Biology subjects

Nie, W.

Publications and source records attributed to Nie, W..

17 recordsLinked to original sources

bioRxiv2026

Intranasal Fritillaria taipaiensis nanovesicles alleviate acute lung injury via the lung-brain axis

Acute lung injury (ALI) is a severe inflammatory syndrome frequently complicated by brain injury, which worsens outcomes. Here, we explored whether regulation of the lung-brain axis represents a therapeutic strategy for the management of ALI. We show that intranasal administration of Fritillaria taipaiensis-derived exosome-like nanovesicles (Ft-ELNs) ameliorates LPS-induced ALI and ALI-associated hypothalamic inflammation in mice. Ft-ELNs preferentially accumulate in the lungs, inhibiting TRPV1 in both the lungs and the hypothalamus to establish the lung-brain axis. In parallel, Ft-ELNs primarily regulate systemic humoral immunity by inhibiting the VEGFR1/PI3K/AKT/NF?B signaling pathway. In vitro experiments further confirmed that Ft-ELNs are efficiently internalized by alveolar epithelial MLE-12 cells, exerting protective effects by suppressing VEGFR1 expression. Mechanistically, we identified Ft-miR1 of Ft-ELNs as the key functional effector that directly targets the Flt1 3'UTR to inhibit VEGFR1 expression. These data suggest that Ft-ELNs attenuate lung-brain axis inflammation by targeting VEGFR1 and may hold potential as novel therapeutic agents for the treatment of severe ALI.

immunology↗

bioRxiv2025

Genomics of sable (Martes zibellina) x pine marten (Martes martes) hybridization

The sable (Martes zibellina) and pine marten (Martes martes) are two Palearctic mustelids with long-recognized hybrids (kidases), whose fertility was controversial for years. Early genetic studies confirmed hybrids beyond F1, but details remained unclear due to low-resolution methods. Both species were hunted for centuries, but anthropogenic pressures during the 20th-century caused severe bottlenecks in the sable followed by hunting bans and large-scale reintroduction programs across much of its range, including the sympatric zone, potentially affecting hybridization. We resequenced 30 individuals from most of the sables range and Eastern part of pine martens. Among samples, we found a broad spectrum of hybrid types with mosaic recombinant chromosomes that confirm hybrid fertility and indicate crossover is not suppressed in kidases. This necessitates re-evaluation of previous research, as we detected notable discrepancies between STR-based ancestry and whole-genome analysis. In pine martens, we revealed mitochondrial DNA introgression from sables, indicating displacement of native pine marten mitochondrial sequences. Pine marten heterozygosity is relatively low ([~]0.5-0.6 hetSNPs/kbp) while sable diversity ([~]1.5-1.8 hetSNPs/kbp) is unexpectedly high for a species with its demographic history, likely reflecting successful reintroduction programs. We dated species divergence at 1.52 (CI: 1.05-2.06) Mya and identified candidate genes associated with ecological, morphological, and dietary differences, as well as hybrid fertility issues. This study is the first to elucidate marten hybridization at the whole-genome level, opening new research directions for understanding hybridization among Holarctic martens, the genetic consequences of reintroduction programs, and comparative adaptomics.

genomics↗

bioRxiv2025

ROMO1 loss in cholinergic neurons induces mitochondrial ultrastructural damage and ALS-like neuromuscular degeneration

Mitochondrial dysfunction is strongly associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron degeneration. However, it remains obscure whether mitochondrial abnormities are sufficient to drive ALS development. Here, we show that selective depletion of reactive oxygen species modulator 1 (ROMO1), an inner mitochondrial membrane-delimited protein, in cholinergic neurons leads to adult-onset, progressive locomotor deficits in mice that closely resemble ALS pathology. ROMO1 ablation in cholinergic neurons induces ALS-like neuromuscular degeneration, as evidenced by age-dependent motor neuron loss, axon degeneration, disrupted cholinergic transmission, neuromuscular junction denervation, and the resultant muscle atrophy. Notably, ROMO1 loss induces early and progressive mitochondrial cristae deformation in motor neurons, preceding the onset of ALS-like syndromes. Our findings support that mitochondrial impairment in vulnerable motor neurons is a sufficient contributor to ALS etiology, positioning mitochondria as a potential therapeutic target.

