Biology subjects

Shi, W.

Publications and source records attributed to Shi, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

A hierarchical cascade of sleep rhythms drive memory consolidation in humans and are disrupted in epilepsy.

The cross-regional interplay of slow oscillations, sleep spindles, and ripples during sleep is believed to support systems memory consolidation but is understudied in humans. Using a validated behavioral task and intracranial neural recordings from orbitofrontal cortex, thalamus, and hippocampus in 19 epilepsy patients, we examined the cross-regional interplay of sleep-oscillations and their role in memory consolidation. Orbitofrontal slow oscillations robustly modulate sleep rhythms both within and across regions. Most combinations of oscillation rates predict overnight memory consolidation, but hippocampal ripple rate and coupled hippocampal-orbitofrontal ripples were the strongest positive predictors of memory consolidation. In contrast, epileptic spikes coupled to sleep oscillations strongly predicted reduced memory consolidation, with the strongest negative effect observed when epileptic spikes were coupled to slow oscillations. These findings provide direct evidence of the hierarchical cascade of sleep oscillations in human memory processing and reveal how epileptic spikes disrupt this process in patients with epilepsy.

neuroscience↗

bioRxiv2025

A Chromosome-Scale Genome of Nanomia septata Reveals Extensive Rearrangement But No Clear Driver of the Unique Colony-Level Organization of Siphonophores

Siphonophores (Cnidaria:Hydrozoa) are pelagic colonial marine invertebrates with many highly specialized bodies (zooids) within a single colony. Their unique biology and ecological importance have made them of particular interest. Recent work revealed siphonophore genomes to be larger than in most other cnidarians. To investigate siphonophores genome biology and develop resources for future studies, we sequenced the genome of a single Nanomia septata to chromosome scale. The haploid genome is 1.5GB across 8 chromosomes, a reduction relative to the 15 chromosomes seen in closely related hydrozoan genomes, and is highly rearranged, consistent with multiple mixing events. Genome expansion occurred through intergenic repeat expansion, with protein-coding genes shorter than in most cnidarians. We found no genomic features clearly associated with siphonophores exceptional colony-level complexity. Gene families that play critical roles in cnidarian development have not expanded, and gene proximity was not generally correlated to their expression across zooids, except in male gonophores. To contextualize these observations, we genome sequenced 20 additional Nanomia specimens across the globe and mapped them to our chromosome-scale reference. Population genomic analyses support three previously recognized species of Nanomia, and at least one additional undescribed species. Overlapping geographic distribution of some Nanomia species suggest reproductive isolation in sympatry. Phylogenetic analyses of genome size indicate Nanomia septata and Nanomia cara have similarly large genomes between 1.5-1.7GB, while Nanomia bijuga and an undescribed species show a secondary reduction to 0.7GB. These results highlight how genomic factors have shaped colony organization and genome diversity within Nanomia.

genomics↗

bioRxiv2025

Diverse and Flexible Strategies Enable Successful Cooperation in Marmoset Dyads

In humans, cooperation relies on advanced social cognition, but the extent to which these mechanisms support cooperation in nonhuman primates remains unclear. To investigate this, we examined freely moving marmoset dyads in a cooperative lever-pulling task. Marmosets successfully coordinated actions, relying on social vision rather than environmental cues. Blocking visual access or replacing the partner with an automated agent disrupted coordination. Causal dependencies between social gaze and pull actions revealed both gaze-dependent and gaze-independent strategies. Cooperation depended on social relationships, including dominance, kinship, and sex. Remarkably, marmosets adapted strategies based on partner identity, indicating rapid social learning and memory. Altogether, these findings show that flexible, cognitively driven cooperation extends more broadly across primates than previously recognized, informing our understanding of cooperative behaviors mechanisms and evolution.

neuroscience↗

bioRxiv2025

Novel HIV-1 fusion peptide immunogens using glycan-engineered alphavirus-like particles

Immunofocusing on conserved, subdominant epitopes is critical for vaccines against highly diverse viruses such as HIV-1, influenza, and SARS-CoV-2. The eight-residue N-terminus of the HIV-1 fusion peptide (FP) is one such example of a promising yet small target. We developed new FP immunogens using three alphavirus-like particles (VLPs) and introduced additional glycans to mask shared carrier-specific epitopes. In two independent guinea pig studies, sequential immunization with heterologous carriers enhanced FP-directed antibody titers, which were further improved with glycan engineering. Separately, using diverse FP variants sharing the same N-terminal six amino acids increased neutralizing antibody titers. When combined, these two strategies led to higher FP-directed titers and, after Env trimer boosting, induced FP-directed neutralizing antibodies against multi-clade wild-type HIV-1 in nearly all animals. These findings established the importance of minimizing recurrent off-target epitopes across immunizations and support the engineered VLPs as a promising platform for peptide immunization. HighlightsO_LINovel HIV-1 fusion peptide immunogens using glycan-engineered alphavirus-like particles C_LIO_LIImproved FP-directed response by minimizing recurrent carrier-specific epitopes across immunizations C_LIO_LIImproved neutralizing response by sequential immunization with diverse FP variants C_LIO_LIFP-directed antibodies neutralizing multi-clade wildtype viruses in nearly all animals C_LI

