Biology subjects

Gao, Y.

Publications and source records attributed to Gao, Y..

At least 109 records · Page 6Linked to original sources

bioRxiv2026

Looking backward for the future: long-term population recovery, habitat associations, and future climatic vulnerability of the critically endangered Sino-Mongolian beaver (Castor fiber birulai) in China

Despite the successful population recovery of the Eurasian beaver (Castor fiber) across much of Eurasia, its subspecies, the Sino-Mongolian beaver (C. f. birulai), remains critically endangered, with an estimated population of approximately 1,500 individuals confined to a small number of isolated and fragmented refugia along the China-Mongolia border. Effective conservation of this highly threatened subspecies requires a holistic perspective that integrates constraints on population dynamics, habitat associations, and future climatic vulnerability. Here, we combined systematic annual field surveys conducted between 2003 and 2023 with historical survey records from 1975 to 1989 in northern Xinjiang, China, to synthesize long-term spatiotemporal population dynamics, evaluate habitat preferences based on nine local environmental variables, and assess future climatic vulnerability using ensemble species distribution models (SDMs) under projected climate change scenarios. We detected a significant and phased population recovery, with beaver colony numbers increasing from 27 (approximately 100 individuals) in 1975 to 227 (681-908 individuals) in 2023. This recovery closely corresponded with major conservation milestones, including the establishment and upgrading of nature reserves, strengthened legislative protection, and enhanced multi-stakeholder collaboration. Habitat analyses further indicated that the Sino-Mongolian beaver preferentially occupied areas characterized by minimal anthropogenic disturbance and stable hydro-geomorphic conditions. Critically, SDM projections revealed that only 14% of the current study area presently exhibits high climatic suitability, and these highly suitable habitats are expected to disappear entirely by the 2050s. Together, our findings provide a comprehensive overview of the historical population recovery and conservation trajectory of the Sino-Mongolian beaver in China, and offer robust scientific support for developing adaptive management strategies in the face of ongoing climate change and increasing human pressures.

ecology↗

bioRxiv2026

MERTK inhibition cooperates with immunomodulatory cyclophosphamide to induce CXCL9⁺ monocyte-macrophage programming and durable anti-tumor immunity in triple negative breast cancer

Triple-negative breast cancer (TNBC) has high rates of recurrence despite chemotherapy and immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) can either suppress or support anti-tumor immunity, but the mechanisms governing these states and therapeutic targets remain unclear. Here, integrating public scRNAseq datasets with TNBC cohorts, we identify a prognostic myeloid signature defined by CXCL9hi/C1Qlow TAM programs, associated with improved survival and increased lymphocyte activation pathways. Using immunocompetent p53-null syngeneic TNBC models spanning basal-like (2153L) and claudin-low (T12) subtypes, we show that immunomodulatory cyclophosphamide (CTX) reprograms hematopoiesis toward the monocytic lineage and induces an interferon (IFN) conditioned tumor milieu that supports CXCL9 monocyte-derived macrophages (Mo.Macs) in basal-like disease. Combining CTX with the next generation MERTK-selective inhibitor UNC2371 (MRX-2843) drives complete remissions in both models, but durable long-term responses occurred selectively in the basal-like subtype model. The expansion of antigen-presenting CXCL9 Mo.Macs and reduction of C1q phagocytic TAMs are observed in responding tumors. Mechanistically, MERTK inhibition relieves MAPK/SOCS1 mediated restraint of IFN signaling driving a positive feedback loop of IRF7/STAT1/IRF1 driven CXCL9 induction. Functionally, tumor control requires CXCL9-CXCR3 dependent CD4 T cell recruitment, accumulation of stem-like memory CD4 T cells, and germinal center like immune organization in tumor-draining lymph nodes. PD-1 blockade further increases durability, preventing recurrence in most treated basal-like tumors. Together, these findings define an IFN licensed, MERTK regulated myeloid checkpoint that can be therapeutically targeted to convert suppressive TNBC microenvironments into durable adaptive immunity, supporting clinical translation of CTX + MRX-2843 based combinations in basal-like TNBC. SignificanceSuppressive myeloid programing limits effective adaptive immune engagement in TNBC usually resulting in ICB treatment resistance and tumor recurrence. This study identifies a therapeutically actionable myeloid interferon checkpoint in which MERTK inhibition stabilizes CXCL9 monocyte-macrophage programming to promote CD4 T cell dependent immune memory and durable tumor control in basal-like TNBC.

