Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 541 records · Page 30Linked to original sources

bioRxiv2025

Role of Age in Mediating the Association Between the Vaginal Microbiota and Preterm Birth

The vaginal microbiota plays a crucial role in vaginal health and pregnancy outcomes. However, the influence of maternal characteristics, especially age, on the relationship between the vaginal microbiota and preterm birth is poorly understood. This study quantifies the effects of race, maternal age, and gestational age on vaginal microbiota composition. Our results demonstrate stronger associations between preterm birth and a less optimal vaginal microbiota in White and Asian women compared to Black or African American women. The microbiota difference between preterm and term births was more pronounced in older reproductive-age women, with Lactobacillus species increasing with age only in term births. Additionally, lower alpha diversity was observed in term pregnancies compared to preterm during both early and late pregnancy, particularly in women aged above 25 years. These findings highlight the mediating role of age in the relationship between the vaginal microbiota and preterm birth.

microbiology↗

bioRxiv2025

Discovery of Chirally-dependent Protein O-2-Hydroxyglutarylation by D2HG and L2HG

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are common in multiple types of human cancer, leading to the accumulation of D-2-hydroxyglutarate (D2HG) and the promotion of tumorigenesis1. Here we discovered a novel O-2- hydroxyglutarylation by D2HG using chemical proteomics and further revealed distinct chiral preferences for D/L2HG modifications. Notably, we identified two kinases, MRCKA and SLK, modified by D2HG and L2HG respectively, and detected reduced phosphorylation of their substrates, suggesting an inhibitory effect of D/L 2HG modifications on the kinases activity.

biochemistry↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2025

Achievement-Based Differences in Cognitive-Emotional Interplay During Classroom Learning: A Multimodal Analysis with Experience Sampling Method

BackgroundThe relationship between cognition and emotion during learning is crucial for educational theories and has been under debate for a long time, from the ancient philosophy to current scientific analyses. However, the relationship may not be uniform and may vary across diverse individual groups. AimsTherefore, this study aims to explore whether the relationship between cognition and emotion varies across different student groups. Furthermore, it examines whether neurophysiological evidence can provide insights into such group differences. SampleThe study involved 22 high school students (11 high-performing and 11 low-performing) over 13 math lessons. Surveys were administered three times during each lesson, yielding a multilevel dataset with 777 samples. MethodsThe experience sampling method was employed to gather data on cognitive and emotional states periodically, as well as their regulations. Simultaneously, multimodal neurophysiological data, including electroencephalograph (EEG), electrodermal activity (EDA), and photoplethysmography (PPG), were collected during classroom learning to analyze the relationship further. ResultsCognitive state, cognitive regulation, emotional state, and emotional regulation were highly correlated overall. In high-performing students, the association was higher than that in low-performing students, especially at the level of within-subject repeated-measures. Multimodal data revealed the common neurophysiological basis of the correlated variation between cognition and emotion, and highlighted different neurophysiological patterns between high and low achievers. ConclusionsThe joint evidence from the experience sampling survey and neurophysiological measures reveals that the cognitive-emotional relationship differs by academic achievement levels, with high achievers revealing a more consistent variation between cognition and emotion. Such co-variation shares a common neurophysiological pattern with features associated with high student-teacher interaction and high concentration, further explaining the group differences.

neuroscience↗

bioRxiv2025

Genetic deconvolution of embryonic and maternal cell-free DNA in spent culture medium of human preimplantation embryos through deep learning