neuroscience↗

bioRxiv2025

TransHLA: A Hybrid Transformer Model for HLA-Presented Epitope Detection

BackgroundPrecise prediction of epitope presentation on human leukocyte antigen (HLA) molecules is crucial for advancing vaccine development and immunotherapy. Conventional HLA-peptide binding affinity prediction tools often focus on specific alleles and lack a universal approach for comprehensive HLA site analysis. This limitation hinders efficient filtering of invalid peptide segments. ResultsWe introduce TransHLA, a pioneering tool designed for epitope prediction across all HLA alleles, integrating Transformer and Residue CNN architectures. TransHLA utilizes the ESM2 large language model for sequence and structure embeddings, achieving high predictive accuracy. For HLA class I, it reaches an accuracy of 84.72% and an AUC of 91.95% on IEDB test data. For HLA class II, it achieves 79.94% accuracy and an AUC of 88.14%. Our case studies using datasets like CEDAR and VDJdb demonstrate that TransHLA surpasses existing models in specificity and sensitivity for identifying immunogenic epitopes and neoepitopes. ConclusionsTransHLA significantly enhances vaccine design and immunotherapy by efficiently identifying broadly reactive peptides. Our resources, including data and code, are publicly accessible at https://github.com/SkywalkerLuke/TransHLA Key PointsO_LIWe developed TransHLA, a deep learning tool for predicting epitopes across all HLA alleles using Transformer and Residue CNN architectures. C_LIO_LIThe model uses ESM2 embeddings to improve predictive accuracy and efficiency. C_LIO_LITransHLA shows superior specificity and sensitivity in identifying immunogenic epitopes and neoepitopes compared to existing models. C_LIO_LIOur approach offers potential advancements in vaccine design and immunotherapy through enhanced peptide analysis. C_LI

bioinformatics↗

bioRxiv2024

Distribution of contezolid in different tissues of mice and human patients infected with Mycobacterium abscessus

BackgroundLinezolid (LZD), while effective against Mycobacterium abscessus (MAB), can cause myelosuppression and peripheral neuropathy. Contezolid (CZD) shares a similar antimicrobial profile with improved safety, but biodistribution data remain limited. This study evaluated CZDs biodistribution in MAB-infected mice and humans and its therapeutic potential across infection sites. MethodsMICs of CZD and LZD against 32 clinical MAB isolates and three reference strains were determined. In MAB-infected mice, drug concentrations were quantified in plasma and pulmonary and cerebral tissues at 2, 4, and 8 hours post-administration. In MAB-infected patients, CZD concentrations in bone, plasma, and cerebrospinal fluid were measured at multiple time points and MAB counts in sputum cultures were assessed daily over 14 days. ResultsRespective MIC50 and MIC90 values were 8 and 32 {micro}g/mL (LZD) and 16 and 32 {micro}g/mL (CZD). Pharmacokinetic CZD and LZD level comparisons revealed peak CZD plasma levels within 2 hours, higher systemic CZD levels, comparable pulmonary tissue concentrations, and slightly lower CZD cerebral tissue penetration. In patients, CZD levels in ankle joint effusion samples reached 2.0885 {micro}g/mL at 6 hours, peaking in the posterior malleolus. Plasma CZD concentrations peaked at 8.2349 {micro}g/mL at 3 hours and dropped to 6.1065 {micro}g/mL by 6 hours, while CSF levels were 0.9295 and 0.792 {micro}g/mL at 3 and 6 hours, respectively. Sputum bacterial burden decreased rapidly within 24 hours of CZD treatment, with near-complete clearance by day 4. ConclusionCZD and LZD exhibit comparable tissue distribution but different site-specific penetration, supporting their potential for treating diverse MAB infections.

microbiology↗

bioRxiv2024

Systematic Discovery of Phage Genes that Inactivate Bacterial Immune Systems

Bacteria have developed numerous defense systems to counter phage infections. However, the extent to which phages possess countermeasures against these defense systems remains unclear. In this study, we combined a phage gene knockout library with a defense system library to analyze the mechanisms by which phages counteract bacterial defense systems. After attempting gene deletions of 105 open reading frames (ORFs) in the DruSM1 phage ({Phi}DruSM1), we successfully generated 73 different ORF knockout phages. By infecting this library with bacteria harboring defense system expression plasmids, we identified inactivators of Druantia type I (Druad1), Brex type I, AVAST type III, Sir2+HerA, DUF4297+HerA, and hhe, as well as an activator of Retron Ec86, in a single phage genome. Synthetic phages incorporating Druad1 effectively eradicated Escherichia coli harboring the robust Druantia type I defense system by altering DNA methylation at m6A sites of the phage. This study highlighted the prevalence of various antidefense mechanisms employed by phages to overcome bacterial defense systems.