cancer biology↗

bioRxiv2026

A consensus spinal cord cell type atlas across mouse, macaque, and human

The spinal cord contains evolutionarily conserved cell types critical for motor function, sensory processing, and autonomic regulation, many of which are implicated in diverse neurological diseases and injuries. Yet the field lacks a comprehensive molecular characterization of cellular diversity in human, macaque, and mouse spinal cord. Here, we present a unified, cross-species cell type atlas based on the integration of single-nucleus gene expression, chromatin accessibility, and spatial transcriptomic data from segments within cervical, thoracic, lumbar, and sacral regions, including motor neurons (MNs) sampled across the entire rostro-caudal axis of the macaque spinal cord. Leveraging the spatial distributions of our molecularly defined cell types, we generated a cell type-guided anatomical map of spinal cord laminae and nuclei. We identified both conserved and species-specific cellular features, including gene expression patterns across distinct MN subtypes in the primate spinal cord. Cross-species cis-regulatory analysis and deep learning sequence models dissected the enhancer logic underlying viral targeting, uncovering conserved transcription factor grammar encoding cellular identity. Together, these results establish a unifying molecular and anatomical taxonomy of spinal cord cell types across species.

neuroscience↗

bioRxiv2026

Global Trends and Hotspots in Grassland Root Functional Traits Research (2000-2025)

Grasslands, as one of the most important terrestrial ecosystems globally, have root functional traits that serve as key indicators of plant responses to environmental changes and hold significant ecological importance. To reveal the current status, research hotspots, and frontier trends in the field of grassland root functional traits, this study analyzed relevant literature from the Web of Science Core Collection database between 2000 and 2025. It employs bibliometric methods and utilizes visualization tools such as CiteSpace for a systematic analysis. The results indicate that research in this field has been continuously increasing since 2000, reflecting a growing research interest. China, the United States, and Germany are the leading countries in terms of publication output. However, collaboration networks among authors, institutions, and countries are still not tight enough to form a truly global cooperative network. Co-occurrence analysis of keywords and literature clustering reveal that the research hotspots in this field are mainly concentrated in six directions: multidimensional characteristics of root functional traits, interactions between root functional traits and climate change, synergistic effects of root functional traits and soil microorganisms, responses of root functional traits to land-use changes, coupling of root functional traits with ecosystem functions, and applications of root functional traits in agriculture and ecological restoration. Future research should focus on promoting innovation and standardization of research methods, conducting long-term monitoring, deeply exploring the mechanisms of root-microbe interactions, implementing cross-scale integrative research and model construction, and building international collaborative networks.

ecology↗

bioRxiv2026

AADAT-Driven Metabolic Control of Malate and CoQ10 Shapes Immune Evasion in Triple-Negative Breast Cancer

Compared to other subtypes of breast cancer, triple-negative breast cancers (TNBC) have fewer treatment options and exhibit a worse prognosis. Through integrated transcriptomic, metabolomic, immunohistochemical, spatial, and clinical analyses, we identify the mitochondrial enzyme, -aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT mRNA and protein were significantly upregulated in human TNBC, and high AADAT expression was associated with reduced intra-tumoral CD8 T-cell density and inferior survival. Genetic silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8 T-cell-dependent manner, enhanced effector T-cell activation, and sensitized tumors to dual PD-1/CTLA-4 blockade. Mechanistically, unbiased metabolomics showed increased malate levels after AADAT knockdown. Additionally, 4-hydroxyphenylpyruvate, an essential precursor for coenzyme Q10(CoQ10) biosynthesis, decreased following AADAT knockdown, suggesting an impaired mitochondrial electron transport chain. CoQ10 supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ10-supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8 T-cell oxidative metabolism, increased the NAD/NADH ratio and reactive oxygen species, and augmented TNF- and IFN-{gamma} production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti-PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival. In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8 T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC. Statement of SignificanceAADAT defines a metabolic-immune axis driving immune evasion and therapy resistance in triple-negative breast cancer. Blocking AADAT or administering oral malate reactivates CD8 T-cell immunity and sensitizes chemo-immunotherapy-resistant tumors to these agents. These findings uncover a readily translatable metabolic vulnerability with potential to improve outcomes for patients with aggressive breast cancer subtypes.

