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Gao, H.

Publications and source records attributed to Gao, H..

At least 109 records · Page 6Linked to original sources
bioRxiv2023

Single nuclei chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry

Single nuclei analysis is allowing robust classification of cell types in an organ that helps to establish relationships between cell-type specific gene expression and chromatin accessibility status of gene regulatory regions. Using breast tissues of 92 healthy donors of various genetic ancestry, we have developed a comprehensive chromatin accessibility and gene expression atlas of human breast tissues. Integrated analysis revealed 10 distinct cell types in the healthy breast, which included three major epithelial cell subtypes (luminal hormone sensing, luminal adaptive secretory precursor, and basal-myoepithelial cells), two endothelial subtypes, two adipocyte subtypes, fibroblasts, T-cells, and macrophages. By integrating gene expression signatures derived from epithelial cell subtypes with spatial transcriptomics, we identify specific gene expression differences between lobular and ductal epithelial cells and age-associated changes in epithelial cell gene expression patterns and signaling networks. Among various cell types, luminal adaptive secretory cells and fibroblasts showed genetic ancestry dependent variability. A subpopulation of luminal adaptive secretory cells with alveolar progenitor (AP) cell state were enriched in Indigenous American (IA) ancestry and fibroblast populations were distinct in African ancestry. ESR1 expression pattern was distinctly different in cells from IA compared to the rest, with a high level of ESR1 expression extending to AP cells and crosstalk between growth factors and Estrogen Receptor signaling being evident in these AP cells. In general, cell subtype-specific gene expression did not uniformly correlate with cell-specific chromatin accessibility, suggesting that transcriptional regulation independent of chromatin accessibility governs cell type-specific gene expression in the breast.

cancer biology↗
bioRxiv2023

BK channel gain-of-function disrupts limb control by suppressing neurotransmission during a critical developmental window

Gain-of-function mutations in BK potassium channels (BK GOF) cause debilitating involuntary limb movements. BK channels modulate action potential shape and neurotransmission in mature neurons, yet some BK GOF mutations also cause neurodevelopmental morbidities. Thus, whether BK GOF impairs limb control by altering the excitation/inhibition of mature motor circuits, or by disrupting their development, remains unclear. To address this issue, we developed a genetic method enabling spatiotemporal control of BK channel expression in neurons of the fruit fly, Drosophila. In concert with high-resolution measurements of limb kinematics, we demonstrate that GOF BK channels act during a narrow neurodevelopmental period to perturb limb control in adult flies. During this period, BK GOF alters synaptic localisation of the key active zone protein Bruchpilot and suppresses excitatory neurotransmission. In a wild-type background, we find that reducing neural activity during neurodevelopment yields similar motor defects to those observed in BK GOF flies. Conversely, enhancing neural excitability during development rescues alterations in limb kinematics in BK GOF flies. Collectively, our results suggest that BK GOF perturbs limb control largely by disrupting activity-dependent aspects of neuronal development.

neuroscience↗
bioRxiv2023

Enhancing Fairness in Disease Prediction with Optimizing Multiple Domain Adversarial Networks

Predictive models in biomedicine need to ensure equitable and reliable outcomes for the populations they are applied to. Unfortunately, biases in medical predictions can lead to unfair treatment and widening disparities, underscoring the need for effective techniques to address these issues. To enhance fairness, we introduce a framework based on a Multiple Domain Adversarial Neural Network (MDANN), which incorporates multiple adversarial components. In an MDANN, an adversarial module is applied to learn a fair pattern by negative gradients back-propagating across multiple sensitive features (i.e., characteristics of individuals that should not be used to discriminate unfairly between individuals when making predictions or decisions.) We leverage loss functions based on the Area Under the Receiver Operating Characteristic Curve (AUC) to address the class imbalance, promoting equitable classification performance for minority groups (e.g., a subset of the population that is underrepresented or disadvantaged.) Moreover, we utilize pre-trained convolutional autoencoders (CAEs) to extract deep representations of data, aiming to enhance prediction accuracy and fairness. Combining these mechanisms, we alleviate biases and disparities to provide reliable and equitable disease prediction. We empirically demonstrate that the MDANN approach leads to better accuracy and fairness in predicting disease progression using brain imaging data for Alzheimers Disease and Autism populations than state-of-the-art techniques.

bioinformatics↗
bioRxiv2023

BRCA1 and BRCA2 germline mutations driven signaling pathway alterations are sufficient to initiate breast tumorigenesis by the PIK3CAH1047R oncogene.

