Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 451 records · Page 25Linked to original sources

bioRxiv2025

BioLogical: a universal analysis framework for biosystem logical dynamic

Complex biosystems exhibit ordered, functional, self-organized features. How-ever, a universal framework for exploring their logical paradigms and dynamic characteristics remains lacking. Here we describe BioLogical, a user-friendly R package, designed for analyzing properties of biosystems. We demonstrate its versatile capacities of deciphering multi-valued logical paradigms, calculating order parameters, and simulating system dynamic, even multi-valued Quine-McCluskey and logical satisfiability analysis. The open-source software is available at https://github.com/YuxiangYao/BioLogical.

systems biology↗

bioRxiv2025

Pyruvate kinase activates SARM1 to exacerbate axonal degeneration in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is a prevalent and disabling complication of diabetes, characterized by progressive axonal degeneration. However, the molecular link between hyperglycemia and axon injury remains unclear. Here, we identify pyruvate kinase M (PKM) as a direct metabolic activator of the NADase SARM1 under high-glucose conditions. Proteomic and biochemical analyses reveal that PKM binds the TIR domain of SARM1 via its C-terminal region, allosterically enhancing NADase activity independently of PKMs glycolytic role. In dorsal root ganglion (DRG) neurons, hyperglycemia strengthens the PKM-SARM1 interaction, driving NAD depletion, axonal fragmentation, and sensory dysfunction. Genetic depletion of PKM protects against streptozotocin-induced neuropathy, preserving nerve fiber density, restoring NAD levels, and alleviating mechanical allodynia. Most notably, we developed Pep-SP1, a competitive inhibitory peptide derived from residues 645-655 of the SARM1 TIR domain, which selectively disrupts the PKM-SARM1 interaction without impairing PKM metabolism or SARM1 catalytic activity. Systemic delivery of Pep-SP1 attenuates axonal degeneration and improves sensory outcomes in diabetic mice. By targeting a disease-potentiating interface, we expand therapeutic strategies beyond catalytic and allosteric inhibition, offering a mechanistically distinct avenue for axon protection with broad relevance to metabolic and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Host adaptation and genome evolution of the broad host range fungal rust pathogen, Austropuccinia psidii

Rust diseases on plants are caused by fungi in the order Pucciniales. Typically, rust fungi have narrow host specificity however the pandemic biotype of Austropuccinia psidii has an unusually broad host range causing disease on over 480 myrtaceous species globally. We assembled and analysed a fully phased chromosome-level genome for the pandemic A. psidii and addressed key outstanding questions of its infection biology. Our research revealed a conserved rust fungal karyotype of 18 haploid chromosomes, in line with fungi for distantly related cereal rusts. We observed chromosomal re-assortment between the two nuclei, with one nucleus carrying 19 and the other 17 chromosomes. The synteny of universal single-copy orthologs is mostly maintained with the distantly related rust fungus Puccinia graminis f. sp. tritici. In contrast, nucleotide composition and methylation profiles of A. psidii are distinct compared to rust fungi with smaller genome sizes that have not undergone massive transposable element expansions. Our analysis of mating type loci supports a tetrapolar mating system for A. psidii with a novel finding of expanded numbers of pheromone peptide precursors. We show that infection dynamics of A. psidii are consistent on four different susceptible host species separated by 65 mya of evolution and that transcriptional regulation during infection reveals two distinct waves of gene expression in early and late infection, including allele-specific expression of candidate effectors. Together, these findings enhance the understanding of the genome biology and pathology of A. psidii, while also providing a valuable resource for future research on this serious rust pathogen.

microbiology↗

bioRxiv2025

Conformational Dynamics of the Nuclear Pore Complex: Insights from Elastic Network Models and Coarse-Grained Simulations

The nuclear pore complex (NPC) serves as the primary channel regulating nucleocytoplasmic transport in eukaryotic cells. In recent years, atomic-resolution structural models of both the constricted and dilated states of the NPC central core have been resolved; however, the molecular mechanisms underlying the transition between these two states remain unclear. This study employed elastic network models (ENM) to identify the first three low-frequency collective motion modes of the NPC scaffold structure, revealing the intrinsic relationship between these modes and the two-state transition of the NPC scaffold. Molecular dynamics (MD) simulations were further utilized to achieve dynamic conformational transitions between the constricted and dilated states of the NPC scaffold, providing detailed insights into the dynamics of this process. Regarding the FG repeat sequences within the nuclear pore channel, simulations based on the inner ring heterotrimeric FG-Nups revealed significant differences in their distribution between the constricted and dilated states. Finally, by integrating multi-scale research findings, we propose a potential nucleocytoplasmic transport regulatory pathway that encompasses both NPC conformational changes and FG barrier dynamic behavior, providing novel support and validation for the dilation model.