cancer biology↗

bioRxiv2026

Brain Age in Conduct Disorder: A Mega-Analysis of the ENIGMA Antisocial Behavior Working Group

Conduct disorder (CD) is the leading global cause of mental health burden in children and adolescents and has recently been hypothesized to be a neurodevelopmental disorder. Although prior research has identified neuroanatomical differences associated with CD, it remains unclear whether these differences reflect atypical brain development. Here, we investigated the difference between an individuals brain age and chronological age as a proxy for variations in brain maturation. Using a pretrained model, we estimated brain age from structural neuroimaging data obtained from 1,119 youth with CD and 1,183 typically developing controls across 14 international cohorts participating in the ENIGMA-Antisocial Behavior Working Group. Youth with CD exhibited a statistically robust but small acceleration in brain age compared to typically developing youth (around 0.50 years), which was restricted to the adolescence-onset subtype of the disorder. Our large-scale, coordinated analysis provides the first evidence of accelerated neurodevelopment as a potential mechanism underlying CD.

neuroscience↗

bioRxiv2026

In vivo Proximity & Spatial Proteomics with CRISPR Screening Identify STXBP1 as a Protective Modifier of a-synuclein Toxicity in Dopamine Neurons.

Parkinsons disease (PD) is a disease of adults involving the loss of dopaminergic neurons after a long, asymptomatic, prodromal period. -synuclein, LRRK2, and VPS35 are linked to familial PD, however, how these mutations predispose dopamine neurons to death during the early prodromal phases remains unclear. Here, we used in vivo native proximity proteomics (iBioID) and dopaminergic neuron-specific subcellular proteomics across multiple PD models to uncover early alterations preceding neuronal loss. Our analyses identified convergent disruptions in synaptic protein abundance, indicating that presynaptic trafficking defects are early events in PD pathogenesis. Using a targeted CRISPR-based genetic screen in dopamine neurons, we demonstrated that mimicking this misregulation of STXBP1 amplifies vulnerability to -synuclein, implicating it as a previously underappreciated toxicity buffering factor. These findings highlight convergent mechanisms that sensitize dopamine neuronal degeneration and that presynaptic vesicle SNARE-complex proteins could serve as key targets for disease-modifying therapies in PD and related neurodegenerative disorders. HighlightsO_LIIn vivo native-BioID mapping of multiple Parkinsons disease (PD) protein interactomes revealed a convergent presynaptic network. C_LIO_LIiBioID analysis on mutant PD proteins (-synuclein A30P, LRRK2 G2019S, VPS35 D620N) uncovered mutation-specific shifts in local proximity networks, notably in endocytic and vesicle recycling pathways. C_LIO_LISpatial proteomics (iBioCoFrac) of dopamine neurons in vivo identified functional modules with reduced levels of key synaptic proteins in PD models. C_LIO_LIComparative proteomics using iBioCoFrac revealed synaptic vesicle regulation as a primary site of molecular convergence and early molecular signatures in dopamine neurons across multiple PD mouse models. C_LIO_LIAn in vivo CRISPR screen pinpointed the presynaptic protein Stxbp1/Munc18-1 as an -synuclein toxicity modifier in dopaminergic neurons. C_LI

neuroscience↗

bioRxiv2026

The novel variant IBDV induces inflammatory responses via VP3-mediated pyroptosis by directly targeting Caspase-9