Noninvasive preimplantation genetic testing for aneuploidy based on embryonic cell-free DNA (cfDNA) released in spent embryo culture media (SECM) has brought hope in selecting embryos that are most likely to implant and grow into healthy babies during assisted reproduction. However, maternal DNA contamination in SECM significantly hampers the reliability of embryonic chromosome ploidy profiles, leading to false negative results, particularly at high contamination levels. Here, we present DECENT (deep copy number variation (CNV) reconstruction), a deep learning method to reconstruct embryonic CNVs and mitigate maternal contamination in SECM from single-cell methylation sequencing of cfDNA. DECENT integrates sequence features and methylation patterns by combining convolution modules, long-short memory, and attention mechanisms to infer the origin of cfDNA reads. The benchmarking study demonstrated DECENTs ability to estimate contamination proportions and restore embryonic chromosome aneuploidies in samples with varying contamination levels. In contaminated SECM clinical samples, including one with more than 80% maternal reads, DECENT achieved consistent CNV recovery with invasive tests. Overall, DECENT contributes to enhancing the diagnostic accuracy and effectiveness of cfDNA-based noninvasive preimplantation genetic testing, establishing a robust groundwork for its extensive clinical utilization in the field of reproductive medicine.

genetics↗

bioRxiv2025

Inferring circadian rhythm disruptions in cancer using phase differences between clock genes

Circadian rhythms exist across various levels of biological activities, from molecular processes to behaviors. Circadian clock genes are closely linked to the onset and progression of cancer; however, systematic analysis of their rhythmic expression in human tumors is still lacking due to difficulties in time-series sampling. In this study, we examined and improved the method for inferring phase differences through clock gene co-expression to investigate circadian rhythms in timestamp-free samples. We found that the co-expression levels of rhythmic genes are primarily determined by phase differences and are influenced by the strength and tissue specificity of rhythmic expression. Thus, we identified evolutionarily conserved rhythmic genes across multiple tissues to construct tissue-specific phase difference matrices. On this basis, we developed a method for inferring phase difference variations and extended it to the single-sample level as ssDistance to evaluate circadian rhythm disruptions in tumors. Results revealed that the significant alterations in phase differences between clock genes in tumors are cancer-type-specific and have complex effects on patient survival. This method provides an effective tool for studying circadian rhythms in large-scale public datasets lacking temporal information.

bioinformatics↗

bioRxiv2025

Evolutionary trajectories of immune escape across cancers

Immune escape is a critical hallmark of cancer progression and underlies resistance to multiple immunotherapies. However, it remains unclear when the genetic events associated with immune escape occur during cancer development. Here, we integrate functional genomics studies of immunomodulatory genes with a tumor evolution reconstruction approach to infer the evolution of immune escape across 38 cancer types from the Pan-Cancer Analysis of Whole Genomes dataset. Different cancers favor mutations in different immunomodulatory pathways. For example, the antigen presentation machinery is highly mutated in colorectal adenocarcinoma, lung squamous cell carcinoma, and chromophobe renal cell carcinoma, and the protein methylation pathway is highly mutated in bladder transitional cell carcinoma and lung adenocarcinoma. We also observe different timing patterns in multiple immunomodulatory pathways. For instance, mutations impacting genes involved in cellular amino acid metabolism were more likely to happen late in pancreatic adenocarcinoma. Mutations in the glucocorticoid receptor regulatory network pathway tended to occur early, while mutations in the TNF pathways were more likely to occur late in B-cell non-Hodgkin lymphoma. Mutations in the NOD1/2 signaling pathway and DNA binding transcription factor activity tended to happen late in breast adenocarcinoma and ovarian adenocarcinoma. Together, these results delineate the evolutionary trajectories of immune escape in different cancer types and highlight opportunities for improved immunotherapy of cancer. SignificanceDespite its critical role in cancer progression, the evolution of immune escape is poorly understood. We integrate functional genomics and tumor evolution reconstruction and infer immune escape trajectories across cancer types. Our results have important implications for developing biomarkers for immunoprevention and treatment strategies for immune escape of cancer.

