (NNMT) as a central metabolic-epigenetic regulator of fibroblast inflammatory memory enabling psoriasis relapse. Single-cell and spatial transcriptomics revealed that dermal fibroblasts acquire a persistent senescence-associated secretory phenotype (SASP) during inflammation, maintaining pro-inflammatory niche in resolved skin that supports CD 8+CD 103+ tissue-resident memory T cell (Trm) differentiation. Multi-omics profiling demonstrated that NNMT depletes S-adenosylmethionine (SAM), reduces H 3K 27me3 deposition, and permits sustained AP-1 occupancy at SASP gene promoters. Fibroblast-specific NNMT ablation or pharmacologic inhibition suppressed SASP activity, limited Trm accumulation, and prevented both initiation and relapse of skin inflammation in mice. These findings establish NNMT as a stromal regulator linking fibroblast metabolism to durable epigenetic memory and propose its targeting to erase inflammatory memory and achieve long-term remission in psoriasis and related immune-mediated diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/721223v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@34b2f4org.highwire.dtl.DTLVardef@1d0bb89org.highwire.dtl.DTLVardef@c8277borg.highwire.dtl.DTLVardef@9825ac_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic Abstract:C_FLOATNO Proposed mechanism through which NNMT-driven fibroblast SASP facilitates the initiation and recurrence of psoriasis C_FIG

immunology↗

bioRxiv2026

Cardiac oxidative stress monitoring enabled by hierarchical mechanical adaptation

Soft bioelectronics have advanced cardiac monitoring through electrophysiological tracking, yet this alone cannot resolve the metabolic pathology essential to surgical decision-making. However, real-time molecular sensing on beating hearts remains unresolved due to deformation-induced sensor failure and stress-induced metabolite artifacts. This challenge is exemplified by ischemia-reperfusion injury (IRI), a major cardiac surgery complication characterized by reactive oxidative species (ROS) bursts, where true pathological ROS signals being confounded by mechanotransduction-induced ROS artifacts. Herein, we propose an enzymatic cardiac oxidative stress biosensor (E-cardiac) with hierarchical mechanical adaptation: macro-scale biofluid-mediated contact, micro-scale fiber reorganization, and nano-scale enzymatic confinement within gold nanoarches dissipate interfacial stress. This produces ultrathin ([~]460 nm), soft (0.79 kPa) E-cardiac with robust electrochemical stability (100% strain), low detection limit (380 nM), rapid adhesion (<3 s), stable biosensing on beating heart, as well as minimal invasive deployment capability. Mechanical analysis and cellular studies confirm mitigated stress-induced ROS and absent PIEZO channel activation. Validated across cardiomyocytes, ex vivo tissues, multi-species ischemia models (mouse, rat, rabbit, pig), rat ischemia-reperfusion injury, and Langendorff hearts simulating graded perfusion deficits, E-cardiac quantitatively differentiates IRI severity (sham < ischemia < reperfusion) as well as detecting the "ECG blind window". The E-cardiac platform provides real-time metabolic feedback for surgical guidance during cardiac procedures, enabling timely intervention before irreversible damage.

bioengineering↗

bioRxiv2026

ARID1A deficiency unleashes centromeric RNA transcription to drive chromosomal instability and boosts PKMYT1 inhibitor efficacy via RNA sensing

Cancer gene-associated mutations and molecular hallmarks of chromosomal instability (CIN) are unexpectedly common in histologically normal cells and tissues. These emerging findings challenge the binary distinction between "normal" and "cancerous" cells and suggest that early tumorigenesis may commence against a background of widespread yet largely tolerated genomic instability. However, it remains largely unexplored how a cancer gene-associated mutation can initiate the development of CIN-like states in non-malignant cells and drive tumor evolution. ARID1A, a chromatin remodeling factor, was identified as the most frequently mutated gene in both gastric normal epithelium and tumors. This distinctive molecular convergence presents an opportunity to elucidate the mechanisms by which a cancer-associated gene facilitates the initiation of early CIN phenotypes and develop effective antitumor strategies. In the present study, using primary human gastric organoids, we employed optical genome mapping (OGM) and live-imaging technologies to demonstrate that ARID1A depletion induced a wide spectrum of structural variants (SVs), copy number variants (CNVs), and chromosomal segregation errors, characteristic features of CIN at a very early stage of gastric tumorigenesis. Mechanistically, ARID1A bound centromere repetitive satellite DNA (satDNA) sequences. Its SWI/SNF-associated chromatin remodeling activity was required for suppressing satDNA transcription and the production of -SatRNA, through restricting RNAPII elongation. Consequently, ARID1A depletion led to overexpression of -SatRNA, and a higher incidence of sister chromatid exchange (SCE), a sensitive indicator of CIN. Importantly, the elevated -SatRNA expression in ARID1A-deficient cells further established a dual therapeutic vulnerability for G2/M checkpoint blockade, such as PKMYT1 inhibitor (PKMYTi), by concurrently aggregating CIN-induced cell death and activating self-dsRNA sensing-mediated innate immune response. Notably, PKMYTi markedly promoted -SatRNA expression, aberrant release of these self-derived dsRNAs into the cytosol and a robust activation of the RIG/MDA5-MAVS-depenent type-I interferon response in ARID1A-depleted cells. As expected, PKMYTi potentiated the efficacy of immunotherapy in ARID1A-deficient gastric tumors. Together, our findings reveal that ARID1A deficiency unleashes centromeric -SatRNA transcription, which sets the molecular stage for tumor evolution and targeted therapy by coordinately inducing CIN and self-dsRNA-induced innate immune responses.