The novel variant infectious bursal disease virus (nVarIBDV), which has been widely prevalent since 2017, threatens the poultry industry by inducing severe bursal atrophy and intense inflammatory responses. Understanding the inflammatory mechanism underlying nVarIBDV infection is critical for preventing virus-induced damage. Pyroptosis, an inflammatory type of programmed cell death, may contribute to the inflammation and bursa of Fabricius damage induced by nVarIBDV. Here, we found that the nVarIBDV infection induced severe inflammatory responses both in vivo and in vitro, which were associated with pyroptosis. Further research revealed that the viral protein VP3 drove pyroptosis induced by nVarIBDV infection by indirectly activating the Caspase-3-GSDME pathway, leading to GSDME cleavage. Mechanistically, VP3 directly interacted with and activated Caspase-9, thereby initiating Caspase-9-Caspase-3-GSDME pathway. More importantly, the Serine 33 of VP3 was identified as the key amino acid for interacting with and activating Caspase-9. Mutation of this residue significantly weakened the ability of VP3 to interact with Caspase-9 and activate the Caspase-9-mediated pyroptosis pathway, altered the binding mode of the Caspase-9-VP3 protein complex, and ultimately reduced the ability of VP3 to induce pyroptosis. In conclusion, our results elucidated a novel mechanism by which nVarIBDV infection induced inflammatory responses whereby viral protein VP3 triggered pyroptosis by targeting the Caspase-9-Caspase-3-GSDME pathway. IMPORTANCEnVarIBDV is globally prevalent and poses a significant threat to the poultry industry by causing inflammation and damage to the bursa of Fabricius. This study revealed that nVarIBDV infection induced inflammatory responses and bursa of Fabricius damage, primarily mediated by the viral protein VP3 targeting Caspase-9 to induce pyroptosis. To our knowledge, this is the first report on the interaction between inflammatory responses induced by IBDV infection and pyroptosis. In addition, serine 33 was identified as the critical amino acid required for maintaining the stability of the interaction between VP3 and Caspase-9 and activation of the Caspase-9-Caspase-3-GSDME cascade pyroptosis pathway and further inflammatory responses. Collectively, our findings not only elucidate a novel mechanism by which nVarIBDV induces pyroptosis and further leads to inflammation but also suggest that the identification of this serine site may represent a potential therapeutic target to block nVarIBDV-induced inflammation and bursa of Fabricius damage.

microbiology↗

bioRxiv2026

Cryo-EM reveals the structural basis of subtype-specific, noncompetitive inhibition of the human P2X3 receptor

P2X receptors are ATP-gated cation channels, and the P2X3 subtype plays crucial roles in peripheral sensory neurons, including in chronic pain and chronic cough. Accordingly, P2X3 has attracted substantial interest as a therapeutic target. Gefapixant, a negative allosteric modulator (NAM) of P2X3, has been approved in some countries for the treatment of chronic cough; however, its limited selectivity for P2X3 homomers over P2X2/P2X3 heteromers is associated with taste disturbance as a prominent adverse effect. These limitations have motivated the development of next-generation NAMs with improved subtype selectivity, but their subtype-specific allosteric inhibition mechanisms are unclear. Here, we report the cryo-EM structure of the human P2X3 receptor in complex with ATP and the P2X3-selective next-generation NAM sivopixant, an investigational drug. Sivopixant binds to an allosteric site at the portal of the central pocket in the extracellular domain, and structure-based mutational analysis by electrophysiology identifies key residues required for sivopixant-dependent inhibition of human P2X3. Comparisons with P2X structures from other subtypes, together with gain-of-function mutants, define a structural basis for subtype-selective allosteric inhibition of the P2X3 receptor. Furthermore, structural comparisons with apo and ATP-bound open states of P2X3 receptors, together with molecular dynamics simulations, revealed that sivopixant expands the upper body domain to suppress the lower-body movements required for channel activation, thereby preventing channel opening even in the presence of ATP.

biophysics↗

bioRxiv2026

Analysis of Urinary Proteome Modifications in Patients with Different Glycated Hemoglobin A1c Levels