evolutionary biology↗

bioRxiv2025

Axon Trafficking Counteracts Aberrant Protein Aggregation in Neurons

Directed axon trafficking of mRNA via ribonucleoprotein complexes (RNPs) is essential for the proper function and survival of neurons. However, the mechanisms governing RNP transport in axons remain poorly understood. Here, we identify Annexin A7 (ANXA7) as a critical adaptor facilitating the retrograde transport of T-cell intracellular antigen 1 (TIA1)-containing RNPs by linking them to the cytoplasmic dynein. Persistent axonal Ca{superscript 2} elevation disrupts ANXA7s linker role, causing the detachment of TIA1 granules from dynein, consequently impairing transport and triggering pathological TIA1 aggregation within axons. Similarly, ANXA7 knockdown decouples TIA1 granules from dynein, severely obstructing trafficking and causing pathological aggregation of TIA1 in axons, which culminates in axonopathy and neurodegeneration both in vitro and in vivo. Conversely, ANXA7 overexpression enhances trafficking and counteracts aberrant aggregation of TIA1-containing RNPs in axons. Our findings elucidate a novel mechanism underlying RNP axonal transport, highlighting its significance in the biology and pathology of central neurons.

neuroscience↗

bioRxiv2025

Associations between epilepsy-related polygenic risk and brain morphology in childhood

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is associated with a complex genetic architecture, but the translation from genetic risk factors to brain vulnerability remains unclear. Here, we examined associations between epilepsy-related polygenic risk scores for HS (PRS-HS) and brain structure in a large sample of neurotypical children, and correlated these signatures with case-control findings in in multicentric cohorts of patients with TLE-HS. Imaging-genetic analyses revealed PRS-related cortical thinning in temporo-parietal and fronto-central regions, strongly anchored to distinct functional and structural network epicentres. Compared to disease-related effects derived from epilepsy case-control cohorts, structural correlates of PRS-HS mirrored atrophy and epicentre patterns in patients with TLE-HS. By identifying a potential pathway between genetic vulnerability and disease mechanisms, our findings provide new insights into the genetic underpinnings of structural alterations in TLE-HS and highlight potential imaging-genetic biomarkers for early risk stratification and personalized interventions.

neuroscience↗

bioRxiv2025

Yeast DNA Polymerase δ Proofreading Nuclease Suppresses Translesion Synthesis and Facilitates Recombination in DNA Lesion Bypass.

Translesion synthesis (TLS) employs specialized polymerases to incorporate nucleotides opposite DNA lesions, allowing replication to continue temporarily without repairing the lesions, while sacrificing replication fidelity (1). TLS depends on a ubiquitin molecule attached to the clamp PCNA at residue Lys164 (2, 3); the precise biochemical and molecular basis how PCNA modification stimulates TLS is still elusive (4-10). In this study, we discovered that DNA polymerase {delta} (Pol {delta}) 3 to 5 "proofreading" exonuclease degrades nascent TLS synthesis opposite pyrimidine dimers and inhibits TLS on both leading and lagging strands. Rad18 E3 ligase and PCNA ubiquitylation become dispensable for TLS when Pol {delta} exonuclease is inactive. Biochemical reconstitution showed that the major UV lesion bypass polymerase Rad30 is intrinsically inefficient at bypassing thymidine dimers and requires multiple turnovers. Pol {delta} exonuclease impedes Rad30 activity both catalytically and non-catalytically during and post-lesion bypass. Importantly, PCNA and PCNA ubiquitylation enhance processivity of Rad30 after thymidine dimer bypass, a critical step for further DNA synthesis extension and overcoming Pol {delta} inhibition. Our study reveals a new paradigm how PCNA ubiquitylation facilitates TLS and the new role of Pol {delta} nuclease in lesion bypass pathway choice and replication fidelity at fork-blocking DNA lesions.

genetics↗

bioRxiv2025

Preclinical Evaluation of P4B-2412 as Phosphodiesterase 4B Radioligand for Positron Emission Tomography Imaging