microbiology↗

bioRxiv2023

The role of neutrophil typing in homeostatic resilience protective model of inflammatory preconditioning

Sepsis is a systemic inflammatory response syndrome (SIRS) characterized by a dysregulated host response to infection that results in organ dysfunction. The response of neutrophils to early inflammation is critical, interferon regulatory factors 4 (IRF4) and interferon regulatory factors 5 (IRF5) are expressed in most cell types of the immune system, but the relationship between the role of IRF4 and IRF5 in preconditioning-protected septic peritonitis mouse model and neutrophils response remains unknown. In this study, we used an E.coli-induced septic peritonitis mouse model and zebrafish model to explore the relationship between neutrophil inflammation and IRF subtype changes in the process of septic peritonitis. Mechanistically, we found that the protein complex formed by polymorphonuclear neutrophils (PMN) and IRF5/MyD88 can secrete pro-inflammatory factors and directly kill invading bacteria. Author SummaryNumerous animal and clinical sepsis studies have shown that markedly impaired recruitment of neutrophils to sites of infection and failure to clear bacteria contribute to excessive inflammation and increased mortality in sepsis. In our previous work, we established an Escherichia coli (E.coli) lethal septic peritonitis model and a preconditioning-protected septic peritonitis mouse model. In the early stage of septic peritonitis, a large number of PMN infiltrate the peritoneal cavity, which produces an inflammatory response to invasive bacteria. In this study, the switching process between pro-inflammatory and anti-inflammatory attracted our attention. Our research shows that IRF5-IRF4 regulatory axis leads to a PMN phenotype switch in sepsis and the expression of IRF5 and IRF4 was related to PMN pro-inflammatory (N1 type) and anti-inflammatory (N2 type) phenotypes, respectively.

immunology↗

bioRxiv2023

Potentiation of host defense through sRNA packaged in OMVs of Xanthomonas oryzae pv. oryzicola

Bacterial outer membrane vesicles (OMVs)-packaged delivery of noncoding small RNAs (sRNAs) can function as novel mediators of interspecies communication. However, the role of which in the interaction between phytopathogenic bacteria and their host plants is unclear. In this study, we characterized differentially packaged sRNAs in Xanthomonas oryzae pv. oryzicola (Xoc) BLS256 OMVs using RNA-Seq, and we selected the most abundant sRNA Xosr001 for further study based on its essential role in the induction of stomatal immunity in rice. Xoc loads Xosr001 into OMVs, which are transferred specifically into the mechanical tissues of rice leaves. We uncovered that OMVs-mediated Xosr001 inhibitors attenuated OsJMT1 transcripts in vivo and reduced the endogenous MeJA contents in rice leaves. Stomatal conductance was measured to show that {Delta}Xosr001 mutant weakened the ability of stomatal re-opening on rice leaves after spray inoculation. Most notably, the transgenic rice lines OsJMT1-HA-OE exhibited attenuated stomatal immunity and disease susceptibility after {Delta}Xosr001 infection compared with Xoc infection. These results define that Xosr001 packaged in Xoc OMVs highlights a smart molecular mechanism to activate stomatal immunity in rice.

plant biology↗

bioRxiv2022

Oncogenic context shapes the fitness landscape of tumor suppression

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the features of this landscape remain poorly understood and cannot be revealed by human cancer genotyping alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. The resulting fitness landscape is rugged (the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context), shows no evidence of diminishing-returns epistasis within variants of the same oncogene, and is inconsistent with expectations of a simple linear signaling relationship among these three oncogenes. Our findings suggest that tumor suppressor effects are strongly context-specific, which limits the set of evolutionary paths that can be taken through the fitness landscape.

cancer biology↗

bioRxiv2022

GenSLMs: Genome-scale language models reveal SARS-CoV-2 evolutionary dynamics.