cancer biology↗

bioRxiv2026

Endogenous mutational mechanisms and metabolic context shape endometrial cancer

Uterine corpus endometrial carcinoma (UCEC) is a common gynecologic malignancy with rising mortality, yet its genome-wide mutational architecture remains incompletely understood. Here we analyze deep whole-genome sequencing data from 440 UCEC tumors from The Cancer Genome Atlas, integrated with transcriptomic and clinical data, to define subtype-specific mutational processes and genomic architectures. We uncover pronounced molecular subtype-specific differences in endogenous mutational mechanisms, retrotransposition activity, structural variation, and chromosomal instability. LINE-1 retrotransposition emerges as a key contributor to genome instability in UCEC, acting as a prominent source of structural variation in copy-number stable tumors and associating with chromothripsis and ecDNA-mediated oncogene amplification in copy-number high tumors. Mutational signature SBS28 contributes significantly to mutations in POLE-deficient tumors and is strongly correlated with SBS10a and SBS10b. Mismatch repair-deficient tumors exhibit a previously unrecognized doublet base substitution signature and a defining imbalance between ID2 and ID1 indel processes, reflecting pervasive DNA template-strand replication slippage and associated with increased tumor immunogenicity. Copy-number low tumors follow a distinct low-mutagenesis evolutionary trajectory characterized by reduced replication stress, low proliferative activity, genomic stability and enrichment of SBS18 associated with oxidative damage. Notably, we identify a consistent inverse association between body mass index and tumor mutational burden in UCEC, suggesting that host metabolic state may influence fundamental cellular processes governing mutation accumulation, promoting tumor development through non-mutagenic mechanisms rather than elevated genomic instability. Together, these findings establish a mutagenesis-centric framework for UCEC that links endogenous mutational mechanisms to tumor architecture and host metabolic context, uncovering previously unrecognized subtype-specific genomic features with important implications for refined risk stratification and therapeutic strategies.

genomics↗

bioRxiv2026

Fatty acid scavenging enables cancer escape from KRAS inhibition

Although inhibitors of oncogenic KRAS have shown clinical efficacy1, resistance to KRAS inhibition is common2, and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3K signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3K{gamma}-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3K{gamma} signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.

cancer biology↗

bioRxiv2026

Sustained Relief of Chronic Pain via a Nav1.7_Targeting ASO_siRNA Conjugate

Chronic pain affects billions globally, yet safe, long-lasting, and non-addictive analgesics remain lacking. Nav1.7 is a genetically validated pain target, but traditional small molecules have repeatedly failed. Therapeutic oligonucleotides-antisense oligonucleotides (ASOs) and siRNAs-offer selective, durable silencing. We developed N02C0702, an ASO-siRNA conjugate (ASC), achieving robust Nav1.7 knockdown and sustained analgesia without additional delivery vehicles. N02C0702 outperformed individual ASO (N02A114) and siRNA (N02S154) moieties at mRNA and protein levels and in pain relief. In CFA-induced inflammatory pain, a single intrathecal dose exceeded naproxen and suzetrigine, while in SNL neuropathic pain, efficacy persisted up to 56 days, comparable to or surpassing pregabalin. Genome-wide RNA sequencing confirmed minimal off-target effects. N02C0702 highlights Nav1.7 as a key analgesic target and demonstrates the ASC platforms potential for chronic pain and other CNS-related pathologies, offering durable, selective, and safe therapeutic effects.

neuroscience↗

bioRxiv2026

NeuroNarrator: A Generalist EEG-to-Text Foundation Model for Clinical Interpretation via Spectro-Spatial Grounding and Temporal State-Space Reasoning

