Biology subjects

Zou, W.

Publications and source records attributed to Zou, W..

At least 19 recordsLinked to original sources

bioRxiv2026

A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

Many cancers evade immunity by converting neutrophils into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), but the chromatin mechanisms that maintain this pathological state remain unclear. Here we show that tumor-induced suppressive neutrophils depend on mSWI/SNF chromatin remodeling. Two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control across syngeneic models, including tumors resistant to PD-1 blockade, and enhanced checkpoint therapy without overt toxicity. Treatment rapidly depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, and blocked tumor explant-induced expansion and suppressive activity of mouse and human PMN-MDSCs. mSWI/SNF antagonism collapsed chromatin accessibility and PU.1/C/EBP{beta} occupancy at regulatory elements that sustain PMN-MDSC identity. Thus, suppressive neutrophils harbor a druggable chromatin vulnerability that can be exploited to restore cancer immunity.

cancer biology↗

bioRxiv2026

Decreased Damage for proton FLASH vs Conventional Dose Rates in Mouse Jejunum Shown by Quantitative Assessment of γ-H2AX

Purpose: FLASH radiation with ultra-high dose rate delivery is less damaging to normal tissue than conventional radiation ( <1 Gy/s). Since radiation depletes oxygen (ROD), this damage reduction might occur via the oxygen effect. ROD experiments have shown an oxygen-independent reduction in dose effectiveness at FLASH dose rates. However, prior in vivo ROD measurements relied on extracellular oxygen probes that could not penetrate cell membranes, leaving intracellular effects unresolved. To investigate the ROD hypothesis more directly, we developed a novel three-component immunohistochemical assay with algorithmic image processing to quantitatively compare DNA damage following FLASH and conventional irradiation in mouse jejunum. Methods: Mice received intravenous EF5 2 hours before proton irradiation at FLASH (103.63 +/- 17.2 Gy/s) or conventional (0.73 +/- 0.1 Gy/s) dose rates of 2.5 Gy or 5 Gy, with unirradiated controls. Mice were euthanized 30 minutes post-irradiation, and 10 cm of jejunum was frozen as a 'Swiss Roll', sectioned, stained, and imaged. Tissue sections were stained for {gamma}-H2AX, DRAQ5, and EF5 to assess DNA double-strand breaks, total DNA content, and hypoxia, respectively. An in-house algorithm identified individual cell nuclei and registered each nucleus with its corresponding {gamma}-H2AX and EF5 signals, enabling quantitative measurement of DNA damage as a function of local tissue hypoxia. Results: Hypoxia was greatest in the villi and, to a lesser extent, the outer jejunal musculature, with substantial inter-animal variation. DNA damage decreased in hypoxic regions. FLASH enhanced the hypoxia-associated reduction in DNA damage compared with conventional dose rate and, separately, revealed an oxygen-independent reduction in DNA damage, suggesting an additional FLASH sparing mechanism. Conclusion: Current results suggest that FLASH compared to conventional dose rate radiation caused less DNA damage with increasing effect at low oxygen levels, a result consistent with ROD as a mechanism. Pronounced tissue heterogeneity in murine jejunum requires further studies to segment the effect for each tissue type.

biophysics↗

bioRxiv2026

Pyroptotic cell-derived factors promote osteoclast differentiation

The NLRP3 D301N substitution, the murine ortholog of the human D303N variant, causes NLRP3 constitutive activation (NLRP3CA) and inflammasome assembly. Here, we show that priming signals induced by lipopolysaccharide (LPS) are sufficient to trigger GSDMD-dependent pyroptosis in NLRP3CA-expressing bone marrow-derived macrophages (BMDMs), but not in wild-type (NLRP3WT) cells. NLRP3CA mice exhibit elevated IL-1{beta} secretion and LDH release in bone marrow supernatants under both basal and LPS-challenged conditions. Other cytokines (e.g., TNF-) increased comparably between genotypes, indicating that NLRP3CA specifically amplifies inflammasome-dependent responses. Conditioned medium (CM) from LPS-treated NLRP3CA BMDMs significantly enhanced osteoclast (OC) differentiation in vivo and in vitro compared to NLRP3WT CM, as did bone marrow supernatants from NLRP3CA mice. This osteoclastogenic activity was largely independent of IL-1{beta}, as demonstrated by experiments using IL-1{beta}-deficient NLRP3CA BMDMs, IL-1{beta}-neutralizing antibodies, and genetic deletion of the IL-1 receptor. The osteoclastogenic factors were primarily soluble proteins, as heat inactivation and proteinase K digestion markedly reduced OC formation. Extracellular vesicles (EVs) from NLRP3CA CM modestly promoted OC differentiation, but EV-depleted supernatants retained full activity, indicating that the primary mediators are soluble proteins not carried within EVs. Together, these findings establish NLRP3CA as a well-controlled model for studying pyroptosis and demonstrate that pyroptotic cells release soluble proteins that drive osteoclastogenesis independently of IL-1{beta}.

