Biology subjects

Zhang, D.

Publications and source records attributed to Zhang, D..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

Genetic architecture of the S-locus supergene revealed in a tetraploid distylous species

SummaryO_LIHeterostyly is a polymorphic floral adaptation controlled by supergenes and maintained in populations by disassortative mating. The molecular basis of distyly has been investigated in several unrelated families. Previous studies have been limited to diploid species and have not included Rubiaceae, which has the highest number of heterostylous species. C_LIO_LIHere, we investigate the genetic architecture of tetraploid Schizomussaenda henryi (Rubiaceae) to identify candidate style-length genes, evidence for hemizygosity and the potential role of gene duplication in the evolution of the S-locus. Chromosome-level genome assemblies and transcriptomic approaches identified the S-locus region comprised of four hemizygous genes. C_LIO_LIThe candidate gene SchzAUX22 may regulate style length and filament growth by acting in the auxin signaling pathway. Comparative studies of the two sub-genomes of S. henryi indicated strong similarities and no significant sub-genome dominance, as expected from autotetraploidy. Evidence from haplotype-resolved assemblies of a short-styled plant indicated that it possessed the ssSS genotype, consistent with autotetraploidy, which was estimated to have originated [~]3.6 Mya. Analysis of Ks values between S-locus genes and their paralogs indicated that the S-locus likely originated through stepwise duplication. C_LIO_LIOur study provides comprehensive genomic analysis of distyly in a polyploid and demonstrates that despite whole genome doubling the S-locus supergene remains intact and functional as an outbreeding mechanism. Our results contrast with many other heterostylous lineages where polyploidy is associated with breakdown of the polymorphism and transitions to self-fertilization. C_LI

plant biology↗

bioRxiv2025

Targeted intervention of senescence induced by a 5' half fragment of tRNASec(NCA) with antisense oligonucleotide extends healthspan and lifespan in mice

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

genetics↗

bioRxiv2025

DiNovo: high-coverage, high-confidence de novo peptide sequencing using mirror proteases and deep learning

Despite the recent advancements driven by deep learning, de novo peptide sequencing is still constrained by incomplete peptide fragmentation and insufficient protein digestion in current single protease-based proteomic experiments. Here, we present a software system, named DiNovo, for high-coverage and confidence de novo peptide sequencing by leveraging the complementarity of mirror proteases. DiNovo is empowered by several innovative algorithms, including a mirror-spectra recognition algorithm independent of pre-sequencing, two sequencing algorithms based on deep learning and graph theory, respectively, and target-decoy mapping, a method for sequencing result evaluation free of prior peptide identification. Compared with the trypsin protease used alone, DiNovo using two pairs of mirror proteases led to two to three times high-confidence amino acids sequenced. Compared with previous single-protease de novo sequencing algorithms, DiNovo achieved much higher sequence coverages. DiNovo also showed great potential as a powerful complement or alternative to database search for peptide identification with quality control.

bioinformatics↗

bioRxiv2025

The conserved nature of nitrogen recycling within the bacterial pouch of Tetraponera ants

Microbial symbioses are fundamental to the nutrition of many animal groups, yet the mechanisms of nutrient provisioning remain poorly understood -- even in social insects, a diverse clade whose global ecological dominance and sophisticated caste systems make them disproportionately well-studied models for symbiosis research. Here, we investigate the functional significance of a specialized and unusual symbiotic organ-- the bacterial pouch--in four ant species within the Tetraponera nigra-group, focusing on the symbionts roles in nitrogen recycling and colony fitness. Bacterial pouch houses a microbial community consistently dominated by the core bacterial symbiont Tokpelaia. Metagenomic sequencing and targeted {superscript 1}N-labeled urea feeding experiments demonstrate that these symbionts assimilate nitrogen from urea into amino acids, transferring them to adult workers and developing larvae that incorporate recycled nitrogen into their tissues. Disruption of this nitrogen-recycling symbiosis severely impairs larval growth and overall colony fitness. Our study highlights the critical role of the bacterial pouch in sustaining colony fitness in nitrogen-limited environments, providing new insights into the pivotal role of microbial symbioses in the ecological success of social insects.

ecology↗

bioRxiv2025

Unleashing the potential of OPM-MEG to study event-related fields against low-frequency artifacts: the case of sentence processing

