Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 397 records · Page 22Linked to original sources

bioRxiv2024

Autophagy-mediated CTR1 turnover orchestrates the reciprocal interaction between autophagy and ethylene signaling

The phytohormone ethylene and autophagy are crucial for plant adaptation to various environmental stresses, yet the integration of these signaling networks into stress responses is not fully understood. Here, we report that ethylene signaling and autophagy reciprocally regulate each other through Constitutive Triple Response 1 (CTR1), a negative regulator of ethylene signaling. Autophagy facilitates the turnover of the CTR1 protein, which interacts with the key autophagy-related protein ATG8 as autophagic cargo. Impaired autophagy attenuates ethylene responses. Conversely, ethylene-insensitive mutants exhibit enhanced autophagic flux, while a constitutive ethylene response mutant is hypersensitive to carbon starvation stress, which induces autophagy. This suggests that ethylene suppresses autophagy during carbon limitation. We further elucidated that ethylene receptors with a receiver domain play a primary role in modulating autophagy, while receptor kinase activity is not essential. Our findings uncover that the autophagic control of CTR1 degradation allows reciprocal cross-regulation between autophagy and ethylene transduction cascades, optimizing stress responses and resilience.

plant biology↗

bioRxiv2024

Dissecting the Genetic Basis of Superior Traits in Thermosensitive Genic Male Sterile Line 1892S Through Genome-Wide Analysis

Hybrid rice has revolutionized food security by leveraging heterosis, a phenomenon where offspring outperform their parents. Sterile lines, crucial for controlled cross-pollination in hybrid breeding, have played a central role in this success. This study delves into the superior alleles of 1892S, a two-line sterile rice line widely used as a female parent in central China. By integrating extensive hybridization data, high-throughput genome sequencing, and bioinformatic analysis (RiceNavi), we elucidate the genetic underpinnings of 1892Ss exceptional adaptability. The results reveal its remarkable compatibility as a female parent in over 114 hybrid varieties, potentially due to the influence of Japonica characteristics contributing to strong hybrid vigor. Furthermore, some favorable alleles were identified that were associated with lodging resistance, high yield potential, and improved nitrogen use efficiency etc. The comprehensive characterization of 1892S provides valuable insights for future hybrid rice breeding programs, ultimately facilitating the development of superior rice varieties.

genomics↗

bioRxiv2024

Expectation modulates learning emotional words: Evidence from a hierarchical Bayesian model

In language acquisition, individuals learn the emotional value of words through external feedback. Previous studies have used emotional words as experimental materials to explore the cognitive mechanism underlying emotional language processing, but have failed to recognize that languages are acquired in a changing environment. To this end, this study aims to combine reinforcement learning with emotional word learning, using a probabilistic reversal learning task to explore how individuals acquire the valence of emotional words in a dynamically changing environment. Our computational modeling on both behavioral and event-related potential (ERP) data revealed that individuals expectations can modulate the learning speed and temporal processing of emotional words, demonstrating a clear negative bias. Specifically, as the expected value increases, individuals respond faster and exhibit higher amplitudes for negative emotional words. These findings shed light on the neural mechanisms of emotional word learning in a volatile environment, highlighting the crucial role of expectations in this process and the preference for processing negative information.

neuroscience↗

bioRxiv2024

Modulation of Neuronal Excitability and Plasticity by BHLHE41 Conveys Lithium Non-Responsiveness

Many bipolar disorder (BD) patients are non-responsive to lithium. The mechanisms underlying lithium (non-)responsiveness are largely unknown. By using gene-set enrichment analysis methods, we found that core clock gene-sets are significantly associated with lithium response. Among the top hits was BHLHE41, a modulator of the molecular clock and homeostatic sleep. Since BHLHE41 and its paralog BHLHE40 are functionally redundant, we assessed chronic lithium response in double-knockout mutant mice (DKO). We demonstrated that DKOs are non-responsive to lithiums effect in various behavioral tasks. Cellular assays and patch clamp recordings revealed lowered excitability and reduced lithium-response in prefrontal cortical layer 2/3 DKO neurons and on hippocampal long-term potentiation. Single-cell RNA sequencing identified that lithium deregulated mitochondrial respiration, cation channel and postsynapse associated gene-sets specifically in upper layer excitatory neurons. Our findings show that lithium acts in a highly cell-specific way on neuronal metabolism and excitability and modulates synaptic plasticity depending on BHLHE40/41.

