Biology subjects

Guo, Z.

Publications and source records attributed to Guo, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

A cohesion optimum underlies chromosome segregation fidelity in oocytes

Chromosome segregation is compromised in eggs from women of both early and advanced reproductive ages. Deteriorating cohesion causes premature separation of sister-chromatids in eggs from older females. We show that the converse is true for oocytes of adolescents, with excessive cohesion impeding segregation. Oocytes from juvenile mice show severe chromosome lagging in anaphase I, leading to nondisjunction or, in extreme cases, failure of the first meiotic division. These defects are suppressed by experimentally weakening cohesion or enhancing its resolution during anaphase I. By contrast, lagging and nondisjunction are rare in the oocytes of young adults because cohesion is inherently weaker. Thus, relative cohesion strength underlies both the frequency and type of segregation errors observed in eggs throughout the female reproductive lifespan. One-Sentence SummaryIn eggs, errors in chromosome segregation arise from age-dependent imbalances in how tightly chromosomes are held together.

cell biology↗

bioRxiv2026

Rewiring c-Myc Transcriptional Activity with an O-GlcNAcylation Targeting Chimera (OGTAC)

c-Myc is a transcription factor that drives tumorigenesis in many cancers. It is notoriously difficult to directly target c-Myc, mainly due to its lack of well-defined druggable pockets. O-linked {beta}-N-acetylglucosamine modification (O-GlcNAcylation) is a post-translational modification (PTM) playing an important role in regulating c-Myc functions in cancer. However, previous studies have primarily relied on global perturbations to investigate c-Myc O-GlcNAcylation, making it difficult to determine its direct functional consequences due to concurrent cellular effects. Here, we report a bifunctional O-GlcNAcylation TArgeting Chimera (OGTAC) molecule, which can induce the proximity of c-Myc and O-GlcNAc transferase (OGT) in living cells, thereby enhancing the O-GlcNAcylation of c-Myc. The c-Myc-targeting OGTAC exhibits anti-proliferation effect against cancer cells. Mapping of c-Myc occupancy on genome indicates that OGTAC rewires c-Myc transcriptional activity and reprograms expression of the downstream oncogene MALAT1, in an O-GlcNAcylation-dependent manner. Overall, OGTAC presents a novel chemically induced proximity (CIP)-based tool to target and rewire c-Myc activity in cancer. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/722559v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d1c640org.highwire.dtl.DTLVardef@2eb70corg.highwire.dtl.DTLVardef@f38970org.highwire.dtl.DTLVardef@c421c8_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

High-throughput, organ-scale 3D tubule tracking using TubuleMAP

Advances in tissue clearing and lightsheet microscopy enable mesoscale imaging of intact and convoluted tubular networks, yet analytical tools to map tubule continuity and assess injury patterns within and across tubules are limited. Here, we introduce TubuleMAP, a semi-automated pipeline for 3D tubule tracking and reconstruction that adapts to various morphological and staining patterns, leverages parallel processing of terabyte-scale data for large-scale analysis of tubular networks, and uses a napari interface for human oversight. Using TubuleMAP, we reconstruct 1,000 intact mouse nephrons in [~]1-millimeter-thick kidney slab with [~]400-fold higher throughput and <1% human effort compared to prior approaches. These reconstructions enable analysis of mesoscale nephron organization, quantitative profiling of pathologic morphologies, whole-nephron cytometry, and identification of rare morphologies at unprecedented scales. We demonstrate generalizability by reconstructing all seminiferous tubules in a mouse testis within a day. TubuleMAP is released as an open-source Python package.

bioengineering↗

bioRxiv2026

Hypermorphic TaARF4 shapes wheat architecture by repressing SPL-mediated developmental timing

Integrating spatial morphogens with temporal developmental clocks is fundamental to optimizing plant architecture and crop yield, yet their molecular interface remains elusive. Here, we characterize Branched shoot 1 (Bsh1), a semi-dominant wheat mutant exhibiting non-canonical upper-aerial branching and aberrant spike development, caused by a T265I substitution in the DNA-binding domain of the auxin response factor TaARF4-A2. Unlike flanking mutations governing protein stability in basal land plants, this central substitution uniquely converts TaARF4-A2 into an auxin-insensitive hypermorphic repressor. The mutant protein disrupts auxin-cytokinin homeostasis and markedly enhances the native repression of SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors, the core timers of developmental phase transitions. This spatial and temporal uncoupling unleashes upper axillary buds from dormancy, promoting aerial branching and diverting resources from reproductive development. Our findings demonstrate how a conserved spatial morphogen effector was evolutionarily rewired in polyploid wheat to dictate the temporal SPL clock, orchestrating species-specific shoot architectural innovation.