immunology↗

bioRxiv2025

Glycosylated IgG antibodies accelerated the recovery of haemorrhagic fever with renal syndrome patients

AbstractHaemorrhagic fever with renal syndrome (HFRS) is a fatal disease caused by Hantaan virus (HTNV) infection. Humoral immunity is essential for effective viral clearance, however, the glycosylation characteristics of immunoglobulin G (IgG) in HFRS patients is not well known. Peripheral blood mononuclear cells from HFRS patients were obtained for B subset analysis using scRNA-seq and flow cytometry. HTNV specific IgG antibody titers were detected by enzyme-linked immunosorbent assay, and IgG glycosylation was analyzed by ultra-performance liquid chromatography. The proportions of the antibody-secreting memory (ASM) B cells and plasmablasts (PB) were significantly expanded among acute HFRS patients. We discovered significantly increased fucosylated IgG and decreased bisecting N-acetylglucosamine during the convalescent phase of HTNV infection. Meanwhile, positive correlations were observed between ASM subsets and galactosylation/sialylation in the IgG Fc region, and between PB subsets and sialylation. Notably, the glycosylation-related genes, such as RPN1 and RPN2, were primarily expressed differentially in the ASM and PB subclusters which were enriched in the N-glycosylation modifications of proteins through asparagine. Our findings indicated that IgG N-glycosylation may play a crucial role in combating HTNV infection and contributing to clinical recovery, which provided new insights for optimizing glycoengineered therapeutic antibodies.

immunology↗

bioRxiv2025

Effect of the S2' site cleavage on SARS-CoV-2 spike

SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2 site, before membrane fusion can occur. We report here a cryo-EM structure of S2 fragment after the S2 cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2 cleavage accelerates membrane fusion, probably by stabilizing fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

biochemistry↗

bioRxiv2025

Energy inefficiency underpinning brain state dysregulation in individuals with major depressive disorder

Disruptions in brain state dynamics are a hallmark of major depressive disorder (MDD), yet their underlying mechanisms remain unclear. This study, building on network control theory, revealed that decreased state stability and increased state-switching frequency in MDD are driven by elevated energy costs and reduced control stability, indicating energy inefficiency. Key brain regions, including the left dorsolateral prefrontal cortex, exhibited impaired energy regulation capacity, and these region-specific energy patterns were correlated with depressive symptom severity. Neurotransmitter and gene expression association analyses linked these energy deficits to intrinsic biological factors, notably the 5-HT2a receptor and excitatory-inhibitory balance. These findings shed light on the energetic mechanism underlying brain state dysregulation in MDD and its associated biological underpinnings, highlighting brain energy dynamics as a potential biomarker by which to explore therapeutic targets and advance precise interventions for restoring healthy brain dynamics in depression.

neuroscience↗

bioRxiv2025

Physical Activity and Depressive Mood Shared the Structural Connectivity between Motor and Reward Network: a population-based study from the UK Biobank

BackgroundExercise has been revealed to leave a positive effect on alleviating depressive symptoms by various existing studies. However, the neural basis behind this phenomenon remains unknown, as well as its underlying biological mechanism.AimsUsing a large neuroimaging cohort from UK Biobank, this study aimed to identify structural connectivity (SC) patterns simultaneously linked with physical activity and depression, as well as its biological interpretation.Method492 participants with major depression disorder (MDD) and 535 healthy controls (HC) were extracted from the UK Biobank dataset. Partial least squares regression was first utilized to explore a replicable SC pattern simultaneously associated with physical activity and depressive mood. The neuromaps toolbox was applied to interpret the biological ontologies of the identified SC pattern. Neuroimaging-transcriptome association and enrichment analyses were conducted to explore its underlying genetic basis, pathways and cell types. The reproducibility and generalizability were tested on another independent MDD dataset (N=3,496) and bipolar disorder (BD) dataset (N=81).ResultsA SC pattern linked with exercise was identified to be both significantly correlated with depressive mood and group discriminative between MDDs and HCs, which primarily located between the motor-related regions and reward-related regions. This pattern was associated with multiple neurotransmitter receptors, such as serotonin and GABA receptors, and enriched in pathways like synaptic signaling and astrocytes cell type. The SC pattern and genetic results were also replicated in another independent MDD dataset and present commonalities with BD.ConclusionsThis study not only initially identified a reproducible shared SC pattern between physical activity and depressive mood, but also elucidated the underlying biological mechanisms, which enhanced our understanding of how exercise helps alleviate depression and may inform the development of novel neuromodulation targets.