neuroscience↗

bioRxiv2024

ATG9A and ARFIP2 cooperate to regulate PI4P levels for lysosomal repair

Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving ER-lysosome membrane contact sites, phosphatidylinositol 4-kinase- 2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P) and oxysterol-binding protein-related proteins (ORPs), lipid transfer proteins. PI4K2A localizes to trans-Golgi network and endosomes yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage, and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing ORP- dependent lipid transfer and promoting retrieval of ATG9A vesicles through recruitment of the adaptor protein complex-3 (AP-3). Our results reveal a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.

cell biology↗

bioRxiv2024

Deletion of wheat alpha-gliadins from chromosome 6D improves gluten strength and reduces immunodominant celiac disease epitopes

Wheat gliadins and glutenins confer valuable end-use characteristics but include amino acid sequences (epitopes) that can elicit celiac disease (CeD) in genetically predisposed individuals. The onset of CeD in these individuals is affected by the amount and duration of the exposure to immunogenic epitopes. Therefore, a reduction of epitopes that result in high immune responses in the majority of CeD patients (immunodominant epitopes) can reduce the incidence of CeD at a population level. We identified deletions encompassing the -gliadins at the three wheat genomes, designated hereafter as{Delta} gli-A2 (PI 704906),{Delta} gli-B2 (PI 704907), and{Delta} gli-D2 (PI 704908). The{Delta} gli-D2 deletion, which eliminates major immunodominant epitopes, significantly increases gluten strength, improves breadmaking quality, and has no negative effects on grain yield or grain protein content. By contrast,{Delta} gli-A2 and{Delta} gli-B2 showed limited effects on breadmaking quality. The stronger effect of the{Delta} gli-D2 deletion on gluten strength is associated with the presence of -gliadins with seven cysteines in GLI-D2 that are absent in GLI-A2 and GLI-B2 loci, which all have -gliadins with six cysteines. We show that -gliadins with seven cysteines are incorporated into the gluten polymer, where they likely function as chain-terminators limiting the expansion of the gluten polymer and reducing its strength. In summary, the publicly available{Delta} gli-D2 deletion developed in this study can be used to simultaneously improve wheat gluten strength and reduce immunodominant CeD epitopes.

plant biology↗

bioRxiv2024

MR Corge: Sensitivity analysis of Mendelian randomization based on the core gene hypothesis for polygenic exposures

SummaryMendelian randomization is being utilized to assess causal effects of polygenic exposures, where many genetic instruments are subject to horizontal pleiotropy. Existing methods for detecting and correcting for horizontal pleiotropy have important assumptions that may not be fulfilled. Built upon the core gene hypothesis, we developed MR Corge for performing sensitivity analysis of Mendelian randomization. MR Corge identifies a small number of putative core instruments that are more likely to affect genes with a direct biological role in an exposure and obtains causal effect estimates based on these instruments, thereby reducing the risk of horizontal pleiotropy. Using positive and negative controls, we demonstrated that MR Corge estimates aligned with established biomedical knowledge and the results of randomized controlled trials. MR Corge may be widely applied to investigate polygenic exposure-outcome relationships. Availability and ImplementationAn open-sourced R package is available at https://github.com/zhwm/MRCorge.

bioinformatics↗

bioRxiv2024

Dual modes of DNA N6-methyladenine maintenance by distinct methyltransferase complexes

Stable inheritance of DNA N6-methyladenine (6mA) is crucial for its biological functions in eukaryotes. Here, we identify two distinct methyltransferase (MTase) complexes, both sharing the catalytic subunit AMT1, but featuring AMT6 and AMT7 as their unique components, respectively. While the two complexes are jointly responsible for 6mA maintenance methylation, they exhibit distinct enzymology, DNA/chromatin affinity, genomic distribution, and knockout phenotypes. AMT7 complex, featuring high MTase activity and processivity, is connected to transcription-associated epigenetic marks, including H2A.Z and H3K4me3, and is required for the bulk of maintenance methylation. In contrast, AMT6 complex, with reduced activity and processivity, is recruited to initiate maintenance methylation immediately after DNA replication. These two complexes coordinate in maintenance methylation. By integrating signals from both replication and transcription, this mechanism ensures the faithful and efficient transmission of 6mA as an epigenetic mark in eukaryotes. Significance statementDNA N6-methyladenine (6mA) has recently been recognized as an epigenetic mark in eukaryotes. The stable inheritance of 6mA is essential for its biological functions. However, the precise mechanisms by which 6mA patterns are faithfully and efficiently transmitted remain largely unknown. Here, we have identified two distinct 6mA methyltransferase (MTase) complexes and elucidated their coordinated role in maintenance methylation. This dual- complex mechanism ensures rapid and accurate methylation at newly replicated loci with proper transcription-associated epigenetic marks.