OPM-MEG (optically pumped magnetometers-magnetoencephalography) offers unprecedented opportunity in its proximity to the brain and in mobility, outperforming other human MEG systems. However, movements induce low-frequency artifacts (up to [~] 3 Hz) in this system, calling for pipelines that could efficiently reduce these low-frequency noises. Although a high-pass filter of e.g., 4 Hz may minimize these artifacts, it may also eliminate many event-related field (ERF) components, such as the N400 response in sentence processing studies. Moreover, as an emerging technology with expensive sensors, many labs are starting with an experimental setup with fewer sensors (e.g., [~] 10), making it challenging to reject principal components based on visually inspecting the topographic field maps. In the current paper, we show that a combination of moderate high-pass filtering (1 Hz) and evoked-biased denoising source separation (evoked-biased DSS) can effectively reveal typical N400 deflections and effects (between nouns and verbs), with a nine-sensor OPM-MEG setup. Our current pipeline paves the way to studying ERFs with OPM-MEG in more budget-friendly setups with a small number of sensors.

neuroscience↗

bioRxiv2025

Chromatin remodeling integrates vertebrate body axis elongation and cell fate determination

The effective elongation of the vertebrate body axis depends on the precise coordination of cell movements and cell fate determination within the posterior tailbud region. However, the specific biological determinant that integrates these cellular processes during vertebrate tail bud elongation has remained unclear. Here, we demonstrate that the spatiotemporal heterogeneity of chromatin condensation states governs both cell fate and cell motility within the mesodermal progenitor zone (MPZ) and the presomitic mesoderm (PSM) during zebrafish tail bud elongation. By integrating biological experiments with computational modeling, we reveal that nuclear volume heterogeneity, mediated by chromatin remodeling, acts as an active driver of collective cell migration. Reducing chromatin condensation heterogeneity in the MPZ through modulation of chromatin modifications impairs collective cell movements and delays tailbud elongation. Single cell ATAC-seq and RNA-seq analyses reveal that global chromatin accessibility heterogeneity and region-specific chromatin remodeling differences in the PSM and MPZ are functionally associated with gene expression pathways involving in cell lineage specification. These findings establish a molecular connection between cell fate determination and tissue-scale cellular dynamics. Collectively, our findings unveil a unifying framework for understanding the coordination of cell fate determination and large-scale cellular movements during tissue morphogenesis.

developmental biology↗

bioRxiv2025

Physical Activity and Depressive Mood Shared the Structural Connectivity between Motor and Reward Network: a population-based study from the UK Biobank

BackgroundExercise has been revealed to leave a positive effect on alleviating depressive symptoms by various existing studies. However, the neural basis behind this phenomenon remains unknown, as well as its underlying biological mechanism.AimsUsing a large neuroimaging cohort from UK Biobank, this study aimed to identify structural connectivity (SC) patterns simultaneously linked with physical activity and depression, as well as its biological interpretation.Method492 participants with major depression disorder (MDD) and 535 healthy controls (HC) were extracted from the UK Biobank dataset. Partial least squares regression was first utilized to explore a replicable SC pattern simultaneously associated with physical activity and depressive mood. The neuromaps toolbox was applied to interpret the biological ontologies of the identified SC pattern. Neuroimaging-transcriptome association and enrichment analyses were conducted to explore its underlying genetic basis, pathways and cell types. The reproducibility and generalizability were tested on another independent MDD dataset (N=3,496) and bipolar disorder (BD) dataset (N=81).ResultsA SC pattern linked with exercise was identified to be both significantly correlated with depressive mood and group discriminative between MDDs and HCs, which primarily located between the motor-related regions and reward-related regions. This pattern was associated with multiple neurotransmitter receptors, such as serotonin and GABA receptors, and enriched in pathways like synaptic signaling and astrocytes cell type. The SC pattern and genetic results were also replicated in another independent MDD dataset and present commonalities with BD.ConclusionsThis study not only initially identified a reproducible shared SC pattern between physical activity and depressive mood, but also elucidated the underlying biological mechanisms, which enhanced our understanding of how exercise helps alleviate depression and may inform the development of novel neuromodulation targets.

neuroscience↗

bioRxiv2025

Ethylene modulates cell wall mechanics for root responses to compaction

Soil stresses impact crop yields, presenting global agricultural challenges. Soil compaction triggers root length reduction and radial expansion driven by the plant hormone ethylene. We report how ethylene controls cell wall properties to promote root radial expansion. We demonstrate how soil compaction stress, via ethylene, upregulates Auxin Response Factor1 in the root cortex, which represses Cellulose Synthase (CESA) genes. CESA repression drives radial expansion of root cortical cells by modifying the thickness and mechanics of their cell walls, which result in a "stiff epidermis-soft cortex" contrast. Our research thus connects ethylene signaling with root mechanics via cell wall strength, and reveals how dynamic regulation of cellulose synthesis crucially controls root growth in compacted soil.

