Biology subjects

Qu, W.

Publications and source records attributed to Qu, W..

13 recordsLinked to original sources

bioRxiv2026

Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection

Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.

neuroscience↗

bioRxiv2026

cGAS inhibition delays TDP-43-driven ALS Pathogenesis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by motor neuron loss and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA splicing. However, the upstream modulators of this process remain poorly defined. Here we identify cyclic GMP-AMP synthase (cGAS) as a central mediator of TDP-43 pathology and associated mis-splicing. cGAS expression was elevated in ALS patient brains and enriched across activated microglia. In human iPSC-derived microglia-motor neuron co-cultures, neuronal TDP-43 pathology triggered microglial cGAS activation, whereas pharmacological inhibition with a potent human cGAS inhibitor reduced phosphorylated TDP-43, restored lysosomal and phagocytic programs, normalized microglial reactivity, and reversed TDP-43-associated RNA splicing defects. In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.

neuroscience↗

bioRxiv2025

Energy Landscape Analysis Reveals Thalamic Modulation of Brain State Transitions During Movie Watching

Understanding how large-scale brain networks dynamically coordinate during complex, real-world experiences remains a crucial topic in contemporary neuroscience. Leveraging naturalistic paradigm, this study employed energy landscape modeling to characterize the temporal dynamics of brain state transitions and their functional significance. Using the Sherlock fMRI dataset, we identified two dominant brain states: a perception- and attention-oriented state, and an introspective, integrative state, each associated with distinct canonical brain networks. State transitions were differentially associated with the recruitment of these networks and manifested as either the "easy" or "hard" route, depending on the energy required for the transition. Notably, we demonstrated that the probability of specific state transitions robustly predicted inter-subject correlation within three clusters: subcortical-rich, salience/attention-rich, and DMN-rich regions. This indicates that flexible reorganization of cortical networks underlies shared neural engagement during ecologically valid experiences. Critically, the thalamus emerged as a central modulator, displaying activity changes and dynamic nucleus-specific thalamocortical connectivity changes tied to distinct transition profiles. Together, our findings shed light on the energetic and network mechanisms that orchestrate brain dynamics during naturalistic cognition and underscore the pivotal role of cortico-thalamo-cortical circuits in governing flexible, collective neural responses to richly structured real-life stimuli.

neuroscience↗

bioRxiv2025

Simple, fast, low-cost method to produce transgenic pollen

There are two main technical bottlenecks in plant genetic transformation: the intracellular delivery of exogenous genes and tissue culture. This study is an elaboration of a method combining needle-free jet injection (NFJI) and vacuum infiltration technology to efficiently introduce exogenous genes into pear (Rosaceae) plant pollen. This method was verified with the model plant tobacco (Solanaceae) wherein the GFP reporter gene was successfully introduced into the pollen and expressed. Then, the gene was transferred to the seeds via pollination, and after the seeds were sown, gene expression was observed at the roots of the seedlings. Furthermore, in this study, the apple (Rosaceae) gene MdGH3.1 was introduced into tobacco using NFJI, resulting in transgenic seedlings that were shorter than the seedlings in the control group and presented fewer, shorter root hairs, confirming that the MdGH3.1 gene was functional. In addition, the applicability of this method to other plant species, including dicotyledonous and monocotyledonous plants, was explored. In particular, when the MdGH3.1 gene was introduced into Arabidopsis (Brassicaceae), the phenotype of the resulting plants was consistent with that of the transgenic tobacco. The results indicate that genes can be effectively delivered into plants by this method without on the need for tissue culture. Moreover, the instruments used in this method are portable, affordable, and easy to operate, allowing for direct utilization in the field, indicating the great application potential of this method.

bioengineering↗

bioRxiv2024

P(all-atom) Is Unlocking New Path For Protein Design

We introduce Pallatom, an innovative protein generation model capable of producing protein structures with all-atom coordinates. Pallatom directly learns and models the joint distribution P(structure, seq) by focusing on P(all-atom), effectively addressing the interdependence between sequence and structure in protein generation. To achieve this, we propose a novel network architecture specifically designed for all-atom protein generation. Our model employs a dual-track framework that tokenizes proteins into residue-level and atomic-level representations, integrating them through a multi-layer decoding process with "traversing" representations and recycling mechanism. We also introduce the atom14 representation method, which unifies the description of unknown side-chain coordinates, ensuring high fidelity between the generated all-atom conformation and its physical structure. Experimental results demonstrate that Pallatom excels in key metrics of protein design, including designability, diversity, and novelty, showing significant improvements across the board. Our model not only enhances the accuracy of protein generation but also exhibits excellent sampling efficiency, paving the way for future applications in larger and more complex systems.

bioinformatics↗

bioRxiv2024

A human forebrain organoid model reveals the essential function of GTF2IRD1-TTR-ERK axis for the neurodevelopmental deficits of Williams Syndrome