neuroscience↗

bioRxiv2025

Neural-physics adaptive reconstruction reveals 3D subcellular nanostructures over a large depth of field

Single-molecule localization microscopy (SMLM) enables volumetric nanoscopy by retrieving 3D molecular positions from engineered 2D fluorescence patterns. However, achieving nanoscale resolution over large axial ranges in complex biological samples remains challenging due to optical aberrations and overlapped single molecules. Here, we introduce LUNAR, a blind SMLM framework that can precisely localize high-density molecules even with inaccurate and highly distorted PSFs. LUNAR employs a self-supervised neural-physics learning strategy that jointly optimizes a physical PSF model and a neural network to infer key molecular parameters, including 3D positions, photon counts, and aberrations. Through simulations and experiments, we show that LUNAR achieves superior robustness to aberrations, high-density performance across diverse PSFs over multiple frames. We showcase its capabilities through whole-cell nanoscopy of mitochondria, nuclear pores, and neuronal cytoskeletons at large imaging depths. By uniting deep learning with physical modeling, LUNAR provides a calibration-free solution for aberration-robust volumetric nanoscopy and establishes a general framework for adaptive, data-driven 3D imaging.

biophysics↗

bioRxiv2025

Patient-Specific Pharmacogenomics unveils xCT Regulation Pathways in Colon Cancer

Colorectal cancer (CRC) represents the third-leading cause of cancer-related deaths. Knowledge covering diverse cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present an in-depth comparative mRNA-seq and microRNA-seq analysis of tissue samples from 32 CRC, pairing tumors with adjacent healthy tissues. The differential expression gene (DEG) analysis revealed an interconnection between nutrients, metabolic programs, and cell cycle pathways. We focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2 genes which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potency of the Xc-system in a cellular setting, we applied a knowledge-based approach for analyzing gene perturbations from CRISPR screens across various cell types as well as using a variety of functional assays in five primary patient-derived organoid cell models to functionally verify our hypothesis. We identified a previously undescribed cell surface protein signature predicting chemotherapy resistance and further highlighted the causality and potential of pharmacological blockage of ferroptosis as promising avenue for cancer therapy. Biological processes such as redox homeostasis, ion/amino acid transporters and de novo nucleotide synthesis were associated with these co-dependent genes in patient specimens. This study highlighted a number of overlooked genes as potential clinical targets for CRC and promotes stem cell-based, patient-individual in vitro model systems as a versatile partner platform to functionally validate in silico predictions, with focus on SLC7A11 and its associated genes in tumorigenesis.

cancer biology↗

bioRxiv2025

Retro Nasal blockade reduces the Neural Processing of Sucrose in the Human Brain

It is assumed "Non-volatile" tastes like sucrose do not activate retro nasal pathways. Recent studies find that sucrose when aerosolized, can reach the retro nasal olfactory region and be perceived. The neural mechanisms by which the human brain interprets sucrose via retro nasal pathways is unknown. We examined neural activity to sucrose with a nose clip on (blocking retro nasal) and nose clip off, in healthy adults (N=34, mean 25 yrs.). We examined the whole brain and ROIs involved in taste, smell, attention, reward and multi-modal integration; insula, postcentral gyrus, amygdala, olfactory cortex, subgenual and pregenual anterior cingulate, nucleus accumbens and OFC. We also examined correlations with subjective ratings of pleasantness and mouth fullness. We also examined the effect of the nose clip on the time to peak activity for sucrose using the bold signal time course. The nose clip on vs off reduced the subjective experience of mouth fullness. Neural activity to sucrose was reduced with the nose clip on in the primary taste, olfactory, attention and reward ROIs and in the rolandic operculum, lingual gyrus and precuneus in the whole brain analyses. The olfactory and prefrontal cortex ROIs tracked subjective mouth fullness, but this was not apparent with the nose clip on. Blocking retro nasal sensation reduces subjective and neural responses to sucrose taste. Retro nasal sensations could play a role in "pure" taste perception. Developing more satisfying low-sugar foods could be achieved by enhancing the perception of sweetness through aroma modulation.

