Biology subjects

Yang, Z.

Publications and source records attributed to Yang, Z..

At least 379 records · Page 21Linked to original sources

bioRxiv2023

Pleiotropic Regulatory Locus1 maintains actin microfilament integrity and concomitant cellular homeostasis facilitating root development in Arabidopsis

Cell functions are based on integrity of actin filaments. The Actin cytoskeleton is typically the target but also the source of signals. An evolutionarily conserved WD-40 protein PRL1 (Pleiotropic Regulatory Locus1) in Arabidopsis was investigated with multilayer functions in development, innate immunity, alternative splicing activation, transcription regulation, genome maintenance, ubiquitination-based protein turnover et al., but the underlying mechanisms are undefined. Here, we show PRL1 maintains actin integrity and concomitant cellular homeostasis. To explore causes for developmental root defect, we found depolymerization of cortical actin cytoskeleton and ROS imbalance in prl1 mutant. Further, we revealed that actin de-polymerization was the fundamental cause and dominant to ROS imbalance (H2O2 and O2{middle dot}-) for retarded root of prl1; NAC085 was up-regulated by and cooperated with actin depolymerization to mediate to stele cell death. Moreover, we revealed stress-related differentially expressed genes and alternative splicing defects were mutually independent and were responses to actin depolymerization in prl1. Our work ravels out cause-effect relationships between actin configuration and downstream hierarchical signals and explores underlying mechanism for functions of PRL1.

plant biology↗

bioRxiv2023

The ATM-E6AP-MASTL axis mediates DNA damage checkpoint recovery

Checkpoint activation after DNA damage causes a transient cell cycle arrest by suppressing CDKs. However, it remains largely elusive how cell cycle recovery is initiated after DNA damage. In this study, we discovered the upregulated protein level of MASTL kinase hours after DNA damage. MASTL promotes cell cycle progression by preventing PP2A/B55-catalyzed dephosphorylation of CDK substrates. DNA damage-induced MASTL upregulation was caused by decreased protein degradation, and was unique among mitotic kinases. We identified E6AP as the E3 ubiquitin ligase that mediated MASTL degradation. MASTL degradation was inhibited upon DNA damage as a result of the dissociation of E6AP from MASTL. E6AP depletion reduced DNA damage signaling, and promoted cell cycle recovery from the DNA damage checkpoint, in a MASTL-dependent manner. Furthermore, we found that E6AP was phosphorylated at Ser-218 by ATM after DNA damage and that this phosphorylation was required for its dissociation from MASTL, the stabilization of MASTL, and the timely recovery of cell cycle progression. Together, our data revealed that ATM/ATR-dependent signaling, while activating the DNA damage checkpoint, also initiates cell cycle recovery from the arrest. Consequently, this results in a timer-like mechanism that ensures the transient nature of the DNA damage checkpoint.

cell biology↗

bioRxiv2023

A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis in KRAS-driven lung cancer

Ferroptosis, a form of non-apoptotic cell death program driven by excessive lipid peroxidation and an important mechanism of tumor suppression, is frequently dysregulated in cancer. However, the mechanisms underlying impaired ferroptosis in oncogene-specific tumors remain poorly understood. Here we report a non- canonical role of lactate dehydrogenase B (LDHB), whose main activity is the conversion of lactate to pyruvate, in protecting KRAS-mutated lung cancer from ferroptosis. Silencing of LDHB impairs intracellular glutathione (GSH) metabolism and drives the hypersensitivity of KRAS-mutant cells to ferroptosis inducers by inhibiting the SLC7A11/GSH/GPX4 axis, a central antioxidant system against lipid peroxidation and ferroptosis by catalyzing GSH synthesis and utilization. Mechanistically, LDHB promotes SLC7A11 expression and GSH biosynthesis, and inhibition of LDHB confers metabolic synthetic lethality with ferroptosis inducers due to increased glutaminolysis and production of reactive oxygen species (ROS) in mitochondria, ultimately triggering ferroptosis of KRAS-driven lung cancer cells. Consequently, combined inhibition of LDHB and SLC7A11 synergistically suppresses tumor growth in multiple KRAS-mutant lung cancer implants and in an autochthonous model of Kras-induced lung adenocarcinoma. Taken together, our results reveal a hitherto unrecognized mechanism of ferroptosis defense by glycolytic LDHB and suggest a new strategy for the treatment of KRAS-dependent lung cancer.