We seek to transform how new and emergent variants of pandemiccausing viruses, specifically SARS-CoV-2, are identified and classified. By adapting large language models (LLMs) for genomic data, we build genome-scale language models (GenSLMs) which can learn the evolutionary landscape of SARS-CoV-2 genomes. By pretraining on over 110 million prokaryotic gene sequences and finetuning a SARS-CoV-2-specific model on 1.5 million genomes, we show that GenSLMs can accurately and rapidly identify variants of concern. Thus, to our knowledge, GenSLMs represents one of the first whole genome scale foundation models which can generalize to other prediction tasks. We demonstrate scaling of GenSLMs on GPU-based supercomputers and AI-hardware accelerators utilizing 1.63 Zettaflops in training runs with a sustained performance of 121 PFLOPS in mixed precision and peak of 850 PFLOPS. We present initial scientific insights from examining GenSLMs in tracking evolutionary dynamics of SARS-CoV-2, paving the path to realizing this on large biological data.

bioinformatics↗

bioRxiv2022

High-Coverage Four-Dimensional Data-Independent Acquisition Proteomics and Phosphoproteomics Enabled by Deep Learning-Driven Multi-Dimensional Prediction

Four-dimensional (4D) data-independent acquisition (DIA)-based proteomics is an emerging technology that has been proven to have high precursor ion sampling efficiency and higher precursor identification specificity. However, the current 4D DIA proteomics is still dependent on the building of project-specific experimental library which is time-consuming and limits the coverage for identification/quantification. Herein, a workflow of 4D DIA proteomics by using the predicted multi-dimensional in silico library was established. A deep learning model Deep4D that could high-accurately predict the CCS and RT of both the unmodified and phosphorylated peptides was developed. By using an integrated 4D in silico library containing millions of peptides, we have identified 25% more protein than using experimental libraries in the DIA proteomics analysis of HeLa cells. We further demonstrate that the introduction of in silico prediction library can greatly complement the experimental library of directly obtained phosphorylated peptides, resulting in a greater increase in the identification of phosphorylated peptides and phosphorylated proteins.

bioinformatics↗

bioRxiv2021

Quantification of Myxococcus xanthus Aggregation and Rippling Behaviors: Deep-learning Transformation of Phase-contrast into Fluorescence Microscopy Images

Myxococcus xanthus bacteria are a model system for understanding pattern formation and collective cell behaviors. When starving, cells aggregate into fruiting bodies to form metabolically inert spores. During predation, cells self-organize into traveling cell-density waves termed ripples. Both phase-contrast and fluorescence microscopy are used to observe these patterns but each has its limitations. Phase-contrast images have higher contrast, but the resulting image intensities lose their correlation with cell density. The intensities of fluorescence microscopy images, on the other hand, are well correlated with cell density, enabling better segmentation of aggregates and better visualization of streaming patterns in between aggregates. However, fluorescence microscopy requires the engineering of cells to express fluorescent proteins and can be phototoxic to the cells. To combine the advantages of both imaging methodologies, we develop a generative adversarial network that converts phase-contrast into fluorescent images. By including an additional histogram-equalized output to the state-of-art pix2pixHD algorithm, our model generates accurate images of aggregates and streams, enabling the estimation of aggregate positions and sizes, but with small shifts of their boundaries. Further training on ripple patterns enables accurate estimation of the rippling wavelength. Our methods are thus applicable for many other phenotypic behaviors and pattern formation studies.

systems biology↗

bioRxiv2021

P5A-ATPases control the ER translocation of Wnt for neuronal migration

Wnt family are conserved secretory proteins required for developmental patterning and tissue homeostasis. The mechanisms underlying intracellular maturation and intercellular signal transduction of Wnt proteins have been extensively studied. However, how Wnt is targeted to the endoplasmic reticulum (ER) for processing and secretion remains elusive. Here we report that CATP-8/P5A-ATPase directs neuronal migration non-cell autonomously in C. elegans by regulating EGL-20/Wnt biogenesis. CATP-8 functions as a translocase to translocate EGL-20/Wnt nascent polypeptide into the ER by interacting with the hydrophobic core region of EGL-20 signal sequence. Such regulation of Wnt biogenesis by P5A-ATPase is conserved in human cells. These findings reveal physiological roles of P5A-ATPase in neural development and identify Wnt proteins as direct substrates of P5A-ATPase for ER translocation.

developmental biology↗

bioRxiv2021

A H3K9me2-Binding Protein AGDP3 Limits DNA Methylation and Transcriptional Gene Silencing in Arabidopsis