Diabetes, a major global public health concern, requires early diagnosis and timely intervention. Glycated hemoglobin A1c (HbA1c) serves as a biomarker of glycemic management, with its levels showing a continuous relationship with the risk of developing diabetes. In this study, urinary proteome modifications were compared between each of the two patient groups with different HbA1c levels ([6.4{+/-}0.7]% and [8.6{+/-}1.6]%) and healthy controls. A total of 1 954 and 5 545 differentially modified peptides were identified in the two groups, respectively. Within each group, differentially modified peptides exhibiting changes from presence to absence or vice versa accounted for 48.8% and 86.5%, respectively. Additionally, results from the randomized grouping test indicated that at least 90.6% and 94.1% of these differentially modified peptides in each group were not randomly generated. In conclusion, urinary proteome modifications comprehensively and systematically reflect changes associated with elevated HbA1c levels, with distinct modification profiles corresponding to different HbA1c levels. These findings suggest that urinary proteome modifications have the potential to reflect HbA1c levels and offer a new perspective for research on the early diagnosis of diabetes.

biochemistry↗

bioRxiv2025

65℃ Short-Term Heating: A Method for Transporting Urine Samples Over Long Distances Without Cold Chain

Biomarkers are measurable changes associated with physiological or pathophysiological processes in the body. Urine, not strictly regulated by homeostatic mechanisms, accumulates extensive variable information and reflects changes in the body earlier and more sensitively, making it an excellent source for biomarker discovery. However, long-distance transport of urine samples usually requires a strictly maintained cold chain throughout the process, resulting in high costs and operational challenges. Here, we propose a urine sample processing method that uses brief heating to inhibit bacterial proliferation and protein degradation. A single urine sample was equally divided into three groups: a pre-heated transport group, a non-heated transport group, and a -80{degrees}C frozen storage control group, with five replicates in each group. Both the pre-heated and non-heated transport groups were transported simultaneously across northern and southern China for five days under ambient temperature conditions. Samples were analyzed using liquid chromatography coupled with tandem mass spectrometry. The results showed that the intra-group overlap rates of identified proteins within the groups treated with 65{degrees}C water bath heating for 15 minutes and -80{degrees}C frozen storage were 97.1% and 97.5%, respectively, demonstrating high reproducibility. There were no significant differences in the number or types of urinary proteins identified between these two groups, with an inter-group overlap rate of 99.9%. Additionally, the pre-heated transport group and frozen storage control group showed no significant difference in the number of bacterial-derived peptides and proteins identified. In contrast, significantly more bacterial-derived peptides and proteins were identified in the non-heated transport group than in both the pre-heated transport and frozen storage control groups. This indicates that heating effectively suppresses bacterial counts in urine samples during five days of transport at ambient temperatures. This approach provides a more economical and convenient solution for long-distance transport of urine samples, eliminating the need for cold chain transportation or preservatives. We also recommend using consistent urine processing methods within the same study to minimize technical variability.

biochemistry↗

bioRxiv2025

Turning aging cells into a live vaccine: engineered senescent cancer cells with adjuvant celecoxib for immunotherapy

The immunoactivation effects of senescent tumor cells are a potential avenue for cancer therapy. They can act as antigen reservoirs for cancer vaccination, but how to maintain strong immunogenicity to induce a robust immunity is underexplored. In this study, we developed an engineered live vaccine composed of hydrogel-encapsulated senescent tumor cells and liposomal celecoxib (STCs+CLX-Lipo@Gel). This vaccine prolongs the in vivo persistence of senescent tumor cells and utilizes liposomal celecoxib (COX2 inhibitor) to promote the recruitment and maturation of dendritic cells (DC). Notably, a single dose can significantly delay melanoma growth by eliciting robust immunity. The vaccine extended the survival of mice with melanoma brain metastases. Moreover, this strategy also demonstrated high efficacy against orthotopic pancreatic tumors. This study presents a comprehensive strategy to boost the immunogenicity of whole-tumor-cell vaccines by leveraging senescent tumor cells and COX2 inhibition, with treatment efficacy in various tumor models. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/694320v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@f08fforg.highwire.dtl.DTLVardef@117d0aborg.highwire.dtl.DTLVardef@849665org.highwire.dtl.DTLVardef@adcf83_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic summary.C_FLOATNO Schematic illustration of the preparation of live-cell vaccines and the tumor-specific immune responses elicited by the vaccine. Created with BioRender.com. C_FIG

bioengineering↗

bioRxiv2025

Structural and biochemical studies of human PP2A(B55) holoenzyme and ENSA protein complex

