Biology subjects

Xiao, J.

Publications and source records attributed to Xiao, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

GplR1, an unusual TetR-like transcription factor in Mycobacterium abscessus, controls the production of cell wall glycopeptidolipids, colony morphology, and virulence

Mycobacterium abscessus is a major human pathogen, mostly infecting people with pre-existing lung conditions such as cystic fibrosis. The production of glycopeptidolipids (GPL) is a major determinant of virulence of this bacterium, with clinical isolates that lack GPL generally exhibiting more aggressive clinical behavior. The current paradigm is that GPL production is abolished in vivo via irreversible, spontaneous mutations taking place as part of in-host evolution. Little is known about the mechanisms or extent to which GPL production may be regulated. Here we describe an unusual TetR-like transcription factor of M. abscessus, MAB_1638, that appears to be a strong positive regulator of the entire GPL biosynthesis and export gene cluster through a combination of direct and indirect mechanisms. The inactivation of mab_1638 abolished GPL production and thus led to stable rough colony morphology, as well as increased virulence in infection models, characteristic of rough, non-GPL-producers. Transcriptome analysis found the mab_1638 mutant had 118 differentially expressed genes, including the GPL locus and a second, recently described GPL-like locus that produces a related glycosylated lipopeptide called GP8L. Chromatin Immunoprecipitation and sequencing revealed a consensus inverted-repeat DNA sequence motif characteristic of genes regulated by mab_1638. Together, mab_1638 appears to encode a transcription factor required for production of GPL and therefore having a profound effect on virulence traits. We propose naming this gene GPL regulator 1 (gplR1). This finding raises the important possibility that M. abscessus strains appearing smooth in laboratory growth conditions may nonetheless downregulate GPL-cluster genes in other conditions, including in-patient conditions, and thus acquire the phenotypic characteristics of rough strains. ImportanceMycobacterium abscessus is an important human pathogen, causing disease that is difficult to treat. M. abscessus strains have been observed to have two distinct colony morphologies, smooth and rough, which substantially impact clinical presentation. Rough strains are associated with later-stage, more severe disease and are more virulent in animal models. Smooth morphology is conferred by a molecule called glycopeptidolipid in the outer cell envelope, and rough morphology is known to occur when mutations inactivate genes required for glycopeptidolipid biosynthesis. Little is known about the possibility that glycopeptidolipid production could be regulated. Here we have identified a transcription factor that is required for glycopeptidolipid biosynthesis, indicating that glycopeptidolipid production is indeed a regulated process, and raising the important possibility that strains exhibiting smooth morphology in the lab may down-regulated GPL production in the human host and thereby acquire the virulence properties of rough strains.

microbiology↗

bioRxiv2025

BioMiner: A Multi-modal System for Automated Mining of Protein-Ligand Bioactivity Data from Literature

Protein-ligand bioactivity data published in the literature are essential for drug discovery, yet manual curation struggles to keep pace with rapidly growing literature. Automated bioactivity extraction remains challenging because it requires not only interpreting biochemical semantics distributed across text, tables, and figures, but also reconstructing chemically exact ligand structures (e.g., Markush structures). To address this bottleneck, we introduce BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW, a multi-modal extraction framework that explicitly separates bioactivity semantic interpretation from ligand structure construction. Within BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW, bioactivity semantics are inferred through direct reasoning, while chemical structures are resolved via a chemical-structure-grounded visual semantic reasoning paradigm, in which multi-modal large language models operate on chemically grounded visual representations to infer inter-structure relationships, and exact molecular construction is delegated to domain chemistry tools. For rigorous evaluation and method development, we further establish BO_SCPLOWIOC_SCPLOWVO_SCPLOWISTAC_SCPLOW, a comprehensive benchmark comprising 16,457 bioactivity entries curated from 500 publications. BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW validates its extraction ability and provides a quantitative baseline, achieving an F1 score of 0.32 for bioactivity triplets. BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOWs practical utility is demonstrated via three applications: (1) extracting 82,262 data from 11,683 papers to build a pre-training database that improves downstream models performance by 3.9%; (2) enabling a human-in-the-loop workflow that doubles the number of high-quality NLRP3 bioactivity data, helping 38.6% improvement over 28 QSAR models and identification of 16 hit candidates with novel scaffolds; and (3) accelerating protein-ligand complex bioactivity annotation, achieving a 5.59-fold speed increase and 5.75% accuracy improvement over manual workflows in PoseBusters dataset. BO_SCPLOWIOC_SCPLOWMO_SCPLOWINERC_SCPLOW and BO_SCPLOWIOC_SCPLOWVO_SCPLOWISTAC_SCPLOW provide a scalable extraction methodology and a rigorous benchmark, paving the way to unlock bioactivity data that previously required extensive human effort. All data and code are available at GitHub.

bioinformatics↗

bioRxiv2025

The GSA Family in 2025: A Broadened Sharing Platform for Multi-Omics and Multimodal Data