Phosphodiesterase 4B (PDE4B) plays a critical role in cAMP hydrolysis and is highly expressed in brain regions associated with neuroinflammation and neurodegenerative disorders. Selective PDE4B radioligands hold significant potential for elucidating disease mechanisms and enabling target occupancy measurements. In this study, we developed [18F]P4B-2412, a novel PDE4B-selective radioligand, and evaluated its utility for PET imaging. [18F]P4B-2412 was synthesized with high radiochemical yield (27.2%), excellent radiochemical purity (99%), and favorable molar activity (66.2 {+/-} 2.5 GBq/mol). In vitro autoradiography revealed high PDE4B binding, while dynamic PET imaging demonstrated high in vivo specificity for PDE4B in rodent brain regions. Notably, [18F]P4B-2412 exhibited excellent metabolic stability in vitro and in vivo. These findings establish [18F]P4B-2412 as a promising PET probe for imaging PDE4B in vivo, offering a valuable tool for investigating neuroinflammation and advancing CNS drug development.

neuroscience↗

bioRxiv2025

Action mechanism of a novel agrichemical quinofumelin against Fusarium graminearum

Modern fungicides have made significant contributions to crop disease management, but the development of resistant fungal strains has caused their failure in disease control. Therefore, developing fungicides with novel action mechanisms is the most effective measure to manage resistance. Quinofumelin, a novel quinoline fungicide, exhibits exceptional antifungal activity against phytopathogens. However, there is currently no available information on its mechanism of action. Here, we used transcriptome and metabolome analysis to observe a co-enrichment pattern of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) within pyrimidine biosynthesis pathway (PBP), identifying down-regulation of dihydroorotate dehydrogenase (DHODH). Exogenous uridine monophosphate (UMP), uridine or uracil (metabolites in PBP) successfully restored quinofumelin-induced inhibition of mycelial growth in Fusarium graminearum and Fusarium asiaticum. Additionally, the deletion of FgDHODHII was determined to be lethal; however, mycelial growth of {Delta}FgDHODHII mutants could be restored by adding UMP, uridine or uracil. These findings indicate that the deficiencies in FgDHODHII are functionally equivalent to complete inhibition of its activity by quinofumelin. Finally, molecular docking, surface plasmon resonance (SPR) and microscale thermophoresis (MST) results strongly support the precise interaction between quinofumelin and FgDHODHII. Collectively, these findings provide compelling evidence for the involvement of de novo uracil biosynthesis as mechanism of action for quinofumelin while identifying FgDHODHII as its specific target.

pathology↗

bioRxiv2025

The miR156/SPL9 interaction mode regulates the anthocyanin accumulation in potato

Anthocyanins are an essential class of flavonoids that represent a large group of plant secondary metabolites. microRNAs (miRNAs) can target TFs related to anthocyanin synthesis and inhibit their expression, thereby affecting the expression level of key downstream structural genes and ultimately regulating the synthesis and accumulation of anthocyanins in plants. Nevertheless, the regulatory function of miR156a in anthocyanin synthesis, especially in potatoes, has yet to be investigated. In this study, the miR156a and its target gene StSPL9 were screened and analyzed from small RNA sequencing, degradome sequencing and transient expression assay. The function of miR156a in anthocyanin synthesis of potato tuber was investigated. Overexpression of miR156a (OE-miR156a) in potato tubers promoted anthocyanin synthesis while concurrently reducing flavonoid synthesis compared with wild-type (WT) potatoes. The miR156a-silenced tubers (STTM-miR156a) achieved using short tandem target mimics (STTM) contained significantly lower anthocyanin content and increased flavonoid accumulation compared to WT and OE-miR156a. Notably, overexpression of StSPL9 in potato yielded identical results. The relative expression levels of the anthocyanin-related structural genes PAL, 4CL, CHS, CHI, F3H, DFR, and UFGT in STTM-miR156a transgenic potato tubers showed the opposite trend to that observed in OE-miR156a potato tubers, as demonstrated by RNA sequencing and quantitative real-time PCR (qRT-PCR). The integrated analysis of the transcriptome and metabolome revealed that the accumulation of flavonoids and flavonols in STTM-miR156a was significantly increased than in the wild type, whereas the contents of anthocyanins and phenolic acids were notably reduced. Further analysis showed that the expression of CHS, FG2, BEATH, and CYP75A were up-regulated in STTM-miR156a, and HCT was downregulated, which resulted in a reduced accumulation of methyl 4-caffeoylquinate, a phenolic acid metabolite. Therefore, it is demonstrated that miR156a indirectly modulates the expression of CHS, BEATH, CYP75A, HCT, and FG2 by targeting and degrading its target gene StSPL9 and other SPL genes, thus influencing anthocyanin accumulation in potato tuber. This study provides valuable insights into the complex regulatory network governing anthocyanin biosynthesis in Solanum species.

