Biology subjects

Gu, H.

Publications and source records attributed to Gu, H..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells

The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms an extensive and highly organized network throughout the body. We have recently discovered that the mechanistic target of rapamycin complex 1 (mTORC1), with RAPTOR as an indispensable component, directs glycolysis and glutaminolysis in lymphatic endothelial cells (LECs) to promote lymphatic vessel formation. However, the role of mTORC1 in regulating LEC metabolism remains incompletely understood. Here, by conducting untargeted metabolomic profiling of control and RAPTOR-deficient LECs, we uncover a global impact of mTORC1 inhibition on amino acid utilization. Specifically, RAPTOR deficiency impairs the conversion of glutamine to glutamic acid, resulting in decreased levels of glutamic acid and aspartic acid, as well as reduced abundance of N-acetyl-glutamic acid and N-acetyl-aspartic acid--two metabolites unexpectedly detected in LECs. Integrated metabolomic and transcriptomic analyses further reveal that impaired glutaminolysis in RAPTOR-depleted LECs is accompanied by an increase in intracellular asparagine, arginine, and metabolites associated with arginine catabolism, potentially driven by upregulation of their respective transporters. In addition, RAPTOR depletion results in abnormal accumulation of branched-chain amino acids (BCAAs) and other essential amino acids primarily involved in protein synthesis. Mechanistically, our data suggest that defective BCAA catabolism and impaired translational control contribute to these metabolic alterations. Collectively, these findings reveal an important role of mTORC1 signaling in coordinating amino acid utilization and suggest that this regulation is critical for lymphatic vessel formation.

cell biology↗

bioRxiv2026

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

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

developmental biology↗

bioRxiv2026

Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer

Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic PIK3CA mutation, Trp53 loss, and MYC overexpression. Using this model together with human EC cell lines, patient-derived organoids (PDOs), xenografts, and patient datasets, we investigated mechanisms underlying resistance to PI3K-targeted therapy. Single-cell profiling reveals that FGFR1/2 upregulation associates with intrinsic resistance, whereas FGFR3 characterizes acquired resistance. Dual FGFR and PI3K inhibition produced superior tumor control compared with either agent alone. Mechanistically, FGFR signaling promotes immune evasion by downregulating MHC-I/HLA-mediated antigen presentation and enriching M2-type tumor-associated macrophages. FGFR inhibition reversed these changes and synergized with anti-PD-1 therapy to enhance antitumor immune responses and establish durable immune memory. Collectively, these findings identify FGFR signaling as a key driver of therapeutic resistance and immune escape in SEC and support FGFR-targeted combination strategies.

cancer biology↗

bioRxiv2026

Comorbid HIV and Cocaine Use Exacerbate Accelerated Brain Aging

BackgroundHIV and cocaine use (CU) each relate to cognitive deficits and brain abnormalities, yet their combined impact on brain aging remains unclear. This study examined how comorbid HIV and CU relate to brain aging and cognitive impairment. MethodsWe trained a morphometry-based brain-age model using harmonized Human Connectome Project-Aging data (HCP-A; n=725) with Gaussian Process Regression. The model was applied to an independent cohort with varying HIV/CU burden (HIV-/CU-, n=34; one disorder [HIV+/CU- or HIV-/CU+], n=72; HIV+/CU+, n=80). Brain age gap (BAG; predicted minus chronological age) was examined in relation to comorbidity burden and neurocognitive impairment (NCI; NIH Toolbox), adjusting for age, sex, education, depression, and image-quality indices. Analyses on SHapley Additive exPlanation (SHAP) values characterized network-wise feature-level contributions to brain age estimates. ResultsA dose-dependent effect of comorbidity burden on BAG was observed, with the HIV+/CU+ group showing the highest BAG. Greater BAG was associated with increased likelihood of NCI, and BAG partially mediated the relationship between comorbidity burden and NCI, with a stronger mediation effect in the two-disorder group than in the one-disorder group. Structural contributors to elevated BAG in the HIV/CU cohort included cortical thickness in the visual, ventral attention, and frontoparietal networks, and sulcal depth in the sensorimotor network. ConclusionComorbid HIV/CU is linked to accelerated structural brain aging. BAG may reflect brain-level alterations underlying the association between comorbid HIV/CU and cognitive impairment, and may help identify network-specific targets for intervention.

neuroscience↗

bioRxiv2026

Promoter editing of starch branching enzyme IIb and granule-bound starch synthase I balances resistant starch content and amylose content in rice

