Biology subjects

Guo, Q.

Publications and source records attributed to Guo, Q..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Distinctive Functionality of Semantic Hubs: Evidence from Semantic Dementia

Semantic cognition relies on a distributed network with multiple candidate hub regions that bind multimodal conceptual information. While the anterior temporal lobe (ATL) is widely regarded as a core semantic hub, the roles of other candidate regions--such as the fusiform gyrus (FFG) and posterior middle temporal gyrus (pMTG)--remain debated, particularly regarding verbal and non-verbal semantic processing within the same sensory modality. This study examined 33 patients with semantic dementia and 20 healthy controls using a comprehensive behavioral battery (word and picture versions of the Pyramid and Palm Trees Test and a word-picture verification task) combined with multimodal neuroimaging, including voxel-based morphometry, diffusion-weighted imaging, and resting-state fMRI. Partial correlation and commonality analyses revealed that (1) the left ATL selectively underpins abstract verbal semantic processing, (2) the left FFG contributes to general semantic processing across verbal and non-verbal stimuli, (3) and the left pMTG plays a critical role in integrating verbal and non-verbal semantic information. White matter tracts linking the left ATL and FFG to the right ATL significantly predicted semantic integration performance, underscoring the importance of inter-hemispheric structural connectivity. Functional measures in contralateral regions, including amplitude of low-frequency fluctuation (ALFF) in the right FFG and degree centrality (DC) in the right pMTG, also predicted integration outcomes, suggesting compensatory network reorganization. These findings highlight functional specialization among semantic hubs and underscore the importance of multimodal, cross-hemispheric approaches for understanding the neural architecture of semantic representation.

neuroscience↗

bioRxiv2025

Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice

Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme and a central factor in energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD+ pool by synthesizing the NAD+ precursor, nicotinamide mononucleotide (NMN), and diminished adipocyte NAMPT activity has been implicated in aging- and obesity-related metabolic dysfunction. Herein, we examined the effects of overexpressing or knocking out NAMPT in adipocytes on metabolic dysfunction and interorgan communication in mice. We generated new adipocyte-specific NAMPT overexpressing(ANOV) mice model. Male ANOV mice are protected from diet-induced metabolic dysfunction including adipose tissue inflammation, glucose intolerance, and insulin resistance. In contrast female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in WT female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD content, and reduced steatosis, suggesting that NAMPT regulates interorgan communication between adipocytes and hepatocytes. Extracellular vesicles (EV) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and improved glucose tolerance in WT obese mice. In contrast, EV from ANKO mice suppressed HepG2 insulin signaling and inhibition of EV release improved glucose tolerance in ANKO female mice. Collectively, these data highlight a novel mechanism by which adipocyte NAD+ metabolism regulates systemic metabolic dysfunction via EVs.

physiology↗

bioRxiv2025

Succinate Dehydrogenase-Deficient Cancer Cells Have Increased Susceptibility to Ym155 Induced DNA Damage

The hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome is caused by inherited mutations in Succinate Dehydrogenase genes (SDHx). Affected individuals are predisposed to developing pheochromocytomas (Pheo), paragangliomas (PGL), renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). Notably, tumors with succinate dehydrogenase subunit B (SDHB) deficiency demonstrate increased metastatic risk, for which treatments remain palliative. Hence, discovering novel therapeutic avenues to improve the prognosis for SDHB-cancer patients is an urgent need. Here we employed human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT) to discover SDH-dependent mitochondria-directed cytotoxic agents. Given the reduced ATP-generating capacity of SDHB-KO cells, we hypothesized they would be uniquely sensitive to futile cycle induction with mitochondrial ionophores (2,4-Dinitrophenol (2-DNP), BAM15, Niclosamide, Nitazoxanide). Indeed, these compounds exhibited preferential cytotoxicity toward SDHB-KO cells. However, the chemotherapeutic compound Ym155 demonstrated the most potent and dramatic (five-fold) preferential cytotoxicity towards SDHB-KO cells. Importantly, the SDH-dependent cytotoxicity of Ym155 was validated in both primary human pheochromocytoma cells and mouse pheochromocytoma (MPC) cells. Furthermore, because few SDH-deficient cell lines are available, we buttressed our findings in additional relevant cell lines by modeling SDH-deficiency using chemical SDH enzyme inhibition with 3-nitropropionic acid (3-NPA). We observed a persistent cooperativity between SDH-deficiency and Ym155 cytotoxicity across multiple cell lineages and disease models. Mechanistically, Ym155-induced cytotoxicity was independent of its primary target, Survivin. Instead, SDH-deficiency sensitized cells to Ym155-induced DNA damage. Strikingly, the phenotype of SDH-deficient Ym155 sensitivity was recapitulated by inhibition of the histone demethylase KDM4, a downstream consequence of SDH deficiency. Thus, the accumulation of succinate in SDH-deficient tumors inhibits KDM4 activity, impairs DNA repair and yields enhanced susceptibility to Ym155-induced reactive oxygen species (ROS) generation. The identified intrinsic susceptibilities of SDHB-deficient cancers has the potential to be therapeutically leveraged.

cancer biology↗

bioRxiv2025

Separately prestored proteasome components to prevent polyspermy

To ensure genome stability across generations, an egg must be fertilized by only a single sperm. However, how sperm actively contribute to preventing polyspermy has remained unknown. Here, we demonstrate that testis-specific 20S proteasome core particles (CPs) are pre-stored within the sperm heads of both mice and humans. Upon fertilization, these testis-specific 20S CPs assemble with oocyte-derived 19S regulatory particles (RPs), forming chimeric proteasomes that efficiently degrade Fetuin B, which is ubiquitinated by the E3 ligase MARCH3. The clearance of Fetuin B triggers ZP2 cleavage and subsequent zona pellucida hardening, thereby blocking additional sperm entry. The newly assembled chimeric proteasome in the zygote represents a novel strategy to prevent polyspermy during fertilization in mammals.

developmental biology↗

bioRxiv2025

Beyond the Anterior Temporal Lobe: Domain-Related Degeneration of Cortical Language Network Dynamics in Semantic Dementia

Semantic dementia (SD) is a neurodegenerative disorder marked by a progressive decline in semantic memory, mainly due to focal atrophy in the anterior temporal lobe (ATL). As the disease advances, atrophy spreads to the perisylvian regions, accompanied by non-semantic language impairments. Despite these clinical findings, the network mechanisms behind cross-domain linguistic deficits remain poorly understood. In this study, we used our recently developed meta-networking framework of cortical language network dynamics to systematically examine domain-specific network disruptions in SD. Using resting-state functional MRI (fMRI) and comprehensive neuropsychological tests across several language domains, we analyzed data from SD patients at two timepoints: baseline (n = 42) and a 2-year follow-up (n = 24). Our findings showed that the framework successfully identified domain-specific language network degeneration. Beyond the ATL, progressive atrophy disrupted the dynamic separation of language networks involved in semantic processing, phonological processing, and speech production. These disruptions were characterized by state-specific hypo- and hyper-connectivity patterns that related to distinct language impairments. At follow-up, atrophy extended to posterior temporal and prefrontal regions, worsening network function. Importantly, the patterns of language network disruption predicted individual language deficits, providing a mechanistic link between structural degeneration, functional network changes, and clinical symptoms.