Single cell transcriptomics studies have begun to identify breast epithelial cell and stromal cell specific transcriptome differences between BRCA1/2 mutation carriers and non-carriers. We generated a single cell transcriptome atlas of breast tissues from BRCA1, BRCA2 mutation carriers and compared this single cell atlas of mutation carriers with our previously described single cell breast atlas of healthy non-carriers. We observed that BRCA1 but not BRCA2 mutations altered the ratio between basal, luminal progenitor and mature luminal cells in breast tissues. A unique subcluster of cells within luminal progenitors is underrepresented in case of BRCA1 and BRCA2 mutation carriers compared to non-carriers. Both BRCA1 and BRCA2 mutations specifically altered transcriptomes in epithelial cells which are an integral part of NF-{kappa}B, LARP1, and MYC signaling. Reduction of MYC signaling and translational machinery in BRCA1/2 mutant epithelial cells is reminiscent of embryonic diapause-like adaptation that occurs in drug tolerant populations of cells. Signaling pathway alterations in epithelial cells unique to BRCA1 mutations included STAT3, BRD4, SMARCA4, HIF2A/EPAS1, and Inhibin-A signaling. BRCA2 mutations were associated with upregulation of IL-6, PDK1, FOXO3, and TNFSF11 signaling. These signaling pathway alterations are sufficient to alter sensitivity of BRCA1/BRCA2-mutant breast epithelial cells to transformation as epithelial cells from BRCA1 mutation carriers overexpressing hTERT + PIK3CAH1047R generated adenocarcinomas, whereas similarly modified mutant BRCA2 cells generated basal carcinomas in NSG mice. Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation. Statement of SignificanceThis study provides a single cell atlas of breast tissues of BRCA1/2 mutation carriers and demonstrates that aberrant signaling due to BRCA1/2 mutations sufficient to initiate breast cancer by mutant PIK3CA.

cancer biology↗
bioRxiv2023

Harnessing Gradients for Self-Assembly of Peptide-Based Nanocapsules: A Pathway to Advanced Drug Delivery Systems

Biological systems often create materials with intricate structures to achieve specialized functions. In comparison, precise control of structures in man-made materials has been challenging. Here, we report a serendipitous discovery of insect cuticle peptides (ICPs) spontaneously forming nanocapsules through a single-step solvent exchange process, where the concentration gradient resulting from mixing of water and aceton drives the localization and self-assembly of the peptides into hollow nanocapsules. The underlying driving force is the intrinsic affinity of the peptides for a particular solvent concentration, while the diffusion of water and acetone creates a gradient interface that triggers peptide localization and self-assembly. This gradient-mediated self-assembly offers a transformative pathway towards next-generation drug delivery systems based on peptide nanocapsules.

bioengineering↗
bioRxiv2023

Transcriptome brings variations of gene expression, alternative splicing, and structural variations into gene-scale trait dissection in soybean

Genome-wide association study (GWAS) identifies trait-associated loci, but due in part to slow decay of linkage disequilibrium (LD), identifying the causal genes can be a bottleneck. Transcriptome-wide association study (TWAS) addresses this by identifying gene expression-phenotype associations or integrating gene expression quantitative trait loci (eQTLs) with GWAS results. Here, we used self-pollinated soybean as a model to evaluate the application of TWAS in the genetic dissection of traits in plant species that exhibit slow LD decay. The first RNA-Seq analysis of a soybean diversity panel was conducted, which identified the genetic regulation of 29,286 genes. Different TWAS solutions were less affected by LD and robust with source of expression that identified known genes related to traits from different development stages and tissues. A novel gene named pod color L2 was identified via TWAS and functionally validated by genome editing. Our introduction of the new exon proportion feature significantly improves the capture of expression variations resulting from structural variations and alternative splicing. As a result, the genes identified by our TWAS approach exhibited a diverse range of causal variations, including SNP, insertion/deletion, gene fusion, copy number variation, and alternative splicing. Using our TWAS approach, we identified genes associated with flowering time, including both previously known candidates and novel genes that had not been linked to this trait before, providing complementary insights with GWAS. In summary, this study supports the application of TWAS for candidate gene identification in species with low rates of LD decay.