biophysics↗

bioRxiv2025

Mechanical Responses of the Giant Nesprin-2

The nesprin protein family serves as a critical physical bridge between the cytoskeleton-a fundamental structural scaffold and mechanotransduction hub of the cell, and the nucleus-an intriguing and emerging mechano-responsive element. Due to the external mechanical cues and the nucleo-cytoskeletal dynamics, the nesprins are physiologically under forces. However, the dynamics of nesprins within physiological forces and loading rates remain largely unexplored. In this study, we employ magnetic tweezers based single-molecule manipulation alongside molecular dynamic simulations and AlphaFold structural predictions to comprehensively investigate the dynamics of force-bearing spectrin repeat (SR) domains of the giant nesprin-2 protein. Through direct quantification, we unveil that the numerous SRs undergo mechanical unfolding and refolding dynamics with distinct transition rates within several pN scale. Furthermore, we show that the giant nesprin-2 could act as an effective molecular absorber adeptly maintaining forces on the nucleoskeleton and cytoskeleton linkage within a few pN across displacement spans exceeding {micro}m. Notably, our findings imply that subtle pN-level mechanical forces intricately modulate nesprin-protein interactions via the dynamics of domain folding and unfolding. Collectively, our study offers a comprehensive understanding of the mechanical characteristics of giant nesprin-2, shedding light on its pivotal role in nucleoskeleton-cytoskeleton mechanotransduction.

biophysics↗

bioRxiv2025

Bioinformatics classification of the MgtE Mg2+ channel and de novo protein design for the stabilization of its novel subclass

MgtE channels play crucial roles in Mg{superscript 2} homeostasis and are implicated in bacterial survival under antibiotic exposure. Previous structural and biophysical studies have predominantly focused on the Thermus thermophilus MgtE, leaving the structural and mechanistic diversity of MgtE family proteins largely unexplored. In this study, using a genome mining approach, we identified diverse MgtE homologs, including a novel subclass termed the "mini-N type," which lacks the canonical cytoplasmic N and CBS domains but possesses a unique small N-like domain. Despite extensive expression screening, mini-N type homologs could not be stably purified. To address this issue, we designed a series of de novo proteins and determined their crystal structures. A selected de novo protein was fused to a mini-N type MgtE, enabling successful purification and preliminary cryo-EM imaging. Our findings demonstrate that de novo designed protein fusions can serve as powerful tools for stabilizing and purifying otherwise unstable membrane proteins, opening new avenues for the structural and functional studies of otherwise inaccessible membrane proteins.

biophysics↗

bioRxiv2025

Xist Repeat A coordinates an assembly of SR proteins to recruit SPEN and induce gene silencing

The lncRNA Xist represents a paradigm to understand the mechanisms of RNA-mediated gene silencing in mammals, which remain largely unresolved. To induce silencing, Xist recruits the RNA-binding protein SPEN through its 5'-proximal Repeat A domain. Yet, how Repeat A recruits SPEN and how SPEN coordinates silencing remain unclear. We report that sequences in Repeat A critical for SPEN recruitment directly bind SR-rich splicing factors. SRSF1, one such factor, is required for optimal SPEN recruitment and its RS-domain recruits SPEN when tethered to Xist. SPEN and SR-protein-binding motifs promote Repeat As association with many proteins, including the m6A machinery and elongating RNA polymerase II. SPEN also represses autosomal genes where its recruitment coincides with SR-protein binding. Our results reveal an unexpectedly essential role for splicing factors in coordinating silencing by Xist and suggest that the sensing of SR-protein-rich assemblies is a general mechanism through which SPEN targets genes for repression.

genetics↗

bioRxiv2025

Alcohol Disrupts Neural Differentiation Through Endoplasmic Reticulum Stress and PERK Pathway Activation

Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line derived from the mouse embryonic brain, were utilized as an in vitro model. As an in vivo model, pregnant mice were exposed to alcohol between gestation days 14 and 16, after which newly formed neurons in the ventricular zone (VZ) were analyzed. To examine the role of endoplasmic reticulum (ER) stress, tunicamycin (TM), and MANF-deficient NE-4C cells were employed. Neural differentiation was assessed using immunofluorescence, immunoblotting and flow cytometry. Alcohol impaired the differentiation of NE-4C cells into neurons and astrocytes without impacting cell migration. It also induced ER stress, preferably activating the PERK pathway. Similarly, ER stress caused by TM and MANF deficiency disrupted neural differentiation and activated PERK. Inhibiting PERK mitigated alcohol-induced impairment of neuronal differentiation. PAE decreased the number of newly formed neurons in the VZ of fetal brain while having little effects on cell survival and proliferation. Inhibiting PERK partially reversed the reduction of new neurons caused by PAE. Thus, alcohol-induced ER stress, particularly PERK activation, may contribute to impaired neurogenesis linked to FASD.

pharmacology and toxicology↗

bioRxiv2025

Stabilized ion selectivity corrects activation drift in kalium channelrhodopsins

Effective optogenetic inhibition of neuronal activity requires tools that can reliably silence neurons across diverse conditions and cell types. Potassium-selective channelrhodopsins (KCRs) have emerged as promising alternatives to chloride-conducting channels for optogenetic inhibition of cellular excitability, but they exhibit dynamic ion selectivity shift under prolonged or intense illumination, causing activation. This inhibition to activation transition limits their utility for silencing circuits. Through behavioral and electrophysiological analyses in Drosophila, and C. elegans, we found that the C29D variant of KCR1 maintains the most stable potassium selectivity among tested variants. While other KCR variants showed excitation defects, KCR1-C29D consistently provided robust in vivo inhibition across cell types, illumination conditions, and species. Electrophysiological recordings revealed that while most KCRs show declining PK/PNa ratios during illumination, KCR1-C29D maintains stable ion selectivity, consistent with its robust silencing capability. This work resolves a key limitation of KCR optogenetics and shows that KCR1-C29D is a superior tool for reliable inhibition. Our findings offer valuable mechanistic and practical insights for the design of next generation optogenetic inhibitors.

neuroscience↗

bioRxiv2025

Role of glutamate 292 and lysine 331 in catalysis for the flavoenzyme (S)-6-hydroxynicotine oxidase from Shinella sp. HZN7

The flavoenzyme NctB from Shinella sp. HZN7 catalyzes the oxidation of (S)-6-hydroxynicotine to 6-hydroxypseudooxynicotine concomitant with dioxygen reduction, which is the same chemistry catalyzed by the well-studied flavoenzyme L-6-hydroxynicotine oxidase (LHNO) from Paenarthrobacter nicotinovorans. However, while both enzymes are members of the flavoprotein amine oxidoreductase (FAO) family, they share only 26% sequence identity and are evolutionarily distant. Furthermore, nearly all FAOs (including LHNO) have a conserved lysine proximal to N5 of the flavin that is known to promote the reaction with O2 in the oxidative half-reaction, yet NctB, unusually, has a glutamate (Glu292) at this position. We report here using transient kinetics that NctB reacts rapidly with dioxygen in the oxidative half-reaction despite lacking the conserved lysine associated with promoting the reaction with O2 in FAO family enzymes. Mutagenesis reveals that a lysine derived from a different sequence position (Lys331) likely accelerates the reaction with dioxygen in NctB, as the K331M mutation results in a 1400-fold decrease in rate constant for reaction with O2. Glu292 forms a salt bridge with Lys331 in the structure of NctB, and a E292T mutation results in a [~]80-fold decrease in rate constant for reaction with O2, suggesting that Glu292 optimizes the positioning and/or properties of Lys331 to promote dioxygen activation. Analysis of pH-rate effects in NctB shows similar pH profiles as in LHNO despite having differences in active site structure. These results indicate that NctB and LHNO convergently evolved to have the same enzymatic function.

biochemistry↗

bioRxiv2025

Lysosomal control of proteostasis and reproductive capacity by conserved LMD-3 protein in C. elegans