The Genome Sequence Archive Family (GSA family) provides a suite of database resources for archiving, retrieving, and sharing multi-omics data for the global academic and industrial communities. It currently comprises four distinct database members: the Genome Sequence Archive (GSA, https://ngdc.cncb.ac.cn/gsa/), the Genome Sequence Archive for Human (GSA-Human, https://ngdc.cncb.ac.cn/gsa-human/), the open Archive for Miscellaneous Data (OMIX, https://ngdc.cncb.ac.cn/omix/), and the Open Biomedical Imaging Archive (OBIA, https://ngdc.cncb.ac.cn/obia). Compared to the 2021 version, the GSA family has significantly expanded by introducing a new database member, the OBIA, and through comprehensive upgrades to the existing ones. Notable enhancements to the existing members include broadening the range of accepted data types, enhancing the quality control systems, fine-tuning the data retrieval system, and refining the data-sharing management mechanisms.

genomics↗

bioRxiv2025

Biodegradable Poly(β-amino amide)s Enable Efficient RNA Delivery and Spleen Targeting

RNA therapeutics are emerging as transformative modalities in clinical applications and have become a key area in life science research. While lipid nanoparticles (LNPs) have become the leading platform for RNA delivery in preventive and therapeutic products, they still face significant challenges in achieving efficient extrahepatic delivery and maintaining long term shelf stability. Here we report the development of a series of biodegradable poly({beta}-amino amide) (PBAA) polymers, detailing their design, synthesis, and performance as gene delivery vehicles both in vitro and in vivo. These cationic polymers, featuring interspersed trialkylamine motifs, provide a readily tunable functional handle and facilitate complexation with gene cargo. The redox-sensitive disulfide motifs introduce a redox-responsive decomposition pathway for the polymer backbone, triggering cargo release during intracellular delivery. The results herein demonstrate that these polymers offer remarkable efficiency in encapsulating and delivering translation-competent cargos, including mRNA and CRISPR-Cas based gene editing tools. Notably, a dodecyl modified PBAA transporter has achieved over 97% gene editing efficiency in vitro, and over 97% spleen-targeting selectivity in a murine model. Additionally, it produces stable nanoparticles that maintain their physicochemical properties at 4 {degrees}C for up to two weeks without addition of excipients such as PEG, offering a cost-effective solution for RNA therapeutics supply chains. As the transformative impact of RNA and other nucleic acids continues to build within the pharmaceutical industry and beyond, it is imperative that the supporting technologies evolve in stride to maximize said impact. The tunable and biodegradable PBAA polymer designs presented herein are illustrative examples of how high-level functional performance can be acheived in conjunction with the critical targeting, formulation, and operational simplicity needed of state-of-the-art transfection and delivery technologies.

biochemistry↗

bioRxiv2025

A novel peptidoglycan deacetylase modulates daughter cell separation in E. coli

Peptidoglycan hydrolases facilitate bacterial cell wall growth by creating space for insertion of new material and allowing physical separation of daughter cells. In Escherichia coli, three peptidoglycan amidases, AmiA, AmiB and AmiC, cleave septal peptidoglycan during cell division. The LytM-domain proteins EnvC and NlpD activate these amidases either from inside the cell or the outer membrane: EnvC binds to the cytoplasmic membrane-anchored divisome components FtsEX, and NlpD and ActS are outer membrane lipoproteins. Here we report the identification of a novel periplasmic deacetylase called SddA that removes acetyl groups from denuded peptidoglycan glycan strands, the products of amidases. SddA is a substrate for the periplasmic protease Prc, suggesting regulation via protein degradation. The sddA gene is co-expressed with the gene encoding EnvC, linking SddA function to amidase activation. Consistent with this link, the deletion of sddA alleviates phenotypes associated with lack of amidase activation, while overexpression of sddA alleviates phenotypes related to a defective Tol-Pal system and causes cell chaining due to reduced septum peptidoglycan cleavage unless envC is co-expressed. We present a model according to which SddA modulates the activation of the septum-splitting amidases during cell division. AUTHOR SUMMARYBacteria surround their cell membrane by the essential peptidoglycan (cell wall) layer to prevent bursting open due to their turgor. During cell division, bacteria produce a septum at midcell, which must be cleaved for daughter cells to separate. Here, we report the identification of a new enzyme, SddA, that modifies a particular type of peptidoglycan material, denuded glycan chains released during the splitting of septal peptidoglycan for daughter cell separation, in the Gram-negative Escherichia coli. We propose a model in which SddA modulates a switch in the septal peptidoglycan splitting, ensuring splitting is activated from the cell membrane in the early stages of cell division and from the outer membrane in the late stages.

microbiology↗

bioRxiv2025

TAC-C uncovers open chromatin interaction in crops and SPL-mediated photosynthesis regulation

