Biology subjects

Gao, Y.

Publications and source records attributed to Gao, Y..

At least 343 records · Page 19Linked to original sources

bioRxiv2023

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex

Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27-Retromer assembly interacts with the WASH complex which nucleates actin filaments establishing the endosomal reycling domain. Crystal structures, modelling, biochemical and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. Mutation of the major VPS35-binding site does not prevent cargo recycling, however it partially reduces endosomal WASH association indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27-Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains. Significance StatementCell surface transmembrane proteins are regulated by a constant cycle of internalization and recycling from intracellular endosomal compartments. The Retromer protein complex and the sorting nexin adaptor protein play a critical role in the retrieval of hundreds of proteins responsible for ion transport, glucose metabolism, neurotransmission, and other cell functions. We have defined the mechanism by which both Retromer and SNX27 engage the actin-nucleating complex called WASH through multiple repeated sequences in the subunit FAM21. Dysfunction in WASH, Retromer and SNX27 are implicated in various disorders including Parkinsons disease, Alzheimers disease, hereditary spastic paraplegia, and this work provides important insights into the assembly of these essential endosomal sorting machineries.

cell biology↗

bioRxiv2023

Chromosome-Level Genome Assembly of Navel orange cv. Gannanzao (Citrus sinensis Osbeck cv. Gannanzao)

Navel orange cv. Gannanzao is a variant of the navel orange cv. Newhall (C. sinensis Osbeck cv. Newhall) that exhibits an earlier maturation, making it commercially valuable. However, the underlying mechanism underneath its early maturation remains unknown. To address this question, we conducted genome sequencing and de novo assembly of navel orange cv. Gannanzao. The assembled genome sequence is 334.57 Mb in length with a GC content of 31.48%. It comprises 318 contigs (N50 = 3.23 Mb) and 187 scaffolds (N50 = 31.86 Mb). The BUSCO test demonstrates 94.6% completeness. The annotation revealed 23,037 gene models, 164.95 Mb of repetitive sequences, and 2,554 ncRNA. Comparative analysis identified 323 fruit ripening-related genes in navel orange cv. Gannanzao genome, while navel orange cv. Newhall genome contained 345 such genes. These genes were organized into 320 orthologous gene families, with 30.3% of them exhibiting differences in gene copy numbers between the two genomes. Additionally, we identified 15 fruit ripening-related genes that have undergone adaptive evolution, suggesting their potential role in advancing fruit maturation in navel orange cv. Gannanzao. Whole genome sequencing and annotation of navel orange cv. Gannanzao provides a valuable resource to unravel the early maturation mechanism of citrus and enriches the genomic resources for citrus research.

genomics↗

bioRxiv2023

Parvalbumin and somatostatin: biomarkers for two parallel tectothalamic pathways in the auditory midbrain

The inferior colliculus (IC) represents a crucial relay station in the auditory pathway, located in the midbrains tectum and primarily projecting to the thalamus. Despite the identification of distinct cell types based on various biomarkers in the IC, their specific contributions to the organization of auditory tectothalamic pathways have remained poorly understood. In this study, we demonstrate that IC neurons expressing parvalbumin (ICPV+) or somatostatin (ICSOM+) represent major, non-overlapping cell types throughout the three IC subdivisions. Strikingly, regardless of their location within the IC, these neurons predominantly project to the primary and secondary auditory thalamic nuclei, respectively. Retrograde tracing data specific to cell types indicate that ICPV+ neurons primarily receive auditory inputs, whereas ICSOM+ neurons integrate polymodal inputs that hold behavioral significance. Furthermore, ICPV+ neurons exhibit significant heterogeneity in both intrinsic electrophysiological properties and presynaptic terminal size compared to ICSOM+ neurons. Notably, approximately one quarter of ICPV+ neurons are inhibitory neurons, whereas all ICSOM+ neurons are excitatory neurons. Collectively, our findings suggest that parvalbumin and somatostatin expression in the IC can serve as biomarkers for two functionally distinct, parallel tectothalamic pathways. This discovery challenges the conventional IC subdivision-based definition of tectothalamic pathways and calls for a reassessment of their functional roles.

neuroscience↗

bioRxiv2023

A novel architecture of PT neuron-based corticothalamic connectivity in the auditory system

