Biology subjects

Gao, Y.

Publications and source records attributed to Gao, Y..

At least 325 records · Page 18Linked to original sources

bioRxiv2023

Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides a new aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define novel molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

cancer biology↗

bioRxiv2023

Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig.

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression of UGT2B31 in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.

genetics↗

bioRxiv2023

Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood. Here, using an RNAi screen in Drosophila against genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity from synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We further demonstrate that neuronal activity stimulates autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a novel trans-synaptic signaling mechanism modulating structural plasticity.

neuroscience↗

bioRxiv2023

The prion-like domain of the chloroplast RNA binding protein CP29A is required for cold-induced phase separation next to nucleoids and supports RNA splicing and translation during cold acclimation

Arabidopsis thaliana is capable of producing photosynthetic tissue with active chloroplasts at temperatures as low as 4{degrees}C, and this process depends on the presence of the nuclear-encoded, chloroplast-localized RNA-binding protein CP29A. In this study, we demonstrate that CP29A undergoes phase separation in vitro and in vivo in a temperature-dependent manner, which is mediated by a prion-like domain (PLD) located between the two RNA recognition motif (RRM) domains of CP29A. The resulting droplets display liquid-like properties and are found in close proximity to chloroplast nucleoids. The PLD is required to support chloroplast RNA splicing and translation in cold-treated tissue. Together, our findings suggest that plant chloroplast gene expression is compartmentalized by inducible condensation of CP29A at low temperatures, a mechanism that could play a crucial role for plant cold resistance.

plant biology↗

bioRxiv2023

Changes in the urinary proteome of rats after short-term intake of magnesium threonate

Magnesium is an important mineral in living organisms and has multiple functions in the human body, wherein it plays an important therapeutic and preventive role in a variety of diseases. In the present study, urine samples of rats before and after gavage of magnesium threonate were collected, and the urinary proteome was identified using the LC-MS/MS technique and analyzed using various databases. The results illustrated that the urinary proteome of rats was significantly altered after short-term intake of magnesium supplements and that the differential proteins and the biological functions were related to magnesium. This study innovatively establishes a method to study nutrients from the perspective of urine proteomics. This work demonstrates that the urinary proteome is capable of reflecting the effects of nutrient intake on the organism in a more systematic and comprehensive manner and has the potential to provide clues for clinical nutrition research and practice.

biochemistry↗

bioRxiv2023

Efficient inhibition of fusion inhibitor HY3000 peptide to SARS-CoV-2 emerging EG.5, EG.5.1 and BA.2.86 variants

SARS-CoV-2 continues to evolve and spread. Recently, the Omicron EG.5 lineage, bearing an additional F456L mutation in spike (S) protein compared to its ancestor XBB.1.9.2, and its sub-variant EG.5.1, which carries a further Q52H mutation, have raised concerns due to their increased prevalence and extended immune escape properties. Additionally, an alarming variant, BA.2.86, has also garnered global concern because it contains over 30 amino acid mutations in its S protein compared to BA.2, including more than 10 changes in receptor-binding domain (RBD), reminiscent of the appearance of the Omicron variant in late 2021. Therefore, there is an urgent need to assess the effectiveness of current vaccines and therapeutics against EG.5, EG.5.1 and BA.2.86. In our previous work, we reported the design and broad-spectrum antiviral activity of a peptide fusion inhibitor HY3000 against SARS-CoV-2 and its variants including XBB.1.5. Here, we continued to evaluate the inhibitory potency of the HY3000 peptide against the prevailing EG.5 and EG.5.1, as well as XBB.1.16, FL.1.5.1, FY.3 and BA.2.86. Our data indicated that the peptide retained its potent inhibitory activities against these variants, indicating its potential as a good virus fusion inhibitor with broad-spectrum therapeutic effect against current and future SARS-CoV-2 variants. Currently, the HY3000 has been finished in Phase II clinical trial in China and has also been approved to conduct clinical investigation by U.S. Food and Drug Administration (FDA), suggesting a good application prospect against the ongoing COVID-19.