Williams Syndrome (WS; OMIM#194050) is a rare disorder, which is caused by the microdeletion of one copy of 25-27 genes, and WS patients display diverse neuronal deficits. Although remarkable progresses have been achieved, the mechanisms for these distinct deficits are still largely unknown. Here, we have shown that neural progenitor cells (NPCs) in WS forebrain organoids display abnormal proliferation and differentiation capabilities, and synapse formation. Genes with altered expression are related to neuronal development and neurogenesis. Single cell RNA-seq (scRNA-seq) data analysis revealed 13 clusters in healthy control and WS organoids. WS organoids show an aberrant generation of excitatory neurons. Mechanistically, the expression of transthyretin (TTR) are remarkably decreased in WS forebrain organoids. We have found that GTF2IRD1 encoded by one WS associated gene GTF2IRD1 binds to TTR promoter regions and regulates the expression of TTR. In addition, exogenous TTR can activate ERK signaling and rescue neurogenic deficits of WS forebrain organoids. Gtf2ird1 deficient mice display similar neurodevelopmental deficits as observed in WS organoids. Collectively, our study reveals critical function of GTF2IRD1 in regulating neurodevelopment of WS forebrain organoids and mice through regulating TTR-ERK pathway.

neuroscience↗

bioRxiv2024

Fertilization-induced synergid cell death by RALF12-triggered ROS production and ethylene signaling

Fertilization-dependent elimination of the persistent synergid cell is essential to block supernumerary pollen tubes and thus to avoid polyspermy in flowering plants. Little is known about the molecular mechanisms ensuring timely induction and execution of synergid cell death. We analysed manually isolated maize synergid cells along their degeneration and show that they are gland cells expressing batteries of genes encoding small secreted proteins under control of the MYB98 transcription factor. This network is down-regulated after fertilization, while genes involved in reactive oxygen species (ROS) production, ethylene biosynthesis and response, senescence, and oxidative stress regulation are induced before synergid elimination and its ultimate fusion with the endosperm. We further show that fertilization-induced RALF12 peptide specifically triggers mitochondrial ROS and apoptosis, while ethylene promotes synergid degeneration. In conclusion, this study sheds light on developmental programmed cell death (dPCD) in plants and provides a unique resource to discover novel PCD regulators.

cell biology↗

bioRxiv2023

Berberine impairs spermatogenesis in mice by modulating ornithine metabolism via gut microbiota regulation

Berberine (BBR) is used to treat diarrhea clinically, its reproductive toxicity, however, is poorly documented. This study aims to investigate the impact of BBR on the male reproductive system. Gradient doses of BBR were administered orally to experimental mice for consecutive 14 days. The gut microbiota, sperm concentration of cauda epididymis, and serum testosterone levels were measured after the last dose for assessing the effects of BBR. Moreover, the metabolome and transcriptome of the mice and microbiota were also investigated. Intragastric BBR administration resulted in a significant decrease in serum testosterone levels and epididymal sperm concentration in mice, which was attributed to a dramatic decrease of Muribaculaceae abundance in the gut microbiota of mice. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment experiments also demonstrated that Muribaculaceae is necessary for spermatogenesis. Metabolomic analysis revealed that BBR affected the arginine and proline metabolism pathways, of which ornithine levels were downregulated after BBR administration. Intragastric administration of M.intestinale and its metabolite ornithine to BBR-treated mice achieved a recovery of sperm concentration and testosterone levels. RNA sequencing of testes showed the genes related to the LDLR-mediated cholesterol-synthesis testosterone pathway were downregulated after BBR administration. The levels of testosterone increased and Ldlr gene became more transcriptionally active in TM3 cells cultured in media supplemented with ornithine. This study for the first time revealed an association between BBR-induced gut Muribaculaceae dysbiosis and defects in spermatogenesis via ornithine metabolism, which provided a candidate and strategy for the treatment of infertility caused by a decreased serum testosterone level-induced by gut microbiota dysbiosis.

pharmacology and toxicology↗

bioRxiv2022

Integrated Network Pharmacology and Experimental Analysis Unveil Modulation of EGFR/MAPK Signaling Cascades in Acute Cerebral Ischemia-Reperfusion Injury by Qing-Tong-Hua-Yu Decoction

ObjectiveBased on network pharmacology, the response of Qing-tong-hua-yu Decoction (QTHY) to the regulation of EGFR/MAPK signaling cascade in cerebral ischemia-reperfusion injury was discussed and the possible mechanism of the protective effect of QTHY on the cerebral ischemia-reperfusion injury was studied. MethodsA compound-target disease-function-pathway network was established and analyzed based on the network pharmacology approach used in Chinese medicine. The correlation, which is between effect of the components of QTHY Decoction against CI/RI with EGFR/MAPK signalling cascade response, was observed. And then the degree of neurological deficits in each group was assessed after cerebral ischemia for 2 hours and reperfusion for 3 hours, 24 hours, 3 days and 7 days. Expression levels of EGFR and p44/42MAPK in ischemic brain tissue at different time points in various groups of rats were tested by Western bolt (WB), real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC). ResultsNetwork pharmacology analysis revealed that QTHY-mediated treatment involved 439 key targets, in which the effect of QTHY groups against CI/RI was associated with EGFR/MAPK signaling cascade. QTHY treatment reduced neurological deficit scores and improved ischemic changes in rats. In addition, QTHY promoted EGFR and p44/42MAPK expression in the SVZ through the EGFR/MAPK signaling cascade, with varying degrees of improvement at different time points. ConclusionQTHY can better improve cerebral ischemia injury in CI / RI rats and exert the neuroprotective effect of cerebral ischemia-reperfusion injury. This may be related to the potential of QTHY to activate the EGFR / MAPK signaling cascade, which is consistent with the results of network pharmacology analysis.