plant biology↗

bioRxiv2025

Scaling up spatial transcriptomics for large-sized tissues: uncovering cellular-level tissue architecture beyond conventional platforms with iSCALE

Recent advances in spatial transcriptomics (ST) technologies have transformed our ability to profile gene expression while retaining the crucial spatial context within tissues. However, existing ST platforms suffer from high costs, long turnaround times, low resolution, limited gene coverage, and small tissue capture areas, which hinder their broad applications. Here we present iSCALE, a method that predicts super-resolution gene expression and automatically annotates cellular-level tissue architecture for large-sized tissues that exceed the capture areas of standard ST platforms. The accuracy of iSCALE were validated by comprehensive evaluations, involving benchmarking experiments, immunohistochemistry staining, and manual annotation by pathologists. When applied to multiple sclerosis human brain samples, iSCALE uncovered lesion associated cellular characteristics that were undetectable by conventional ST experiments. Our results demonstrate iSCALEs utility in analyzing large-sized tissues with automatic and unbiased tissue annotation, inferring cell type composition, and pinpointing regions of interest for features not discernible through human visual assessment.

genomics↗

bioRxiv2025

Pseudomonads coordinate innate defense against viruses and bacteria with a single regulatory system

Bacterial cells live under the constant existential threats imposed by other bacteria and viruses. Their mechanisms for contending with these threats are well documented; however, the regulation of these diverse defense elements remains poorly understood. Here we show that bacteria can mount a genome-wide, coordinated, and highly effective immune response against bacterial and viral threats using a single regulatory pathway. Bioinformatic analyses revealed that Pseudomonas species broadly possess a specialized form of the Gac/Rsm regulatory pathway (GRP), which our prior work in Pseudomonas aeruginosa implicated in activating interbacterial antagonism defense mechanisms in response to neighbor cell death. Proteomic studies comparing GRP-activated and -inactivated strains derived from diverse Pseudomonas species showed that the pathway regulates a large and variable suite of factors implicated in defense against both bacterial and phage threats. Focusing on P. protegens, we identify profound phenotypic consequences of these factors against multiple forms of bacterial antagonism and several phage. Together, our results reveal that bacteria, like more complex organisms, couple danger sensing to the activation of an immune system with antibacterial and antiviral arms.

microbiology↗

bioRxiv2025

D-LMBmapX: Generalized Deep-Learning Pipeline for Automated Whole-brain Neural Circuitry Profiling Across Any Developmental Stages

Understanding whole-brain circuitry development is essential for uncovering the origins of disorders linked to abnormal neural wiring, yet progress has been limited by the lack of tools for accurate, comprehensive analysis. Brain development is highly dynamic and region-specific, with pronounced inter-individual variability during early stages, and no existing method achieves whole-brain profiling at arbitrary stages. The rapidly changing morphology of developing axons further complicates segmentation. Here, we present D-LMBmapX, a deep learning pipeline for automated whole-brain circuitry profiling across postnatal development. D-LMBmapX constructs sample-inferred atlases from flanking anchor stages, enabling accurate registration at any time point. By developing a foundation model for generalised axon and soma segmentation, it supports quantitative mesoscale developmental connectomics, demonstrated through spatial-temporal profiling of catecholaminergic projections. D-LMBmapX also enables robust cross-modality and cross-dimensional registration, including precise alignment of single 2D slices to 3D references, and offers generalizable strategies for 5D analysis of diverse biomedical spatial datasets.

neuroscience↗

bioRxiv2025

Coro1a promotes the multivesicular body and plasma membrane fusion by facilitating PKM2-mediated SNAP-23 phosphorylation