cancer biology↗

bioRxiv2023

Self-supervised learning for DNA sequences with circular dilated convolutional networks

Due to their intrinsic properties, DNA molecules commonly exhibit long-range interactions along a linear sequence representation. Taking this information into account when modeling DNA sequences is therefore important for obtaining more accurate sequence-based inference. Many deep learning methods have recently been developed for this purpose, but they still suffer from two major issues. First, the existing methods can only handle short DNA fragments, thereby losing longerrange interactions. Second, the current methods require massive supervised labeling while missing most order information within the sequences. Consequently, there is a need to develop an efficient deep neural network modeling framework to extract wide contextual information for more accurate sequence-based inference tasks. Our new framework, named Revolution, takes full DNA sequences as input, without any condensation, and can give accurate predictions for DNA sequences up to 10kbp. In variant effect prediction, our method increases the Area Under the Receiver Operating Characteristics (AUROC) by 19.61% on 49 human tissues on average. Revolution is also demonstrated to work on the plant sequences by improving 2.36% AUROC on average for predicting open chromatin regions (OCRs). The data, models, and code can be freely accessed at https://github.com/wiedersehne/Revolution-DNAPretraining.

bioinformatics↗

bioRxiv2023

Structure of the Native Chemotaxis Core Signalling Unit from E-gene lysed E. coli cells

Motile bacteria detect ambient chemical gradients and control their locomotion via conserved chemotaxis signaling networks, enabling cells to locate nutrients, potential hosts and other important biological niches. The sensory apparatus of the chemotaxis pathway is an array of core-signaling units (CSU) composed of transmembrane chemoreceptors, the histidine kinase CheA and an adaptor protein CheW. Although chemotaxis pathways represent the best understood signaling systems, a detailed mechanistic understanding of signal transduction has been hindered by the lack of a complete structural picture of the CSU and extended array. In this study, we present the structure of the complete CSU from phage E-gene lysed E. coli cells, determined using cryo-electron tomography and sub-tomogram averaging to 12 [A] resolution. Using AlphaFold2, we further predict the atomic structures of the CSUs constituent proteins as well as key protein-protein interfaces, enabling the assembly an all-atom CSU model, which we conformationally refine using our cryoET map. Molecular dynamics simulations of the resulting model provide new insight into the periplasmic organization of the complex, including novel interactions between neighboring receptor ligand binding domains. Our results further elucidate previously unresolved interactions between individual CheA domains, including an anti-parallel P1 dimer and non-productive binding mode between P1 and P4, enhancing our understanding of the structural mechanisms underlying CheA signaling and regulation.

microbiology↗

bioRxiv2023

Structural characterization of HIV-1 Env heterotrimers bound to one or two CD4 receptors reveals intermediate Env conformations

HIV-1 envelope (Env) exhibits distinct conformational changes in response to host receptor (CD4) engagement. Env, a trimer of gp120/gp41 heterodimers, has been structurally characterized in a closed, prefusion conformation with closely associated gp120s and coreceptor binding sites on gp120 V3 hidden by V1V2 loops, and in fully-saturated CD4-bound open Env conformations with changes including outwardly rotated gp120s and displaced V1V2 loops. To investigate changes resulting from sub-stoichiometric CD4 binding, we solved 3.4[A] and 3.9[A] single-particle cryo-EM structures of soluble, native-like Envs bound to one or two CD4 molecules. Env trimer bound to one CD4 adopted the closed, prefusion Env state. When bound to two CD4s, the CD4-bound gp120s exhibited an open Env conformation including a four-stranded gp120 bridging sheet and displaced gp120 V1V2 loops that expose the coreceptor sites on V3. The third gp120 adopted an intermediate, occluded-open state that included gp120 outward rotation but maintained the prefusion, three-stranded gp120 bridging sheet and showed only partial V1V2 displacement and V3 exposure. We conclude that engagement of one CD4 molecule was insufficient to stimulate CD4-induced conformational changes, while binding two CD4 molecules led to Env opening in CD4-bound protomers only. Together, these results illuminate HIV-1 Env intermediate conformations and illustrate the structural plasticity of HIV-1 Env.