DNA methylation is critical for tuning gene expression to prevent potentially deleterious gene-silencing. The Arabidopsis DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1) initiates active DNA demethylation and is required for the prevention of DNA hypermethylation at thousands of genomic loci. However, the mechanism recruiting ROS1 to specific loci is not well understood. Here, we report the discovery of Arabidopsis AGENET Domain Containing Protein 3 (AGDP3) as a cellular factor required for ROS1-mediated DNA demethylation, and targets ROS1 to specific loci. We found that AGDP3 could bind to the H3K9me2 mark by its AGD12 cassette. The crystal structure of the AGDP3 AGD12 in complex with an H3K9me2 peptide reveals the molecular basis for the specific recognition, that the dimethylated H3K9 and unmodified H3K4 are specifically anchored into two different surface pockets. Interestingly, a histidine residue located in the methylysine binding aromatic cage enables AGDP3 pH-dependent H3K9me2 binding capacity. Considering the intracellular pH correlates with the histone acetylation status, our results provide the molecular mechanism for the regulation of ROS1 DNA demethylase by the gene silencing H3K9me2 mark and the potential crosstalk with active histone acetylation mark.

plant biology↗

bioRxiv2020

New insight into bacterial iron competition: A-to-I editing in ferric enterobactin uptake

Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by the adenosine deaminase RNA-specific family of enzymes, is a frequent post-transcriptional modification in metazoans. Research on A-to-I editing in bacteria is limited, and the importance is underestimated. In this study, we show that bacteria may use A-to-I editing as an alternative strategy to promote uptake of metabolic iron. The T408A editing event of xfeA in Xanthomonas oryzae pv. oryzicola (Xoc) senses extracytoplasmic iron and changes the hydrogen bonding network of ligand channel domains. The frequency of A-to-I RNA editing during iron-deficient conditions increased by 76.87%, which facilitated the passage of iron through the XfeA outer membrane channel. When bacteria were subjected to high iron concentrations, the percentage of A-to-I editing in xfeA decreased, which reduced iron transport via XfeA. Furthermore, A-to-I RNA editing increased expression of multiple genes in the chemotaxis pathway, including methyl-accepting chemotaxis proteins (MCPs) that sense concentrations of exogenous ferric enterobactin (Fe-Ent) at the cytoplasmic membrane. A-to-I RNA editing helps Xoc move towards an iron-rich environment and supports our contention that editing in xfeA facilitates entry of a ferric siderophore. Overall, our results reveal a new signaling mechanism that bacteria use to facilitate iron uptake and improve their competitiveness.

microbiology↗

bioRxiv2019

Visual impairment, spectacle wear and academic performance among junior high school students in western China

In September 2013, 2248 students from 36 junior high schools in Shaanxi Province underwent assessment of visual acuity (VA), completed a questionnaire about their spectacle use and were administered a standardized mathematics examination. Among 2,248 students (mean age 13.6 years, 52% male), visual impairment was present in 699 (31%, 95% Confidence Interval 29-33%). Spectacle wear was observed in 360 of 966 children needing glasses (37%). Ownership of spectacles among children needing glasses was associated with poorer uncorrected vision in the better-seeing eye (P <0.001) and paternal educational (p=0.001), but not age, sex, boarding at school, both parents having out-migrated for work or maternal education. Spectacle ownership among children with visual impairment was associated with better test performance (P=0.035). Therefore, visual impairment and non-wear of spectacle were common. Wearing spectacles was associated with better academic performance in this cross-sectional analysis, consistent with recent trial results among younger children.

scientific communication and education↗

bioRxiv2019

Moxifloxacin efficacy against Mycobacterium abscessus in vivo using zebrafish model

Moxifloxacin (MFX) showed good activity in vitro against Mycobacterium abscessus (M. abscessus) and was suggested as one of the antibiotic regimens for adults with M. abscessus disease. However, some other studies showed that MFX showed less or none activity against M. abscessus. In our study we aim to evaluate MFX activity against M. abscessus using zebrafish (ZF) model in vivo. MIC of each drugs were determined by broth microdilution method. M. abscessus labeled by CM-DiI, were micro-injected into ZF. Survival curves were determined by recording dead ZF every day. After 4 days of incubation ZF were lysed. Colony-forming unit (CFU) were enumerated and results are expressed as mean log10 CFU per ZF. Bacteria dissemination and fluorescence intensity in ZF were observed and analyzed. Inhibition rate was also calculated. In our study MFX showed good activity in vitro. But in vivo MFX showed limited restriction to M. abscessus. The association between increased survival and high dose of MFX is not significant. Same results were observed in bacterial fluorescence intensity and inhibition rates, with no significant difference when compared with no drug group (P > 0.05). However, significant difference was observed in azithromycin (AZM) group. MFX showed limited efficacy on Mycobacterium abscessus in vivo using ZF model. MFXs activity in vivo need to be confirmed.

microbiology↗