During the formation of endosomal pathway-dependent extracellular vesicles (EVs), intraluminal vesicles in multivesicular bodies (MVBs) fuse with the plasma membrane (PM), releasing intraluminal vesicles to produce exosomes. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, membrane fusion effector, is essential in this process. However, which SNARE complex is involved in MVB and PM fusion and how its assembly is regulated remain elusive. We have demonstrated that neddylation of Coro1a inhibits EV secretion by inducing Rab7-mediated degradation of MVBs. Here, we find that Coro1a increases EV biogenesis by promoting the assembly of SNARE complex STX-12-SNAP-23-VAMP-7 in a neddylation-independent manner. Coro1a activates PKM2 to enhance SNAP-23 phosphorylation in the presence of neddylation inhibitor MLN4924, which drives SNAP-23 to recruit more STX-12 and VAMP7, leading to increased formation of the STX-12-SNAP-23-VAMP-7 complex. Correspondingly, Coro1a-induced EV biogenesis is eliminated by PKM2 inhibitor or SNAP-23 silencing independent of neddylation. Reduced EVs from tumors due to Coro1a knockout cannot be observed in MLN4924-treated tumor mice with PKM2 inhibitor treatment either. Furthermore, Coro1a increases in tumor tissues from lung tumor patients with tumor progression, and high Coro1a indicates unfavorable survival of tumor patients, suggesting that increased Coro1a-mediated enhanced EV production from tumors accelerates tumor progression. Altogether, our data demonstrate that Coro1a facilitates EV biogenesis by promoting the assembly of STX-12-SNAP-23-VAMP-7 complex during MVB and PM fusion independent of neddylation, thereby being involved in the progression of EV-related diseases.

cell biology↗

bioRxiv2025

Analysis of crosslinking sites suggests C. elegnas PIWI Argonaute exhibits flexible conformations for target recognition

Small RNAs play critical roles in gene regulation in diverse processes across organisms. Crosslinking, ligation, and analyses of sequence hybrid (CLASH) experiments have shown PIWI and Argonaute proteins bind to diverse mRNA targets, raising questions about their functional relevance and the degree of flexibility in target recognition. As crosslinking-induced mutations (CIMs) provides nucleotide-resolution of RNA binding sites, we developed MUTACLASH to systematically analyze CIMs in piRNA and miRNA CLASH data in C. elegans. We found CIMs are enriched at the nucleotide positions of mRNA corresponding to the center of targeting piRNAs and miRNAs. Notably, CIMs are also enriched at nucleotides with local pairing mismatches to piRNA. In addition, distinct patterns of CIMs are observed between canonical and non-canonical base pairing interactions, suggesting that the worm PIWI Argonaute PRG-1 adopts distinct conformations for canonical vs. non-canonical interactions. Critically, non-canonical miRNA or piRNA binding sites with CIMs exhibit more regulatory effects than those without CIMs, demonstrating CIM analysis as a valuable approach in assessing functional significance of small RNA targeting sites in CLASH data. Together, our analyses reveal the landscapes of Argonaute crosslinking sites on mRNAs and highlight MUTACLASH as an advanced tool in analyzing CLASH data.

molecular biology↗

bioRxiv2025

Predicting Mutation-Induced Relative Protein-Ligand Binding Affinity Changes via Conformational Sampling and Diversity Integration with Subsampled Alphafold2 in Few-Shot Learning

Predicting the impact of mutations on protein-ligand binding affinity is crucial in drug discovery, particularly in addressing drug resistance and repurposing existing drugs. Current structure-based methods are constrained by their dependence on known protein-ligand complex structures. The absence of structural data for mutated proteins, along with the potential of mutations to modify protein conformational states, brings challenges for reliable predictions. The downstream application of conformational sampling of Alphafold, such as the prediction of binding free energy changes induced by mutation, has not been fully explored. To tackle the challenge, we propose a few-shot learning approach that integrates AlphaFold2 subsampling, ensemble docking, and Siamese learning to predict the relative binding affinity changes induced by mutations. We validate our approach for predicting binding affinity changes in 31 variants of the mutated Abelson tyrosine kinase (ABL). The conformation ensembles for each ABL variant are generated using AlphaFold2 subsampling. The most likely conformational states are selected by Gaussian fitting to construct the pairwise structural inputs and compute relative binding energies. Then the relative binding affinities are derived by averaging the values predicted by the Siamese learning model across the constructed conformational pairs. By benchmarking on the Tyrosine kinase inhibitors (TKI) dataset and the direct binding affinity using the refined set of PDBbind database, our proposed approach achieves an increased Spearman correlation coefficient for five out of six TKI molecules across 31 mutants when estimating relative binding affinities. Although the proposed method is validated on the ABL, it can be transferred and applied to other drug-target interaction predictions when the conformational flexibility of proteins needs to be considered. We anticipate the approach will be valuable for predicting binding energy changes induced by mutations in proteins or ligands, facilitating drug discovery efforts.