genetics↗
bioRxiv2023

Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2

Persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer (OC), the fifth leading cause of cancer- related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long noncoding RNA (lncRNA) overexpressed in high-grade serous OC (HGSOC) and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in OCSC and how this oncogenic lncRNA contributes to drug resistant disease are incompletely understood. Here we generated HOTAIR knock-out (KO) HGSOC cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show that loss of HOTAIR function re-sensitized OC cells to platinum treatment and decreased the population of OCSC. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability, as well as expression of key stemness-associated genes ALDH1A1, Notch3, Sox9, and PROM1. HOTAIR KO altered both the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste 2 (EZH2) to catalyze H3K27 tri-methylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in OCSC and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate OC progression and resistance to platinum-based chemotherapy.

cancer biology↗
bioRxiv2023

Focusing antibody responses to the fusion peptide in rhesusmacaques

Immunodominance of antibodies targeting non-neutralizing epitopes and the high level of somatic hypermutation within germinal centers (GCs) required for most HIV broadly neutralizing antibodies (bnAbs) are major impediments to the development of an effective HIV vaccine. Rational protein vaccine design and non-conventional immunization strategies are potential avenues to overcome these hurdles. Here, we report using implantable osmotic pumps to continuously deliver a series of epitope-targeted immunogens to rhesus macaques over the course of six months to elicit immune responses against the conserved fusion peptide. Antibody specificities and GC responses were tracked longitudinally using electron microscopy polyclonal epitope mapping (EMPEM) and lymph node fine-needle aspirates, respectively. Application of cryoEMPEM delineated key residues for on-target and off-target responses that can drive the next round of structure-based vaccine design.

immunology↗
bioRxiv2023

Integrative Multi-omic Profiling of Two Human Decedents Receiving Pig Heart Xenografts Reveals Strong Perturbations in Early Immune-Cell and Cellular Metabolism Responses.

BackgroundRecent advances in xenotransplantation in living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use and first in human trials. Major obstacles remain though, including a lack of knowledge of the genetic incompatibilities between pig donors and human recipients which may led to harmful immune responses against the xenograft or dysregulation of normal physiology. In 2022 two pig heart xenografts were transplanted into two brain-dead human decedents with a minimized immunosuppression regime, primarily to evaluate onset of hyper-acute antibody mediated rejection and sustained xenograft function over 3 days. MethodsWe performed multi-omic profiling to assess the dynamic interactions between the pig and human genomes in the first two pig heart-xenografts transplants into human decedents. To assess global and specific biological changes that may correlate with immune-related outcomes and xenograft function, we generated transcriptomic, lipidomic, proteomic and metabolomics datasets, across blood and tissue samples collected every 6 hours over the 3-day procedures. ResultsSingle-cell datasets in the 3-day pig xenograft-decedent models show dynamic immune activation processes. We observe specific scRNA-seq, snRNA-seq and geospatial transcriptomic changes of early immune-activation leading to pronounced downstream T-cell activity and hallmarks of early antibody mediated rejection (AbMR) and/or ischemia reperfusion injury (IRI) in the first xenograft recipient. Using longitudinal multiomic integrative analyses from blood in addition to antigen presentation pathway enrichment, we also observe in the first xeno-heart recipient significant cellular metabolism and liver damage pathway changes that correlate with profound physiological dysfunction whereas, these signals are not present in the other xenograft recipient. ConclusionsSingle-cell and multiomics approaches reveal fundamental insights into early molecular immune responses indicative of IRI and/or early AbMR in the first human decedent, which was not evident in the conventional histological evaluations.

systems biology↗
bioRxiv2023

A novel bacterial signal transduction system specifically senses and responds to peptidoglycan damage

The peptidoglycan (PG) layer is a mesh-like structure within the cell envelope essential for maintenance of cell shape and resistance to osmotic stress, and therefore is a primary target of many important and widely used antibiotics, such as {beta}-lactams. In Gram-negative bacteria, while signal transduction systems that monitor the state of the inner- and outer-membranes have been extensively studied and well understood, much less is known about how cells sense and respond to PG-targeting stresses. Here we show that a novel bacterial two-component system (PghKR) from Shewanella oneidensis is capable of sensing and responding to PG damage. This system is specifically activated in cells exposed to various PG-targeting antibiotics or carrying a defect in PG synthesis, resulting in induced expression of blaA and relV, which encode a {beta}-lactamase conferring resistance to {beta}-lactams and a small ppGpp synthetase responsible for antibiotic tolerance, respectively. Intriguingly, the PghKR homologs are widespread among several classes of Proteobacteria and the periplasmic domain of sensor kinase PghK contains a family 9 carbohydrate-binding module that is required for signal perception, implying that the signals could be the glycan fragments of PG. Overall, our results provide critical insights into the regulation of PG homeostasis in Gram-negative bacteria.