molecular biology↗

bioRxiv2024

Construction of mirror-image RNA nanostructure for enhanced biostability and drug delivery efficiency

The development of stable and efficient drug delivery systems is crucial for advancing therapeutic applications. Here, we present a novel approach involving the construction of a mirror-image RNA (L-RNA) nanostructure to enhance biostability and drug delivery efficiency. Specifically, we utilized L-RNA to create a three-way junction structure, which was then conjugated with small interfering RNA (siRNA) and chemotherapy agents for targeted drug delivery. Our findings demonstrate that this L-RNA nanostructure significantly improves therapeutic efficiency due to its enhanced stability compared to natural D-RNA. In additionally, the conjugated folic acid (FA) group dramatically enhance the specificity and endosomal escape efficiency of the nanoparticles, which benefit the combinatorial drug delivery. This work highlights the potential of mirror-image RNA nanostructures as robust platforms for drug delivery applications.

biochemistry↗

bioRxiv2024

Single-Cell and Spatial Transcriptomic Analyses Deciphering the Three-Layer Architecture of Human Tuberculosis Granulomas

BackgroundGranulomas (defining tuberculosis histopathological feature) are central to the hosts defense against Mycobacterium tuberculosis, critically influencing patient outcomes. However, knowledge of human granulomas structure and function are incomplete. This study employs single-cell and spatial transcriptomics to dissect human granulomas cellular composition, structure, communication and function from 19 pulmonary, lymphatic and skeletal samples. ResultsOur study identified nine key immune-activated/signaling-active cell clusters. Notably, we delineated a three-layered granuloma structure: a core with macrophages (Macro-c09, Macro-c10) and occasional fibroblasts (Fib-c03); a fibroblast-rich (Fib-c01) periphery; and an immune-infiltrated intermediate layer comprising diverse immune-cells recruited by strong signaling-molecules (SPP1/MIF) from core/periphery cells. This study also shows granuloma heterogeneity across individuals and tissues. ConclusionsBy merging scRNA-seq with ST-seq, we offer an intricate single-cell perspective of granulomas spatial-structure and formation mechanisms, identify signaling-molecules and significantly changed genes as potential targets for host-directed tuberculosis immunotherapy, highlight fibroblasts crucial role in granuloma formation, and provide an important reference/improved understanding of TB.

microbiology↗

bioRxiv2024

DMRIntTk: integrating different DMR sets based on density peak clustering

BackgroundIdentifying differentially methylated regions (DMRs) is a basic task in DNA methylation analysis. However, due to the different strategies adopted, different DMR sets will be predicted on the same dataset, which poses a challenge in selecting a reliable and comprehensive DMR set for downstream analysis. ResultsHere, we develop DMRIntTk, a toolkit for integrating DMR sets predicted by different methods on a same dataset. In DMRIntTk, the genome is segmented into bins and the reliability of each DMR set at different methylation thresholds is evaluated. Then, the bins are weighted based on the covered DMR sets and integrated into DMRs by using a density peak clustering algorithm. To demonstrate the practicality of DMRIntTk, DMRIntTk was applied to different scenarios, including different tissues with relatively large methylation differences, cancer tissues versus normal tissues with medium methylation differences, and disease tissues versus normal tissues with subtle methylation differences. The results show that DMRIntTk can effectively trim the regions with small methylation differences in the original DMR sets and therefore it can enhance the proportion of DMRs with higher methylation differences. In addition, the overlap analysis suggests that the integrated DMR sets are quite comprehensive, and the functional analysis indicates the integrated disease-related DMR sets are significantly enriched in biological pathways, which are associated with the pathological mechanisms of the diseases. ConclusionsConclusively, DMRIntTk can help researchers obtaining a reliable and comprehensive DMR set from many prediction methods.

bioinformatics↗

bioRxiv2024

Short-Term Warming Induces Cyanobacterial Blooms and Antibiotic Resistance in a Freshwater Lake as Revealed by Metagenomics Analysis