Electroencephalography (EEG) provides a non-invasive window into neural dynamics at high temporal resolution and plays a pivotal role in clinical neuroscience research. Despite this potential, prevailing computational approaches to EEG analysis remain largely confined to task-specific classification objectives or coarse-grained pattern recognition, offering limited support for clinically meaningful interpretation. To address these limitations, we introduce NeuroNarrator, the first generalist EEG-to-text foundation model designed to translate electrophysiological segments into precise clinical narratives. A cornerstone of this framework is the curation of NeuroCorpus-160K, the first harmonized largescale resource pairing over 160,000 EEG segments with structured, clinically grounded natural-language descriptions. Our architecture first aligns temporal EEG waveforms with spatial topographic maps via a rigorous contrastive objective, establishing spectro-spatially grounded representations. Building on this grounding, we condition a Large Language Model through a state-space-inspired formulation that integrates historical temporal and spectral context to support coherent clinical narrative generation. This approach establishes a principled bridge between continuous signal dynamics and discrete clinical language, enabling interpretable narrative generation that facilitates expert interpretation and supports clinical reporting workflows. Extensive evaluations across diverse benchmarks and zero-shot transfer tasks highlight NeuroNarrators capacity to integrate temporal, spectral, and spatial dynamics, positioning it as a foundational framework for time-frequency-aware, open-ended clinical interpretation of electrophysiological data.

bioinformatics↗

bioRxiv2026

Minimal biophysical rules are sufficient for the emergence of computational intelligence at the neuronal scale

How intelligence emerges from the brains complex microscopic physical system is a central question for neuroscience and artificial intelligence. Constrained by the genomic bottleneck that precludes synapse-by-synapse specification, we propose and validate a microscopic structure-function concise-constraint sufficiency hypothesis. We develop the Neuro-Informed Generative Connectome (NIGC) framework, and show that connectomes generated under a concise set of biophysical constraints (geometric embedding, node propensity modulation, a global energy budget and maximum-entropy selection) closely match the structural statistics of a measured mouse V1 microcircuit (similarities, 0.997). In parallel, using the generated connectome as the fixed reservoir of an echo state network (ESN), training only a linear readout achieves 90% accuracy on an auditory multi-classification task. Moreover, multidimensional biologically consistent functional phenotypes, such as hierarchical transmission delays and low-dimensional spatiotemporal trajectories, are obtained without fitting functional matrices or time courses. Further, by combining single-constraint ablations, pathological perturbations and cross-modal validation, we clarify how specific structural constraints map onto functional consequences. Together, these results delineate sufficient conditions for computational intelligence emergence at the microscopic scale, and provide an auditable benchmark for first-principles understanding of brain construction.

neuroscience↗

bioRxiv2026

Cost-effective hybrid long- and short-read sequencing enables accurate somatic structural variant detection

Somatic structural variant (SSV) calling typically requires matched normal data. Incorporating relatively inexpensive short-read sequencing not only provides essential germline information but can also replace a substantial portion of long-read sequencing, thereby enabling more cost-effective somatic SV detection. Here, we present SomaSV, a hybrid sequencing framework that integrates 30x tumor long-read data with matched normal data comprising 10x long-read and 30x short-read sequencing. This design achieves high-accuracy somatic SV detection while remaining cost-competitive. Comprehensive benchmarking demonstrates that SomaSV outperforms current state-of-the-art methods by more than 13% in F1 score while reducing sequencing costs by approximately 19%. Moreover, SomaSV identifies clinically relevant cancer-associated genes, including CLDN4 and ROBO2, highlighting its potential for discovering valuable biomarkers to support early cancer screening and diagnosis. The source code for SomaSV can be accessed at https://github.com/eioyuou/SomaSV.

bioinformatics↗

bioRxiv2026

A single-cell atlas and aging clock define biological age and risk-associated stem cell states in human hematopoiesis

Aging of hematopoietic stem and progenitor cells (HSPCs) impairs regenerative capacity and predisposes to hematological diseases. Here, we constructed a comprehensive single-cell transcriptomic atlas comprising 186,123 CD34+ HSPCs spanning early prenatal development (6 post-conception weeks) to late adulthood (74 years). We identified two conserved core molecular programs (MPs) of inflammaging and RNA splicing / protein homeostasis. Leveraging these programs, we developed a machine learning-based stem cell aging clock from 84 donors. Applying this clock to acute myeloid leukemia (AML), we define Transcriptional Age Deviation (TAD), a novel metric of biological age divergence. We found that a biologically "younger" state (low TAD), reflecting oncofetal reprogramming, is a powerful independent predictor of poor survival in two large AML cohorts. Low TAD was associated with high-risk genetics and therapy resistance, and critically, it re-stratified patient outcomes within each ELN 2022 risk category. Our work establishes a quantitative link between stem cell aging biology and AML prognosis, offering a robust tool to refine clinical risk assessment.

bioinformatics↗