molecular biology↗

bioRxiv2023

BnIR: a multi-omics collaborative resource and tool platform for Brassica napus biological study

In the post-GWAS era, multi-omics techniques have shown great power and potential for candidate gene mining and functional genomics research. However, due to the lack of effective data integration and multi-omics analysis platforms, such techniques have not still been applied widely in rapeseed, an important oil crop worldwide. Here, we constructed a rapeseed multi-omics database (BnIR; http://yanglab.hzau.edu.cn/BnIR), which provides datasets of six omics including genomics, transcriptomics, variomics, epigenetics, phenomics and metabolomics, as well as numerous "variation-gene expression-phenotype" associations by using multiple statistical methods. In addition, a series of multi-omics search and analysis tools are integrated to facilitate the browsing and application of these datasets. BnIR is the most comprehensive multi-omics database for rapeseed so far, and two case studies demonstrated its power to mine candidate genes associated with specific traits and analyze their potential regulatory mechanisms. Short SummaryIn this study, we developed BnIR (http://yanglab.hzau.edu.cn/BnIR), a multi-omics database for rapeseed that integrates six omics datasets and "variation-gene expression-phenotype" associations. The database is equipped with a range of multi-omics tools for streamlined browsing and analysis. Through multiple case studies, we demonstrated BnIRs potential to identify candidate genes associated with specific traits and investigate their regulatory mechanisms.

bioinformatics↗

bioRxiv2023

Heritable maize microbiomes contribute to local adaptation and host stress resilience

Beneficial interactions with microorganisms are pivotal for crop performance and resilience. However, it remains unclear how heritable the microbiome is with respect to the host plant genotype and to what extent host genetic mechanisms can modulate plant-microbe interactions in the face of environmental stress. Here, we surveyed the root and rhizosphere microbiome of 129 accessions of locally adapted Zea mays, sourced from diverse habitats and grown under control and different stress conditions. We quantified treatment and host genotype effects on the microbiome. Plant genotype and source environment were predictive of microbiome composition. Genome wide association analysis identified host genetic variants linked to both rhizosphere microbiome composition and source environment. We identified transposon insertions in a candidate gene linked to both the abundance of a keystone microbe Massilia and source total soil nitrogen, finding mutant plants to show a reduction in lateral root density. We conclude that locally adapted maize varieties exert patterns of genetic control on their root and rhizosphere microbiomes that follow variation in their home environments, consistent with a role in tolerance to prevailing stress.

genetics↗

bioRxiv2022

ESCRT recruitment to mRNA-encoded SARS-CoV-2 spike induces virus-like particles and enhanced antibody responses

Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely-arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8+ T-cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared to conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for three months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.

immunology↗

bioRxiv2022

Mutation divergence over space in tumour expansion

Mutation accumulation in tumour evolution is one major cause of intra-tumour heterogeneity (ITH), which often leads to drug resistance during treatment. Previous studies with multi-region sequencing have shown that mutation divergence among samples within the patient is common, and the importance of spatial sampling to obtain a complete picture in tumour measurements. However, quantitative comparisons of the relationship between mutation heterogeneity and tumour expansion modes, sampling distances as well as the sampling methods are still few. Here, we investigate how mutations diverge over space by varying the sampling distance and tumour expansion modes using individual based simulations. We measure ITH by the Jaccard index between samples and quantify how ITH increases with sampling distance, the pattern of which holds in various sampling methods and sizes. We also compare the inferred mutation rates based on the distributions of Variant Allele Frequencies (VAF) under different tumour expansion modes and sampling sizes. In exponentially fast expanding tumours, a mutation rate can always be inferred in any sampling size. However, the accuracy compared to the true value decreases when the sampling size decreases, where small sampling sizes result in a high estimate of the mutation rate. In addition, such an inference becomes unreliable when the tumour expansion is slower such as in surface growth.

cancer biology↗

bioRxiv2022

HAPNEST: efficient, large-scale generation and evaluation of synthetic datasets for genotypes and phenotypes

