Biology subjects

Wang, G.

Publications and source records attributed to Wang, G..

At least 127 records · Page 7Linked to original sources

bioRxiv2025

miR-486-3p ameliorates aging-related impaired angiogenesis in adult moyamoya disease by targeting Forkhead Box O4

ObjectiveInvestigate miR-486-3ps role in alleviating age-related angiogenic decline in Moyamoya disease (MMD) by regulating senescent endothelial cells. MethodsClinical analysis of 151 MMD patients correlated age with postoperative angiogenesis (DSA grading). Senescent HUVECs (SA-{beta}-gal>80%) exhibited elevated SASP factors (IL-6/IL-8/MCP-1). Functional assays (EdU/Transwell/Matrigel) and bioinformatics identified miR-486-3p targets, validated via luciferase/Western blot. ResultsPatients [≥]35 years had 3.67-fold higher risk of poor angiogenesis (OR=3.67). Senescent HUVECs showed 10-16-fold higher SASP secretion (p<0.01). miR-486-3p overexpression increased proliferation (EdU+25%), migration (1.7-fold), and tube formation (+40% branches) in senescent cells (p<0.01) and enhanced angiogenesis in vivo (p<0.001). miR-486-3p directly targeted FOXO4, reducing its luciferase activity (-35%) and protein levels (-37%) (p<0.01), suppressing SASP. ConclusionmiR-486-3p enhances post-revascularization angiogenesis in MMD by inhibiting FOXO4-mediated SASP, offering a therapeutic target and predictive biomarker.

molecular biology↗

bioRxiv2025

Mechanistic Insights into Human Antimicrobial Peptide-Induced Activation of a Broadly Conserved Bacterial Signaling System

Antimicrobial peptides (AMPs) represent a promising class of therapeutics against bacterial pathogens. While their direct bactericidal mechanisms are well-characterized, how bacteria sense and respond to these peptides at sublethal concentrations remains poorly understood. Here, we investigate the activation of the Escherichia coli PhoQ-PhoP signaling system by the human antimicrobial peptide LL-37 and its derivatives (KR-12 and RI-10). We demonstrate that these peptides exhibit variable antimicrobial potency but surprisingly similar abilities to activate the PhoQ-PhoP pathway, indicating that signaling function is separable from bactericidal activity. Notably, sublethal concentrations of these peptides induce significant cell elongation, a phenotype dependent on PhoQ and mediated by the upregulation of QueE, which interferes with bacterial cell division. Contrary to the previous model suggesting peptides activate PhoQ passively by displacing its inhibitor MgrB, we observed enhanced cell elongation in{Delta} mgrB strains across all tested peptides, including RI-10, lacking antibacterial activity. Our findings suggest peptides actively stimulate PhoQ through a mechanism independent of MgrB dissociation, providing a more refined understanding of the peptide signaling through the PhoQ-PhoP system. These insights into bacterial adaptation mechanisms against host-derived peptides may guide the development of peptide therapeutics with enhanced efficacy against drug-resistant pathogens. Significance statementAntimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics, yet how bacteria detect and respond to these host defense molecules remains poorly understood. This study investigates the interaction between bacterial sensing systems and AMPs at the genetic and molecular levels. Unlike other eukaryotes with multiple cathelicidin peptides, humans have only one cathelicidin that produces various active fragments through processing. Rather than creating multiple detectors, E. coli deploys an elegant solution, the PhoQ-PhoP signaling system that recognizes the conserved antimicrobial region shared by all LL-37 fragments. We demonstrate that peptides directly stimulate PhoQ independent of their bactericidal activity, even in the absence of inhibitor MgrB, inducing cell elongation. These insights may inform the development of effective peptide-based therapeutics against drug-resistant pathogens.

microbiology↗

bioRxiv2025

Inter-brain similarity and connectivity based on EEG hyperscanning during patient-acupuncturist interactions