plant biology↗

bioRxiv2026

Clinical grade cryopreservation unlocks transplant ready human pancreatic and stem cell derived islets for diabetes therapy

Pancreatic islet transplantation can restore endogenous insulin production and offers a potential cure for diabetes, but its clinical impact has been limited by the inability to preserve large numbers of functional islets for timely use. Cryopreservation could provide an on-demand supply, yet conventional methods cause ice formation, cell injury, and loss of insulin secretion. We developed CryoMesh, a vitrification platform that combines a low-toxicity cryoprotectant with a thermally conductive, biocompatible mesh to enable ultra-rapid cooling and rewarming for ice-free cryopreservation. This approach supports long-term, clinical-scale preservation of both human pancreatic and stem cell-derived islets while maintaining viability, architecture, mitochondrial integrity, and glucose-responsive insulin secretion. Human islets preserved for up to one year restored normoglycemia in diabetic mice, with complete recovery of function and no increase in immunogenicity or loss of potency. The combination of high viability, recovery, and functional preservation at clinical scale has not been achieved previously. By decoupling islet isolation and manufacture from transplantation, CryoMesh enables extended quality, potency, and safety testing, cost-effective batch production, and global banking and distribution. These capabilities remove a major barrier to curative cell therapy for diabetes and establish a generalizable strategy for preserving complex multicellular therapeutics. One Sentence SummaryA clinical scale vitrification platform enables long-term banking of human pancreatic and stem cell-derived islets for transplantation.

cell biology↗

bioRxiv2026

Identification of scavenger receptor BI as a scavenger of free heme that is essential for protection against hemolysis

Severe hemolysis is a life-threatening condition with limited therapeutic options. Although haptoglobin and hemopexin sequester hemoglobin and heme, these protective systems are rapidly saturated during acute hemolysis, leading to the accumulation of cytotoxic free heme. In this study, we identify scavenger receptor BI (SR-BI) as a critical mediator of free heme clearance. SR-BI binds heme and facilitates its hepatic uptake under pathological conditions. Mice lacking hepatic SR-BI exhibit impaired heme clearance and increased susceptibility to heme- and hemolysis-induced lethality. Pharmacological upregulation of hepatic SR-BI via imatinib or adenoviral delivery confers protection against heme toxicity. Using a humanized model of sickle cell disease (SCD), we further demonstrate that sickle hepatopathy significantly reduces hepatic SR-BI expression compared to non-SCD littermates, potentially increasing vulnerability to heme-induced injury. Notably, adenoviral-mediated SR-BI upregulation rescues SCD mice from heme toxicity. These findings reveal a previously unrecognized mechanism of heme detoxification via hepatic SR-BI and identify a promising therapeutic target for hemolytic disorders. One-Sentence SummaryIdentification of scavenger receptor BI as a targetable scavenger of heme in hemolysis

physiology↗

bioRxiv2026

Comprehensive study on ferredoxin isoforms in the cyanobacterium Synechocystis sp. PCC 6803

Ferredoxins are central to cellular metabolism by mediating electron flow in energy conversion reactions. The focus of this study was to systematically examine twelve ferredoxin and ferredoxin-like proteins from Synechocystis sp. PCC 6803 to identify their properties, activities, and functions in electron transfer. Using electron paramagnetic resonance spectroscopy, we detected cluster types consistent with major ferredoxin families including plant-type [2Fe-2S], adrenodoxin, thioredoxin, and bacterial-type [4Fe- 4S] ferredoxins. In addition, we found that the ssr3184 ferredoxin-like protein exchanged between a [3Fe-4S] or a [4Fe-4S] cluster, pointing to a possible functional change in response to changes in oxygen or cellular redox poise. Electrochemical measurements demonstrated that these ferredoxins constitute a broad potential window, from -243 mV to -520 mV vs SHE. Investigations on their capacity to support electron-transfer focused on reactions with two major redox hubs: Photosystem I and pyruvate:ferredoxin oxidoreductase and included testing of binding interactions with nitrite reductase. Expression profiling under multiple environmental conditions was also used to predict function and revealed distinct regulatory patterns. Collectively, these findings identified a group of core ferredoxins that directly support photosynthetic electron transfer, and more specialized ones that may serve other functions. In summary, Synechocystis utilizes a suite of ferredoxins to maintain cellular redox homeostasis under dynamic environmental conditions.