neuroscience↗

bioRxiv2025

Circulating Exosomal PCNA: A Biomarker for Early and Pan-Cancer Detection

Detecting multiple cancers with a single, non-invasive liquid biopsy test remains a challenge, as no universally shared cancer biomarker with clinical significance has been identified in bodily fluids. In this study, we identified proliferating cell nuclear antigen (PCNA), a well-established pathological cancer biomarker in tissue biopsies, as being secreted into peripheral bodily fluids within exosomes. Our research demonstrated that cultured cancer cells continuously release large quantities of exosomal PCNA into their surrounding media. Furthermore, we confirmed its presence in human serum. Most importantly, cancer patients exhibited significantly higher levels of exosomal PCNA in their sera compared to healthy individuals. To assess its diagnostic potential, we evaluated the sensitivity and specificity of exosomal PCNA in a cohort of cancer patients and healthy controls. Receiver operating characteristic (ROC) analysis revealed a sensitivity of 77.2% and a specificity of 94.4%. These findings establish exosomal PCNA in peripheral bodily fluids as a promising universal biomarker for the early detection, diagnosis, and monitoring of multiple cancers through liquid biopsy.

cancer biology↗

bioRxiv2024

Single-cell analysis reveals distinct immune characteristics of hepatocellular carcinoma in HBV-positive versus HBV-negative cases

Infection with the Hepatitis B virus (HBV) is a key risk factor for Hepatocellular carcinoma (HCC) development and progression. It is widely recognized that immunopathological mechanisms are pivotal in developing HBV-related HCC. Nevertheless, the specific mechanisms by which HBV-induced modifications within the tumor microenvironment (TME) contribute to HCC pathogenesis are still not well understood. Here, we utilized single-cell RNA sequencing to analyze and compare the immune landscapes between HBV-positive and HBV-negative HCC. We discovered that HBV infection significantly modifies the immune cell makeup and state, and leads to the suppression and exhaustion of T cells within the TME. Specifically, an increase in SLC4A10+ CD8+ T cells and IFITM3+ macrophages was observed, along with the upregulation of the gene SLC35F1 in various immune cell subtypes. These findings offer valuable insights into the alteration of the immunological microenvironment in HCC associated with HBV infection, suggesting possible targets for immunotherapeutic intervention.

bioinformatics↗

bioRxiv2024

Pan-cancer N-glycoproteomic atlas of patient derived xenografts uncovers FAT2 as a therapeutic target for head and neck cancers

Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central role in cellular signaling. Despite this, their promise remains largely untapped due to the technical challenges inherent to profiling cell surface proteins. Here, we employed N-glycoproteomics to analyze 85 patient-derived xenografts (PDX), constructing Glyco PDXplorer - an in vivo pan-cancer atlas of cancer-derived cell surface proteins. We developed a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validated FAT2 as a head and neck squamous cancer (HNSC) enriched surface protein with limited expression in normal tissue. Functional studies revealed that FAT2 is essential for HNSC growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR) T cells targeting FAT2 demonstrated potent anti-tumor activity in HNSC models. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal resource to inform therapeutic target discovery for multiple cancers. HIGHLIGHTSO_LIPan-cancer landscape of cancer-derived cell surface proteins detected in vivo C_LIO_LIDevelopment of a multi-omic discovery pipeline to prioritize proteins with optimal expression profiles as immunotherapy targets C_LIO_LIIdentification and validation of FAT2 as a head and neck squamous cancer enriched surface protein with minimal expression in normal tissues C_LIO_LIFAT2 coordinates cell surface organization, adhesion, growth and survival through the integrin-PI3K-AKT pathway C_LIO_LIFAT2 CAR T cells demonstrate anti-tumour activity in pre-clinical models C_LI

cancer biology↗

bioRxiv2024

CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes

Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting 59 million individuals worldwide. Impairment of atrial cardiomyocyte (aCM) gene regulatory mechanisms predisposes to atrial fibrillation. The transcription factor TBX5 is essential for normal atrial rhythm, and its inactivation causes loss of aCM enhancer accessibility, looping, and transcriptional identity. Here we investigated the mechanisms by which TBX5 regulates chromatin organization. We found that TBX5 recruits CHD4, a chromatin remodeling ATPase, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). As a component of the NuRD complex, CHD4 functions to repress gene transcription. However, combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions. Genes repressed by CHD4 in aCMs included sarcomeric proteins from non-CM cell lineages. Genes activated by CHD4 in aCMs were characterized by TBX5-enhanced CHD4 recruitment, which enhanced chromatin accessibility and promoted the expression of aCM identity genes. This mechanism of TBX5 recruitment of CHD4 was critical for sinus rhythm because Chd4AKO mice had increased vulnerability to AF from electrical pacing and a fraction had spontaneous AF. Our findings reveal that CHD4 is essential for maintaining aCM gene expression, aCM identity, and atrial rhythm homeostasis.