Largely topographical projections from different modules of the thalamus, such as the primary, secondary and association sensory thalamus, to hierarchically defined cortical areas have been recognized across sensory systems. However, how corticothalamic projections, which are believed to be crucial for the remarkable flexibility and precision exhibited by our sensory systems, are organized remained poorly understood compared with the thalamocortical counterpart. Here we report that, first, the primary auditory thalamus received direct inputs from cortical L5 neurons. Second, in contrast to the robust thalamocortical topography, L5 neurons in each of the primary, secondary and association auditory cortical regions project to each individual module of the auditory thalamus at the macroscale. Third, the association cortex provided the most L5 inputs to all thalamic modules followed by the secondary and primary auditory cortices. Lastly, L5 axon terminals were mainly varicosity-type and evenly distributed across thalamic modules, but those in the polymodal association module were the largest. Our data suggest that all the modules of the auditory thalamus may be under the modulation of common L5 inputs. This fully-connected-like corticothalamic architecture urges a revision of the traditional hierarchical model in the sensory systems.

neuroscience↗

bioRxiv2023

OBMeta: a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases

Gut dysbiosis is closely associated with obesity and related metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). The gut microbial features and biomarkers have been increasingly investigated in recent studies, which require further validation due to the limited sample size and various confounding factors that may affect microbial compositions. So far, it lacks a comprehensive bioinformatics pipeline providing automated statistical analysis and integrating independent studies for cross validation simultaneously. OBMeta aims to streamline the standard metagenomics data analysis from diversity analysis, comparative analysis, functional analysis, to co-abundance network analysis. In addition, a curated database has been established with a total of 88 public research projects, covering three different phenotypes (Obesity, T2D, and NAFLD) and more than five different intervention strategies (exercise, diet, probiotics, medication, and surgery). With OBMeta, users can not only analyze their own research projects, but also search and match public datasets of interest for cross-project validation. Moreover, OBMeta provides cross-phenotype and cross-intervention-based advanced validation that maximally supports preliminary findings from an individual study. To summarize, OBMeta is a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases. OBMeta is freely available at: http://obmeta.met-bioinformatics.cn/. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/552363v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b58a9borg.highwire.dtl.DTLVardef@19efa47org.highwire.dtl.DTLVardef@418597org.highwire.dtl.DTLVardef@1a9bc3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

ERK signaling drives evolutionary expansion of the mammalian cerebral cortex

The molecular basis for cortical expansion during evolution remains largely unknown. Here, we found that FGF-extracellular signal-regulated kinase (ERK) signaling promotes the self-renewal and expansion of cortical radial glial (RG) cells. Furthermore, FGF-ERK signaling induces Bmp7 expression in cortical RG cells, which increases the length of the neurogenic period. We demonstrate that ERK signaling and SHH signaling mutually inhibit each other in cortical RG cells. We also provide evidence that ERK signaling is elevated in cortical RG cells during development and evolution. We conclude that the evolutionary expansion of the mammalian cortex, notably in human, is driven by ERK-BMP7-GLI3R signaling pathway in cortical RG cells, which participates in a positive feedback loop through antagonizing SHH signaling. We also propose that the molecular basis for cortical evolutionary dwarfism, exemplified by the lissencephalic mouse which originated from a larger and gyrencephalic ancestor, is due to mouse cortical RG cells receiving higher SHH signaling that antagonizes ERK signaling.

neuroscience↗

bioRxiv2023

Neo-epitope identification by weakly-supervised peptide-TCR binding prediction

The identification of T cell neo-epitopes is fundamental and computational challenging in tumor immunotherapy study. As the binding of pMHC - T cell receptor (TCR) is the essential condition for neo-epitopes to trigger the cytotoxic T cell reactivity, several computational studies have been proposed to predict neo-epitopes from the perspective of pMHC-TCR binding recognition. However, they often failed with the inaccurate binding prediction for a single pMHC -TCR pair due to the highly diverse TCR space. In this study, we proposed a novel weakly-supervised learning framework, i.e., TCRBagger, to facilitate the personalized neo-epitope identification with weakly-supervised peptide-TCR binding prediction by bagging a sample-specific TCR profile. TCRBagger integrates three carefully designed learning strategies, i.e. a self-supervised learning strategy, a denoising learning strategy and a Multi-Instance Learning (MIL) strategy in the modeling of peptide-TCR binding. Our comprehensive tests revealed that TCRBagger exhibited great advances over existing tools by modeling interactions between peptide and TCR profiles. We further applied TCRBagger in different clinical settings, including (1) facilitating the peptide-TCR binding prediction under MIL using single-cell TCR-seq data. (2) improving the patient-specific neoantigen prioritization compared to the existing neoantigen identification tools. Collectively, TCRBagger provides novel perspectives and contributions for identifying neo-epitopes as well as discovering potential pMHC-TCR interactions in personalized tumor immunotherapy.