biochemistry↗

bioRxiv2026

Density-dependent facilitation of livestock by small mammal ecosystem engineers

Small mammals and large herbivores have co-evolved in grasslands for millions of years, yet how they interplay remains unclear. Although large herbivores can significantly affect the smaller ones, the reversal effect is largely unknown. On the Qinghai-Tibetan Plateau, plateau pikas (Ochotona curzoniae) are often considered pests that compete with livestock at high densities. Using field experiments, we show that the presence of pikas facilitates weight gains of yaks (Bos grunniens) by improving vegetation composition at a moderate density level. Compared to the pika-present treatment, pika removal dramatically increased cover of the poisonous Stellera forbs by two-fold, reducing the abundance and protein content of palatable grasses and sedges, yak foraging efficiency, and yak weight gain by up to 42%. Notably, we found a humped relationship between yak weight gains and pika burrow densities in the pika-present plots; the facilitative effect of pikas on yaks was highest at about 200 burrows/ha, but shifted to a competitive effect at pika densities exceeding 400 burrows/ha. These results provide the first empirical evidence that maintaining a moderate density of small mammalian herbivores can benefit growth performance of livestock by improving vegetation composition. Our study highlights the significance of moderate populations of ecosystem-engineering small mammals in sustaining pastoral productivity in rangelands.

ecology↗

bioRxiv2026

Celastrol alleviates SGLT2 inhibitor-induced diabetic hyperketonemia by inhibiting hepatic ketogenesis

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([≤] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

molecular biology↗

bioRxiv2026

The mechanism of Hsa_circ_0000629 in bronchial asthma through sponge adsorption of miR-212-5p/NLRP3

To explore the mechanism of Hsa_circ_0000629 adsorbing miR-212-5p/ nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) through sponge in bronchial asthma. Twenty BALB/C mice were randomly divided into a normal control group and an asthma group. Pathological changes in lung tissue were observed via HE staining. Human bronchial epithelial cells (16HBE) were transfected with Hsa_circ_0000629 overexpression group (Hsa_circ_0000629-over), Hsa_circ_0000629 siRNA (Hsa_circ_0000629-si), mimic NC, miR-212-5p mimic, inhibitor NC, miR-212-5p inhibitor, and LPS+Hsa_circ_0000629 si. LPS-induced asthmatic cell models (LPS group) and untransfected 16HBE cells (NC group) served as controls. qRT-PCR was used to measure Hsa_circ_0000629, miR-212-5p and NLRP3 expression. ELISA assessed interleukin 18 (IL-18), interleukin 1{beta} (IL-1{beta}), interleukin 6 (IL-6) and tumor necrosis factor - (TNF-) levels. Cell proliferation and the apoptosis were evaluated by EDU assay and flow cytometry, respectively. Western blot analyzed Cleaved-caspase 1, 3 and 9 proteins expression. Dual-luciferase assay verified the binding sites of Hsa_circ_0000629 to miR-212-5p and NLRP3 to miR-212-5p. HE staining revealed inflammatory cell infiltration, bronchial wall thickening, smooth muscle hyperplasia, and alveolar destruction in asthmatic mice. Compared with the controls, Hsa_circ_0000629 and NLRP3 expression were significantly increased, while miR-212-5p expression was decreased in asthmatic lung tissues. In 16HBE cells, Hsa_circ_0000629-over and LPS groups showed elevated Hsa_circ_0000629 and NLRP3 expression but reduced miR-212-5p levels. Silencing Hsa_circ_0000629 in LPS-treated cells (LPS+Hsa_circ_0000629-si) reversed these effects. Overexpression of miR-212-5p counteracted Hsa_circ_0000629-induced NLRP3 upregulation, while miR-212-5p inhibition enhanced NLRP3 expression. LPS exposure increased TNF-, IL-18, IL-6, and IL-1{beta} levels, reduced cell proliferation, and promoted apoptosis. These changes were attenuated by Hsa_circ_0000629 silencing or miR-212-5p overexpression. Western blot confirmed that Hsa_circ_0000629 overexpression upregulated Cleaved-Caspase 1, 3, and 9, whereas miR-212-5p mimic or Hsa_circ_0000629-si reversed this trend. Dual-luciferase assays demonstrated targeted interactions among Hsa_circ_0000629, miR-212-5p, and NLRP3. Interference with Hsa_circ_0000629 expression can alleviate LPS induced apoptosis in 16HBE cells and inhibit the expression of inflammatory factors by targeting the miR-212-5p/NLRP pathway, which may be a new target for the treatment of asthma.