Increasing attention is being focused on the glycemic index (GI) of daily food for humans, and the resistant starch content (RSC) is an important indicator of GI for starch-rich staple foods. In recent years, some studies revealed that the loss function of single or multiple key enzymes in the primary pathway of starch synthesis substantially increases RSC in rice, such as starch branching enzyme IIb (BEIIb) and soluble starch synthase IIIa (OsSSIIIa). However, a noteworthy negative characteristic of these high RSC mutants is the substantially increased amylose content (AC). AC as a major determinator of rice eating quality, must not be higher than an acceptable limit for most consumers. To solve this problem, in this study, we adopted two promoter editing (PE) editing strategies to develop rice germplasms with a better balance of RSC and AC: one is to edit the promoter of BEIIb in a low AC rice variety, another is to edit the promoter of Waxy (Wx) gene in a BEIIb loss of function mutant. Using AC[≤]20%, which is the range of premium quality rice in China as a criteria, we finally obtained 2 homozygous lines with significantly increased RSC ([≥]5%) in the NG46 background by promoter editing of BEIIb and 1 homozygous line in the YouTang2 (YT2, a BEIIb mutant) background by promoter editing of Wx gene. Further analysis revealed that AC and the amount of long-chain branches of amylopectin are positively correlated with RSC in the population of BEIIb PE lines. However, unexpectedly, the Wx PE-line with substantially decreased AC (17.7%) also showed significantly increased RSC (16.9%). Our study not only produces useful germplasms for the high RSC rice breeding in the future but also provides an insight into understanding the relationship between AC and RSC in defective BEIIb rice.

plant biology↗

bioRxiv2026

ProMeta: A meta-learning framework for robust disease diagnosis and prediction from plasma proteomics

The plasma proteome offers a dynamic window of human health, capturing the real-time intersections between genetics and physiology. However, the application of deep learning to proteomics is currently hindered by a reliance on large-scale labeled datasets, rendering standard models ineffective for rare or novel diseases where patient samples are inherently scarce. Here, we present ProMeta, a meta-learning framework designed to enable robust disease modeling under extreme data restrictions. By integrating knowledge-guided pathway encoding with bi-level meta-optimization, ProMeta projects unstructured proteomic profiles into biologically interpretable functional tokens. This architecture allows the model to learn a global initialization containing transferable biological priors from biobank-scale data, facilitating rapid adaptation to novel tasks. Through comprehensive benchmark experiments, ProMeta consistently outperformed transfer learning and traditional machine learning baselines in both disease diagnosis and prediction tasks. In the most challenging 4-shot scenarios (utilizing only 2 cases and 2 controls), the model achieved robust generalization with an average AUROC of [~] 0.69, representing a 24.6% relative improvement over the best-performing baseline methods. Mechanistic investigation revealed that ProMeta disentangles cases from controls in the latent space prior to task-specific adaptation, confirming the acquisition of universal biological rules rather than rote memorization. Furthermore, gradient-based interpretation identified disease-specific protein biomarkers and functional pathways consistent with known pathophysiology. Collectively, ProMeta overcomes the data-scarcity bottleneck in precision medicine, providing a scalable, interpretable framework for characterizing the full spectrum of human diseases, particularly for rare conditions lacking extensive clinical cohorts.

bioinformatics↗

bioRxiv2025

Spatiotemporal dynamics and migration pathways of the transboundary Beet Webworm Loxostege sticticalis (Linnaeus) between Northern China and Mongolia in 2022

Clarifying the population dynamics, source-landing relationships, and migration pathways of the beet webworm Loxostege sticticalis (Linnaeus) both domestically and internationally, as well as understanding the meteorological mechanisms shaping these patterns, is pivotal for remote, accurate, and location-specific pest forecasting. Based on light trap data from northern China and field survey data from Mongolia in 2022, we simulated the migration trajectories, source regions, and primary landing areas of L. sticticalis, and analyzed the synoptic systems and processes during its migration. The results indicate frequent exchange of L. sticticalis populations between China and Mongolia in 2022. The L. sticticalis migrants initiating their flights from Mongolia primarily undertook a southeastward migration pathway, supplemented by eastward cyclonic and southwestward paths. The main landing areas were located in North China and Northeast China, with migration events potentially extending to Shandong, Heilongjiang, and Xinjiang provinces. Populations originating from North China exhibited a capacity for migrating into Northeast China and Mongolia through 1 to 5 consecutive nights of flight. During this period, the Northeast China Cold Vortex (NCCV) and the Mongolian Cyclone alternately regulated the synoptic circulation pattern governing the migration of L. sticticalis. The spatiotemporal distributions and intensities of these systems were key determinants of the transboundary migration routes and distances of L. sticticalis. The NCCV dominated, and the precipitation and downdrafts it induced were crucial for the massive landing of L. sticticalis in northern China.