The study of patient-clinician relationships is a vital branch of interpersonal interaction research. Acupuncture attaches great importance to positive patient-clinician interactions; thus, it serves as a typical example of patient-clinician interaction research. Based on electroencephalography (EEG) hyperscanning, this study explored inter-brain similarity based on spatial correlations between two brains as well as inter-brain connectivity of different regions through different frequency bands. Regarding inter-brain similarity, both acupuncture and sham acupuncture significantly decreased spatial correlation during certain sessions during acupuncture. Regarding inter-brain connectivity, acupuncture enhanced not only the connectivity of the beta frequency band in the right temporoparietal regions but also the connectivity of the fast-ripple frequency band in the right and left temporoparietal regions. These results suggest that inter-brain similarity should be emphasized in patient-clinician relationship research. Moreover, high-frequency oscillations (HFOs) potentially play an important role in inter-brain connectivity in addition to the classical EEG low-frequency bands.

neuroscience↗

bioRxiv2025

TCA cycle rewiring underpins implantation and histone acetylation programming

Metabolism has emerged as a key regulator of stem cell differentiation and their epigenomes. This coupling is particularly evident during the exit from naive pluripotency in vitro. However, our understanding of the dynamics of the metabolic rewiring especially at implantation remains rudimentary. In this study, we reconstruct the intracellular metabolite routings in pre- and post-implantation mouse embryos and during dynamic pluripotency transitions of cultured stem cells. Our findings reveal that, instead of a simple TCA cycle shutdown, there is a spatio-temporally programmed rewiring of the TCA cycle at implantation. Focusing on the spectrum of pluripotent cells, we identify pyruvate as a key metabolic nexus. Indeed, pyruvate carboxylase and malic enzyme activity establish cyclical carbon flow, which is essential for maintaining a balanced metabolic and transcriptional state and timely exit from naive pluripotency. Additionally, we discover that formative and primed pluripotent cells exhibit increased glutamine contribution to the TCA cycle, reduced oxidative TCA activity, and reciprocal reductive glutamine metabolism. This metabolic rewiring supports increased histone acetylation turnover, primarily using glutamine as a carbon source, supplemented by pyruvate cycling. Thus, we uncover diverse nutrient strategies that are functionally coupled to epigenome programming and dynamic pluripotency cell state transitions at the time of implantation.

developmental biology↗

bioRxiv2025

Reference-guided genome assembly at scale using ultra-low-coverage high-fidelity long-reads with HiFiCCL

Population genomics using short-read resequencing captures single nucleotide polymorphisms and small insertions and deletions but struggles with structural variants (SVs), leading to a loss of heritability in genome-wide association studies. In recent years, long-read sequencing has improved pangenome construction for key eukaryotic species, addressing this issue to some extent. Sufficient-coverage high-fidelity (HiFi) data for population genomics is often prohibitively expensive, limiting its use in large-scale populations and broader eukaryotic species and creating an urgent need for robust ultra-low coverage assemblies. However, current assemblers underperform in such conditions. To address this, we propose HiFiCCL, the first assembly framework specifically designed for ultra-low-coverage high-fidelity reads, using a reference-guided, chromosome-by-chromosome assembly approach. We demonstrate that HiFiCCL improves ultra-low-coverage assembly performance of existing assemblers and outperforms the state-of-the-art assemblers on human and plant datasets. Tested on 45 human datasets ([~]5x coverage), HiFiCCL combined with hifiasm reduces the length of misassembled contigs relative to hifiasm by an average of 21.19% and up to 38.58%. These improved assemblies enhance germline structural variant detection, reduce chromosome-level mis-scaffolding, enable more accurate pangenome graph construction, and improve the detection of rare and somatic structural variants based on the pangenome graph under ultra-low-coverage conditions.

bioinformatics↗

bioRxiv2025

THLANet: A Deep Learning Framework for Predicting TCR-pHLA Binding in Immunotherapy Applications