bioinformatics↗

bioRxiv2023

Ribosome Heterogeneity in Development and Disease

The functional ribosome is composed of [~]80 ribosome proteins. With the intensity-based absolute quantification (iBAQ) value, we calculate the stoichiometry ratio of each ribosome protein. We analyze the ribosome ratio-omics (RibosomeR), which reflects the holistic signature of ribosome composition, in various biological samples with distinct functions, developmental stages, and pathological outcomes. The RibosomeR reveals significant ribosome heterogeneity among different tissues of fat, spleen, liver, kidney, heart, and skeletal muscles. During tissue development, testes at various stages of spermatogenesis show distinct RibosomeR signatures. During in vitro neuronal maturation, the RibosomeR changes reveal functional association with certain molecular aspects of neurodevelopment. Regarding ribosome heterogeneity associated with pathological conditions, the RibosomeR signature of gastric tumors is functionally linked to pathways associated with tumorigenesis. Moreover, the RibosomeR undergoes dynamic changes in macrophages following immune challenges. Taken together, with the examination of a broad spectrum of biological samples, the RibosomeR barcode reveals ribosome heterogeneity and specialization in cell function, development, and disease. One-Sentence SummaryRatio-omics signature of ribosome deciphers functionally relevant heterogeneity in development and disease.

molecular biology↗

bioRxiv2023

Aster-dependent non-vesicular transport facilitates dietary cholesterol uptake

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence SummaryIdentification of a targetable pathway for regulation of dietary cholesterol absorption

physiology↗

bioRxiv2023

The ChickenGTEx pilot analysis: a reference of regulatory variants across 28 chicken tissues

Chicken is a valuable model for understanding fundamental biology, vertebrate evolution and diseases, as well as a major source of nutrient-dense and lean-protein-enriched food globally. Although it is the first non-mammalian amniote genome to be sequenced, the chicken genome still lacks a systematic characterization of functional impacts of genetic variants. Here, through integrating 7,015 RNA-Seq and 2,869 whole-genome sequence data, the Chicken Genotype- Tissue Expression (ChickenGTEx) project presents the pilot reference of regulatory variants in 28 chicken tissue transcriptomes, including millions of regulatory effects on primary expression (including protein-coding genes, lncRNA and exon) and post-transcriptional modifications (alternative splicing and 3 untranslated region alternative polyadenylation). We explored the tissue-sharing and context-specificity of these regulatory variants, their underlying molecular mechanisms of action, and their utility in interpreting adaptation and genome-wide associations of 108 chicken complex traits. Finally, we illustrated shared and lineage-specific features of gene regulation between chickens and mammals, and demonstrated how the ChickenGTEx resource can further assist with translating genetic findings across species. One-Sentence SummaryThe ChickenGTEx provides a multi-tissue reference of regulatory variants for chicken genetics and genomics, functional genomics, precision breeding, veterinary medicine, vertebrate evolution and even human biomedicine.

genetics↗

bioRxiv2023

Pesticide-induced resurgence of the brown planthopper is mediated by diverse actors that promote juvenile hormone biosynthesis and female fecundity