molecular biology↗

bioRxiv2025

Accumbal acetylcholine signals associative salience

Learning is driven by prediction errors, which determine what is learned, and salience, which controls the learning rate. Dopamine in the nucleus accumbens correlates with prediction errors, but salience mechanisms are less clear. We hypothesized that acetylcholine acts as a salience signal, as it regulates dopamine-induced plasticity. To test this, we recorded acetylcholine and dopamine dynamics in rats across three learning tasks. Our findings reveal a characteristic pattern of evolving neuromodulator responses during learning. First, indiscriminate cholinergic dips appeared, then dopamine responses differentiated based on predicted value, followed by the cholinergic dips also varying by value. Stable performance required this full pattern, and acetylcholine dips could be decoupled from value by changing reward contingencies. The observed acetylcholine dynamics fit an associative salience term predicted by hybrid attentional associative learning models, suggesting that dopamine and acetylcholine act complementarily to determine the content and rate of learning. TeaserAcetylcholine shapes learning rate by signaling the salience of predictive cues.

neuroscience↗

bioRxiv2025

Insights into the spool-like architecture and infectionstrategy of the archaeal virus SEV1

Archaeal viruses are well known for their diverse morphologies and extreme stability. In this study, we used cryo-electron tomography to analyze the structure of SEV1 and its infection strategies in its native state. The results show that SEV1 nucleocapsid adopts a coil-stacking architecture which displays a degree of flexibility. VP4, whose homologues are widespread in the thermo-acidic environment globally, is identified as the major capsid protein and binds genomic DNA forming a "beads-on-a-string" arrangement. Simulations in various extreme environments indicate that the envelope of SEV1 is crucial to the thermostability. SEV1 infects the host by membrane fusion revealed by the membrane fusion assay. The infected cell undergoes cytoplasm condensation to form a "viral factory", leading to the successive production of nascent virions. A series of assembly intermediates of SEV1 are identified revealing an integrated picture of the virus assembly process. The nascent virions are found to be released through virus-associated pyramids (VAPs), composed of unique proteins encoded by SEV1 distinct from other known VAP proteins. Our study provides novel insights to the survival strategies of SEV1, a flexible and enveloped archaeal virus, by using the unique "coil-stacking" architecture and the characteristic infection strategies.

microbiology↗

bioRxiv2025

Sequestration of SerRS through LLPS Impairs Localized Translation and Contributes to Antibiotic Persistence