Adaptive immunity is a targeted immune response that enables the body to identify and eliminate foreign pathogens, playing a critical role in the anti-tumor immune response. Tumor cell expression of antigens forms the foundation for inducing this adaptive response. However, the human leukocyte antigens (HLA)-restricted recognition of antigens by T-cell receptors (TCR) limits their ability to detect all neoantigens, with only a small subset capable of activating T-cells. Accurately predicting neoantigen binding to TCR is, therefore, crucial for assessing their immunogenic potential in clinical settings. We present THLANet, a deep learning model designed to predict the binding specificity of TCR to neoantigens presented by class I HLAs. THLANet employs evolutionary scale modeling-2 (ESM-2), replacing the traditional embedding methods to enhance sequence feature representation. Using scTCR-seq data, we obtained the TCR immune repertoire and constructed a TCR-pHLA binding database to validate THLANets clinical potential. The models performance was further evaluated using clinical cancer data across various cancer types. Additionally, by analyzing divided complementarity-determining region (CDR3) sequences and simulating alanine scanning of antigen sequences, we unveiled the 3D binding conformations of TCRs and antigens. Predicting TCR-neoantigen pairing remains a significant challenge in immunology, THLANet provides accurate predictions using only the TCR sequence (CDR3{beta}), antigen sequence, and class I HLA, offering novel insights into TCR-antigen interactions. Author summaryT-cell receptor (TCR) recognition of peptide-human leukocyte antigen (pHLA) complexes is fundamental to immune responses. However, predicting their binding poses a significant challenge due to the intricate dynamics of their interactions. We developed THLANet, a novel deep learning model, to address this challenge by integrating the ESM-2 and Transformer-Encoder modules. This approach enhances sequence feature encoding, improving the models generalization capability and enabling accurate predictions of TCR-pHLA binding in clinical datasets. Using data processed from open-source databases, THLANet outperformed existing methods, such as PanPep and pMTnet, in precision-recall metrics across multiple epitopes. Additionally, THLANet demonstrates superior capability in identifying critical binding sites within 3D structures, providing structural insights into TCR-pHLA interactions. THLANet offers a robust framework for advancing immunotherapy research, with potential applications in the development of personalized medicine.

bioinformatics↗

bioRxiv2025

Hypertension-Induced Neurovascular and Cognitive Dysfunction at Single-Cell Resolution

Arterial hypertension is a leading cause of cognitive impairment, attributed to cerebrovascular insufficiency, blood-brain barrier disruption, and white matter damage. However, the molecular mechanisms by which hypertension affects brain cells remain unclear. Using scRNA-seq in a mouse model of hypertension induced by angiotensin II, we mapped neocortical transcriptomic changes before (3 days) and after (42 days) onset of neurovascular and cognitive deficits. Surprisingly, evidence of endothelial transport disruption and senescence, stalled oligodendrocyte differentiation, interneuronal hypofunction and network imbalance emerged after just 3 days. By 42 days, when cognitive impairment becomes apparent, deficits in myelination and axonal conduction, as well as neuronal mitochondrial dysfunction developed. These findings reveal a previously unrecognized early vulnerability of endothelial cells, interneurons, and oligodendrocytes, and provide the molecular bases for the subsequent neurovascular dysfunction and cognitive impairment in hypertension. In addition, the data constitute a valuable resource for future mechanistic studies and therapeutic target validation.

neuroscience↗

bioRxiv2025

Hepatic isomiR landscaping reveals new biological insights into metabolic dysfunction in steatotic liver disease

Post-transcriptionally modified microRNA (miRNA), called isomiRs, expand the repertoire of transcripts that can leveraged for therapeutic targets and biological insights. However, the expression of isomiRs has not been characterized in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we assessed the isomiR expression profile in liver biopsies from 79 patients with MASLD and modeled their potential role in disease biology. MiRNAs represented 75% of the sequencing reads and over 65% of them were attributed to isomiRs, demonstrating their higher expression and diversity compared to canonically annotated miRNAs. Differential expression and machine-learning analyses were used to identify 173 isomiRs associated to MASLD severity and 58 isomiRs associated to fibrosis score. Candidate target mRNAs were identified for each isomiR based on sequence complementarity. Using matched mRNA sequencing data, and supported by data from an independent study, we proposed key dysregulated mRNA targets involved in a selection of 33 disease-associated pathways. Importantly, isomiRs offered novel and unique mRNA targets compared to the canonical miRNA, e.g. isomiR-122 targeting INSIG1 (insulin and cholesterol metabolism), and isomiR-21 targeting HMGCS2 and PPARA (PARR and TGF-beta signaling). Our work advances knowledge regarding the role of isomiRs in MASLD and lays a foundation for therapeutic targets identification. HighlightsOur results provide a comprehensive analysis of microRNA (isomiRs) in liver tissue. Machine learning identified isomiRs whose expression is associated with MASLD. Multi-omic analysis uncovered novel isomiR regulatory mechanisms involved in MASLD.