The reproductive capacity declines markedly with female age in humans. Similarly, C. elegans exhibit a rapid age-dependent decline in fecundity shortly after reaching adulthood. Emerging evidence suggests a significant link between proteostasis disruption and reduced fertility in both worms and humans, but the regulatory mechanisms governing this connection are not fully understood. Here, we report that LMD-3, a LysM domain protein, regulates proteostasis and reproductive capacity in C. elegans. The deficiency of lmd-3 leads to striking defects in oxidation resistance and constitutively high cellular stress responses, such as ER stress response and cytosolic stress response. We demonstrate that lysosome-localized LMD-3 protein interacts with vitellogenin and V-type ATPase, which drives proton-transporting and lysosomal lumen acidification. LMD-3 regulation of lysosomal function is essential for maintaining yolk protein homeostasis and reproductive health. We also identify that vitamin B12 (meCbl) supplementation revert the fecundity decline of lmd-3 mutants by reducing oxidative stress and improving lysosomal function. Together, these findings emphasize the role of LMD-3 in sustaining protein homeostasis and oocyte quality control, and establish a model system to find potent therapeutic strategies to increase reproductive health.

cell biology↗

bioRxiv2025

decemedip: hierarchical Bayesian modeling for cell type deconvolution of immunoprecipitation-based DNA methylomes

MeDIP-seq is an enrichment-based DNA methylation profiling technique that measures the abundance of methylated DNA. While this technique offers efficiency advantages over direct methylation profiling, it does not provide absolute quantification of DNA methylation necessary for cell type deconvolution. We introduce decemedip, a Bayesian hierarchical model for cell type deconvolution of methylated sequencing data that leverages reference atlases derived from direct methylation profiling. We demonstrate its accuracy and robustness through simulation studies and validation on cross-platform measurements, and highlight its utility in identifying tissue-specific and cancer-associated methylation signatures using MeDIP-seq profiling of patient-derived xenografts and cell-free DNA. decemedip is available at https://github.com/nshen7/decemedip.

genomics↗

bioRxiv2025

Safeguarding spermatogenesis from retrotransposon insertions by forming ecDNA

Retrotransposon mobilization in germline cells enables the rewriting of genetic information to drive genome innovation, species evolution, and adaptation through the generation of de novo mutations. However, uncontrolled mobilization can cause DNA breaks and genome instability, often leading to sterility. How germ cells balance retrotransposon-induced genome innovation with the need for genomic integrity remains poorly understood. Here, we used Drosophila spermatogenesis as a model to investigate retrotransposon mobilization dynamics. Although many retrotransposon families are transcriptionally active, we found that the LTR-retrotransposon nomad completes the full mobilization cascade--including mRNA export, protein translation, and reverse transcription--to produce double-stranded DNA (dsDNA) the most efficiently. Strikingly, despite successfully generating dsDNA, nomad rarely achieves genomic reintegration. Instead, its newly synthesized DNA predominantly forms extrachromosomal circular DNA (ecDNA). These findings suggest that ecDNA formation acts as a protective mechanism to sequester retrotransposon-derived DNA and prevent widespread genomic integration during spermatogenesis, thereby preserving genome stability while allowing limited retrotransposon activity.

genomics↗

bioRxiv2025

The Effects of Alginate Oligosaccharides (AOS) with Degree of Polymerization (DP) 2, 3, 4, 5, 6, and 7 on Tomato Yields

This study evaluated the effects of alginate oligosaccharide (AOS) fractions with degrees of polymerization (DP) 2-7 on tomato (Solanum lycopersicum L.) growth, yield, fruit quality, physiology, nutrient uptake, and defense responses under greenhouse conditions. AOS application significantly enhanced total yield, increasing from 2.5 kg/plant in the control to 4.2 kg and 4.0 kg in DP 2 and DP 3, respectively (p < 0.001). Marketable yield, fruit number, and average fruit weight also improved, with the highest values observed in DP 2 and DP 3 treatments. Fruit quality parameters, including total soluble solids (6.2 {degrees}Brix) and lycopene content (4.8 mg/100 g), were significantly higher in these groups. Plant growth metrics, such as height (70 cm), leaf number (25 leaves), and biomass accumulation, were markedly increased. Physiological traits, including photosynthetic rate (18.5 {micro}mol CO2 m-{superscript 2} s-{superscript 1}), chlorophyll content, and stomatal conductance, were also enhanced. Nutrient uptake of nitrogen, phosphorus, and potassium, as well as antioxidant enzyme activities (PAL, peroxidase, catalase, and SOD), were significantly elevated, while malondialdehyde (MDA) content was reduced. These findings suggest that AOS, particularly DP 2 and DP 3, effectively promote tomato productivity, fruit quality, and stress tolerance through improved physiological performance and defense activation.