Pesticide-induced resurgence, increases in pest insect populations following pesticide application, is a serious threat to the sustainable control of many highly damaging crop pests. Resurgence can result from pesticide-enhanced pest reproduction, however, the molecular mechanisms mediating this process remain unresolved. Here we show that brown planthopper (BPH) resurgence in rice crops following exposure to sublethal doses of the pesticide emamectin benzoate (EB) results from the coordinated action of a suite of genes that regulate juvenile hormone (JH) levels, resulting in increased JH titer in adult females and enhanced fecundity. We demonstrate that EB treatment at sublethal levels results in profound changes in female BPH fitness including increased egg maturation and oviposition. This enhanced reproductive fitness results from the EB-mediated upregulation of key genes involved in the regulation of JH, including JHAMT and Kr-h1 and the downregulation of allatostatin (AstA) and allatostatin receptor (AstAR) expression. AstA signaling is known to inhibit the production of JH in the corpora allata and hence EB exposure diminishes this inhibitory action. We find that the changes in gene expression following EB exposure are caused by the allosteric action of this insecticide on its molecular target, the glutamate-gated chloride channel (GluCl). Collectively, these results provide mechanistic insights into the regulation of negative pesticide-induced responses in insects and reveal some key actors involved in the JH-signaling pathway that underpin pesticide resurgence. SignificancePesticides remain a key means of controlling many of the worlds insect pests. However, in some cases, pesticide applications can result in resurgence of pest populations due to pesticide-induced increases in fecundity. In the current study, we show that pesticide resurgence in the brown planthopper (BPH) following exposure to the insecticide emamectin benzoate (EB) results from the transcriptional reprogramming of a diverse suite of positive and negative regulators of juvenile hormone (JH), a critical regulator of insect development and reproduction. This in turn leads to profound increases in female BPH reproductive fitness and enhanced fecundity. Our findings unravel some of the molecular mechanisms mediating pesticide-induced pest resurgence and inform the development of novel strategies to control highly damaging crop pests.

ecology↗

bioRxiv2023

Tumor-derived exosomal miR-222-3p induce cancer-associated fibroblasts activation to foster progression of renal cancer

The interaction between tumor-derived exosomes and stroma is crucial for tumor progression. However, the mechanisms by which tumor cells influence stromal changes are not yet fully understood. Our study revealed that high-metastatic renal cancer cells are more effective in converting normal fibroblasts into cancer-associated fibroblasts (CAFs) compared to low-metastatic renal cancer cells. Meanwhile, high-metastatic renal cancer cells secrete more exosomal miR-222-3p, which can directly target PANK3, activate NF-kB signaling pathway in fibroblasts and induce intracellular metabolic reprogramming to produce more lactic acid through Warburg effect. The activated CAFs further promote renal cancer progression by secreting lactic acid and inflammatory cytokines, including IL-6 and IL-8. Patients with renal cancer who have high levels of serum exocrine miR-222-3p are more likely to experience progression. These findings suggest that the intercellular communication between renal cancer cells and fibroblasts is facilitated by tumor exosomes. Targeting this communication may hold promise for the prevention and treatment of renal cancer.

cancer biology↗

bioRxiv2023

A Common Pathway for Detergent-Assisted Oligomerization of Aβ42

Amyloid beta (A{beta}) aggregation is a slow process without seeding or assisted nucleation. Sodium dodecyl sulfate (SDS) micelles stabilize A{beta}42 small oligomers (in the dimer-tetramer range); subsequent SDS removal leads to a 150-kD A{beta}42 oligomer. Dodecylphosphorylcholine (DPC) micelles also stabilize an A{beta}42 tetramer. Here we characterize the detergent-assisted oligomerization pathway by solid-state NMR spectroscopy and molecular dynamics simulations. SDS and DPC-induced oligomers have the same structure, implying a common oligomerization pathway. An antiparallel {beta}-sheet formed by the C-terminal region, the only stable structure in SDS and DPC micelles, is directly incorporated into the 150-kD oligomer. Three Gly residues (at positions 33, 37, and 38) create holes that are filled by the SDS and DPC hydrocarbon tails, thereby turning a potentially destabilizing feature into a stabilizing factor. These observations have implications for endogenous A{beta} aggregation at cellular interfaces.

biophysics↗

bioRxiv2023

The Single-Cell Transcriptome Program of Nodule Development Cellular Lineages in Medicago truncatula

Legumes can establish a symbiotic relationship with nitrogen-fixing rhizobia by developing nodules after root exposure to lipo-chito-oligosaccharides secreted by the bacteria. Nodule development initiates with anticlinal mitotic divisions in the pericycle and endodermal and inner cortical cells, establishing cell lineages that ultimately form each nodule compartment. We characterized these lineages by isolating and sequencing the transcriptome of Medicago truncatula single nuclei derived from uninoculated roots and roots undergoing early nodule development at 24, 48, and 96 hours after inoculation. To enrich samples for cells responding to the rhizobia, we complemented the analysis of the Medicago wild-type genotype A17 with a mutant for the autoregulation of nodulation, sunn-4. Analysis of cell lineage trajectories derived from the cortex indicates that their transcriptome is initially enriched for cytokinin perception and signaling while repressing auxin accumulation. As these cells differentiate to form nodules, expression of genes related to auxin biosynthesis, transport, and signaling was enhanced, while genes involved in cytokinin degradation were activated as lineages bifurcated to form the nodule meristem and infection zones. While the contribution of auxin and cytokinin in nodule development has been recognized, this single-cell resource quantifies the expression of each of their regulators, receptors and targets as cells divide and differentiate to form each nodule compartment.