bioinformatics↗

bioRxiv2025

STEAMBOAT: Attention-based multiscale delineation of cellular interactions in tissues

Spatial-omics technologies profile cells in their native spatial context within tissues, enabling more complete understanding of cellular properties. However, a key computational challenge remains: identifying cellular interactions that underlie cell types and states - interactions that are essential for spatial organization and provide a biologically grounded framework for understanding cell identities and spatial patterns. These interactions span different distances and thus require multiscale modeling, which remains a major gap in existing methods. Here, we introduce SO_SCPLOWTEAMBOATC_SCPLOW, an interpretable machine learning framework that leverage a self-supervised, multi-head attention model to uniquely decompose gene expression of a cell into multiple key factors: intrinsic cell programs, neighboring cell communication, and long-range interactions. By applying SO_SCPLOWTEAMBOATC_SCPLOW to diverse tissues in health and disease across various spatial-omics technologies, we demonstrate its ability to uncover critical multiscale cellular interactions, capturing classical contact signaling and revealing previously unrecognized patterns of cellular communication. SO_SCPLOWTEAMBOATC_SCPLOW provides a powerful approach for spatial-omics analysis, offering new insights into the multiscale spatial organization of cells and their communication across a wide range of biological contexts.

bioinformatics↗

bioRxiv2025

Gap-free genomes and transcriptomes uncover race-specific effectors in watermelon wilt pathogen Fusarium oxysporum f. sp. niveum

Watermelon (Citrullus lanatus L.) is one of the worlds most economically important fruit crops, yet it is susceptible to devastating diseases such as vascular wilt caused by Fusarium oxysporum f. sp. niveum (Fon), with limited effective control measures. Fon evolves rapidly in the field to overcome host resistance and global watermelon production is constantly threatened by new pathogenic races. High-quality genomic resources are key to understanding the molecular mechanisms underlying Fon virulence evolution for disease management. Here, we de novo assembled and annotated gapless genomes of three physiological races of Fon (race 1, 2, and 3), and dissected the mechanisms behind their distinctive virulence through comparative genomics and transcriptomics. Whole-genome alignments identified core and accessory chromosomes in Fon where each race carried a unique set of accessory chromosomes or regions. Comparative transcriptomics of Fon infection revealed distinctive temporal patterns of gene expression even among core gene families, particularly those related to cell wall degradation enzymes. Effectoromic prediction and comparative analysis in three gap-free genomes identified 13 race-specific effectors (RSEs) in FonR3, one (FonRSE1) of which was a critical virulence factor of FonR3 on watermelon as demonstrated via functional experiments. The gap-free genome assemblies and annotations, and the RSEs are valuable resources for studying Fon pathobiology and genome evolution, adding in the design of improved disease control strategies.

genomics↗

bioRxiv2025

Multiple evolutionary events in host plant adaptation in Lepidoptera

The evolution of insect host adaptation is a key component of insect-plant coevolution, a complex process often shaped by multiple evolutionary events. In this study, we identified two UDP-glycosyltransferase (UGT) genes, SfruUGT33T10 and SfruUGT33F32, in the fall armyworm Spodoptera frugiperda, which play critical roles in the tolerance of benzoxazinoids (BXs), secondary metabolites in maize. These two detoxification enzymes exhibited distinct glycosylation patterns for BXs and varying detoxification efficiencies, reflecting independent evolutionary trajectories. Phylogenetic analyses revealed that SfruUGT33T10 originated independently within Noctuidae, while SfruUGT33F32 resulted from tandem duplication within the UGT33F gene family and may have undergone neofunctionalization within the Spodoptera genus. Our findings provide evidence that the evolution of these two UGT paralogs contributed to the variation in the tolerance to maize BXs among different Lepidopteran species. This research underscores the significance of multiple independent evolutionary routes in host plant adaptation and offer new insights into the complex evolutionary processes underlying insect-plant interactions.