Existing methods for simulating synthetic genotype and phenotype datasets have limited scalability, constraining their usability for large-scale analyses. Moreover, a systematic approach for evaluating synthetic data quality and a benchmark synthetic dataset for developing and evaluating methods for polygenic risk scores are lacking. We present HAPNEST, a novel approach for efficiently generating diverse individual-level genotypic and phenotypic data. In comparison to alternative methods, HAPNEST shows faster computational speed and a lower degree of relatedness with reference panels, while generating datasets that preserve key statistical properties of real data. These desirable synthetic data properties enabled us to generate 6.8 million common variants and nine phenotypes with varying degrees of heritability and polygenicity across 1 million individuals. We demonstrate how HAPNEST can facilitate biobank-scale analyses through the comparison of seven methods to generate polygenic risk scoring across multiple ancestry groups and different genetic architectures.

bioinformatics↗

bioRxiv2022

Hypothalamic supramammillary neurons that project to the medial septum control wakefulness

The hypothalamic supramammillary nucleus (SuM) plays a key role in controlling wakefulness, but the downstream target regions participating in this control process remain unknown. Here, using circuit-specific fiber photometry and single-neuron electrophysiology together with electroencephalogram, electromyogram and behavioral recordings, we find approximately half of SuM neurons that project to the medial septum (MS) are wake-active. Optogenetic stimulation of axonal terminals of SuM-MS projection induces a rapid and reliable transition to wakefulness from NREM or REM sleep, and chemogenetic activation of SuMMS projecting neurons significantly increases wakefulness time and prolongs latency to sleep. Consistently, chemogenetically inhibiting these neurons significantly reduces wakefulness time and latency to sleep. Therefore, these results identify the MS as a functional downstream target of SuM and provide evidence for a causal role for this hypothalamic-septal projection in wakefulness control.

neuroscience↗

bioRxiv2022

Spateo: multidimensional spatiotemporal modeling of single-cell spatial transcriptomics

Cells do not live in a vacuum, but in a milieu defined by cell-cell communication that can be measured via emerging high-resolution spatial transcriptomics approaches. However, analytical tools that fully leverage such data for kinetic modeling remain lacking. Here we present Spateo (aristoteleo/spateo-release), a general framework for quantitative spatiotemporal modeling of single-cell resolution spatial transcriptomics. Spateo delivers novel methods for digitizing spatial layers/columns to identify spatially-polar genes, and develops a comprehensive framework of cell-cell interaction to reveal spatial effects of niche factors and cell type-specific ligand-receptor interactions. Furthermore, Spateo reconstructs 3D models of whole embryos, and performs 3D morphometric analyses. Lastly, Spateo introduces the concept of "morphometric vector field" of cell migrations, and integrates spatial differential geometry to unveil regulatory programs underlying various organogenesis patterns of Drosophila. Thus, Spateo enables the study of the ecology of organs at a molecular level in 3D space, beyond isolated single cells.

systems biology↗

bioRxiv2022

Self-regulation of PIN1-driven auxin transport by cell surface-based auxin signaling in Arabidopsis

PIN-FORMED (PIN)-driven auxin transport contributes to establishing and maintaining a dynamic auxin concentration gradient alongside plant tissues, which drives the majority of developmental processes in plants. To maintain developmental plasticity in ever-changing environments, plants have evolved self-organizing feedback machinery between auxin signaling and its transport, which has been shown to play essential roles in many fundamental plant processes. However, the molecular mechanism behind this mutual regulation has not yet been clarified. Here, we identified a cell surface-triggered auxin signaling that regulates the PIN1-mediated auxin efflux and further developmental patterning in Arabidopsis. Auxin was able to stimulate PIN1 phosphorylation in plants through transmembrane kinases (TMKs), key components in auxin signaling, at the plasma membrane. TMK1 and TMK4 directly interacted with and phosphorylated PIN1 and functioned redundantly in the regulation of PIN1 polarity in plant cells. The phosphorylation sites in PIN1 proteins, targeted by both auxin and TMKs, were required for PIN1 trafficking and polarity, which further controlled auxin responses and downstream developmental patterning in Arabidopsis. Therefore, our findings provide a direct mechanism for the self-regulation between auxin signaling and transport that drives the auxin flows and proper development in plants.