ecology↗

bioRxiv2025

Glucose and Oxygen Metabolism Coordinate Human Cortical Developmental Decisions

Defining metabolic regulation of neurodevelopmental programs is essential to approach developmental disorders and injuries driven by alterations in metabolism. In vitro cultures are the only available method to temporally perturb and study living human brain cells throughout neurogenesis, however most culture systems use supraphysiologic conditions of essential nutrients, glucose and oxygen. We probed how environmental exposure to endogenous-like concentrations impact metabolic state and developmental progression of cortical cell types using organoids. Nutrient accessibility globally impacted metabolic state, yet developmental responses to metabolic changes were cell type-specific. Metabolomic and transcriptomic datasets reveal increased TCA metabolites and amino acids and oxidative phosphorylation (OXPHOS) genes, under physiologic glucose conditions. Oxygen level had a modest, yet specific, molecular impact on deep layer excitatory neurons. We assessed consequences of metabolic changes on fate and observed that physiologic glucose expanded the human-enriched population of cortical stem cells, outer radial glia, and their progeny, upper layer excitatory neurons. Alterations in oxygen, instead, affected production of neurogenic progenitors and neuronal differentiation, with higher oxygen availability supporting shifts toward mitochondrial metabolism necessary for maturing cell types. We functionally tested this transition by inhibiting glycolysis; total inhibition promoted neuronal differentiation, whereas inhibition of anaerobic glycolysis/lactate production led to oRG expansion. Lactate signaling was sufficient to suppress oRG development and promote self-renewal of neurogenic progenitors. These data suggest that refined metabolic switches and decreased reliance on glucose are required for transition from stem cell self-renewal to more mature, diversified progenitor subtypes, where switch from anaerobic to aerobic metabolism discretely impacts progenitor diversification.

neuroscience↗

bioRxiv2025

Butyrate rescues chlorpyrifos-induced social deficits through inhibition of class I histone deacetylases

Chlorpyrifos (CPF) is a widely used organophosphate pesticide effective through inhibiting acetylcholinesterase, which leads to the accumulation of acetylcholine and continuous nerve stimulation. In addition to its well-known acute toxicity, exposure to CPF has also been linked to chronic conditions such as an increasing risk of autism spectrum disorder (ASD) and adverse effects on gut health, including disturbances to the gut microbiome and metabolism. However, the underlying mechanism of CPFs contribution to ASD remains unclear, and the roles of the gut microbiome and gut metabolites in CPF-induced neurodevelopmental toxicity remain elusive. Using a high-throughput social behavior assay, we found that embryonic exposure to CPF induced lasting social deficits in zebrafish. Through a small-scale screen of common health beneficial gut microbiome metabolites, we discovered that butyrate effectively rescued CPF-induced social deficits. RNA sequencing of zebrafish brain tissues revealed that early exposure to CPF induced a lasting suppression of neuronal genes, including many ASD risk genes, and elevated expression of circadian genes. Butyrate partially reversed the suppression of key neuronal genes. Butyrate is a non-selective inhibitor of histone deacetylases (HDACs). Through a series of loss-of-function experiments utilizing CRISPR-Cas9-induced knockouts and selective chemical inhibitors, we found that the class I HDAC, HDAC1, most likely mediates butyrates rescue effect. Metabolomics analysis detected changes in several nitrogen metabolism-related pathways in the zebrafish gut following CPF exposure. Metagenomics analysis revealed an increase in abundance of the denitrifying bacteria Pseudomonas and a reduction in the nitric oxide-sensitive bacteria Aeromonas in the CPF-exposed zebrafish gut microbiome. Our results connect CPF-exposure with changes in the gut microbiome, metabolome, epigenetics, gene expression, and behavior, inspiring a novel hypothesis for the underlying molecular mechanisms of CPF-induced neurodevelopmental toxicity. In the long run, our findings may help elucidate how CPF exposure contributes to autism risk and inspire therapeutic developments.