evolutionary biology↗

bioRxiv2025

CanASM: A comprehensive database for genome-wide allele-specific DNA methylation identification and annotation in cancer

Allele-specific DNA methylation (ASM) provides critical insights into the complex genetic and epigenetic mechanisms regulating gene transcription. Emerging evidence suggests that ASM is particularly enriched in gene enhancer regions, and recent studies have demonstrated that ASM is increased in cancer tissues compared with normal tissues. Despite the increasing recognition of ASM as a potential biomarker in tumorigenesis, systematic resources dedicated to identifying and annotating ASMs in cancer contexts remain limited. In this study, we developed CanASM (https://bioinfor.nefu.edu.cn/CanASM/), the first comprehensive database specifically designed to identify and annotate ASM in cancer. In CanASM, ASM sites identified from bisulfite sequencing data across 31 cancer types and their matched normal tissue samples are cataloged. Importantly, CanASM includes extensive regulatory annotations for ASMs, including associated genes, cis-regulatory elements and transcription factor binding colocalizations, transcription factor affinity changes, etc. Users can query and explore ASMs using various parameters, such as single-nucleotide variations (SNVs), chromosomal coordinates, and gene names. The current version of CanASM includes 5,003,877 unique SNV-CpG pairs, including 3,056,776 index SNVs, of which 2,634,406 are single-nucleotide polymorphisms (SNPs), and 4,157,508 CpGs. With an intuitive interface for browsing, querying, analyzing, and downloading, CanASM serves as a valuable resource for researchers investigating cancer-associated genetic variations and epigenetic regulation in cancer. Author summaryIdentifying target genes and regulatory mechanisms of cancer-associated genetic variants remains a major challenge in the post-GWAS era. Existing databases like Pancan-meQTL and ASMdb have contributed to uncovering the role of genetic variants in cancer by linking DNA variations to methylation. However, they lack comprehensive regulatory annotations for such sites and rely solely on genomic proximity for target gene prediction, overlooking distal interactions. Our analysis using 3D interaction data reveals that over 94.8% of ASMs exhibit distal regulatory relationships, emphasizing their critical role in cancer epigenetics. Furthermore, these databases cover a limited number of cancer types (Pancan-meQTL: 23, ASMdb: 8). To address these limitations, we developed CanASM, a database that provides ASMs identified from BS-seq data for 31 human cancers, along with multidimensional regulatory annotations for ASM sites. This includes target genes, cis-regulatory elements (enhancers, ATAC-seq regions, insulators, 3D interactions, CpG islands), TFBSs, and GWAS cancer trait associations. Additionally, CanASM offers three interactive tools for analyzing TF binding affinity changes, predicting ASM target genes through 3D interactions, and identifying cell marker variations. As a comprehensive resource for SNV-driven epigenetic regulation in cancer, CanASM is helpful for in-depth research in cancer genetics and epigenetics.