immunology↗

bioRxiv2026

CHPT1-LCAT rewires lipolysis towards ferroptosis

Ferroptosis is driven by iron-dependent lipid peroxidation, yet how metabolic flux through central lipid pathways is selectively routed towards pro-ferroptotic lipid species remains unclear. Here, through an unbiased chemical-genetic screen targeting core metabolic enzymes, we identify diacylglycerol (DAG) as a licensing lipid intermediate whose pro-ferroptotic activity depends on its intracellular routing. Systematic manipulation of lipolytic flux reveals that ferroptotic vulnerability is not determined by bulk lipolytic output or downstream intermediates, but by the selective channelling of DAG into a distinct metabolic fate. Mechanistically, DAG is selectively routed through a previously unrecognized intracellular metabolic axis composed of choline phosphotransferase 1 (CHPT1) and lecithin-cholesterol acyltransferase (LCAT). We uncover an enzymatically active intracellular pool of LCAT (iLCAT) that cooperates with CHPT1 on Golgi-trans-Golgi network membranes to generate polyunsaturated cholesteryl esters that execute ferroptosis. Functionally, enforced DAG routing through this axis suppresses tumour growth via ferroptosis in vivo, whereas hepatocyte-specific inhibition of the CHPT1-iLCAT axis attenuates lipid peroxidation and disease progression in metabolic dysfunction-associated steatohepatitis. Together, these findings establish subcellular lipid routing, rather than lipid abundance per se, as a fundamental determinant of ferroptotic vulnerability.

cell biology↗

bioRxiv2026

Programming Biomolecular Interactions with All-Atom Generative Model

Biomolecular interactions lie at the core of cellular life, spanning diverse molecular modalities from small molecules to nucleic acids and proteins. Nevertheless, design strategies remain separated despite shared physicochemical principles of molecular recognition. Here we present AnewOmni, a unified generative framework trained on more than 5 million biomolecular complexes, that enables transferable molecular design across molecular scales by assembling chemically meaningful building blocks at atomic resolution. We further introduce programmable graph prompts to support user-defined chemical, topological, and geometric steering during generation, exploring hybrid and unconventional chemistries beyond canonical structures. We demonstrate that transferable learning of interaction patterns and physical constraints across molecular modalities is possible, via an atom-to-block latent space capturing both atomic details and structural priors. The framework successfully designed small molecules, peptides, and nanobodies targeting the challenging KRAS G12D switch II pocket, as well as orthosteric peptides and allosteric small-molecule inhibitors for PCSK9 in the absence of known binding site, achieving 23%-75% success with only low-throughput validation, bypassing modality-specific high-throughput screening. AnewOmni is the first to succeed in functional molecular design across all scales, from small chemical entities to large biologics, and represents a stepstone towards general molecular reasoning engines, advocating a generative foundation model for biomolecular interactions to enter regimes where data and human intuition remain limited.

bioengineering↗

bioRxiv2026

Combined Antibiotic and Herbicide Pollution Accelerates the Horizontal Transfer of Antibiotic Resistance Genes in Coastal Microbial Communities