neuroscience↗

bioRxiv2025

Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell-derived neuroendocrine tumors of sympathetic (catecholamine-producing) or parasympathetic (nonsecretory) origin, frequently driven by dysregulation of hypoxia-inducible factor (HIF) signaling, particularly HIF-2. Although often benign, PPGLs can metastasize unpredictably, with limited therapeutic options once disseminated. Progress has been hindered by the lack of robust preclinical models, especially those that capture their molecular complexity and microenvironmental influences. To address this gap, we established patient-derived tumor organoids (PDOs) from 35 PPGLs, encompassing a broad spectrum of clinical and molecular phenotypes. The organoids retained key immunohistochemical, genomic, transcriptomic, and catecholamine-secretory features of their parental tumors. PPGL organoids cultured under hypoxic conditions generally exhibited enhanced viability, supporting hypoxia as a driver of cell survival. Hypoxia activated HIF-1 and expanded ASCL1+ cell populations, suggesting a lineage shift toward an immature chromaffin state. In contrast, long-term normoxic cultures activated hypoxia inducible factor 2 (HIF-2) and acquired a hybrid sympathoblast-mesenchymal identity in subpopulations with upregulation of extracellular matrix and cell cycle markers, independent of genotype. These features resemble high-risk neuroblastoma subtypes and establish a molecular parallel suggestive of shared lineage plasticity and pathogenic programs, detectable in primary PPGLs. Drug screening across a library of up to 51 drugs and combinations revealed both shared and unique vulnerabilities, with response rates to approved therapies matching clinical observations. The CDK4/6 inhibitor abemaciclib, previously unexplored in PPGLs, elicited the strongest activity. Abemaciclib-responsive PDOs and their matched tumors, including a metastatic sample, exhibited epithelial mesenchyme transition enrichment, nominating potential biomarkers for patient stratification. Our results establish PDOs as a novel platform for modeling neuroendocrine tumor biology, reveal microenvironment-driven plasticity in PPGLs, with potential translational relevance, and identify actionable vulnerabilities in a disease with few effective systemic therapies. Main findingsO_LIPDOs can be successfully generated from PPGLs of various genetic backgrounds and reflect parental tumor properties C_LIO_LIPDO cultures grown in hypoxia retain main molecular features of parental tumors, have increased viability and a more immature developmental/biosynthetic profile C_LIO_LILong term PDOs grown for 4 weeks in normoxia activate HIF2, drift toward a hybrid sympathoblast-mesenchymal-like identity resembling relapsed/therapy resistant neuroblastomas, features that can be detected in primary tumors C_LIO_LIA subset of PDOs respond to Abemaciclib, a drug class not previously used therapeutically in PPGLs C_LI

cancer biology↗

bioRxiv2025

Control of Chloroplast Integrity by the Jasmonate Signaling Pathway is Linked to Growth-Defense Balance

Chloroplasts play a central role in plant responses to environmental stress. Little is known, however, about how chloroplast homeostasis is maintained during stress responses that place high metabolic and bioenergetic demands on the cell. As a chloroplast-derived retrograde signal, jasmonate (JA) promotes broad-spectrum immunity by triggering the degradation of JAZ transcriptional repressors that act in the nucleus to control chloroplast metabolism. Here, we manipulated JAZ abundance to investigate how chloroplast integrity and function is maintained at high levels of defense. A jaz decuple mutant (jazD) lacking 10 of 13 JAZs exhibited strong growth-defense antagonism without loss of photosynthetic efficiency. Treatment of jazD with the JA-receptor agonist coronatine triggered rapid loss of chlorophyll and the turnover of chloroplast proteins and lipids, leading to the collapse of photosynthetic activity and cell death. These findings were supported by global transcript and metabolite profiling over a time course of coronatine treatment. Genetic screens identified MYC2 and the JAZ-destabilizing F-box protein, COI1, as positive regulators of coronatine-induced chloroplast dismantling in jazD plants. These results demonstrate how the progressive loss of JAZ repression drives a continuum of MYC2-dependent growth-defense tradeoffs, including disassembly of the photosynthetic apparatus as a terminal response. In highlighting the critical role for JAZ proteins in maintaining chloroplast integrity at high levels of defense, our results provide insight into the general mechanism by which jasmonate governs chloroplast metabolism to balance growth and stress responses. One sentence summaryThis study shows that the jasmonate-mediated leaf transition from growth- to defense-oriented metabolism culminates in the disassembly of the photosynthetic apparatus.