bioinformatics↗

bioRxiv2025

WormAI: Artificial Intelligence of Networks for Nematode Phenotyping

The nematode Caenorhabditis elegans is a key model organism in biological research due to its genetic similarity to humans and its utility in studying complex processes. Traditional image analysis methods, such as those using ImageJ, are labour-intensive, which has led to the integration of AI. This study introduces an AI framework with three machine learning models: WormGAN, a Generative Adversarial Network for generating synthetic nematode images to enhance training data; WormDET, for precise movement tracking; and WormREG, for accurate anatomical measurements. Together, these tools significantly improve the efficiency and accuracy of phenotypic analysis. WormAI demonstrates substantial potential for high-throughput dataset analysis, advancing research in systems biology, drug discovery, and aging. This framework streamlines workflows, enabling faster and more precise discoveries in C. elegans studies.

bioinformatics↗

bioRxiv2025

Genomic Insights into the Demographic History and Local Adaptation of Wild Boars Across Eurasia

Wild boars exhibit genetic and phenotypic diversity shaped by migrations and local adaptations. Its expansion across Eurasia, especially in central Asia, remains underexplored. Here, we present newly sequenced whole-genome data of 47 wild boars from Eastern Asia, Central Asia, and Europe, combined with 49 existing genomes, creating a comprehensive dataset of 96 individuals. Our analyses show that Asian wild boars and Southeast Asian Suids split [~]3.6 Mya, with Central Asian and Southern Chinese ancestors diverging [~]1.8 Mya. The split between Central Asian and European-Near East ancestors occurred [~]0.9 Mya, followed by a European-Near East divergence [~]0.6 Mya. We identify signatures of local adaptation in Central Asian populations, including two positively selected variants in LPIN1, associated with cold adaptation, and a missense mutation in ALPK2, linked to meat traits. These findings provide insights into wild boar dispersal and adaptation, and shed light on domestic pigs breeding.

evolutionary biology↗

bioRxiv2025

ASTRO: Automated Spatial Whole-Transcriptome RNA-Expression Workflow

MotivationDespite significant advances in spatial transcriptomics, the analysis of formalin-fixed paraffin-embedded (FFPE) tissues, which constitute most clinically available samples, remains challenging. Additionally, capturing both coding and noncoding RNAs in a spatial context poses significant challenges. We recently introduced Patho-DBiT, a technology designed to address these unmet needs. However, the marked differences between Patho-DBiT and existing spatial transcriptomics protocols necessitate specialized computational tools for comprehensive whole-transcriptome analysis in FFPE samples. ResultsHere, we present ASTRO, an automated pipeline developed to process spatial transcriptomics data. In addition to supporting standard datasets, ASTRO is optimized for whole-transcriptome analyses of FFPE samples, enabling the detection of various RNA species, including non-coding RNAs such as miRNAs. To compensate for the reduced RNA quality in FFPE tissues, ASTRO incorporates a specialized filtering step and optimizes spatial barcode calling, increasing the mapping rate. These optimizations allow ASTRO to spatially quantify coding and non-coding RNA species in the entire transcriptome and achieve robust performance in FFPE samples. AvailabilityCodes are available at GitHub (https://github.com/gersteinlab/ASTRO).

bioinformatics↗

bioRxiv2025

Nucleoporins shape germ granule architecture and balance small RNA silencing pathways

Animals have evolved distinct small RNA pathways, including piRNA and siRNA, to silence invasive and selfish nucleic acids. piRNA pathway factors are concentrated in perinuclear germ granules that frequently associate with nuclear pore complexes (NPCs). However, the factors mediating germ granule-NPC association and the functional relevance of such association remain unknown. Here we show that the conserved nucleoporins NPP-14 (NUP-214) and NPP-24 (NUP-88), components of the cytoplasmic filaments of NPC, play critical roles in anchoring germ granule to NPC and in attenuating piRNA silencing In C. elegans. Proximity labeling experiments further identified EPS-1 (enhanced piRNA silencing) as a key germ granule factor contributing to germ granule-NPC interaction. In npp-14, npp-24, or eps-1 mutant animals, we observed fewer but enlarged, unorganized germ granules, accompanied by the over-amplification of secondary small RNAs at piRNA targeting sites. Nonetheless, we found this enhancement of piRNA silencing comes at the cost of dampened RNAi efficiency and RNAi inheritance. Together, our studies uncovered factors contributing to germ granule-NPC association and underscored the importance of spatial organization of germ granules in balancing small RNA silencing pathways.

genetics↗