cell biology↗

bioRxiv2026

Neural mechanisms of impaired self-compassion in depressed adolescents during social exclusion

Background: Self-compassion has shown to be an effective emotion regulation strategy, but its neural mechanisms remain understudied in adolescents with depression who suffer from social exclusion. This study employed event-related potentials to investigate the psychophysiological mechanisms underlying impaired self-compassion in adolescents with depression during social exclusion. Methods: Thirty-seven adolescents with major depressive disorder (age = 16.46 +/- 2.02) and thirty-two demographically matched healthy controls (age = 16.54 +/- 2.29) completed a social exclusion scenario imagination task. This task presented participants with social exclusion scenarios, asking them to imagine themselves as the excluded individual and subsequently rate their negative emotions. The regulation session required participants to use self-compassionate statements to regulate their emotional responses while imagining and rate how much self-compassion they have engaged in; the non-regulation required them not to use those statements and rate their negative emotions immediately following imagination. EEG signals were recorded during the task, and the late positive potential (LPP) was analyzed to examine the neural responses associated with self-compassion regulation following social exclusion. Results: Compared with the non-regulation condition, both groups showed less negative emotion during the self-compassion regulation condition. Adolescents with depression exhibited significantly lower self-compassion ratings than healthy controls, and showed a significantly smaller decrease in negative emotions. Higher self-compassion ratings were correlated with greater emotion regulation effect, particularly in adolescents with depression. Furthermore, LPP amplitudes were significantly higher in adolescents with depression than in healthy controls during both regulation and non-regulation conditions. Conclusions: Adolescents with depression were characterized by impairment in using self-compassion to downregulate negative emotions when confronted with social exclusion. LPP amplitudes were consistently elevated in adolescents with depression, underscoring their potential as a critical focus for psychophysiologically-informed therapies.

neuroscience↗

bioRxiv2026

Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine

As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid-neutrophil-adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPAR activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.

cancer biology↗

bioRxiv2026

Identification of Human Transferrin Receptor as an Entry Co-receptor for Parvovirus B19 Infection of Human Erythroid Progenitor Cells

Parvovirus B19 (B19V), a member of the genus Erythroparvovirus within the Parvoviridae family, infects human erythroid progenitor cells (EPCs) of bone marrow and fetal liver, and causes various hematological disorders. The minor capsid protein VP1 of B19V contains a unique N-terminal region (VP1u) that facilitates virus binding and internalization into EPCs via its receptor-binding domain (RBD). We previously identified tyrosine protein kinase receptor UFO (AXL) as a proteinaceous receptor for B19V infection of EPCs. In this study, we employed an ascorbate peroxidase 2 (APEX2)-based proximity labeling method to identify host proteins that are associated with B19V VP1u during entry. This analysis revealed human transferrin receptor 1 (hTfR) as a key host protein associated with VP1u. hTfR knockdown in UT7/Epo-S1 cells, a B19V-permissive human megakaryoblastoid leukemia cell line, showed significantly reduced B19V internalization and replication. Biolayer interferometry (BLI) assays confirmed a direct interaction between B19V VP1u and hTfR extracellular domain (ECD). Inhibition of VP1u interaction with hTfR ECD, either by a monoclonal antibody targeting the apical domain of the ECD or human ferritin, a natural ligand of hTfR that binds the apical domain, significantly reduced VP1u binding to hTfR, as well as B19V internalization and B19V replication in ex vivo-expanded EPCs. Furthermore, mutant RBD proteins that bear amino acid substitutions in the three helical domains nearly abolished RBD binding to hTfR and significantly reduced the ability to inhibit B19V infection of EPCs. Collectively, our findings establish hTfR as a B19V entry co-receptor that mediates B19V internalization into its natural host EPCs. SignificanceB19V causes severe hematological disorders, including transient aplastic crisis, chronic pure red cell aplasia, and hydrops fetalis, by selectively infecting erythroid progenitor cells (EPCs). Despite its clinical impact, no approved antivirals or vaccines exist, largely due to limited understanding of viral entry mechanisms. A unique feature of B19V is the externalization of the VP1 unique region (VP1u) from the viral capsid, which mediates receptor engagement. Our prior studies identified AXL as an attachment receptor for B19V. Here, we identify that human transferrin receptor 1 (hTfR) acts as a critical co-receptor that directly binds VP1u and promotes viral internalization. Inhibition of the VP1u-hTfR interaction by competitive binding of hTfR with either an anti-hTfR monoclonal antibody or human ferritin significantly reduces B19V internalization and replication in ex vivo-expanded EPCs, highlighting a link between VP1u binding to the apical domain of hTfR and viral internalization. RBD mutants that disrupt its interaction with hTfR barely inhibited B19V infection in EPCs. These findings support a receptor-switch model in which AXL mediates attachment and hTfR drives internalization. Defining these mechanisms provides a foundation for developing antiviral strategies targeting B19V entry into EPCs.