Climate change poses significant risks to freshwater ecosystems, potentially exacerbating harmful cyanobacterial blooms and antibiotic resistance. We investigated these dual threats in Cosseys Reservoir, New Zealand, by simulating short-term warming scenarios and assessing the role of oxidative stress. Microcosms were subjected to Base (22{degrees}C), Normal (24{degrees}C), and projected Future (27{degrees}C) temperatures, with additional treatments including reactive oxygen species (ROS). Metagenomic analysis revealed substantial restructuring of microbial communities under warming conditions. Cyanobacterial abundance increased from 6.11% (initial) to 20.53% at 24{degrees}C and 10.66% at 27{degrees}C. Notably, ROS addition mimicked the effects of temperature increase on cyanobacterial proliferation. Toxin-producing families, including Microcystaceae and Nostocaceae, proliferated significantly. The microcystin synthesis gene (mcy) showed a strong positive association (R{superscript 2} = 0.88) with cyanobacterial abundance. Moreover, cyanobacteria exhibited enhanced nutrient acquisition (pstS gene, R{superscript 2} = 0.69) and upregulated nitrogen metabolism pathways under warming conditions. Concurrently, we observed a marked increase in antibiotic resistance gene (ARG) abundance with rising temperatures. The relative abundance of multidrug resistance genes was consistently high across all conditions (50.82 % of total ARGs). ROS stress further intensified ARG proliferation, particularly for efflux pump genes (e.g., acrB, adeJ, ceoB, emrB, MexK, muxB). Co-association network analysis identified key antibiotic-resistant bacteria (e.g., Streptococcus pneumoniae, Acinetobacter baylyi) and ARGs (e.g., acrB, MexK, rpoB2, bacA) central to resistance dissemination under warming conditions. This study demonstrates that even modest temperature increases (2-5{degrees}C) can promote both cyanobacterial blooms and antibiotic resistance in freshwater ecosystems over short time scales. The synergistic effects of temperature and oxidative stress underscore the complex challenges posed by climate change to water quality and public health. HighlightsO_LIShort-term warming promotes toxic cyanobacteria and antibiotic resistance in freshwater. C_LIO_LIHarmful cyanobacteria and their metabolic potential increase under warming conditions. C_LIO_LIReactive oxygen species mimic and exacerbate temperature effects. C_LIO_LIOxidative stress response genes strongly correlate with ARG abundance. C_LIO_LICo-association networks identify key host pathogen central to resistance spread. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/602497v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@157fc25org.highwire.dtl.DTLVardef@16b1103org.highwire.dtl.DTLVardef@29fa6eorg.highwire.dtl.DTLVardef@1f88650_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Target of rapamycin (TOR) regulates CURLY LEAF (CLF) translation in response to environmental stimuli

The target of rapamycin (TOR)-Polycomb repressive complex 2 (PRC2) pathway is a crucial link that translates environmental and developmental cues into chromatin, thus reprogramming transcription. While the PRC2 methyltransferase Curly leaf (CLF) is known to be specifically involved, the underlying mechanism remains unclear. This study sheds light on how TOR fine-tunes CLF protein levels by promoting translation re-initiation mediated by eIF3h. We found that the second upstream open reading frame (uORF) located in the 5 leader region of the CLF transcript significantly represses its translation (by 50%). Plants lacking this uORF leader displayed reduced sensitivity to TOR inhibition and impaired induction of stress-responsive genes. Interestingly, this uORF sequence exhibits partial conservation across diverse plant species, suggesting a potential role in adaptation to various environmental conditions. Our findings reveal a dynamic mechanism within the TOR-PRC2 pathway, highlighting its responsiveness to environmental stimuli.

plant biology↗

bioRxiv2024

MetaGXplore: Integrating Multi-Omics Data with Graph Convolutional Networks for Pan-cancer Patient Metastasis Identification

The spread of cancer cells from the primary tumor to distant anatomical sites, known as tumor metastasis, poses a significant challenge in clinical prognosis, impairing treatment efficacy and reducing patient survival time. Current methods for predicting and diagnosing tumor metastasis rely heavily on extensive examinations and subjective clinical judgments. Accurate and rapid prediction of tumor metastasis likelihood remains an unresolved challenge, crucial for guiding effective clinical interventions and extending patient survival. Additionally, identifying key genes highly associated with metastasis probability is a pressing issue, essential for providing valuable insights into the potential identification of tumor metastasis-specific biomarkers. We developed MetaGXplore, a pioneering Graph Convolutional Neural Network (GCN)-based framework designed to predict metastasis probability by integrating pan-cancer multi-omic datasets with a protein-protein interaction network, while also identifying key genes involved in the metastatic process. Multi-omics datasets offer a comprehensive view of cancer biology, enhancing accuracy in metastasis forecasting through superior deep learning algorithms. Our classification model results were interpreted with GNNExplainer. The efficacy of MetaGXplore was validated via model evaluations, graph structure analysis, and multi-omics data assessment. Enrichment analysis of key genes further explored their biological roles.