plant biology↗

bioRxiv2025

Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity

The DNA-incorporating nucleoside analogs azacytidine (AZA) and decitabine (DEC) have clinical efficacy in blood cancers, yet the precise mechanism by which these agents kill cancer cells has remained unresolved - specifically, whether their anti-tumor activity arises from conventional DNA damage or DNA hypomethylation via DNA methyltransferase 1 (DNMT1) inhibition. This incomplete mechanistic understanding has limited their broader therapeutic application, particularly in solid tumors, where early clinical trials showed limited efficacy. Here, through the assessment of drug sensitivity in over 600 human cancer models and comparison to a non-DNA-damaging DNMT1 inhibitor (GSK-3685032), we establish DNA hypomethylation, rather than DNA damage, as the primary killing mechanism of AZA and DEC across diverse cancer types. In further support of an epigenetic killing mechanism, CRISPR drug modifier screens identified a core set of chromatin regulators, most notably the histone deubiquitinase USP48, as AZA and DEC protective factors. We show that USP48 is recruited to newly hypomethylated CpG islands and deubiquitinates non-canonical histones, establishing USP48 as a key molecular link between the two components of epigenetic gene regulation: DNA methylation and chromatin modification. Furthermore, loss of USP48, which occurs naturally through biallelic deletions in human cancers, sensitized both hematologic and solid tumors to DNMT1 inhibition in vitro and in vivo. Our findings elucidate the epigenetic mechanism of action of AZA and DEC and identify a homeostatic link between DNA methylation and chromatin state, revealing new therapeutic opportunities for DNMT1 inhibitors in solid tumors.

cancer biology↗

bioRxiv2025

CD4+ T cells promote fibrosis during metabolic dysfunction-associated steatohepatitis

Unresolved inflammation and fibrosis are the two key features of metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can evolve into cirrhosis and liver cancer. Although innate immunity has been well studied in MASH, the role of CD4 T cells remains underexplored despite their potential to coordinate immune responses by providing help to other immune cells, promoting inflammation, or regulating immune activity through effector and regulatory subsets. To better understand the role of CD4+ T cells in the pathogenesis of MASH, we comprehensively characterized hepatic CD4+ T cells in murine and human MASH at a single-cell protein, transcriptional, and functional level. Mass cytometry and CITE-sequencing revealed a marked shift in intrahepatic CD4 T-cell composition in MASH, with enrichment of Th1, regulatory, and cytotoxic CD4 T cells. Similar phenotypic changes were mirrored in the peripheral blood and validated in human MASH samples. Functional assays demonstrated increased production of IFN{gamma} and TNF by hepatic CD4 T cells, highlighting their proinflammatory effector activity. Transcriptomic profiling identified Tnfrsf4 (OX40) upregulation in hepatic CD4 T cells during MASH. Therapeutic blockade of the OX40L-OX40 axis reversed hepatic fibrosis and improved histologic disease scores in mice with established MASH, and also decreased inflammatory markers in a human ex vivo liver model. Together, these studies provide a proteogenomic single-cell atlas for hepatic CD4 T cells and uncover a CD4 T cell-dependent immunopathogenic circuit as a promising immunotherapeutic target to alleviate MASH and liver fibrosis.

immunology↗

bioRxiv2025

Multiplex Proteomics of Lewy Body Dementia Reveals Cerebrospinal Fluid Biomarkers of Disease Pathology and Progression