genomics↗

bioRxiv2024

Microbial virulome and resistome in deep-sea cold seeps pose minimal public health risks

Deep-sea cold seeps host high microbial biomass and biodiversity that thrive on hydrocarbon and inorganic compound seepage, exhibiting diverse ecological functions and unique genetic resources. However, potential health risks from pathogenic or antibiotic-resistant microorganisms in these environments remain largely overlooked, especially during resource exploitation and laboratory research. Here, we analyzed 165 metagenomes and 33 metatranscriptomes from 16 global cold seep sites to investigate the diversity and distribution of virulence factors (VFs), antibiotic resistance genes (ARGs), and mobile genetic elements (MGEs). A total of 2,353 VFs are retrieved in 689 MAGs, primarily associated with non-pathogenic functions like adherence. Additionally, cold seeps harbor nearly 100,000 ARGs, as important reservoirs, with high-risk ARGs presenting at low abundance. Compared to other environments, microorganisms in cold seeps exhibit substantial differences in VF and ARG counts, with potential horizontal gene transfer facilitating their spread. These virulome and resistome profiles provide valuable insights into the evolutionary and ecological implications of pathogenicity and antibiotic resistance in extreme deep-sea ecosystems. Collectively, these results indicate that cold seep sediments pose minimal public health risks, shedding lights on environmental safety in deep-sea resource exploitation and research. ImportanceUnderstanding pathogenicity and antibiotic resistance in environmental reservoirs like deep-sea cold seeps is critical for assessing public health risks, particularly with increasing human activities such as deep-sea mining. This study offers the first comprehensive analysis of virulome, resistome, and mobilome profiles in cold seep microbial communities. While cold seeps act as reservoirs for diverse ARGs, high-risk ARGs are rare, and most VFs contribute to non-pathogenic ecological functions. These results highlight the minimal threat to public health posed by cold seeps, providing a reference for monitoring the spread of pathogenicity and resistance in extreme ecosystems and informing environmental safety assessments during deep-sea resource exploitation.

microbiology↗

bioRxiv2024

Multi-modal refinement of the human heart atlas during the first gestational trimester

1.Forty first-trimester human hearts were studied to lay groundwork for further studies of principles underlying congenital heart defects. We first sampled 49,227 cardiac nuclei from three fetuses at 8.6, 9.0, and 10.7 post-conceptional weeks (pcw) for single-nucleus RNA sequencing, enabling distinction of six classes comprising 21 cell types. Improved resolution led to identification of novel cardiomyocytes and minority autonomic and lymphatic endothelial transcriptomes, among others. After integration with 5-7 pcw heart single-cell RNAseq, we identified a human cardiomyofibroblast progenitor preceding diversification of cardiomyocyte and stromal lineages. Analysis of six Visium sections from two additional hearts was aided by deconvolution, and key spatial markers validated on sectioned and whole hearts in two- and three-dimensional space and over time. Altogether, anatomical-positional features including innervation, conduction and subdomains of the atrioventricular septum translate latent molecular identity into specialized cardiac functions. This atlas adds unprecedented spatial and temporal resolution to the characterization of human-specific aspects of early heart formation.

developmental biology↗

bioRxiv2024

Language model generates cis-regulatory elements across prokaryotes

Deep learning had succeeded in designing Cis-regulatory elements (CREs) for certain species, but necessitated training data derived from experiments. Here, we present Promoter-Factory, a protocol that leverages language models (LM) to design CREs for prokaryotes without experimental prior. Millions of sequences were drawn from thousands of prokaryotic genomes to train a suite of language models, named PromoGen2, and achieved the highest zero-shot promoter strength prediction accuracy among tested LMs. Artificial CREs designed with Promoter-Factory achieved a 100% success rate to express gene in Escherichia coli, Bacillus subtilis, and Bacillus licheniformis. Furthermore, most of the promoters designed targeting Jejubacter sp. L23, a halophilic bacterium without available CREs, were active and successfully drove lycopene overproduction. The generation of 2 million putative promoters across 1,757 prokaryotic genera, along with the Promoter-Factory protocol, will significantly expand the sequence space and facilitate the development of an extensive repertoire of prokaryotic CREs.

bioinformatics↗