microbiology↗

bioRxiv2023

Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon response uniformly across models. The induction of an interferon response is partially due to the inhibition of Sox4 translation by Zotatifin. A similar induction of interferon-stimulated genes was observed in breast cancer patient biopsies following Zotatifin treatment. Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC. One Sentence SummaryTargeting EIF4A sensitizes TNBC to immune therapy and chemotherapy by suppressing Sox4, inducing an interferon response, and reprograming the tumor immune microenvironment.

cancer biology↗

bioRxiv2023

Cryo-EM structures of human SID-1 transmembrane family proteins and implications for their low-pH-dependent RNA transport activity

Human SIDT1 and SIDT2 are closely related members of the systemic RNA interference (RNAi)-defective (SID-1) transmembrane family. Both mediate RNA internalization and intracellular transport and are involved in various biological processes. However, the molecular basis of RNA uptake, especially for exogenous small RNAs, remains elusive. Here, we present the cryo-electron microscopy (cryo-EM) structures of human SIDT1 and SIDT2. Both structures reveal the overall architecture of a dimeric arrangement contributed by the {beta}-strand-rich extracellular domain (ECD) and the transmembrane domain (TMD) with 11 passes, highlighting the remarkable structural congruence. The in situ assays confirm that SIDT1 and SIDT2 exist as dimers or higher-order oligomers. We demonstrate that for both SIDT1 and SIDT2, the ECD binds small RNAs, such as dietary plant-derived miRNA, only under acidic conditions. In addition, RNA binding under low pH can trigger higher-order assembly of the ECD dimer, suggesting the potential importance of oligomerization during RNA uptake. Our results illustrate the molecular features of the conserved SID-1 family proteins to elucidate the mechanism of the low pH-dependent activation of RNA uptake mediated by SIDT1 and SIDT2. This study provides a promising understanding of the molecular basis of the nucleic acid delivery platform, which may potentially open new avenues for the design and optimization of RNA-based therapies.

biochemistry↗

bioRxiv2023

White matter tract microstructure, macrostructure, and associated cortical gray matter morphology across the lifespan

Characterizing how, when and where the human brain changes across the lifespan is fundamental to our understanding of developmental processes of childhood and adolescence, degenerative processes of aging, and divergence from normal patterns in disease and disorders. We aimed to provide detailed descriptions of white matter pathways across the lifespan by thoroughly characterizing white matter microstructure, white matter macrostructure, and morphology of the cortex associated with white matter pathways. We analyzed 4 large, high-quality, publicly-available datasets comprising 2789 total imaging sessions, and participants ranging from 0 to 100 years old, using advanced tractography and diffusion modeling. We first find that all microstructural, macrostructural, and cortical features of white matter bundles show unique lifespan trajectories, with rates and timing of development and degradation that vary across pathways - describing differences between types of pathways and locations in the brain, and developmental milestones of maturation of each feature. Second, we show cross-sectional relationships between different features that may help elucidate biological changes occurring during different stages of the lifespan. Third, we show unique trajectories of age-associations across features. Finally, we find that age associations during development are strongly related to those during aging. Overall, this study reports normative data for several features of white matter pathways of the human brain that will be useful for studying normal and abnormal white matter development and degeneration.

neuroscience↗

bioRxiv2023

Multi-omics analysis reveals signatures of selection and loci associated with complex traits in pigs

Selection signatures that contribute to phenotypic diversity, especially morphogenesis in pigs, remain to be further elucidated. To reveal the regulatory role of genetic variations in phenotypic differences between Eastern and Western pig breeds, we performed a systematic analysis based on seven high-quality de novo assembled genomes, 1,081 resequencing data representing 78 domestic breeds, 162 methylomes, and 162 transcriptomes of skeletal muscle from Tongcheng (Eastern) and Landrace (Western) pigs at 27 developmental stages. Selective sweep uncovers different genetic architectures behind divergent selection directions for the Eastern and Western breeds. Notably, two loci showed functional alterations by almost fixed missense mutations. By integrating time-course transcriptome and methylome, we revealed differences in developmental timing during myogenesis between Eastern and Western breeds. Genetic variants under artificial selection have critical regulatory effects on progression patterns of heterochronic genes like GHSR and BDH1, by the interaction of local DNA methylation status, particularly during embryonic development. Altogether, our work not only provides valuable resources for understanding pig complex traits, but also contributes to human biomedical research.