neuroscience↗

bioRxiv2025

Loss of the tumor suppressor PTEN activates cell-intrinsic interferon signaling to drive immune resistance

Loss of the tumor suppressor PTEN is strongly associated with a lack of response to immune checkpoint blockade therapies in cancer patients, but the underlying mechanisms are not fully understood. We have developed a transformation model where knocking out PTEN in human mammary epithelial cells drives dependence on the p110{beta} subunit of PI3K and, notably, elicits a robust induction of endogenous retroviral elements (ERVs) and activation of the interferon signaling. This constitutive cell-intrinsic interferon response, hallmarked by hyperactivated STAT1, is also observed in human tumors with a PTEN-low status. We further find that PTEN deficiency renders cancer cells resistant to the cytotoxic effects of immune cells and interferon-{gamma}. Notably, PTEN loss also results in a dependency on an activated DNA damage response pathway, leading to an exquisite vulnerability to CDK12 inhibition. Our study suggests an interferon adaptation model in which tumors driven by PTEN deficiency inherently activate the interferon response, enabling them to adapt to interferon cytotoxicity and gain resistance to immunotherapies.

cancer biology↗

bioRxiv2025

STARNet enables spatially resolved inference of gene regulatory networks from spatial multi-omics data

Biological tissues are composed of distinct microenvironments that spatially orchestrate gene expression and cell identity. However, the regulatory principles governing domain-specific cellular functions remain poorly understood due to the lack of effective methods for mapping gene regulatory networks (GRNs) in situ. To address this gap, we introduce STARNet, a representation learning approach that leverages heterogeneous hypergraph modeling of spatial transcriptomic and epigenomic data to resolve tissue-domain-specific regulatory interactions. By integrating graph neural networks with contrastive learning in a self-supervised framework, STARNet learns unified embeddings that preserve both multi-modal molecular features and anatomical spatial context, enabling accurate and domain-resolved GRN reconstruction within complex tissues. Benchmarking on both simulated and real datasets demonstrates that STARNet achieves state-of-the-art performance. We further demonstrate its broad applicability across diverse biological contexts, including neural development, genetic disease risk, and drug-induced developmental toxicity. In the mouse brain, it delineates region-specific regulatory networks and reconstructs spatiotemporal programs underlying neural stem cell differentiation. In human genetics, it provides a mechanistic link between genotypes and phenotypes by showing how genome-wide association study (GWAS) variants for complex diseases perturb hippocampus-specific GRNs. In developmental toxicology, STARNet reveals that drug-induced disruptions of GRNs in defined embryonic regions underlie tissue-specific vulnerability. Collectively, STARNet offers a powerful and versatile framework for resolving the spatial regulatory logic of complex tissues, providing multi-angle insights into tissue patterning, development, and disease mechanisms.

bioinformatics↗

bioRxiv2025

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

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

neuroscience↗

bioRxiv2025

In vivo exposure of mixed microplastic particles in mice and its impacts on the murine gut microbiome and metabolome

Microplastics (MPs) are emerging environmental contaminants due to increasing global plastic production and waste. Microplastics, defined as plastic particles less than 5 mm in diameter, are formed through degradation of larger plastics via sunlight, weathering, and microbes. These plastic compounds are widely detected in water, soil, food, as well as human stool and blood. The gut microbiome, often referred to as our second genome, is important in human health and is the primary point of contact for orally ingested microplastics. To investigate the impact of ingested MPs on the gut microbiome and the metabolome, 8 weeks-old male and female C57/BL6 mice were orally gavaged mixed plastic (5 um) exposure consisting of polystyrene, polyethylene, and the biodegradable/biocompatible plastic, poly-(lactic-co-glycolic acid) twice a week for 4 weeks at 0, 2, or 4 mg/week (n = 8/group). Fecal pellets were collected for bacterial DNA extraction and metagenomic shotgun sequencing, and serum was subjected to targeted and untargeted metabolomics. MPs exposure resulted in significant sex-specific and dose-dependent changes to the gut microbiome composition along with substantial regulation of the predicted metabolic pathways. Untargeted metabolomics in serum showed that a low MPs dose displayed a more prominent effect on key metabolic pathways such as amino acid metabolism, mitochondrial function, and inflammation. Additionally, SCFA-targeted metabolomics showed significant changes in neuroprotective SCFAs levels in both sexes by MPs exposure. In conclusion, our study has demonstrated that microplastics dysregulate the gut microbiome and serum metabolome, providing critical insights into potential human disease risks associated with microplastic contamination.

