Biology subjects

Guo, N.

Publications and source records attributed to Guo, N..

At least 19 recordsLinked to original sources

bioRxiv2026

D-Mannose treats obesity by increasing adipose Treg cells and suppressing gut Firmicutes

Early-life microbiota represent an indispensable factor for the proper development and function of host metabolism and the immune system. We have demonstrated that neonatal exposure to antibiotics for the first 3 weeks (NeoATB) leads to obesity in adulthood, characterized by gut microbiota dysbiosis and dysregulated immune responses. Here, we demonstrate that feeding D-mannose suppresses NeoATB-induced obesity, accompanied by improved glucose tolerance and decreased insulin resistance. Mechanistically, D-mannose feeding decreased hypoxia and increased oxygenation and recovery of metabolic activity of adipocytes. D-mannose restored CD4+Foxp3+ST2+ Tregs, leading to a reduction of Th1 pro-inflammatory cells in the adipose tissue of NeoATB mice. Significantly, we revealed that D-mannose treatment reversed the dysregulated ratios of phylum Firmicutes to phylum Bacteroidetes in obese NeoATB mice, which was surprisingly attributed to D-mannose-mediated suppression of the growth of Firmicutes rather than an increase in the growth of Bacteroidetes. These findings should have therapeutic implications for the treatment of obesity in human patients.

immunology↗

bioRxiv2026

Multi-omic profiling of human thymic B cells reveals intrathymic Ig-class switching and differentiation into multiple memory B cell subsets

Primarily recognized as the site for T cell development, the thymus supports a complex interplay between thymic stromal cells and developing thymocytes, which is essential for T cell maturation and the establishment of central tolerance. Emerging evidence indicates that thymic B cells contribute to tolerance induction by functioning as antigen-presenting cells. However, their developmental pathways and functional roles remain poorly understood. Using tissue mass cytometry, we localized B cells in the thymus and their orientation towards other cells in the medulla. We characterized the heterogeneity of thymic B cells using single-cell RNA sequencing of cells isolated from human thymi, identifying naive, germinal center-like, plasma cell, and multiple memory B cell populations. We identified a distinct pre-B cell subset with local thymic B cell development potential, that can develop due to the inhibition of Notch signaling by Deltex1, a Notch antagonist. Using BCR repertoire analysis, we explored clonal diversity, somatic hypermutation patterns and class switch recombination of thymic B cells. Spectral flow cytometry further validated the surface phenotype of thymic B cell populations and confirmed the presence of distinct CD21-CD27- memory compartments with heterogeneous surface immunoglobulin isotype usage. In doing so we provide novel insights into the unique biology of human thymic B cells, their development, and their differentiation in the human thymus. We conclude that the human thymus supports local B cell development and differentiation into medullary memory-like populations that undergo class switching with limited somatic hypermutation, suggesting secondary lymphoid-like B cell programs adapted to central tolerance induction. One Sentence SummaryThe human thymus is not only a primary lymphoid organ for T cell development, but also a secondary site for the development and maturation of unique populations of B cells.

immunology↗

bioRxiv2025

MS4MS: LLMs-driven Multi-agent System for Small-molecule Identification via LC-MS/MS

Small molecule identification is central to research fields such as drug discovery, but in complex systems like Traditional Chinese Medicine (TCM), traditional mass spectrometry analysis methods remain constrained by bottlenecks including insufficient database coverage, fragmented analysis workflows, and poor result interpretability. To address these limitations, we developed MS4MS, a large language model-driven multi-agent system that enables an end-to-end automated pipeline from raw data to small molecule identification. Validation on a public benchmark demonstrates that MS4MS achieves state-of-the-art performance in molecular formula prediction. Furthermore, its innovative small molecule identification agent enables efficient and interpretable compound elucidation. Verification using herbal extracts indicates MS4MSs outstanding performance regarding analytical coverage and the discrimination of isomers. Consequently, MS4MS offers a novel, accurate, interpretable, and high-throughput end-to-end automated strategy for small molecule identification, overcoming the analytical bottlenecks of traditional mass spectrometry in natural products and complex TCM systems.

bioinformatics↗

bioRxiv2025

High-salt diet disturbs the physiological uterine endothelial junction remodeling during pregnancy