The serine/threonine protein phosphatase 2A (B55) holoenzyme (PP2A(B55)), a key cell cycle regulator, is tightly regulated by ENSA, whose phosphorylation at Ser67 inhibits PP2A(B55). The structural basis for how pENSA orchestrates this inhibition to govern mitotic progression remains unclear. In this study, we disapproved the previous hypothesis of direct ENSA-PP2A A subunit interaction, and showed that the ENSA-PP2A(B55) interaction requires the PP2A holoenzyme. We then determined cryo-EM structure of the PP2A(B55)-ENSAS67D complex at 3.03 [A] resolution, which reveals four distinct regions of ENSA, each engaging specific sites on the B55 or C subunits. The structure reveals an extended, inhibited conformation of the PP2A(B55) holoenzyme, which contrasts sharply with the contracted, active state of apo PP2A(B55). pENSA binding induces the C subunit to shift away from the B55 subunit, with the pS67-containing motif inserting into the catalytic site of C subunit and locking the PP2A(B55) holoenzyme in an inactive state. Our work also revealed novel ligand-binding surfaces on B55, and expanded definition of the short linear motif (SliM). Overall, our work provided novel insights into PP2A regulation during cell cycle, and offers new avenues for the discovery of specific PP2A(B55) inhibitors and modulators.

biophysics↗

bioRxiv2025

Low-order assemblies drive oncogenic RTK fusion signaling without condensation

Receptor tyrosine kinase (RTK) fusions are a large class of oncoproteins found in [~]5% of cancers. Key questions remain, however, about how RTK fusions transmit oncogenic signals, including how these largely cytoplasmic proteins activate downstream pathways that originate at the plasma membrane. Fusions are multimeric and can form mesoscale condensates in cancer cells, and condensation has been implicated as an essential mechanism to enable signal transmission from the cytoplasm. However, whether condensates play a causal role, or whether smaller diffuse assemblies are sufficient to transduce signals, has been challenging to establish. Here we apply advanced microscopy, single-cell analysis, and synthetic fusions to determine the principles by which multimerization and condensation drive signaling from cytoplasmic RTK fusions. For EML4-ALK, a prominent fusion that forms condensates, we found poor correlation between condensation and signaling. By contrast, EML4-ALK activity was abundant in the diffuse phase, and the kinetics of diffuse-phase activity aligned more closely with downstream Erk signaling than did kinetics of signaling within condensates. Synthetic RTK fusions showed that cytoplasmic ALK or RET fusion dimers--and even constitutively active monomers--were sufficient to induce strong Ras-Erk signaling despite the absence of condensates, and diffuse fusions were sufficient to transform cells in vitro and in subcutaneous tumor models. A panel of various other cancer-driving RTK fusions showed that low-order multimerization was universal across fusions, whereas mesoscale condensation was rare and did not correlate with signaling. Our results suggest that low-order fusion multimerization is sufficient to drive its phosphorylation, which is necessary and sufficient to trigger downstream oncogenic signaling.

cancer biology↗

bioRxiv2025

White-Matter BOLD Mediates Time-Varying Cortico-Cortical Functional Connectivity

Functional connectivity (FC) measurements in the brain using BOLD fMRI have largely focused on correlations between gray-matter (GM) BOLD signals, ignoring the possible relevance of white-matter (WM) in delineating neural networks. We first employed a tract-informed mediation framework to test whether WM pathways contribute indirect, bundle-specific effects to cortico-cortical coupling. Using resting-state fMRI data from the Human Connectome Project, we quantified pathway-level mediation effects across GM-WM-GM units and found that WM BOLD signals significantly mediated GM-GM associations, with clear tract-dependent heterogeneity. Building upon this, we examined how dynamic features of WM BOLD signals relate to time-varying intra-cortical FC. We found that temporal variability of WM signals, rather than their mean amplitudes, more closely tracked fluctuations in GM-GM dynamic connectivity, with correlations reaching approximately 0.4 across specific tracts. Together, these results indicate that WM BOLD signals are related to how cortical regions interact, underscoring their integral role in large-scale brain network organization.