genomics↗

bioRxiv2023

Functional copy number variation in SQUALENE EPOXIDASE-LIKE genes affects photosystem II efficiency in Arabidopsis

In this study, we found a single quantitative trait locus for photosystem II efficiency ({Phi}PSII) in the Arabidopsis Ler-0 x Col-0 recombinant inbred line population. This locus on chromosome 5 is caused by genetic variation in a cluster of tandemly repeated SQUALENE EPOXIDASE-LIKE (SQE-like) genes, with unknown function. We show the QTL is caused by variation in the SQE5, SQE6 and SQE7 genes affecting {Phi}PSII in a dose-dependent manner, due to a combination of functional copies. Col-0 carries only one functional copy, SQE5, while Ler-0 carries functional copies of SQE6 and SQE7. Overexpression of a functional copy of SQE6 enhances {Phi}PSII to exceed that of the Ler-0 parent in Arabidopsis, but does not affect {Phi}PSII in tobacco. Phylogenetic analysis of the SQE and SQE-likes in 135 plant species revealed that the SQE-likes are evolutionary confined to two sister families, the Cleomaceae and Brassicaceae, and diversified independently. The tandem cluster of four SQE-like genes in Arabidopsis is likely the result of two recent gene duplication events, one generating SQE5 from SQE4, the next one generating SQE6 and SQE7 from SQE5. The involvement of SQE-like genes in photosynthesis will open up new avenues to determine the function of these novel genes.

plant biology↗

bioRxiv2023

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

KRASG12C inhibitors including adagrasib and sortorasib have shown clinical promise in targeting KRASG12C-mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurring KRASG12C and STK11/LKB1 mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies of Lkb1-deficient KRASG12Cand KrasG12D lung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed {Delta}Np63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked by Krt6a upregulation. Notably, higher KRT6A expression at baseline correlated with shorter overall survival in KRAS-mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.

cancer biology↗

bioRxiv2023

Identification of functional white matter networks in BOLD fMRI

White matter signals in resting state blood oxygen level dependent functional magnetic resonance (BOLD-fMRI) have been largely discounted, yet there is growing evidence that these signals are indicative of brain activity. Understanding how these white matter signals capture function can provide insight into brain physiology. Moreover, functional signals could potentially be used as early markers for neurological changes, such as in Alzheimers Disease. To investigate white matter brain networks, we leveraged the OASIS-3 dataset to extract white matter signals from resting state BOLD-FMRI data on 711 subjects. The imaging was longitudinal with a total of 2,026 images. Hierarchical clustering was performed to investigate clusters of voxel-level correlations on the timeseries data. The stability of clusters was measured with the average Dice coefficients on two different cross fold validations. The first validated the stability between scans, and the second validated the stability between subject populations. Functional clusters at hierarchical levels 4, 9, 13, 18, and 24 had local maximum stability, suggesting better clustered white matter. In comparison with JHU-DTI-SS Type-I Atlas defined regions, clusters at lower hierarchical levels identified well defined anatomical lobes. At higher hierarchical levels, functional clusters mapped motor and memory functional regions, identifying 50.00%, 20.00%, 27.27%, and 35.14% of the frontal, occipital, parietal, and temporal lobe regions respectively.