microbiology↗

bioRxiv2026

Population genomics reveals multi-scale mechanisms sustaining schistosomiasis re-emergence in a near-elimination setting

In China, sustained snail control, environmental management, and mass drug administration with praziquantel reduced schistosomiasis to near-elimination levels, yet re-emergence in Sichuan Province during the early 2000s exposed vulnerabilities in late-stage control. We conducted a novel investigation of Schistosoma japonicum re-emergence in Sichuan in order to identify the processes underlying re-emergence and to showcase how genomic data can be used in such investigations. We sequenced whole genomes from 270 miracidia collected from 53 human hosts across 17 villages in 2007 - the year after re-emergence was documented. Population genomic analyses revealed a broadly cohesive regional parasite population with weak geographic structuring. Genome-wide diversity was substantial, and demographic reconstructions revealed no recent decline in effective population size, demonstrating that parasite populations were not demographically fragmented at the onset of re-emergence, hinting at maintenance in reservoir populations. At finer spatial scales, several villages exhibited low diversity and elevated inbreeding, consistent with localized transmission maintained by small founding populations. Estimates of pairwise genetic relatedness revealed dense within-village sibling clusters alongside second- and third-degree relationships spanning villages, and rare first- and second-degree cross-village links. These findings are consistent with highly focal transmission with episodic parasite dispersal across villages, leading to a regional transmission network. Inferred minimum worm burden across hosts varied from 1 to 11 adult worm pairs, indicating heterogeneity in within-host parasite diversity, although uneven sampling limited inference. Together, these findings indicate that schistosomiasis re-emergence in this near-elimination setting was likely facilitated by a diverse parasite population maintained in reservoir populations, and that transmission, while predominantly local was occurring across a network of connected villages. This work illustrates how population genomics can reveal mechanisms driving re-emergence in late-stage elimination in complex, multi-host transmission systems. Author SummarySchistosomiasis is a parasitic disease that affects millions of people worldwide. Understanding the factors that contribute to persistence and transmission, even in the face of control programs, is central to reducing and ultimately eliminating the disease. In China, decades of intensive control efforts have dramatically reduced infections, yet the disease continued to persist in some regions. In this study, we analyzed the genomes of 270 parasite larvae collected from infected humans across 17 villages in Sichuan Province, China, shortly after schistosomiasis re-emerged in the region. By examining genetic relationships among parasites, we reconstructed patterns of transmission across villages and within individual infections. Our findings suggest that, despite major reductions in human infection prevalence, parasite populations sizes do not show signatures of recent population decline, indicating that non-human hosts may serve as key reservoirs promoting persistence. We also find that local transmission pathways, including clonal infections infecting multiple humans derived from a relatively small number of snail hosts, maintain parasite transmission pathways. Collectively, these findings suggest non-human hosts, intact local transmission pathways, and regional connectivity together enabled re-emergence, highlighting important challenges for elimination programs

genomics↗

bioRxiv2025

WormTagDB: A Systematic Survey of Endogenously Tagged Proteins in C. elegans and Roadmap Towards the Tagged Proteome