bioinformatics↗

bioRxiv2025

Genetic and functional analysis of unproductive splicing using LeafCutter2

Alternative splicing commonly generates unproductive mRNA transcripts that harbor premature termination codons1, leading to their degradation by nonsense-mediated decay (NMD). These events reduce overall protein expression levels of affected genes, potentially contributing to gene regulation and disease mechanisms. Here, we present LeafCutter2, which enables identification and quantification of unproductive splicing from short-read RNA-seq data. LeafCutter2 requires minimal gene annotations (start and stop codons) to annotate NMD-inducing splicing events, and identifies differential unproductive splicing between groups, providing insights into its contributions to differential gene expression. Moreover, LeafCutter2 enables mapping of unproductive splicing quantitative trait loci (u-sQTLs), which often colocalize with expression QTLs and GWAS loci. Applying LeafCutter2 to RNA-seq data across human and 6 non-human species, we uncovered a broad landscape of unproductive splicing, which varies widely across tissues. Strikingly, we observed a conserved developmental-stage-specific increase in unproductive splicing during testis maturation across all species. In Alzheimers disease (AD), we analyzed RNA-seq data from the AD Functional Genomics consortium FunGen-xQTL project and identified unproductive splicing events in 18 AD risk genes, including TSPAN14, PICALM, and CASS4, likely mediating genetic effects on disease risk. We performed an integrative analysis using gene expression QTLs, protein expression QTLs, and AD GWAS data, showing that unproductive splicing provides unique regulatory insights beyond traditional approaches. Thus, LeafCutter2 represents a powerful tool for understanding the functional impact of alternative splicing on gene expression and disease mechanisms.

genomics↗

bioRxiv2025

Noninvasive ultrasound targeted modulation of calcium influx in splenic immunocytes potentiates antineoplastic immunity attenuating hepatocellular carcinoma proliferation

The spleen, as the largest immune organ, plays a pivotal role in modulating immune responses, particularly in the context of carcinogenesis and tumor progression. Non-pharmacological manipulation, particularly splenic ultrasound stimulation (SUS), has demonstrated significant immunomodulatory efficacy in alleviating chronic inflammatory diseases, suggesting its potential to revitalize splenic immunocompetence suppressing tumor proliferation, yet remains underexplored. This study applied low-frequency pulsed focused ultrasound (FUS) noninvasively stimulating the spleen (FUS sti. spleen) to investigate the efficacy in enhancing antitumor immunity and suppressing hepatocellular carcinoma (HCC). The results showed that FUS sti. spleen significantly suppressed tumor proliferation, achieving a suppression rate of >70% for H22-HCC and >83% for Hepa1-6-HCC, along with significantly prolonged survival. Comprehensive flow cytometry, single-cell RNA sequencing (scRNA-seq) and cytokine analyses demonstrated that SUS profoundly reshaped the splenic and intratumoral immune landscape, specifically activating cytotoxic CD8+ T cells and NK cells while suppressing immunosuppressive cell populations. Mechanistically, FUS facilitated calcium influx in splenic immunocytes, activating multiple signaling pathways, such as TNF, NF{kappa}B, MAPK, HIF-1, and ErbB, thereby counteracting tumor-driven immunosuppressive polarization while potentiating robust immune activation that impedes malignant progression and neoplastic proliferation. Leveraging above insights, we developed spleen-targeted nanodroplets encapsulating bioavailable calcium ions (STNDs@Ca{superscript 2}), which, upon FUS stimulation, undergo cavitation-mediated controlled release of Ca{superscript 2}, further amplifying immunocyte activation and tumor suppression, achieving a remarkable H22-HCC suppression rate of over 90%. This study highlights the therapeutic potential of ultrasound-mediated splenic immunomodulation, both as a standalone intervention and in synergy with STNDs@Ca{superscript 2}, as a novel and noninvasive strategy for cancer immunotherapy.

biophysics↗

bioRxiv2025

Effects of Exercise and Konjac on Lipid Metabolism and Mechanism in Obese Rats

ObjectiveTo study the effects of exercise and konjac on body weight and lipid metabolism in obese rats, and the possible mechanism of exercise combined with konjac on body weight and lipid metabolism. MethodsFifty male Sprague Dawley rats were randomly divided into 5 groups. After six weeks of intervention, blood lipid, body weight, liver weight, inflammatory factors, oxidative stress markers and proteins were measured. ResultsWeight and liver weight in HFD group were significantly higher (P<0.05, P<0.01) than those in CON group. Compared with HFD group, blood lipid index in intervention group were significantly decreased; The levels of MDA (P<0.01, P<0.05, P<0.05) and SOD (P<0.05) in intervention group were significantly decreased; the GSH levels in HAE group and HKE group were significantly increased(P<0.01, P<0.05); the levels of IL-6, TNF-, and leptin in HAE group (P<0.05, P<0.05, P<0.01) and HKE group (P<0.01, P<0.01, P<0.05) were significantly decreased; ApoA5 in intervention group was significantly increased (P<0.01), SREBP-1c and LXR was significantly decreased (P<0.01). ConclusionKonjac or exercise alone can improve the lipid metabolism, and the comprehensive effect is better. The mechanism of regulating lipid metabolism may be related to the expression of LXR, SREBP-1c and ApoA5.