microbiology↗
bioRxiv2023

The landscape of tolerated genetic variation in humans and primates

Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole genome sequencing data for 809 individuals from 233 primate species, and identified 4.3 million common protein-altering variants with orthologs in human. We show that these variants can be inferred to have non-deleterious effects in human based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases. One Sentence SummaryDeep learning classifier trained on 4.3 million common primate missense variants predicts variant pathogenicity in humans.

genomics↗
bioRxiv2023

A global catalog of whole-genome diversity from 233 primate species

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology, and is urgent given severe threats these species are facing. Here, we present high coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human-specific. This study will open a wide range of research avenues for future primate genomic research. One-Sentence SummaryThe whole genome sequences of 233 primate species provide insight into the determinants of genetic diversity, phylogenomics, and human uniqueness.

genomics↗
bioRxiv2023

Two haplotype-resolved genomes of highly heterozygous AAB allotriploid bananas provide insights into subgenome asymmetric evolution and banana wilt control

Bananas (Musa spp.) are one of the most important tropical fruits and staple food, which are of great significance to human societies. Plantain and Silk are two important banana subgroups, which are both triploid hybrids (AAB) between the wild diploid Musa acuminata and M. balbisiana. In this study, we reported the first haplotype-resolved genome assembly of Plantain and Silk bananas with genome size of approximately 1.4 Gb. We discovered widespread asymmetric evolution in the subgenomes of Plantain and Silk, which could be linked to frequent homologous exchanges (HEs) events. This is the first study to uncover the genetic makeup of triploid banana and verify that subgenome B harbors a rich source of resistance genes. Of the 88,078 and 94,988 annotated genes in Plantain and Silk, only 58.5% and 59.4% were present in all three subgenomes, with >50% genes containing differently expressed alleles in different haplotypes. We also found that Plantain is more resistant to banana Fusarium wilt, exhibiting a much faster defense response after pathogenic fungi infection. Many differentially expressed genes in abscisic acid, ethylene, jasmonic acid and salicylic acid pathways were identified in Plantain. Our analysis revealed that MpMYB36 promotes the biosynthesis of secondary cell wall and deposition of lignin by directly binding to the promoter of MpPAL and MpHCT, which allows Plantain to inhibit the penetration of early infection. Moreover, the insertion of the key carotenoid synthesis gene (CRTISO) may be the potential genetic basis for the richness of carotenoids in Plantain. Our study provides an unprecedented genomic basis for basic research and the development of elite germplasm in cultivated bananas.

plant biology↗
bioRxiv2023

Long-term stress shapes dynamic reconfiguration of functional brain networks across multi-task demands

Exposure to sustained stress can have a profound impact on the brain, emotion and cognition, with either adaptive or maladaptive effects. Human functional brain networks are dynamically organized to enable rapid and flexible adaptation to meet ever-changing task demands. Yet, little is known about how long-term stress alters the dynamic reconfiguration of functional brain networks across multi-task demands. Here we show prominent changes in the dynamic reconfiguration of large-scale brain networks during resting-state, emotional and working-memory processing under long-term stress. Hidden Markov Model analysis detected several latent brain states and switching processes involving the default mode, emotional salience and executive-control networks that are dominant to rest, emotion and working memory, respectively. Critically, long-term stress increased persistent time on brain states relevant to goal-directed demands and cognitive control, with more frequent transitions to these brain states when compared to controls. Furthermore, long-term stress led to higher correlations of the occupancy and persistency of brain states linked to psychological distress and behavioral performance. Our findings provide a neurocognitive framework whereby long-term stress shapes the way the brain adapts to varying task demands and increases the sensitivity of functional brain networks to psychological and behavioral responses. These changes can be both adaptive and maladaptive, reflecting the complex effects of long-term stress on brain function.

neuroscience↗
bioRxiv2023

A hierarchical strategy to decipher protein dynamics in vivo with chemical cross-linking mass spectrometry