Endogenous protein tagging in Caenorhabditis elegans enables direct visualization and manipulation of proteins in vivo, providing native readouts of expression, localization, and dynamics. No coordinated effort currently exists to comprehensively tag proteins on a large scale, resulting in patchy coverage that limits comprehensive proteome analyses. We systematically reviewed 2,500 primary research articles, identifying 778 that report novel endogenous tags, and integrated these with the Caenorhabditis Genetics Center strain records to catalog >90% of all existing tagged alleles. In total, we found that 1,554 unique genes (~8% of the proteome) have been endogenously tagged. Gene Ontology enrichment analysis revealed that cytoskeletal proteins, transcription factors, and RNA-binding proteins dominate the tagged proteome, while membrane proteins, metabolic enzymes, and mitochondrial components remain largely untagged, reflecting both technical barriers and research priorities that have shaped the last decade of tagging efforts. We created WormTagDB (https://wormtagdb.rc.duke.edu), an interactive, community-updatable resource that consolidates all known endogenously tagged alleles and provides precomputed CRISPR guide and homology-arm primer designs for N- and C-terminal knock-ins across all protein-coding genes. This will enable researchers to easily identify existing alleles to prevent redundant strain generation and rapidly initiate new knock-in experiments. A systematic effort to tag every C. elegans gene would deliver the first complete metazoan visual proteome, providing comprehensive insights into protein localization, dynamics, and regulation, revealing new protein associations and molecular processes.

genetics↗

bioRxiv2025

Spatial and Single-Cell Transcriptomics Decipher the Crosstalk Environment of DEFB1+ Cancer Cells and IFI30+ Macrophages in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a rare but highly aggressive primary liver malignancy distinguished by a profoundly heterogeneous tumor microenvironment, which underlies its limited response to targeted and immune-based therapies. Deciphering the cellular composition and intercellular signaling within this complex ecosystem is critical to understanding ICC progression and to identifying actionable therapeutic targets. Here, we integrated single-cell RNA sequencing and spatial transcriptomics to construct a comprehensive cellular and transcriptional atlas of human ICC. Our analyses revealed a continuous trajectory of T-cell state transition from activation to exhaustion, with CD8+ proliferating T cells exhibiting two distinct exhaustion programs, namely terminal and progenitor-like exhaustion. Notably, DEFB1+ cholangiocytes and IFI30+ macrophages displayed a strong positive correlation across independent ICC cohorts and were found in close spatial proximity within the tumor microenvironment. Mechanistically, their interaction appears to be mediated by the TGFB1 - TGFBR1 signaling pathway, contributing to tumor progression and immunotherapy resistance. Together, these findings delineate the cellular architecture and spatial organization of the ICC microenvironment, uncovering a key cholangiocyte-macrophage axis that shapes immune dysfunction and offers a potential therapeutic entry point to enhance immunotherapy efficacy in ICC.

bioinformatics↗

bioRxiv2025

Adipocytes are dispensable in shaping the ovarian cancer tumor microenvironment in the omentum

The omentum, a specialized adipose tissue within the peritoneum, is a primary niche for ovarian cancer (OC) dissemination during peritoneal carcinomatosis. Traditionally, omental adipocytes are thought to promote OC growth by supplying lipids, supported by evidence that global FABP4 deficiency reduces tumor progression. Here, we generated mice lacking mature adipocytes in the peritoneum, including the omentum. ID8p53-/-Brca2-/-, BPPNM, and KPCA OC cells retained a propensity to seed regions typically associated with adipocytes, even without mature adipocytes. However, the lack of mature adipocytes did not suppress peritoneal OC expansion, whereas removing the adipocyte-free omentum did. Murine and human single-cell RNA sequencing revealed that endothelial FABP4 was high in the omentum. Indeed, endothelial cell-selective deficiency of FABP4 reduced OC growth in the peritoneum. These findings prompt a reevaluation of adipocyte contributions to OC progression and suggest a key role of the omental vasculature in supporting OC metabolic growth.

cancer biology↗

bioRxiv2025

Modulating inter-mitochondrial contacts to increase membrane potential for mitigating blue light damage