A high-salt diet (HSD) induced excessive sodium intake is a major risk factor for various diseases. However, its specific effects on uterine endothelial cell and pregnancy outcomes remain poorly understood. In this study, we demonstrated that HSD induces gestation specific hypertension and adverse pregnancy outcomes in murine models. The proper spiral artery remodeling, which involved the decidual vascular endothelia, is thought to be essential for normal regulation of gestational blood pressure. We explored the molecular basis for the adaptation of vascular endothelial cell based on the transcriptome data, and uncovered the significant changes for the cell junction in the endothelia during this process. Furthermore, it was revealed that HSD induced more salt accumulation in the uteri and triggered the disturbed vascular endothelium cytoskeletal remodeling, which was associated impaired trophoblast cell invasion and incorporation into the vascular wall. Overall, our study identifies unique roles of decidual endothelium for pregnancy vascular remodeling, and demonstrates that HSD disrupts physiological spiral artery remodeling through endothelial maladaptation, which may concurrently induce systemic endothelial damage in maternal systemic vascular.

physiology↗

bioRxiv2025

Tissue-embedded CD4⁺ plasticity structures mucosal immunity in IBD-related inflammation

CD4 T helper (Th) cell responses to commensal microbiota are linked to Inflammatory Bowel Disease (IBD), yet how Th programs coexist and evolve in human tissues remains poorly defined. Here, we profiled CD4 memory T cells in intestinal biopsies using immunological and histological approaches to map their phenotypes, functional states, and spatial relationships across disease states. A marked expansion of CD4 T cells concomitant with a ROR{gamma}t Th population with elevated T-bet expression was linked to progression of inflammation. Moreover, Foxp3 cells co-expressing ROR{gamma}t emerged within the inflamed niche, indicating regulatory-Th17 plasticity. Trajectory visualization revealed a potential branched differentiation path towards either regulatory or tissue-resident Th17-like fates, with both termini expressing activation and proliferation markers. Correlation network analysis connected pro-inflammatory CD4 states to T-betGranzyme-B CD8 subsets, indicative of crosstalk between helper and cytotoxic lineages. Histology corroborated this organization, showing frequent interactions between CD4 and CD8 cells in the lamina propria and epithelial border. In functional assays, TCR stimulation during active disease revealed broad suppression of CD4 pro-inflammatory cytokines concomitant with expansion of Foxp3 cells. Conversely, HLA-DR+CD38+ memory subset retained multifunctionality, producing elevated levels of pro-inflammatory cytokines. Together, these results provide insight into a dynamic, tissue-embedded CD4 landscape in IBD. HighlightsO_LIIBD inflammation shapes CD4+ T-cell plasticity and tissue-residency programming. C_LIO_LICorrelated CD4+ and cytotoxic CD8+ T cells co-localize in inflamed mucosa. C_LIO_LIMucosal CD4 memory T cells show hypo-responsiveness in active IBD. C_LIO_LIHLA-DR+CD38+ memory CD4 T cells amplify inflammation via cytokine output. C_LI

immunology↗

bioRxiv2025

Bacteriophage protein Dap2 inhibits bacterial type III secretion system and synergizes with Dap1 to evade anti-phage immunity

The evolutionary arms race between bacterial immunity and phages has driven the emergence of sophisticated anti-defense systems (ADSs). However, certain ADSs exhibit incomplete suppression of their cognate defense systems, suggesting functional cooperation between multiple ADSs targeting the same bacterial safeguard. In this study, we characterize Dap2, a protein encoded by a Pseudomonas aeruginosa phage PaoP5, which directly binds to the Lon protease to prevent the degradation of the phage-encoded HNH endonuclease. Deletion of dap2 in PaoP5 exhibits significantly impaired genome packaging due to insufficient levels of HNH. Strikingly, Dap2 synergizes with its genomically adjacent partner Dap1, a previously identified HNH-binding protein providing partial Lon resistance, to achieve complete protection of HNH. Beyond anti-defense activity, Dap2 disrupts host virulence by sequestering the type III secretion system (T3SS) transcriptional activator ExsA, suppressing bacterial pathogenicity while redirecting metabolic resources toward phage progeny production. This study unveils a dual functional ADS that simultaneously modulates bacterial virulence and anti-phage immunity, both aimed at ensuring phage survival and maximizing progeny production. Furthermore, it elucidates a novel mechanism whereby phages employ synergistic ADS pairs (Dap1/Dap2) to achieve complete neutralization of a bacterial defense system, when individual components provide only partial protection. These findings significantly enhance our understanding of the intricate evolutionary arms race between phages and their bacterial hosts.

microbiology↗

bioRxiv2025

Obesity Increases Atherosclerosis Susceptibility via Inter-tissue miR-30e-SLC7A11 Axis