Protein dynamics are essential for their various functions. Meanwhile, the intracellular environment would affect protein structural dynamics, especially for the intrinsically disordered proteins (IDPs). Chemical cross-linking mass spectrometry (CXMS) can unbiasedly capture the protein conformation information in cells and can also represent the protein dynamics. Here, we proposed a hierarchy deciphering strategy for protein dynamics in vivo. With the prior structure from AlphaFold2, the steady local conformation can be extensively evaluated. On this basis, the full-length structure of multi-domain proteins with various dynamic features can be characterized using CXMS. Furthermore, the complementary strategy with unbiased sampling and distance-constrained sampling enables an objective description of the intrinsic motion of the IDPs. Therefore, the hierarchy strategy we presented herein could help us better understand the molecular mechanisms of protein functions in cells.

cell biology↗
bioRxiv2023

Uncovering the Hidden Gems of Psoriasis Literature: An Neural Language Model-Assisted Interactive Web Tool

BACKGROUNDThe comprehensive data on psoriasis research are numerous and complex, making it difficult to retrieve and classify manually. The ability to quickly mine literature based on various fine topics using deep learning natural language processing technology to assess research topics and trends in the field of psoriasis disease will have a significant impact on doctors research and patients health education METHODA neural topic model is used to identify fine topics of psoriasis literature published in the PubMed database from 2000 to 2021. Dermatologists evaluate the algorithm-modeled topics, summarize the categories into the most effective topics, and perform linear trend model analysis. The accurate classified topics are presented on an interactive web page to identify research hotspots and trends. RESULTSAt the categorical level, after review by clinicians, 158 out of 160 generated topics were found effective and categorized into 8 groups: Therapeutic methods (34.34%), pathological mechanisms (23.46%), comorbidity (20.04%), Clinical manifestations and differential diagnosis (12.77%), experimental modalities and methods (3.22%), diagnostic tools (2.99%), epidemiology (1.75%), and meetings/guidelines (1.43%). A linear regression model had good accuracy (MSE=0.252602, SSE=42.1845) and strong correlation (R-Squared=0.898009). ANOVA results showed that categories significantly impacted the model (p<=0.05), with experimental modalities and methods having the strongest relationship with year, and clinical manifestations and differential diagnosis having the weakest. An interactive web tool (https://psknlr.github.io) facilitates quick retrieval of titles, journals, and abstracts in different categories, as well as browsing literature information under specific topics and accessing corresponding article pages for professional knowledge on psoriasis. CONCLUSIONSThe neural topic model and interactive web tool can effectively identify the research hotspots and trends in psoriasis literature, assisting clinicians and patients in retrieving and comparing pertinent topics and research accomplishments of various years.

bioinformatics↗
bioRxiv2023

Cyclic di-GMP interact with putrescine via a PilZ domain receptor YcgR

The cell motility is one of the key pathogenic factors that contribute to the virulence of Dickeya oryzea, which is a prevalent bacterial pathogen capable of infecting a range of crops and plants. We showed recently that the bacterial second messenger c-di-GMP, and the putrescine-mediated quorum sensing (QS) system, are both involved in the regulation of the bacterial motility in D. oryzea EC1. In this study, we set to determine whether and how there two signaling mechanisms work together to modulate the bacterial motility. The results showed that the second messenger signaling system interacts with the putrescine QS system via the c-di-GMP receptor YcgR, which could promote the activity of SpeA, the rate-limiting enzyme in the putrescine biosynthesis pathway, thereby increasing the intracellular putrescine levels. However, it was shown that this facilitative effect could be inhibited by c-di-GMP molecules. In addition, we demonstrated the dominance of c-di-GMP over putrescine in the regulation of bacterial motility. The findings from this study provide the first insight into the interaction between c-di-GMP and putrescine in bacteria and provide a valuable reference for the study of intracellular second messenger system and polyamine-mediated quorum sensing system in other bacteria. ImportanceDickea oryzea is a major bacterial pathogen capable of infesting many plants and crops, causing significant economic damage to rice and banana production especially. Bacterial motility is a key pathogenic factor of D. oryzea to compete for food resources and infect their host species, which is negatively regulated by c-di-GMP and positively regulated by putrescine, respectively. However, the connection between c-di-GMP and putrscine in regulating the motility of D.oryzea is not understood. Here we revealed the link and the mechanism of interaction between them, showing that c-di-GMP interact with putrescine via a receptor of c-di-GMP. The significance of our research is in providing the first insight into the interaction between c-di-GMP and putrescine and the methods and experimental designs in our study will provide a valuable reference for subsequent studies on the link between c-di-GMP and putrescine in other bacteria and even the regulatory mechanisms of complex bacterial motility networks, respectively.

pathology↗