biochemistry↗

bioRxiv2025

Characteristics of Tactile Orientation Perception: Oblique Effect, Active vs Passive Exploration, and Serial Dependence

Orientation perception is one of the most fundamental aspects of somatosensory perception, similar to its visual counterpart. In the current study, we examined several features of tactile orientation perception and their interactions, aiming to better understand the underlying mechanisms. We found that active exploration exhibits better orientation acuity compared to passive exploration. We also observed an exploration-independent and paradigm-independent robust anisotropy (i.e., tactile oblique effect) in tactile orientation acuity where the proximal-distal axis demonstrates superior orientation acuity compared to oblique and medial-lateral orientations. Finally, we demonstrated that, similar to its visual counterpart, tactile orientation perception showed a systematic attractive serial dependence effect, in which current orientation perception is biased towards the previous trial. However, this attractive effect is driven by post-perceptual processing/response rather than the stimulus per se.

neuroscience↗

bioRxiv2025

C9orf50 is a Targetable Spliceosome Regulator for Cancer Immunotherapy

Cancer cells harbor cell-intrinsic programs capable of sculpting immunogenic landscapes, yet molecular brakes that enforce immune evasion remain poorly defined. Here, we identify C9ORF50, a previously uncharacterized intrinsically disordered protein, as a liquid-liquid phase separation-driven regulator of RNA processing and actionable immunotherapy target. Genetic ablation of C9ORF50 induces selective intron retention in spliceosome component transcripts, leading to cytoplasmic accumulation of immunogenic double-stranded RNA (dsRNA). This dsRNA activates type I interferon pathway that in turn orchestrates a chemokine secretory program critical for T cell recruitment. The resultant enhancement of tumor immunogenicity and reprogramming of tumor immune microenvironment drives robust antitumor immunity, effectively converting immunologically "cold" tumors to "hot" phenotypes. Therapeutic targeting of C9ORF50 via RNA interference achieved robust tumor suppression in syngeneic models, suggesting its translational relevance. Notably, C9ORF50 exhibits tumor-predominant expression, with minimal baseline levels detected in healthy tissues or immune cell populations, underscoring its potential safety as a therapeutic target. Our study not only identifies C9ORF50 as a novel LLPS-dependent regulator of RNA splicing but also establishes it as a promising and potentially safe therapeutic target for cancer immunotherapy.

cancer biology↗

bioRxiv2025

The entorhinal spatial map integrates visual identity information of landmarks

The location and identity of landmarks provide spatial and nonspatial information of an environment, respectively, to guide spatial navigation. While the medial entorhinal cortex (MEC) is essential for representing spatial information, it is unclear whether it also encodes landmark identity. Here, we conducted two-photon calcium imaging of the MEC when mice navigated in multiple virtual environments, and discovered a general ability of the MEC to encode landmark identity through cue cells, which responded to individual landmarks during virtual navigation. Cue cells represented landmark identity by exhibiting more distinct activity patterns between visually disparate landmarks than identical ones. The representation was modulated by the spatial shift of cue cell activity relative to landmark location. Moreover, the identity encoding by the same cue cell population changed between different environments but was maintained within the same environment despite increased experience. In contrast, landmark location encoding by cue cells was regulated by experience, suggesting different mechanisms underlying the encodings of landmark identity and location. Finally, compared to cue cells, grid cells weakly encoded landmark identity but more robustly encoded landmark location. Thus, the MEC integrates both spatial and nonspatial information during navigation, but potentially through different circuit mechanisms.

neuroscience↗