neuroscience↗

bioRxiv2025

Structure of human lymphoid-specific helicase HELLS in its autoinhibitory state

Helicase, Lymphoid Specific (HELLS), also known as Lymphoid-Specific Helicase (LSH), is a member of the SNF2 chromatin-remodeling family that regulates DNA methylation and heterochromatin organization. Unlike most chromatin remodelers, HELLS is catalytically inactive in its apo form and requires the DNA-binding protein CDCA7 for activation, though the underlying mechanism has remained unclear. Here, we combine biochemical, biophysical and cryo-electron microscopy analyses to define the structural basis of HELLS autoinhibition. HELLS alone assembles into a hexameric (trimer of dimers) architecture stabilized by interactions between its N-terminal coiled-coil (CC) domain and ATPase Lobe-1, while ATPase Lobe-2 remains flexible and disengaged. The CC domain functions both as an oligomerization scaffold and as an autoinhibitory module that restricts catalytic activity. Binding of CDCA7 and DNA promotes formation of an active HELLS-CDCA7-DNA ternary complex. CDCA7 recognizes hemimethylated CpG dinucleotides in both B-form and non-B-form DNA and stimulates HELLS ATPase activity. Together, these findings reveal the mechanism of HELLS autoinhibition and its activation by CDCA7 and DNA, providing new insight into how the HELLS-CDCA7-DNA ternary complex maintains DNA methylation and heterochromatin integrity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/692698v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@106b73borg.highwire.dtl.DTLVardef@1e7b33aorg.highwire.dtl.DTLVardef@a7be6eorg.highwire.dtl.DTLVardef@c75a5b_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIHELLS alone assembles into an inactive hexameric trimer-of-dimers C_LIO_LIThe N-terminal coiled-coil mediates oligomerization C_LIO_LICDCA7 and DNA binding activate the HELLS-CDCA7-DNA complex C_LIO_LIThe complex recognizes hemimethylated CpG in non-B-form DNA C_LI

molecular biology↗

bioRxiv2025

Engineering an Anaerobic Microenvironment to Empower Hydrogenase-Catalyzed Hydrogen Therapy for Diabetic Wound Healing

The inherent oxygen sensitivity of hydrogenases has long restricted their applications to anaerobic systems. Here, we present a hybrid peptide-nanocluster hydrogel that establishes a self-sustaining anaerobic microenvironment to enable hydrogenase-catalyzed hydrogen therapy under aerobic conditions. This system integrates a custom-designed Fmoc-KYF peptide hydrogel with integrated silver nanoclusters (AgNCs), which host an engineered [NiFe]-hydrogenase (3S1C-Hyd-2). Mechanistic studies combining molecular dynamics simulations and spectroscopic analysis revealed that hydrophobic pockets within the peptide network trap oxygen molecules, while photoexcited AgNCs rapidly deplete invasive O2. Our design ensures stable hydrogen evolution, effectively overcoming the oxygen sensitivity that has long restricted hydrogenase applications in biomedical contexts. In vitro, the in-situ-generated hydrogen effectively scavenges reactive oxygen species, suppresses pro-inflammatory cytokine production. In a diabetic mouse model, this light-activated system markedly accelerates wound closure (87% by day 11), reduces oxidative stress, promotes macrophage polarization toward a reparative phenotype, enhances angiogenesis, and upregulates tissue repair pathways, as confirmed by transcriptomic profiling. Our work establishes a new bioengineering paradigm for constructing anaerobic microenvironments through synergistic material-enzyme-light interactions, offering a versatile platform for hydrogenase-enabled therapeutic interventions in oxidative stress-related diseases.

biochemistry↗

bioRxiv2025

U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis

TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including UNC13A and STMN2, disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement in vivo, positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.

neuroscience↗