neuroscience↗

bioRxiv2021

DeepMHCII: A Novel Binding Core-Aware Deep InteractionModel for Accurate MHC II-peptide Binding Affinity Prediction

Computationally predicting MHC-peptide binding affinity is an important problem in immunological bioinformatics. Recent cutting-edge deep learning-based methods for this problem are unable to achieve satisfactory performance for MHC class II molecules. This is because such methods generate the input by simply concatenating the two given sequences: (the estimated binding core of) a peptide and (the pseudo sequence of) an MHC class II molecule, ignoring the biological knowledge behind the interactions of the two molecules. We thus propose a binding core-aware deep learning-based model, DeepMHCII, with binding interaction convolution layer (BICL), which allows integrating all potential binding cores (in a given peptide) and the MHC pseudo (binding) sequence, through modeling the interaction with multiple convolutional kernels. Extensive empirical experiments with four large-scale datasets demonstrate that DeepMHCII significantly outperformed four state-of-the-art methods under numerous settings, such as five-fold cross-validation, leave one molecule out, validation with independent testing sets, and binding core prediction. All these results with visualization of the predicted binding cores indicate the effectiveness and importance of properly modeling biological facts in deep learning for high performance and knowledge discovery. DeepMHCII is publicly available at https://weilab.sjtu.edu.cn/DeepMHCII/.

bioinformatics↗

bioRxiv2021

The first report and biological characteristics of Helcococcus ovis isolated from clinical bovine mastitis in a Chinese dairy herd

Helcococcus ovis (H. ovis) was first reported in ovine subclinical mastitis milk and post-mortem examinated organs in Spain and the United Kingdom in 1999, subsequently, it appeared in cattle, horse, goat, and human. However, isolation and characterization of the strain in clinical bovine mastitis is unknown. Therefore, our objective was to identify the pathogen in clinical bovine mastitis. A total of 4 strains from 34 bovine mastitis milk samples were identified, there are tiny and transparent colonies from clinical bovine mastitis milk samples in a Chinese dairy farm, however, these colonies could not be identified using on-farm biochemical tests. The isolates were transported to Mastitis Diagnostic Laboratory of China Agricultural University in Beijing. The colonies were identified as a mixture of H. ovis and Arcanobacterium pyogenes according to microscopic examination and 16S rRNA gene sequencing and the phylogenetic tree was constructed using 16S rRNA gene sequence of H. ovis isolates. In addition, the growth curve and biochemistry test were performed, we also examined the antimicrobial resistance profiles and constructed murine mammary infection model. Our results showed that the H. ovis were closely related to the strains isolated from China and Japan, growth speed of H. ovis was relatively slower than Strep.agalactiae, the phenotypic characteristics were similar to CCUG37441 and CCUG39041 except to lactose, isolates were sensitive to most of antimicrobials except daptomycin, H. ovis could lead to murine mastitis. In this report, we firstly described the characteristics of H. ovis that are associated with clinical bovine mastitis in China.

microbiology↗

bioRxiv2020

Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice

Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and the development of neuropathic pain in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CX3CR1creER/+:R26LSL-hM4Di/+ transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) exclusively in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain initiation and maintenance. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1{beta}). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after peripheral nerve injury. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.

neuroscience↗

bioRxiv2018

Replication timing shapes the cancer epigenome and the nature of chromosomal rearrangements

HighlightsO_LIReplication timing alterations are conserved in cancers of different cell origins\nC_LIO_LILong-range epigenetic deregulation in cancer involves altered replication timing\nC_LIO_LICancer late-replicating loci are hypomethylated and acquire facultative heterochromatin\nC_LIO_LIReplication timing status potentiates cis and trans chromosomal rearrangements\nC_LI\n\nSummaryReplication timing is known to facilitate the establishment of epigenome, however, the intimate connection between DNA replication timing and changes to the genome and epigenome in cancer remain uncharted. Here, we perform Repli-Seq and integrated epigenome analysis and show that early-replicating loci are predisposed to hypermethylation and late-replicating loci to hypomethylation, enrichment of H3K27me3 and concomitant loss of H3K9me3. We find that altered replication timing domains correspond to long-range epigenetically deregulated regions in prostate cancer, and a subset of these domains are remarkably conserved across cancers from different tissue origins. Analyses of 214 prostate and 35 breast cancer genomes reveal that late-replicating DNA is prone to cis and early-replicating DNA to trans chromosomal rearrangements. We propose that differences in epigenetic deregulation related to spatial and temporal positioning between early and late replication potentiate the landscape of chromosomal rearrangements in cancer.

genomics↗