BackgroundWith obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health later on. Previous studies showed that microRNA-30e (miR-30e) level is elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown. MethodsMiRNA data mining and RT-PCR validations were used to demonstrate the positive association among serum level of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (RNA-seq and single-nucleus RNA-seq), metabolomics, and in silico analysis were used to establish a miR-30e-5p-SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific Slc7a11 knockout (EC-Slc7a11-/-) and gain or loss of function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis. ResultsThe level of adipocyte-derived miR-30e-5p was significantly upregulated in obese humans with coronary artery disease and obese and atherosclerotic mice. Via serum exosomes, the adipocyte-generated miR-30e-5p targeted SLC7A11 mRNA in vascular ECs. SLC7A11 deficiency due to miR-30e-5p targeting dysregulated glutamate/cystine metabolism increased glycolysis, reduced oxidative phosphorylation, and impaired mitochondrial function. The EC dysfunction could be rectified by SLC7A11 overexpression or miR-30e-5p antagonism. Exogenously delivered miR-30e-5p phenocopied the increased atherosclerosis in EC-Slc7a11-/- mice. In contrast, miR-30e-5p antagomir treatment reduced atherosclerosis in Apoe-/- and ob/ob mice. ConclusionOur multi-omics approaches demonstrates that the adipose-derived miR-30e-5p downregulated SLC7A11 mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.

molecular biology↗

bioRxiv2025

Hydroxychloroquine-functionalized Ionizable Lipids Mitigate Inflammatory Responses in mRNA Therapeutics

Lipid nanoparticle (LNP)-based mRNA therapeutics, highlighted by the success of SARS-CoV-2 vaccines, face challenges due to inflammation caused by ionizable lipids. These ionizable lipids can activate the immune system, particularly when co-delivered with nucleic acids, leading to undesirable inflammatory responses. We introduce a novel class of anti-inflammatory ionizable lipids functionalized with hydroxychloroquine (HCQ), which suppresses both lipid-induced and nucleic acid-induced immune activation. These HCQ-functionalized LNPs (HL LNPs) exhibit reduced proinflammatory responses while maintaining efficient mRNA delivery. Structural and physicochemical analyses revealed that HCQ-functionalization results in a distinct particle structure with significantly improved stability. The efficacy of HL LNPs was demonstrated across various therapeutic contexts, including a prophylactic vaccination model against varicella-zoster virus (VZV) and CRISPR-Cas9 gene editing targeting PCSK9. Notably, HL LNPs showed robust mRNA expression after repeated administration, addressing concerns of inflammation and ensuring sustained therapeutic effects. These findings highlight the potential of HCQ-functionalized LNPs in expanding the safe use of mRNA therapeutics, particularly for applications requiring repeated dosing and in scenarios where inflammation-induced side effects must be minimized.

bioengineering↗

bioRxiv2025

Yeast HMGB protein Hmo1 is a multifaceted regulator of DNA damage tolerance

The chromosome architecture protein Hmo1 in Saccharomyces cerevisiae is categorized as an HMGB protein as it consists of two structure-specific DNA binding HMGB motifs. However, it deviates from canonical HMGB proteins that have acidic C-terminal domains (CTDs) by bearing a basic one. Hmo1 plays diverse functions in gene regulation and genome integrity. There is evidence implicating Hmo1 in DNA damage tolerance (DDT) that enables DNA replication to bypass lesions on the template. Hmo1 is believed to direct DNA lesions to the error-free template switching (TS) pathway of DDT and aids in the formation of the key TS intermediate sister chromatid junction (SCJ), but the underlying mechanism(s) has yet to be resolved. In this work, we took genetics and molecular biology approaches to further investigate the role of Hmo1 in DDT. We found extensive functional interactions of Hmo1 with components of the genome integrity network in cellular response to the genotoxin methyl methanesulfonate (MMS), implicating Hmo1 in multiple processes in the execution or regulation of homology-directed DNA repair, replication-coupled chromatin assembly, and cell cycle checkpoint. Notably, our data pointed to a role of Hmo1 in directing SJC to the nuclease-mediated resolution pathway instead of the helicase/topoisomerase mediated dissolution pathway for processing/removal. They also suggested that Hmo1 modulates both the recycling of parental histones and the deposition of newly synthesized histones at the replication fork to ensure proper chromatin formation on nascent DNA that is important for DDT. We found evidence that Hmo1 antagonizes the function of histone H2A variant H2A.Z (also known as Htz1 in yeast) in DDT. We also found that Hmo1 is required for DNA damage checkpoint signaling induced by MMS as wells as for DNA negative supercoiling as a proxy of chromatin structure. Moreover, we obtained evidence indicating that the CTD of Hmo1 may or may not be required for its function in DDT depending on the genetic background of the host. Taken together, our findings demonstrate that Hmo1 can contribute to, or regulate, multiple processes of DDT via different mechanisms.