Mitochondrial membrane potential (MMP) is essential for mitochondrial functions, yet current methods for modulating MMP lack precise spatial and temporal control. Here, we present an optogenetic system that enables reversible formation of inter-mitochondrial contacts (mito-contacts) with high spatiotemporal precision. Blue light stimulation induces rapid formation of mito-contacts, which fully dissipate upon cessation of illumination. These light-induced mito-contacts can enhance MMP, leading to increased ATP production under stress conditions. Moreover, in human retinal cells and C. elegans, high MMP induced by mito-contacts alleviates the deleterious effects of prolonged blue light exposure, restoring energy metabolism and extending organismal lifespan. This optogenetic approach provides a powerful tool for modulating MMP and offers potential therapeutic applications for diseases linked to mitochondrial dysfunction.

biophysics↗

bioRxiv2025

Activation of the noncanonical inflammasome-GSDMD pathway triggers pyroptosis in bone marrow and promotes periosteal bone formation

Evidence indicating that inflammation is commonly associated with ectopic osteogenesis in certain autoimmune and infectious conditions challenges the dogma that inflammatory responses always suppress bone formation. In this study, we find that systemic administration of lipopolysaccharide (LPS) to mice causes not only inflammation in bone marrow, as expected, but also stimulates periosteal bone formation. This response can be reproduced in vitro as bone marrow supernatants from LPS-treated mice induce robust osteogenesis of skeletal stem cells (SSCs) compared to supernatants from PBS-treated counterparts. Periosteal bone accrual is partly dependent on periosteal leptin receptor-positive (LepR)+ SSCs but not bone marrow LepR+ or adiponectin (Adq)+ SSCs and correlates with pyroptosis within bone marrow. Consistent with the dependence of periosteal osteogenesis on pyroptosis, this response is slightly attenuated in Nlrp3-/- or caspase-1-/-mice but significantly inhibited in caspase-11-/-, caspase-1-/-;caspase-11-/-, or Gsdmd-/-mice. Our study reveals a novel role for pyroptosis in which lysed cells release intracellular contents that stimulate osteoprogenitors and promote osteogenic differentiation within the periosteal compartment.

cell biology↗

bioRxiv2025

Cross-modal Denoising and Integration of Spatial Multi-omics data with CANDIES

Spatial multi-omics data offer a powerful framework for integrating diverse molecular profiles while maintaining the spatial organization of cells. However, inherent variations in data quality and noise levels across different modalities pose significant challenges to accurate integration and analyses. In this paper, we introduce CANDIES, which leverages a conditional diffusion model and contrastive learning to effectively denoise and integrates spatial multi-omics data. With our innovative model and algorithm designs, CANDIES not only enhances the quality of spatial multi-omics data, but also yields a unified and comprehensive joint representation, thereby empowering many downstream analysis. We conduct extensive evaluations on diverse synthetic and real datasets, including spatial CITE-seq data from human skin biopsy tissue, MISAR-seq data from the mouse brain, spatial ATAC-RNA-seq data from the mouse embryo and 10x visium data from human lymph nodes. CANDIES shows superior performance on various downstream tasks, including denoising, spatial domain identification, spatiotemporal trajectories reconstruction, and spatial association mapping for complex human traits. In particular, we show that CANDIES representations can be integrated with the rich resources from genome-wide association studies (GWASs), allowing the spatial domains to be linked with complex human traits, yielding spatially resolved interpretation of complex traits in their relevant tissues.

bioinformatics↗

bioRxiv2024

MOSTPLAS: A Self-correction Multi-label Learning Model for Plasmid Host Range Prediction

Plasmids play an essential role in horizontal gene transfer among diverse microorganisms, aiding their host bacteria in acquiring beneficial traits like antibiotic and metal resistance. Identifying the host bacteria where a plasmid can transfer, replicate or persist provides insights into how plasmids promote bacterial evolution. Plasmid host range prediction tools can be categorized as alignment-based and learning-based. Alignment-based tools have high precision but fail to align many newly sequenced plasmids with characterized ones in reference databases. In contrast, learning-based tools help predict the host range of these newly discovered plasmids. Although previous researches have demonstrated the existence of broad-host-range (BHR) plasmids, there is no database providing their detailed and complete host labels. Without adequate well-annotated training samples, learning-based tools fail to extract discriminative feature representations and obtain limited performance. To address this problem, we propose a self-correction multi-label learning model called MOSTPLAS. We design a pseudo label learning algorithm and a self-correction asymmetric loss to facilitate the training of multi-label learning model with samples containing some unknown missing positive labels. Experimental results on multi-host plasmids generated from the NCBI RefSeq database, metagenomic data, and real-world plasmid sequences with experimentally determined host range demonstrate the superiority of MOSTPLAS.