Antibiotic-tolerant persisters contribute to the emergence of resistance, posing a significant challenge to the efficacy of antibiotic therapies. Despite extensive research, the mechanisms underlying persistence remain inadequately understood. By tracking the evolution of exponential-phase bacterial populations subjected to intermittent high-dose ertapenem exposure, we characterized the evolved strains in terms of tolerance. Mutant strains, harboring mutations in the seryl-tRNA synthetase gene (serS), exhibited abrupt growth arrest upon serine depletion during exponential growth, resembling the persistence phenotype induced by serine hydroxamate (SHX). Under serine starvation, the mutated SerRS protein was sequestrated into liquid-liquid phase separation (LLPS)-driven condensates, disrupting their composition and impairing localized translation. This event precipitated growth arrest and dormancy in the SerST strain, triggering persistence. Our findings reveal an unrecognized role for aminoacyl-tRNA synthetases (aaRSs) in modulating bacterial condensates and provide insights into the molecular mechanisms underlying bacterial persistence. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/630848v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1a69521org.highwire.dtl.DTLVardef@188b087org.highwire.dtl.DTLVardef@fd897forg.highwire.dtl.DTLVardef@14e1b6a_HPS_FORMAT_FIGEXP M_FIG SerRS Recruitment Disrupts Localized Translation in DeaD-marked Condensates. Upon serine starvation, SerRST partitions into LLPS-driven DeaD-marked condensates, impairing their localized translation activity and suggesting mechanisms underlying persistence arising during exponential phase. These evolutionarily conserved condensates orchestrate a robust translation program to enable stress responses and instruct cell fate decisions in bacterial populations. C_FIG

microbiology↗

bioRxiv2024

RNAGenesis: Foundation Model for Enhanced RNA Sequence Generation and Structural Insights

RNA molecules are central to gene regulation, catalysis, and molecular recognition, and offer broad opportunities for therapeutic applications. However, uncovering their complex sequence, structure, and function relationships, particularly for non-coding RNAs, remains a formidable challenge. Here, we introduce RNAGenesis, a Generalist RNA foundation model that integrates sequence representation, structural prediction, and de novo functional design within a single generative framework. Trained on diverse clustered non-coding RNAs, RNAGenesis leverages a BERT-style encoder, query-based latent compression, and a diffusion-guided decoder enhanced by inference-time alignment with gradient guidance and beam search strategies. Through comprehensive evaluations, RNAGenesis achieves state-of-the-art performance on 11 of 13 tasks in the BEACON benchmark and surpasses structure-aware models in inverse folding, 3D structure prediction, and de novo structure design. We further introduce RNATx-Bench, a dedicated benchmark for RNA therapeutics comprising over 100,000 experimentally validated sequences. RNAGenesis demonstrates strong predictive performance across ASOs, siRNAs, shRNAs, circRNAs, and untranslated region (UTR) variants. Furthermore, RNAGenesis enables functional RNA design, including aptamers targeting IGFBP3 and structurally constrained sgRNA scaffolds. Wet-lab validation confirms aptamer binding with KD values as low as 4.02 nM and up to 2.5-fold improvement in editing efficiency across CRISPR-Cas9, base editing, and prime editing systems. These results position RNAGenesis as a next-generation general-purpose RNA foundation model with broad utility for computational modeling and experimental therapeutic design.

bioinformatics↗

bioRxiv2024

Reshaping epigenomic landscapes in facilitating the speciation of bread wheat

Polyploidization is a driving force of wheat evolution and speciation, yet its impact on epigenetic regulation and gene expression remains unclear. Here, we constructed a high-resolution epigenetic landscape across leaves, spikes, and roots of hexaploidy wheat and its tetraploid and diploid relatives. Inter-species stable-expression genes exhibited conserved amino acid sequences under strong purifying selection, while dynamic-expression genes were linked to species-specific adaptation. During hexaploidization, dominant D-subgenome homoeolog expression was suppressed via reduced activating epigenetic signals, converging expression with the A and B subgenomes. Proximal chromatin regions near genes were more stable, whereas distal regions, particularly enhancer-like elements mediated by H3K27ac and H3K4me3, exhibit higher dynamism. Sequence variations in these enhancers lead to differential gene regulation, influencing traits such as spike development. For instance, the two haplotypes of dCRE region of TaDEP-B1 resulted in significant differences in its expression and spikelet numbers. We also observed a coevolution of transcription factors and their binding sites, particularly within the expanded ERF family, which regulates spike morphology. This study highlights the interplay between sequence variation and epigenetic modifications in shaping transcriptional regulation during wheat speciation, offering valuable insights for genetic improvement.

plant biology↗