genetics↗

bioRxiv2024

DeepPrep: An accelerated, scalable, and robust pipeline for neuroimaging preprocessing empowered by deep learning

Neuroimaging has entered the era of big data. However, the advancement of preprocessing pipelines falls behind the rapid expansion of data volume, causing significant computational challenges. Here, we present DeepPrep, a pipeline empowered by deep learning and workflow manager. Evaluated on over 55,000 scans, DeepPrep demonstrates a 11-fold acceleration, exceptional scalability, and robustness compared to the current state-of-the-art pipeline, providing a promising solution to meet the scalability requirements of neuroimaging.

neuroscience↗

bioRxiv2023

Pan-genome analysis of different morphotypes reveals genomic basis of Brassica oleracea domestication and differential organogenesis

The domestication of Brassica oleracea has resulted in diverse morphological types with distinct patterns of organ development. Here we report a graph-based pan-genome of B. oleracea constructed with high-quality genome assemblies of different morphotypes. The pan-genome harbors over 200 structural variant (SV) hotspot regions enriched with auxin and flowering-related genes. Population genomic analyses reveal that early domestication of B. oleracea focused on leaf or stem selection. Gene flows resulting from agricultural practices and variety improvement are detected among different morphotypes. Selective sweep analysis identifies an auxin-responsive SAUR gene and a CLE family gene as the crucial players in the leaf-stem differentiation during the early stage of B. oleracea domestication, and the BoKAN1 gene as instrumental in shaping the leafy heads of cabbage and Brussels sprouts. Our pan-genome and functional analyses further discover that variations in the BoFLC2 gene play key roles in the divergence of vernalization and flowering characteristics among different morphotypes, and variations in the first intron of BoFLC3 are involved in fine-tuning the flowering process in cauliflower. This study provides a comprehensive understanding of the pan-genome of B. oleracea and sheds light on the domestication and differential organ development of this globally important crop species.

plant biology↗

bioRxiv2023

Uncover spatially informed shared variations for single-cell spatial transcriptomics with STew

MotivationThe recent spatial transcriptomics (ST) technologies have enabled characterization of gene expression patterns and spatial information, advancing our understanding of cell lineages within diseased tissues. Several analytical approaches have been proposed for ST data, but effectively utilizing spatial information to unveil the shared variation with gene expression remains a challenge. ResultsWe introduce STew, a Spatial Transcriptomic multi-viEW representative learning method, to jointly analyze spatial information and gene expression in a scalable manner, followed by a data-driven statistical framework to measure the goodness of model fit. Through benchmarking using Human DLPFC data with true manual annotations, STew achieved superior performance in both clustering accuracy and continuity of identified spatial domains compared with other methods. STew is also robust to generate consistent results insensitive to model parameters, including sparsity constraints. We next applied STew to various ST data acquired from 10x Visium and Slide-seqV2, encompassing samples from both mouse and human brain, which revealed spatially informed cell type clusters. We further identified a pro-inflammatory fibroblast spatial niche using ST data from psoriatic skins. Hence, STew is a generalized method to identify both spatially informed clusters and disease-relevant niches in complex tissues. AvailabilitySource code and the R software tool STew are available from github.com/fanzhanglab/STew. Contactfan.3.zhang@cuanschutz.edu Supplementary informationSupplementary data are provided.

bioinformatics↗

bioRxiv2023

High-resolution Dynamic Human Brain Neural Activity Recording Using 3T MRI

Despite extensive research over decades, a non-invasive technique capable of capturing neural activities in the human brain with high spatiotemporal resolution is still lacking. The recently proposed direct imaging of neuronal activity (DIANA) using ultrahigh-field magnetic resonance imaging (MRI) has shown promise, but the translation from anesthetized mice to awake humans poses a significant challenge. Here we present Time Resolved ImaGing of Global Electroneurophysiological Record (TRIGGER), a novel technique that enables the direct detection of neural activity in the awake human brain using 3T MRI. In 18 participants, visual responses were captured at 5-mm spatial resolution and 1.4-ms temporal resolution. Importantly, the delay in stimulus presentation reliably corresponded to the latency of neural responses on a millisecond scale. Furthermore, when stimuli were presented to one visual field, the responses in two hemispheres exhibited the expected time difference. This non-invasive mapping approach holds the potential to elucidate neural dynamics underlying human brain function and disorders.

neuroscience↗

bioRxiv2022

Identification of plasma proteins associated with oesophageal cancer chemotherapeutic treatment outcomes using SWATH-MS