neuroscience↗

bioRxiv2023

Rof is a key regulator of Rho and transcription termination in bacteria

Transcription is crucial for the expression of genetic information and its efficient and accurate termination is required for all living organisms. Rho-dependent termination could rapidly terminate unwanted premature RNAs and play important roles in bacterial adaptation to changing environments. Although Rho has been discovered for about five decades, the regulation mechanisms of Rho-dependent termination are still not fully elucidated. Here we report the cryogenic electron microscopy structure of Rho-Rof antitermination complex. The structure shows that Rof binds to the open-ring Rho hexamer and inhibits the initiation of Rho-dependent termination. Rofs N-terminal -helix is key in facilitating Rof-Rho interactions. Rof binds to Rhos primary binding site (PBS) and excludes Rho from binding with PBS ligand RNA at the initiation step. Further in vivo assays in Salmonella Typhimurium show that Rof is required for virulence gene expression and host cell invasion, unveiling a novel physiological function of Rof and transcription termination in bacterial pathogenesis.

microbiology↗

bioRxiv2023

Unified cross-modality integration and analysis of T-cell receptors and T-cell transcriptomes

Single-cell RNA sequencing and T-cell receptor sequencing (scRNA-seq and TCR-seq, respectively) technologies have emerged as powerful tools for investigating T-cell heterogeneity. However, the integrated analysis of gene expression profiles and TCR sequences remains a computational challenge. Herein, we present UniTCR, a unified framework designed for the cross-modality integration and analysis of TCRs and T-cell transcriptomes for a series of challenging tasks in computational immunology. By utilizing a dual-modality contrastive learning module and a single-modality preservation module to effectively embed each modality into a common latent space, UniTCR demonstrates versatility across various tasks, including single-modality analysis, modality gap analysis, epitope-TCR binding prediction and TCR profile cross-modality generation. Extensive evaluations conducted on multiple scRNA-seq/TCR-seq paired datasets showed the superior performance of UniTCR. Collectively, UniTCR is presented as a unified and extendable framework to tackle diverse T-cell-related downstream applications for exploring T-cell heterogeneity and enhancing the understanding of the diversity and complexity of the immune system.

bioinformatics↗

bioRxiv2023

Multi-omics map revealed PPARalpha activation protecting against myocardial ischemia-reperfusion injury by maintaining cardiac metabolic homeostasis

Timely percutaneous coronary intervention is the most effective initial therapy for the acute myocardial infarction (MI). However, the mechanism in energy metabolism underlying time-dependent coronary reperfusion remains largely unknown. Here, we generated an integrative map of cardiac cells using bulk and single-nucleus RNA-seq combined with metabolomics profiling of hearts with reperfusion at distinct time points post MI in rat. We found early time reperfusion (ETR), but not late time reperfusion (LTR) reduced myocardial injury by maintaining cardiac energy homeostasis. PPAR was identified as a key regulator for maintaining fatty acid metabolism after MI/R injury. Importantly, pretreatment with FDA-approved PPAR agonist, fenofibrate, improved the transcriptional signatures, and ameliorated the function of the MI/R injured hearts, particularly in the ETR. Together, our data not only deciphered the protective effect of ETR by maintaining cardiac energy homeostasis, but also provided insights into the translational potential of PPAR activation in alleviating MI/R injury.

cell biology↗

bioRxiv2023

A Hybrid Transistor with Transcriptionally Controlled Computation and Plasticity

Organic electrochemical transistors (OECTs) are ideal devices for translating biological signals into electrical readouts and have applications in bioelectronics, biosensing, and neuromorphic computing. Despite their potential, developing programmable and modular methods for living systems to interface with OECTs has proven challenging. Here we describe hybrid OECTs containing the model electroactive bacterium Shewanella oneidensis that enable the transduction of biological computations to electrical responses. Specifically, we fabricated planar p-type OECTs and demonstrated that channel de-doping is driven by extracellular electron transfer (EET) from S. oneidensis. Leveraging this mechanistic understanding and our ability to control EET flux via transcriptional regulation, we used plasmid-based Boolean logic gates to translate biological computation into current changes within the OECT. Finally, we demonstrated EET-driven changes to OECT synaptic plasticity. This work enables fundamental EET studies and OECT- based biosensing and biocomputing systems with genetically controllable and modular design elements.

bioengineering↗

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↗