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/708170v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@4c2513org.highwire.dtl.DTLVardef@116256corg.highwire.dtl.DTLVardef@f30846org.highwire.dtl.DTLVardef@1a44e00_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG The extensive use of herbicides and antibiotics in aquaculture has led to compounded pollution of coastal waters, marked by the co-occurrence of herbicides, antibiotic residues, and antibiotic resistance genes (ARGs). Plasmid-mediated conjugative transfer is a major driver of the dissemination and evolution of ARGs, yet the influence of herbicides alone or in combination with antibiotics on this process in aquatic bacterial communities remains unclear. In this study, we demonstrated that triazine herbicides, alone and in combination with a fluoroquinolone antibiotic, significantly promote the conjugative transfer of the broad-host-range RP4 plasmid. Using Escherichia coli DH5 as a donor, we observed increased plasmid transfer to multiple recipients, including E. coli HB101, Pseudomonas putida KT2440, and a natural coastal seawater microbial community. The enhanced transfer under co-exposure was associated with several interacting mechanisms, including elevated intracellular reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, increased cell membrane permeability, altered extracellular polymeric substance (EPS) composition, and upregulated expression of conjugation-related genes. Overall, this work underscores the potential role of combined herbicide and antibiotic contamination in shaping the microbial resistome of coastal ecosystems and provides insights to inform strategies for mitigating the spread of antibiotic resistance.

microbiology↗

bioRxiv2026

Type 2 diabetes amplifies environmental Pb toxicity and intergenerational risk

Type 2 diabetes (T2D) and environmental lead (Pb) exposure intersect as prevalent global health challenges. Prior studies report elevated blood Pb in T2D, but the underlying mechanism and directionality remain unresolved. Here we show that T2D fundamentally alters Pb toxicokinetics, converting otherwise modest exposure into progressive organ injury and heritable risk. In a human cohort, elevated blood Pb in T2D specifically associated with impaired renal function rather than glycaemic control or adiposity. In db/db mice, diabetes increased oral Pb absorption through delayed gastrointestinal transit and epithelial barrier dysfunction, leading to enhanced systemic retention. With sustained exposure, renal Pb accumulation induced tubular stress that reduced effective clearance, creating a feed-forward loop in which diabetes promotes Pb retention and retained Pb accelerates kidney injury. Chronic Pb exposure exacerbated diabetic kidney injury without inducing hyperglycaemia, and short-course chelation attenuated renal stress markers. Beyond somatic toxicity, combined paternal T2D and Pb exposure programmed renal and neurobehavioral phenotypes across generations via sperm RNA. These findings redefine Pb from a passive environmental exposure to a context-dependent driver of disease, identify T2D as a vulnerability state that reshapes toxicant handling, and establish a mechanistic link between metabolic disease, environmental exposure and intergenerational risk. This work highlights the need for vulnerability-informed clinical management and environmental regulation in populations burdened by T2D.

genetics↗

bioRxiv2026

IntravChip: a vascularized and perfused microfluidic model of the primary tumor microenvironment to collect intravasated tumor cells

Hematogenous metastasis is initiated when tumor cells (TCs) intravasate into the vasculature, yet intravasation remains poorly understood because it is difficult to observe in vivo and intravasated TCs are challenging to isolate. To address these challenges, we developed IntravChip, a continuously perfused microfluidic platform containing a vascularized primary tumor microenvironment (TME) enabling the observation of TC intravasation, and a downstream chamber to collect intravasated TCs. The IntravChip can support a high TC concentration in the TME while maintaining complete vascular perfusion, which we found was necessary to collect intravasated cells. Using MDA-MB-231 breast TCs, we identified an optimal initial TC seeding density that, by day 9, yields a densely populated TME and 100-440 collected intravasated TCs. We validated the IntravChip across several TC types, showing that MDA-MB-231 and MV3 TCs have the highest intravasation rates while MCF-7 TCs have low intravasation efficiency. We also show that the IntravChip is compatible with super-resolution nano-imaging. Our devices enabled high-quality STORM imaging, which revealed that H3K9me3 nanodomains are significantly differentially distributed in intravasated MDA-MB-231 tumor cells compared to those residing in the TME. Finally, the IntravChip was validated as a platform to test the effects of anti-cancer drugs on tumor cells and on the vasculature. We showed that a 5 M concentration of sorafenib reduced intravasation events by 69% without impacting the morphology of the microvascular networks (MVNs), while a 10 M concentration led to a significant decrease in vessel diameter. This platform enables quantitative analysis of TC intravasation, collection of intravasated TCs for characterization, and screening of anti-metastatic therapies.