Lewy body dementia (LBD), which encompasses Parkinsons disease dementia (PDD) and Dementia with Lewy bodies (DLB), lacks established biofluid markers of its complex clinical and neuropathological heterogeneity. Multiplex proteomic tools, such as the recently developed NUcleic acid Linked ImmunoSandwich Assay (NULISATM), can assess a diverse array of neurodegenerative targets and address these biomarker gaps. We used this platform to analyze 852 baseline and longitudinal cerebrospinal fluid (CSF) samples from control, PD, and DLB subjects from the Parkinsons Disease Biomarker Program (PDBP). We then examined LBD protein signatures across different clinical diagnoses, patterns of cognitive progression, and underlying neuropathologies. Of the 124 markers analyzed, 54 were significantly altered in PD with cognitive impairment and/or DLB compared to controls, many serving as informative clinical classifiers in machine learning models. We also identified 15 proteins with significant baseline and/or longitudinal changes linked to cognitive progression. To identify neuropathological signatures, we stratified 209 cases by the presence of underlying synuclein and amyloid-beta (A{beta}) pathology using CSF alpha-synuclein seed amplification assay (Syn-SAA) results and NULISA pTau-217 levels, respectively. Select synaptic markers were decreased relative to synucleinopathy but increased relative to A{beta} accumulation, complicating their interpretation in cases with co-pathology. These neuropathological analyses were replicated in an independent cohort of 917 cases from the Alzheimers Disease Neuroimaging Initiative (ADNI). Overall, these results highlight the utility of multiplex proteomic analysis in the identification of candidate CSF biomarkers of disease heterogeneity in LBD. One Sentence SummaryThis multiplex proteomic analysis using the recently released NULISA platform revealed unique targets of Lewy body dementia progression and neuropathology.

systems biology↗

bioRxiv2025

Single cell multi-omic whole genome sequencing and chromatin accessibility profiling reveals genome-epigenome coevolution in colorectal cancer

Epigenetic alterations co-evolve with genetic mutations to drive carcinogenesis and treatment response. Resolving genome-epigenome coevolution requires accurate multi-omic single cell measurement. Here we develop a new technology called "double ATAC" (dATAC) for high-throughput, high-quality, concurrent whole genome sequencing and chromatin accessibility profiling of individual somatic cells. dATAC is a "one pot" method that uses two rounds of tagmentation to sequentially label open chromatin regions and then the whole genome, and produces data of the same quality as current leading single-omic methods. Using colorectal cancer as a model system, we apply dATAC to reveal convergent reorganisation of the epigenome across expanding drug-resistant clones during 5-FU chemotherapy exposure, remarkable stoichiometry of chromatin accessibility at somatic copy number alterations, and the clonal expansion of copy-number altered T cells in the stroma of metastatic disease. dATAC is a robust single cell technology to accurately profile genome-epigenome coevolution across tissues, diseases and species.

molecular biology↗

bioRxiv2025

Structural basis for prohibitin-mediated regulation of mitochondrial m-AAA protease

Mitochondrial function critically dependents on protein quality control systems, with the m-AAA protease plays a key role at the inner mitochondrial membrane (IMM). The evolutionarily conserved prohibitins (PHBs) are essential modulators of this protease across species, yet the molecular mechanisms remain unclear. Here, we present the Cryo-EM structure of the Chaetomium thermophilum PHB (CtPHB) complex, revealing a cage-like assembly composed of 11 copies of PHB1/PHB2 heterodimers. Electron microscopic and biochemical analyses suggest that m-AAA proteases are enclosed within the PHB complex through interactions mediated by their SPFH-interacting motif (SIM) exposed in the intermembrane space. Further in situ cryo-ET directly visualizes these cage-protease assemblies in native mitochondria. Disruption of their interface leads to elevated m-AAA protease activity and diminished mitochondrial stress resistance. These data establish PHB complexes as spatial organizers that compartmentalize m-AAA proteases in membrane microdomains to fine tune proteolytic homeostasis. Our findings reveal the critical role of the PHB complex in maintaining mitochondrial proteostasis, providing a unified mechanistic model to explain and reconcile the pleiotropic, and often contradictive phenotypes of PHBs and m-AAA protease in mitochondrial physiology and various disease conditions.