pharmacology and toxicology↗

bioRxiv2025

PROFET Predicts Continuous Gene Expression Dynamics from scRNA-seq Data to Elucidate Heterogeneity of Cancer Treatment Responses

Single-cell RNA sequencing profiles cellular heterogeneity but captures only static snapshots, limiting inference of gene expression dynamics. We developed PROFET (Particle-based Reconstruction Of generative Force-matched Expression Trajectories), a framework that reconstructs continuous, nonlinear single-cell trajectories from sparsely sampled scRNA-seq time series. PROFET combines a particle-based gradient-flow algorithm with simulation-free force matching to accurately infer cellular dynamics. Across mouse and human in vitro datasets and an in vivo axolotl regeneration dataset, PROFET achieved 2.6-12.5X lower prediction error than ten state-of-the-art trajectory inference methods. Applying PROFET to newly generated scRNA-seq data from a palbociclib-treated MCF7 cell line and three published breast cancer patient datasets, we reconstructed treatment-response trajectories and identified a resistant cell subpopulation exhibiting large phenotypic shifts and enrichment of the surface markers UNC5B, TLR3, PCDH19, PROCR, SLITRK6, and SEMA6B. PROFET provides a biologically grounded framework for reconstructing cell-state dynamics from static single-cell data across development, regeneration, and therapeutic response.

bioinformatics↗

bioRxiv2025

Lycopene Suppresses Lung Cancer Progression via PI3K/AKT Pathway Inhibition and Apoptosis Induction: Mechanistic and Safety Insights from Preclinical Models

BackgroundLung cancer remains a leading cause of cancer-related mortality, necessitating novel therapeutic strategies with minimal side effects. Lycopene, a natural carotenoid, has shown potential anticancer properties, yet its efficacy and mechanisms in lung cancer models require systematic exploration. ObjectiveThis study aimed to evaluate the antitumor effects of lycopene in both in vivo and in vitro lung cancer models, elucidate its molecular mechanisms, and assess systemic safety. MethodsIn vivo, tumor-bearing mice received intratumoral injections of lycopene at varying concentrations (10, 20, 40 mg/kg) to evaluate tumor regression . In vitro, A549 and LLC lung cancer cell lines were treated with lycopene (0-40 M) to assess the ability of clonogenic survival, tumor new cell, cell invasion and promoting apoptosis.Western blot and immunohistochemistry were used to detect related pathways and apoptotic proteins, and target genes were silenced or overexpressed to verify the correctness of the pathways. Systemic toxicity was analyzed through blood biochemical profiling and histopathological examination (HE staining) of major organs at 40 mg/kg. ResultsLycopene significantly reduced tumor volume in mice in a dose-dependent manner (p<0.05). Systemic toxicity assessments revealed no abnormalities in hepatic, renal, or hematological parameters, and organ histology remained unaffected at 40 mg/kg. In vitro, lycopene suppressed colony formation, tumor new cell, cell invasion numbers, and increased apoptosis rates about 60%. Mechanistically, lycopene downregulated phosphorylated PI3K and AKT levels, indicating pathway inhibition. Interference of PI3K gene silencing or overexpression suggests that the PI3K/AKT pathway is the main target for lycopene to produce apoptotic effects. ConclusionLycopene exerts potent antitumor effects by inhibiting the PI3K/AKT pathway and promoting apoptosis in lung cancer cells, while demonstrating a favorable safety profile at therapeutic doses. These findings highlight its potential as an adjunctive therapy for lung cancer management.

cancer biology↗

bioRxiv2025

Enhancing Neural Synchrony with Endogenous-like 1/f Noise Stimulation

Aperiodic components of neural activity, characterized by endogenous 1/f noise dynamics, are hypothesized to support the emergence of large-scale cortical order and cognitive flexibility. Here, we combine computational modeling and human brain stimulation to elucidate the role of 1/f noise in modulating neural synchrony. Using a coupled oscillator model, we demonstrate that ubiquitous 1/f noise does more effectively enhances phase synchrony than spectrally flat (white) noise. Crucially, we identify a competitive synergy between noise intensity and the 1/f spectral exponent: starting from optimal white noise-induced synchrony, increasing the 1/f exponent while decreasing noise intensity leads to a further enhancement of synchrony, which peaks at a specific parameter regime before diminishing. To experimentally validate these findings, we developed a transcranial 1/f noise stimulation (tFNS) system and applied it to human subjects. Compared to spectrally white noise stimulation, the tFNS more robustly enhanced corticospinal synchrony, consistent with model predictions. These results uncover a functional advantage of scale-free brain noise in driving coordinated neural dynamics, offering a new framework for optimizing non-invasive brain stimulation. More broadly, our findings suggest that the brain may harness stochastic facilitation through adaptive modulation of its aperiodic activity to support ordered macro-dynamics.