bioengineering↗

bioRxiv2026

A Discrete Language of Protein Words for Functional Discovery and Design

Proteins can preserve conserved functions despite extensive sequence and structural divergence, suggesting that functional organization is governed by distributed constraints not captured by conventional representations. Here we develop a hierarchical sequence-based representation framework that compresses proteins into context-dependent latent states while preserving multiscale organizational information. Using this framework, we identified previously uncharacterized ciliary proteins lacking detectable sequence and structure homology, including ADMAP1, which is required for normal sperm axonemal organization and motility in mice. Discrete latent protein states captured species-level organizational signatures correlated with major evolutionary groups and revealed expansion of intrinsically disordered regulatory environments in eukaryotes. Autoregressive sampling within this latent space further enabled design of synthetic actin-remodeling proteins that maintained robust F-actin severing activity despite extensive sequence rewiring across key functional interfaces. These findings demonstrate that distributed protein organization can be inferred directly from sequence, linking functional discovery, evolutionary analysis, and protein design within a shared representational framework.

bioinformatics↗

bioRxiv2026

Disrupted Sleep-Dependent Neural Oscillations and Transcriptomic Changes in the Cacna1g Loss-of-Function Mouse Model Implicated in Schizophrenia

Sleep is an essential biological process for maintaining brain function, and impaired sleep microarchitecture is a well-established feature of schizophrenia (SCZ). Rare loss-of-function variants in CACNA1G, encoding the T-type calcium channel CaV3.1, confer substantial risk for SCZ, implicating sleep-regulatory circuits in disease pathophysiology. Here, we first show that among individuals with SCZ, carriers of rare CACNA1G missense variants exhibit more pronounced alterations in sleep neurophysiology than non-carriers, identifying a human phenotype suggestive of altered channel function. Motivated by this observation, we examined the consequences of Cacna1g loss of function in mice. Cacna1g deficiency produced profound disruptions in sleep microarchitecture, including reduced sleep spindles, altered slow oscillations, impaired spindle-slow oscillation coupling, and reduced cortical synchrony--closely recapitulating neurophysiological signatures observed in individuals with schizophrenia. Beyond sleep structure, Cacna1g loss disrupted the normal coordination of brain rhythms across the 24-hour cycle, most notably abolishing diurnal modulation of theta oscillations. At the molecular level, Cacna1g loss uncoupled sleep-wake state from gene and protein regulation, producing widespread, sleep-phase-biased transcriptional and synaptic alterations across brain regions and cell types, particularly in cortical excitatory neurons. These network and molecular disruptions were accompanied by behavioral hyperactivity during the active phase. Together, these findings establish CACNA1G/CaV3.1 as a key regulator linking sleep-dependent brain dynamics to molecular homeostasis and behavior, and provide a mechanistic framework through which genetic risk for SCZ may drive disease-relevant sleep and circuit dysfunction. One Sentence SummaryLoss of CACNA1G disrupts sleep rhythms and gene regulation, creating a mismatch between brain state and behavior linked to schizophrenia.

neuroscience↗

bioRxiv2026

Exploring DNA methylation profiles in the pathogenesis of human osteoporosis via whole-genome bisulfite sequencing

BackgroundOsteoporosis is a prevalent bone metabolic disorder characterized by reduced bone mass, disruption of bone microarchitecture, and increased bone fragility, leading to a heightened risk of fracture. This condition significantly impairs patients quality of life and increases mortality risk. Emerging evidence suggests that DNA methylation may play a crucial role in regulating the expression of genes related to bone metabolism, thereby influencing the development of osteoporosis. However, the precise relationship between DNA methylation and osteoporosis remains unclear and warrants further investigation. ResultsOur study revealed significant differences in both the quantity and ratio of DNA methylation between individuals with osteoporosis and non-osteoporosis controls, with differences predominantly occurring in CpG islands. GO/KEGG enrichment analyses highlighted distinct osteoporosis-related gene pathways. Notably, we identified six genes, MSX1, HOXD4, AXIN2, WNT5A, TGFB1, and STAT3, respectively, that are potentially involved in the pathogenesis of osteoporosis and are broadly involved in various diseases and biological processes. ConclusionsThese findings indicate distinct methylation patterns between osteoporosis patients and healthy individuals, with differential methylation levels in genes associated with osteoporosis. This research offers new insights into the epigenetic mechanisms underlying osteoporosis.

genetics↗