bioengineering↗

bioRxiv2025

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging

To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and both sexes. We found that around one quarter of 536 organ-specific cell types and 1,828 finer-grained subtypes exhibited significant age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, indicating systemic signals that coordinate these changes. Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying these shifts. Moreover, [~]40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

genomics↗

bioRxiv2025

Multiplexed Data-Independent Acquisition (mDIA) to Profile Extracellular Vesicle Proteomes

Extracellular vesicles (EVs) have gained increasing attention with their intriguing biological functions and their molecular cargoes serving as potential biomarkers for various diseases, including cancers. A relatively lower abundance of EV proteins compared to cellular counterparts necessitates sensitive and accurate quantitative proteomic strategies. Multiplexed proteomics combined with data-independent acquisition (mDIA) has shown promise for improving sensitivity and quantification over traditional DDA and label-free methods. Despite this, mDIA pipelines that utilize various types of spectral libraries and search software suites have not been thoroughly evaluated with EV proteome samples. In this study, we aim to establish a robust mDIA pipeline based on dimethyl labeling for quantitative proteomics of EVs. EVs were isolated using the extracellular vesicle total recovery and purification (EVtrap) technique and processed directly through an on-bead one-pot sample preparation workflow to obtain digested peptides. We evaluated different mDIA pipelines, including library-free and library-based DIA on the timsTOF HT platform. Results showed that library-based DIA, with project-specific spectral libraries generated from StageTip-based fractionation, outperformed other pipelines in protein identification and quantification. We demonstrated for the first time EV proteome landscape changes caused by the IDH1 mutation and inhibitor treatment in intrahepatic cholangiocarcinoma, highlighting the utility of mDIA in EV-based biomarker discovery.

biochemistry↗

bioRxiv2025

Humans underestimate their body mass in microgravity: evidence from reaching movements during spaceflight

Astronauts consistently exhibit slower movements in microgravity, even during tasks requiring rapid responses. The sensorimotor mechanisms underlying this general slowing remain debated. Two hypotheses have been proposed: either the sensorimotor system adopts a conservative control strategy for safety and postural stability, or the system underestimates body mass due to reduced inputs from proprioceptive receptors. To dissociate these opinions, we studied twelve taikonauts aboard the China Space Station performing a classical hand-reaching task. Compared to their pre-flight performance and to an age-matched control group, participants showed increased movement durations and altered kinematic profiles in microgravity. Model-based analyses of motor control parameters revealed that these changes stemmed from reduced initial force generation in the feedforward control phase followed by compensatory feedback-based corrections. These findings providing support for the body mass underestimation hypothesis while being inconsistent with the strategic slowing hypothesis. Importantly, the sensory estimate of bodily property in microgravity is biased but immune from sensorimotor adaptation, calling for an extension of existing theories of motor learning.

neuroscience↗

bioRxiv2025

Developing a general AI model for integrating diverse genomic modalities and comprehensive genomic knowledge

Advances in next-generation sequencing technologies have vastly expanded the availability of diverse genomic, epigenomic and transcriptomic data, presenting the opportunity to develop a general AI model that integrates comprehensive genomic knowledge into a unified model. Unlike previous predictive models, which are typically specialized to certain tasks, our general AI model unifies a wide range of genomic modalities, such as nascent RNA and ultra-high-resolution chromatin organization, within a multi-task architecture. Using ATAC-seq and DNA sequences as inputs, we incorporated diverse genomic modalities as output, and the model exhibits strong generalizability across different cell types and tissues in all tasks we trained. It accurately predicts gene-level transcription measured by various nascent RNA assays, and effectively captures enhancer-associated transcription. Additionally, it also accurately captures the potential functions of non-coding genetic variants and regulatory elements. Additionally, we extended the model trained on human data to a mouse general model, achieving accurate predictions of genomic modalities, such as high resolution chromatin contact maps with limited data availability, which are further validated using an established mouse inner-ear study. This comprehensive approach offers a powerful tool for understanding genome regulation in both human and mouse species.

bioinformatics↗