bioinformatics↗

bioRxiv2024

PlasGO: enhancing GO-based function prediction for plasmid-encoded proteins based on genetic structure

Plasmid, as a mobile genetic element, plays a pivotal role in facilitating the transfer of traits, such as antimicrobial resistance, among the bacterial community. Annotating plasmid-encoded proteins with the widely used Gene Ontology (GO) vocabulary is a fundamental step in various tasks, including plasmid mobility classification. However, GO prediction for plasmid-encoded proteins faces two major challenges: the high diversity of functions and the limited availability of high-quality GO annotations. Thus, we introduce PlasGO, a tool that leverages a hierarchical architecture to predict GO terms for plasmid proteins. PlasGO utilizes a powerful protein language model to learn the local context within protein sentences and a BERT model to capture the global context within plasmid sentences. Additionally, PlasGO allows users to control the precision by incorporating a self-attention confidence weighting mechanism. We rigorously evaluated PlasGO and benchmarked it against six state-of-the-art tools in a series of experiments. The experimental results collectively demonstrate that PlasGO has achieved commendable performance. PlasGO significantly expanded the annotations of the plasmid-encoded protein database by assigning high-confidence GO terms to over 95% of previously unannotated proteins, showcasing impressive precision of 0.8229, 0.7941, and 0.8870 for the three GO categories, respectively, as measured on the novel protein test set.

bioinformatics↗

bioRxiv2024

Stochastic growth and selective stabilization generate stereotyped dendritic arbors

Stereotyped dendritic arbors are shaped by dynamic and stochastic growth during neuronal development. It remains unclear how guidance receptors and ligands coordinate branch dynamic growth, retraction, and stabilization to specify dendritic arbors. We previously showed that extracellular ligand SAX-7/LICAM dictates the shape of the PVD sensory neuron via binding to the dendritic guidance receptor DMA-1, a single transmembrane adhesion molecule. Here, we perform structure-function analyses of DMA-1 and unexpectedly find that robust, stochastic dendritic growth does not require ligand-binding. Instead, ligand-binding inhibits growth, prevents retraction, and specifies arbor shape. Furthermore, we demonstrate that dendritic growth requires a pool of ligand-free DMA-1, which is maintained by receptor endocytosis and reinsertion to the plasma membrane via recycling endosomes. Mutants defective of DMA-1 endocytosis show severely truncated dendritic arbors. We present a model in which ligand-free guidance receptor mediates intrinsic, stochastic dendritic growth, while extracellular ligands instruct dendrite shape by inhibiting growth.

neuroscience↗

bioRxiv2024

Complete telomere-to-telomere assemblies of two sorghum genomes to guide biological discovery

Sorghum is a C4 crop well-known for its high efficiency of biomass accumulation and adaptation to drought and hot environments. This study reports the assembly of complete genome sequence of two sorghum genomes using a combination of ultra-long reads from Oxford Nanopore Technology, high-fidelity long reads from Pacbio and Hi-C reads. The accuracy and completeness of the T2T assemblies were comprehensively validated using a range of parameters, including coverage depth assessment, BUSCO, LTR assembly index, ect. Our T2T assembly of BTx623 identified 36.25 Mb of new sequence, in addition to dozens of misoritation and mispositioning of large DNA segments in the BTx623-v3. Correcting these assembly errors in the reference genome is critical for exploiting genetic information in these complex regions in sorghum. Comparison of the two T2T genomes shed new insights on variation of centromeres in sorghum. The two high-quality T2T genomes represent an important resource for sorghum improvement and gene discovery. They would serve as the new reference genomes to unlock the full potential of global sequence variation of this valuable crop.

genomics↗

bioRxiv2024

PIKfyve controls dendritic cell function and tumor immunity

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-{kappa}B pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

cancer biology↗