molecular biology↗

bioRxiv2025

The targeting of non-fibrillar polyQ via distinct VCP-proteasome coupling

The aggregation of proteins containing expanded poly-glutamine (polyQ) repeat sequences is a cytopathological hallmark of several dominantly inherited neurodegenerative diseases (ND), including Huntingtons disease (HD). Previously, we observed that long polyQ repeats form a fibrillar core, surrounded by amorphous and soluble intermediates, which compared to the fibrils, are more readily taken up by autophagosomes 1. In this study, we investigated how the alternative major degradation pathway in cultured cells, ubiquitin proteasome system (UPS), interacts with the different pools of polyQ. We observed that the AAA+ ATPase, valosin-containing protein VCP/p97, in collaboration with proteasomes, plays a crucial role in degrading non-fibrillar polyQ. As both VCP and proteasomes were recruited to the polyQ intermediates peripheral to the fibrils, we imaged these regions by in situ cryo-ET for subtomogram averaging. VCP predominantly adopts an ATP-bound state, often in an active processing conformation with resolved NPLOC4-like cofactor density. The region was also enriched with the 26S proteasome (26S), 20S proteasome core (20S), and 19S regulatory particles (19S). Distance analysis of the macromolecules revealed a striking proximity between VCP and the 20S in situ. This is likely mediated by VCPs C-terminal hydrophobic-tyrosine-X (HbYX) motif, which binds the 20S via hydrophobic interactions, as confirmed by cryo-EM single-particle analysis (SPA) and in vitro assays. Our study highlights a distinct VCP-20S coupling mechanism, where VCP functionally overlaps with the 19S complex in substrate unfolding, facilitating the degradation of polyQ intermediates by the 20S catalytic core.

biochemistry↗

bioRxiv2025

OctopusV and TentacleSV: a one-stop toolkit for multi-sample, cross-platform structural variant comparison and analysis

Structural variants (SVs) significantly influence genomic variability and disease, but their accurate analysis across multiple samples and sequencing platforms remains challenging. We developed OctopusV, a tool that standardizes ambiguous breakend (BND) annotations into canonical SV types (inversions, duplications, translocations) and integrates variant calls using flexible set operations, such as union, intersection, difference, and complement, enabling cohort-specific variant identification. Together with TentacleSV, an automated pipeline, OctopusV provides an end-to-end solution from raw data to final callsets. Evaluations show improved precision, recall, and consistency, highlighting its value in cancer genomics and rare disease diagnostics. Both tools are available at https://github.com/ylab-hi/OctopusV and https://github.com/ylab-hi/TentacleSV.

bioinformatics↗

bioRxiv2025

Deciphering the molecular mechanisms of FET fusion oncoprotein-DNA hollow co-condensates

Biomolecules such as nucleic acids and proteins can undergo liquid-liquid phase separation to form biomolecular condensates with diverse architectures. However, fundamental questions surrounding the biophysical principles that govern condensate architecture and their potential biotechnological applications remain unresolved. Here, we report that the FUS/EWS/TAF15 family fusion oncoprotein FUS-ERG forms hollow co-condensates with double-stranded DNA containing GGAA microsatellites. Through a combination of biochemical assays, super-resolution imaging, and mathematical modeling, we reveal that the interior surface of hollow co-condensates exhibits properties distinct from those of the external surface, a phenomenon we term nested asymmetric phase separation. Furthermore, we demonstrate that the self-organization and morphology control of FUS-ERG hollow co-condensates can be harnessed for DNA-based information manipulation, enabling targeted DNA deletion within dsDNA libraries and facilitating dynamic, hierarchical data selection. These findings provide critical insights into the biophysical mechanisms underlying multicomponent phase-separated cellular bodies and establish a foundation for leveraging condensate morphology in biotechnology.

biophysics↗

bioRxiv2025

Developing Foundation Models for Predicting Viral Animal Host Range in Intelligent Surveillance

Emerging human infectious viruses originating from animals continue to pose a persistent threat to global public health. Understanding the host range of animal viruses is crucial for identifying potential spillover pathways and mitigating the risk of future pandemics. Here, we present VirHRanger, a prediction method that integrates foundation models trained on viral genome and protein sequences, alongside genomic and protein compositional traits, viral phylogeny, and protein-protein interactions. To systematically predict the animal host range, VirHRanger incorporates host taxonomy-aware neural networks trained on a comprehensive collection of animal-virus associations spanning mammals, birds, and arthropods. Within a dataset of 4,006 virus species spanning 99 viral families, our model achieved robust performance with a micro-averaged AUROC of 0.938 across all host categories, demonstrating its effectiveness in capturing generalizable host signals from viral genetic data. On a dataset of 315 novel viruses, which are associated with key reservoir animal hosts and insect vectors, VirHRanger notably outperformed the homology-based method, exhibiting a strong generalizability to novel viruses. Furthermore, VirHRanger identified host range variations among closely related viruses within the Coronaviridae family and successfully predicted the ability of SARS-CoV-2 to infect humans and other animal hosts. These findings highlight the potential of VirHRanger to transform sequencing data into timely insights for disease control during the early stages of zoonotic outbreaks.