bioinformatics↗

bioRxiv2024

Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions

Contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules (T-tubules), we hypothesize that the PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, while the ubiquitously expressed extended synaptotagmin 2 does not show a preference for PM curvature. At the mechanistic level, we find that the low complexity region (LCR) and the MORN motifs of junctophilins can independently bind to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins, Eps15-homology domain containing proteins (EHDs), that interact with the MORN_LCR motifs and facilitate junctophilins preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

cell biology↗

bioRxiv2024

AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use. To understand the scope of its benefits in damage reduction and potential limitations, this study evaluated the effects of AB-free kava on a panel of health indicators in mice exposed to 2 - 4 weeks of daily tobacco smoke exposure. Our comprehensive assessments included global transcriptional profiling of the lung and liver tissues, analysis of lung inflammation, evaluation of lung function, exploration of tobacco nicotine withdrawal, and characterization of the causal PKA signaling pathway. As expected, Tobacco smoke exposure perturbed a wide range of biological processes and compromised multiple functions in mice. Remarkably, AB-free kava demonstrated the ability to globally mitigate tobacco smoke-induced deficits at the molecular and functional levels with promising safety profiles, offering a unique promise to mitigate tobacco smoke-related health damages. Further pre-clinical evaluation and clinical translation are warranted to fully harness the potential of AB-free kava in combating tobacco smoke-related harms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/599576v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1f6ee4corg.highwire.dtl.DTLVardef@96e062org.highwire.dtl.DTLVardef@16579a0org.highwire.dtl.DTLVardef@1140a8e_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Selection of Fluorinated Aptamer Targeting RNA Element with Different Chirality

The development of RNA aptamers with high specificity and affinity for target molecules is a critical advancement in the field of therapeutic and diagnostic applications. This study presents the selection of a 2-fluoro modified mirror-image RNA aptamer through the in vitro SELEX process. Using a random RNA library, we performed iterative rounds of selection and amplification to enrich aptamers that bind specifically to the viral frameshift element which contains the opposite chirality. The unnatural chirality of the aptamer improved its enzymatic stability, and the incorporation of 2-fluoro modifications was crucial in enhancing the binding affinity of the aptamers. After nine rounds of SELEX, the enriched RNA pool was sequenced and analyzed, revealing the dominant aptamer sequences. The selected 2-fluoro modified mirror-image RNA aptamer demonstrated a dissociation constant of approximately 1.6 M, indicating moderate binding affinity with the target and exceptional stability against nuclease degradation. Our findings highlight the potential of 2-fluoro modified mirror-image RNA aptamers in enhancing the stability and utility of RNA-based therapeutics and diagnostics, paving the way for future applications in diverse biomedical fields.

biochemistry↗

bioRxiv2024

Photoactivated SOPP3 enables APEX2-mediated proximity labeling with high spatio-temporal resolution in live cells

Protein interactome characterized via proximity labeling (PL) and proteomic analysis is important for mechanism study in biomedical research. However, exogenous H2O2 required for engineered peroxidase, like APEX2, is cytotoxic, while biotin ligases-based PL have poor temporal resolution. Here, we showed that SOPP3, an engineered photosensitizer, could trigger APEX2 mediated PL within seconds under blue light illumination, without exogenous H2O2 or cytotoxicity. We demonstrated that APEX2 plus photoactivated SOPP3 could catalyze spatially restricted biotinylation at endoplasmic reticulum-mitochondria contact sites and cell-cell interface. Through fusing APEX2 and SOPP3 as a chimeric probe, we showed that APEX2-SOPP3 also works well in multiple subcellular locations, including cell surface. Notably, either APEX2 plus SOPP3, or chimeric APEX2-SOPP3 requires 10 folds lower illumination power, compared to that for light-oxygen-voltage protein alone mediated PL, and has better response to illumination in terms of PL in time course with little cytotoxicity. Thus, this new PL technology paves an avenue to characterize molecular dynamics of key biomedical events with high spatial-temporal resolution, efficiency, and flexible applicability.

molecular biology↗