plant biology↗

bioRxiv2022

ABLs and TMKs are co-receptors for extracellular auxin

Extracellular perception of auxin, an essential phytohormone in plants, has been debated for decades. Auxin binding protein 1 (ABP1) physically interacts with quintessential transmembrane kinases (TMKs) and was proposed to act as an extracellular auxin receptor, but its role was disputed because abp1 knockout mutants lack obvious morphological phenotypes. Here we identified two new auxin-binding proteins, ABL1 and ABL2, that are localized to the apoplast and directly interact with the extracellular domain of TMKs in an auxin-dependent manner. Furthermore, functionally redundant ABL1 and ABL2 genetically interact with TMKs and exhibit functions that are overlapping with those of ABP1 as well as independent of ABP1. Importantly, the extracellular domain of TMK1 itself binds auxin and synergizes with either ABP1 or ABL1 in auxin binding. Thus, our findings discovered new auxin receptors ABL1 and ABL2 having functions overlapping with but distinct from ABP1 and acting together with TMKs as co-receptors for extracellular auxin.

plant biology↗

bioRxiv2022

EEG-LLAMAS: an open source, low latency, EEG-fMRI neurofeedback platform

Simultaneous EEG-fMRI is a powerful multimodal technique for imaging the brain, but its use in neurofeedback experiments has been limited by EEG noise caused by the MRI environment. Neurofeedback studies typically require analysis of EEG in real time, but EEG acquired inside the scanner is heavily contaminated with ballistocardiogram (BCG) artifact, a high-amplitude artifact locked to the cardiac cycle. Although techniques for removing BCG artifacts do exist, they are either not suited to real-time, low-latency applications, such as neurofeedback, or have limited efficacy. We propose and validate a new open-source BCG removal software called EEG-LLAMAS (Low Latency Artifact Mitigation Acquisition Software), which adapts and advances existing artifact removal techniques for low-latency experiments. We first used simulations to validate LLAMAS in data with known ground truth. We found that LLAMAS performed better than the best publicly-available real-time BCG removal technique, optimal basis sets (OBS), in terms of its ability to recover EEG waveforms, power spectra, and slow wave phase. To determine whether LLAMAS would be effective in practice, we then used it to conduct real-time EEG-fMRI recordings in healthy adults, using a steady state visual evoked potential (SSVEP) task. We found that LLAMAS was able to recover the SSVEP in real time, and recovered the power spectra collected outside the scanner better than OBS. We also measured the latency of LLAMAS during live recordings, and found that it introduced a lag of less than 50ms on average. The low latency of LLAMAS, coupled with its improved artifact reduction, can thus be effectively used for EEG-fMRI neurofeedback. This platform enables closed-loop experiments which previously would have been prohibitively difficult, such as those that target short-duration EEG events, and is shared openly with the neuroscience community.

neuroscience↗

bioRxiv2022

Streptomyces alleviate abiotic stress in plant by producing pteridic acids

Soil microbiota can confer fitness advantages to plants and increase crop resilience to drought and other abiotic stressors. However, there is little evidence on the mechanisms correlating a microbial trait with plant abiotic stress tolerance. Here, we report that Streptomyces effectively alleviates the drought and salinity stress by producing spiroketal polyketide pteridic acid H (1) and its isomer F (2), both of which promote root growth in Arabidopsis at a concentration of 1.3 nM under abiotic stress. Pteridic acids induce stress response genes expression in salinity-stressed Arabidopsis seedlings. The bifunctional biosynthetic gene cluster of pteridic acids and antimicrobial elaiophylin is confirmed in vivo and mainly disseminated by vertical transmission which is geographically distributed in various environments. This discovery reveals a perspective for understanding plant-Streptomyces interactions and provides a promising approach for utilising beneficial Streptomyces and their secondary metabolites in agriculture to mitigate the detrimental effects of climate change.

microbiology↗

bioRxiv2022

NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice

AbstractTransplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation is limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells (iPSCs) together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarct, neuronal death and glial scarring, and promoted the motor function recovery. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

neuroscience↗