bioinformatics↗

bioRxiv2025

scBSP: A fast and accurate tool for identifying spatially variable features from high-resolution spatial omics data

Emerging spatial omics technologies empower comprehensive exploration of biological systems from multi-omics perspectives in their native tissue location in two and three- dimensional space. However, sparse sequencing capacity and growing spatial resolution in spatial omics present significant computational challenges in identifying biologically meaningful molecules that exhibit variable spatial distributions across different omics. We introduce scBSP, an open-source, versatile, and user-friendly package for identifying spatially variable features in high-resolution spatial omics data. scBSP leverages sparse matrix operation to significantly increase computational efficiency in both computational time and memory usage. In diverse spatial sequencing data and simulations, scBSP consistently and rapidly identifies spatially variable genes and spatially variable peaks across various sequencing techniques and spatial resolutions, handling two- and three-dimensional data with up to millions of cells. It can process high-definition spatial transcriptomics data for 19,950 genes across 181,367 spots within 10 seconds on a typical desktop computer, making it the fastest tool available for handling such high-resolution, sparse spatial omics data while maintaining high accuracy. In a case study of kidney disease using 10x Xenium data, scBSP identified spatially variable genes representative of critical pathological mechanisms associated with histology.

bioinformatics↗

bioRxiv2025

Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through auto-inhibition.

The endosomal-lysosomal network is a hub of organelles that orchestrate the dynamic sorting of hundreds of integral membrane proteins to maintain cellular homeostasis. VPS29 is a central conductor of this network through its assembly into Retromer, Retriever and Commander endosomal sorting complexes, and its role in regulating RAB GTPase activity. Two VPS29 isoforms have been described, VPS29A and VPS29B, that differ solely in their amino-terminal sequences. Here we identify a third VPS29 isoform, which we term VPS29C, that harbours an extended amino-terminal sequence compared to VPS29A and VPS29B. Through a combination of AlphaFold predictive modelling, in vitro complex reconstitution, mass spectrometry and molecular cell biology, we find that the amino-terminal VPS29C extension constitutes an autoinhibitory sequence that limits access to a hydrophobic groove necessary for effector protein recruitment to Retromer, and association with Retriever and Commander. VPS29C is therefore unique in its ability to uncouple Retromer-dependent cargo sorting from the broader roles of VPS29A and VPS29B in regulating the endosomal-lysosomal network through accessory protein recruitment. Our identification and characterisation of VPS29C points to additional complexity in the differential subunit assembly of Retromer, an important consideration given the increasing interest in Retromer as a potential therapeutic target in neurodegenerative diseases. SIGNIFICANCE STATEMENTThe endosomal-lysosomal network is essential for normal cellular function with network defects being associated with numerous neurodegenerative diseases. Two heterotrimeric complexes, Retromer and Retriever, control transmembrane protein recycling through the network. Of these, reduced Retromer expression is observed in Alzheimers disease and Retromer mutations lead to familial Parkinsons disease. Here, we identify and characterise a new isoform of VPS29, a subunit shared between Retromer and Retriever. We reveal how this isoform, VPS29C, adopts an auto-inhibitory conformation to limit its association into Retriever and restrict the binding of VPS29C-containing Retromer to accessory proteins vital for regulating network function. By revealing added complexity in Retromer assembly and function, we provide new insight into Retromers potential as a therapeutic target in neurodegenerative diseases.

cell biology↗