biophysics↗

bioRxiv2025

Exposure to per- and polyfluoroalkyl substances elicits cell type-specific impacts on p53 and TGF-β signaling pathways

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals extensively used as plastic additives. Their environmental persistence and potential for bioaccumulation have raised significant toxicological concerns. This study evaluates the cytotoxic and molecular effects of Perfluorooctanoic acid (PFOA) and its replacement compound, Perfluoro(2-methyl-3-oxohexanoic) acid (GenX), in human-derived skin (A375), liver (HepG2), kidney (SN12C), and colon (SW620) cell lines. The experimental design assessed cell viability, gene expression, and perturbations in key cellular stress pathways, with a particular focus on TGF-{beta}/SMAD-mediated inflammation and the p53-driven DNA damage response. Our results demonstrate compound- and cell-type-specific toxicity, with GenX displaying reduced cytotoxicity compared to PFOA across all cell types. Molecular analyses revealed that both PFAS compounds induced alterations in the TGF-{beta}/SMAD pathway, consistent with a pro-inflammatory cellular state. Additionally, we observed activation of the DNA damage response, as evidenced by increased expression of ATM, ATR, and p53, alongside ribosomal stress-related changes in RPL5 and RPL11. Notably, while skin and liver cells exhibited similar response profiles, kidney and colon cells showed divergent modulation of SMAD signaling, suggesting tissue-specific susceptibility and mechanistic differences. These findings contribute to a deeper understanding of the differential toxicological profiles of legacy and replacement PFAS, with implications for health risk assessment and regulatory policy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/652004v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@ce20aaorg.highwire.dtl.DTLVardef@c29608org.highwire.dtl.DTLVardef@1081ae6org.highwire.dtl.DTLVardef@11e0401_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Exercise Conditioning Enhances Insulin Sensitivity with Metabolic and Glycemic Control Driven by Hepatic Silencing of HMGB1 in Type 2 Diabetic Mice

Type 2 Diabetes (T2D) is characterized by chronic insulin resistance and inflammation. Exercise induces hyperglycemia control in T2D more than pharmacologic therapies alone. High Mobility Group Box 1 (HMGB1) is a ubiquitous nuclear factor for T2D progression. We hypothesize that hepatic silencing of HMGB1 in T2D and exercise will increase insulin sensitivity and shift metabolic routes, decrease liver damage and improve metabolic health in T2D mice. MethodsLiver HMGB1 KO (HMGB1{Delta}) was induced with AAV8-TBG in HMGB1 flox mice (AAV8-EGFP was used as wildtype controls). T2D mice were induced with a low-dose STZ and a high-fat diet. T2D mice ran for four weeks (1hr daily). Dual Energy X-Ray Absorptiometry (DEXA), A1C, glycemia, HMGB1, metabolomics and metabolic cage analysis were performed pre- and post-exercise. RT-PCR, immunoblotting and immunohistochemistry for glucose metabolism markers were performed in tissue samples. ResultsT2D HMGB1{Delta} mice show 20% less hyperglycemia compared to controls with a strong correlation between reduced HMGB1 levels and lower A1C following exercise. Additionally, fat percentage, liver damage, and glycogen storage were significantly reduced. These findings highlight the high potential effect of exercise potentiated has via HMGB1 governed mechanisms and highlights HMGB1 as a therapeutic target for managing hyperglycemia in T2D. ARTICLE HIGHLIGHTSHMGB1 hepatic silencing in Type 2 Diabetic mice is a promising therapeutic target for enhancing Insulin sensitivity. Combination of hepatic HMGB1 silencing and exercise potentiates the metabolic benefits and liver protection in Type 2 Diabetic mice. Shift in metabolic routes and carbohydrate metabolism due to regulation of hepatic HMGB1 expression makes HMGB1 an ideal target for pharmacologic intervention. However, our study also underscores the value of exercise as the primary focus of diabetic glucose control aided by enhanced therapeutic targeting of HMGB1 for chronic inflammation and hyperglycemia.

molecular biology↗