plant biology↗

bioRxiv2023

The tRNA Gm18 Methyltransferase TARBP1 Promotes Hepatocellular Carcinoma Progression via Metabolic Reprogramming of Glutamine

Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. In current study, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a novel driver gene critical for glutamine metabolic reprogramming in tumor through the CRISPRi/Cas9 screening. Our in vivo and in vitro assays demonstrated that TARBP1 is the methyltransferase of Guanosine 2-O-methylation targeting position 18 (G18) of tRNAGln (TTG/CTG) and tRNASer (TGA/GCT), and loss of Gm18 modification diminishes the stability of tRNAs. Therefore, TARBP1 is critical for maintaining efficient translation of mRNA, in particular the glutamine transportor-ASCT2 (also known as SCL1A5). Importantly, TARBP1 is frequently amplified and overexpressed in HCC, consequentially promotes the protein synthesis of ASCT2 and glutamine import to fuel the growth of cancer cell, which is associated with poor patient survival. Taken together, this study reveals the critical role of TARBP1 in HCC progression through glutamine metabolic reprogramming and provides a potential target for tumor therapy.

cancer biology↗

bioRxiv2023

Common computations in automatic cue combination and metacognitive confidence reports

It is well known that sensory information from one modality can automatically affect judgments from a different sensory modality. However, it remains unclear what determines the strength of the influence of an irrelevant sensory cue from one modality on a perceptual judgment for a different modality. Here we test whether the strength of multisensory impact by an irrelevant sensory cue depends on participants objective accuracy or subjective confidence for that cue. We created visual motion stimuli with low vs. high overall motion energy, where high-energy stimuli yielded higher confidence but lower accuracy in a visual-only task. We then tested the impact of the low- and high-energy visual stimuli on auditory motion perception. We found that the high-energy visual stimuli influenced the auditory motion judgments more strongly than the low-energy visual stimuli, consistent with their higher confidence but contrary to their lower accuracy. A computational model assuming common principles underlying confidence reports and multisensory integration captured these effects. Our findings show that automatic multisensory integration follows subjective confidence rather than objective performance and suggest the existence of common computations across vastly different stages of perceptual decision making.

neuroscience↗

bioRxiv2023

Whole genome sequencing reveals autooctoploidy in the Chinese sturgeon and its evolutionary trajectories

The Order Acipenseriformes, which include sturgeons and paddlefishes, represent "living fossils" with complex genomes that are good models for understanding whole genome duplication (WGD) and ploidy evolution in fishes. Here we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis (Chinese sturgeon), a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes. Our results show that A. sinensis is a complex autooctoploid species containing four kinds of octovalents (8 n), a hexavalent (6 n), two tetravalents (4 n), and a divalent (2 n). We propose based on an analysis taking into account delayed rediploidization that its octoploid genome composition results from two rounds of homologous whole genome duplications (WGDs), and further provide insight into the timing of its ploidy evolution. This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy composition and evolutionary trajectories of polyploidy fishes.

genomics↗

bioRxiv2023

Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex

The prefrontal cortex (PFC) is critical for myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, using Patch-seq and single-nucleus multiomic analyses, we identified genes and regulatory networks governing the maturation of distinct neuronal populations in the PFC of rhesus macaque. We discovered that specific electrophysiological properties exhibited distinct maturational kinetics and identified key genes underlying these properties. We unveiled that RAPGEF4 is important for the maturation of resting membrane potential and inward sodium current in both macaque and human. We demonstrated that knockdown of CHD8, a high-confidence autism risk gene, in human and macaque organotypic slices led to impaired maturation, via downregulation of key genes, including RAPGEF4. Restoring the expression of RAPGEF4 rescued the proper electrophysiological maturation of CHD8-deficient neurons. Our study revealed regulators of neuronal maturation during a critical period of PFC development in primates and implicated such regulators in molecular processes underlying autism.

neuroscience↗