Oesophageal adenocarcinoma (OAC) is an aggressive cancer with a five-year survival of <15%. Current chemotherapeutic strategies only benefit a minority (20-30%) of patients and there are no methods available to differentiate between responders and non-responders. We performed quantitative proteomics using Sequential Window Acquisition of all THeoretical fragment-ion spectra-Mass Spectrometry (SWATH-MS) on albumin/IgG-depleted and non-depleted plasma samples from 23 patients with locally advanced OAC prior to treatment. Individuals were grouped based on tumour regression (TRG) score (TRG1/2/3 vs TRG4/5) after chemotherapy, and differentially abundant proteins were compared. Protein depletion of highly abundant proteins led to the identification of around twice as many proteins. SWATH-MS revealed significant quantitative differences in the abundance of several proteins between the two groups. These included complement c1q subunit proteins, C1QA, C1QB and C1QC, which were of higher abundance in the low TRG group. Of those that were found to be of higher abundance in the high TRG group, GSTP1 was found to exhibit the lowest p-value and highest classification accuracy and Cohens kappa value. Concentrations of these proteins were further examined using ELISA-based assays. This study provides quantitative information relating to differences in the plasma proteome that underpin response to chemotherapeutic treatment in oesophageal cancers.

cancer biology↗

bioRxiv2022

Impact of various vaccine boosters on neutralization against Omicron following prime vaccinations with inactivated or adenovirus-vectored vaccine

Since the first report on November 24, 2021, the Omicron SARS-CoV-2 variant is now overwhelmingly spreading across the world. Two SARS-CoV-2 inactivated vaccines (IAVs), one recombinant protein subunit vaccine (PRV), and one adenovirus-vectored vaccine (AdV) have been widely administrated in many countries including China to pursue herd immunity. Here we investigated cross-neutralizing activities in 341 human serum specimens elicited by full-course vaccinations with IAV, PRV and AdV, and by various vaccine boosters following prime IAV and AdV vaccinations. We found that all types of vaccines induced significantly lower neutralizing antibody titers against the Omicron variant than against the prototype strain. For prime vaccinations with IAV and AdV, heterologous boosters with AdV and PRV, respectively, elevated serum Omicron-neutralizing activities to the highest degrees. In a mouse model, we further demonstrated that among a series of variant-derived RBD-encoding mRNA vaccine boosters, it is only the Omicron booster that significantly enhanced Omicron neutralizing antibody titers compared with the prototype booster following a prime immunization with a prototype S-encoding mRNA vaccine candidate. In summary, our systematical investigations of various vaccine boosters inform potential booster administrations in the future to combat the Omicron variant.

immunology↗

bioRxiv2021

Reference genomes of 545 silkworms enable high-throughput exploring genotype-phenotype relationships

The silkworm Bombyx mori is a domestic insect for silk production and a lepidopteran model. The currently available genomes limit a full understanding of its genetic and phenotypic diversity. Here we assembled long-read genomes of 545 domestic and wild silkworms and constructed a high-resolution pan-genome dataset. We found that the silkworm population harbors extremely variable genomes containing 7,308 new gene families, 4,260 (22%) core gene families, and 3,432,266 non-redundant SVs. We deciphered a series of causal genes and variants associated with domestication, breeding, and ecological adaptation traits, and experimentally validated two of those genes using CRISPR-Cas9 or RNA interference. This unprecedented large-scale genomic resource allows for high-throughput screening of interesting traits for functional genomic research and breeding improvement of silkworms and may serve as a guideline for traits decoding in other species.

genomics↗

bioRxiv2021

Transcriptional regulation of neural stem cell expansion in adult hippocampus

Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a blueprint of RGL symmetric self-renewal for stem cell community. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

neuroscience↗

bioRxiv2020

Single point mutations can potentially enhance infectivity of SARS-CoV-2 revealed by in silico affinity maturation and SPR assay

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates the viral cell attachment and serves as a promising target for therapeutics development. Mutations on the S-RBD may alter its affinity to cell receptor and affect the potency of vaccines and antibodies. Here we used an in-silico approach to predict how mutations on RBD affect its binding affinity to hACE2 (human angiotensin-converting enzyme2). The effect of all single point mutations on the interface was predicted. SPR assay result shows that 6 out of 9 selected mutations can strengthen binding affinity. Our prediction has reasonable agreement with the previous deep mutational scan results and recently reported mutants. Our work demonstrated in silico method as a powerful tool to forecast more powerful virus mutants, which will significantly benefit for the development of broadly neutralizing vaccine and antibody.

bioinformatics↗