Cis-regulatory elements (CREs) direct precise gene expression for development and environmental response, yet their spatial organization in crops is largely unknown. We introduce Transposase-Accessible Chromosome Conformation Capture (TAC-C), a method integrating ATAC-seq and Hi-C to capture fine-scale chromatin interactions in four major crops: rice, sorghum, maize, and wheat. TAC-C reveals that chromatin interaction frequency aligns with genome size and gene expression, exhibiting distinct loop structures between C3 and C4 plants, particularly in C4-specific enzymes coding genes. Integrating chromatin structure with population genetics data highlights that chromatin loops connect distal regulatory elements to phenotypic variation. Asymmetrical open chromatin interactions among subgenomes, driven by transposon insertions and sequence variations, contribute to biased homoeolog expression. Furthermore, TaSPL7/15 regulate photosynthesis-related genes through chromatin interactions, with enhanced photosynthetic efficiency and starch content in Taspl7&15 mutant. TAC-C provides new insights into the spatial organization of regulatory elements in crops, especially for SPL-mediated photosynthesis regulation in wheat. TeaserTAC-C Reveals Chromatin Interactions and SPL-Mediated Photosynthesis Regulation in Crops.

plant biology↗

bioRxiv2025

DeepMM: Identify and correct Metagenome Misassemblies with deep learning

Accurate metagenomic assemblies are essential for constructing reliable metagenome-assembled genomes (MAGs). However, the complexity of microbial genomes continues to pose challenges for accurate assembly. Current reference-free assembly evaluation tools primarily rely on hand-crafted features and suffer from poor generalization across different metagenomic data. To address these limitations, we propose DeepMM, a novel deep learning-based visual model de-signed for the identification and correction of metagenomic misassemblies. DeepMM transforms alignments between assemblies and reads into a multi-channel image for misassembly feature learning and applies contrastive learning to bring different views of misassemblies closer. Fur-thermore, DeepMM offers a fine-tuning process to match different sequencer data. Our results show that DeepMM outperforms state-of-the-art methods in identifying misassemblies, achieving the highest AUPRC score in five CAMI datasets. DeepMM provides accurate correction of misassemblies, significantly improving downstream binning results, increasing the number of near-complete MAGs from 905 to 1006 in a large real metagenomic sequencing dataset derived from a diarrhea-predominant Irritable Bowel Syndrome (IBS-D) cohort.

bioinformatics↗

bioRxiv2025

Time-dependent Mitochondrial Remodeling in Experimental Atrial Fibrillation and Potential Therapeutic Relevance

BACKGROUNDChanges in mitochondria have been implicated in atrial fibrillation (AF), but their manifestations and significance are poorly understood. Here, we studied changes in mitochondrial morphology and function during AF and assessed the effect of a mitochondrial-targeted intervention in a large animal model. METHODS AND RESULTSAtrial cardiomyocytes (ACMs) were isolated from dogs in electrically-driven AF for periods of 24 hours to 3 weeks and from humans with/without longstanding persistent AF. Mitochondrial Ca2+-concentration ([Ca2+]Mito), reactive oxygen species (mtROS) production, membrane potential ({Delta}{Psi}m), permeability transition-pore (mPTP) opening and flavin adenine dinucleotide (FAD) were measured via confocal microscopy; nicotine adenine dinucleotide (NADH) under ultraviolet light. mtROS-production increased within 24 hours and superoxide-dismutase type-2 was significantly reduced from 3-day AF. [Ca2+]Mito and mPTP-opening frequency/duration increased progressively during AF. Mitochondrial depolarization was detectable 24 hours after AF-onset. NADH increased by 15% at 24-hour AF, concomitant with increased pyruvate-dehydrogenase expression, then gradually decreased. Mitochondria enlarged and elongated at 24-hour and 3-day AF, followed by progressive fragmentation, rupture and shrinkage. Mitochondrial fusion protein-1 (MFN1) was reduced from 3-day to 3-week AF and phosphorylated dynamin-related protein-1 (p-DRP1ser-616) increased after 1 week of canine AF and in human AF. Addition of the mitochondrial antioxidant MitoTempo attenuated action-potential shortening and L-type Ca2+-current (ICaL)-downregulation in canine and human AF ACMs in vitro. Administration of the orally-active mitochondrial-targeted ubiquinone mitoquinone to dogs during 3-week AF prevented mitochondrial Ca2+-overload, mtROS-overproduction, structural damage and abnormalities in {Delta}{Psi}m and respiration. Functionally, mitoquinone reduced AF-induced Ca2+-current downregulation, action-potential abbreviation, contractile dysfunction and fibrosis, preventing AF-substrate development and AF-sustainability. CONCLUSIONSMitochondria show a series of changes during AF, with early hyperfunction and enhanced ROS-generation, followed by progressive damage and dysfunction. Mitochondrial-targeted therapy prevents mitochondrial dysfunction and attenuates adverse AF-related remodeling, positioning mitochondrial protection as a potential novel therapeutic target in AF.

pathology↗

bioRxiv2025

Decoding cellular transcriptional regulatory networks governing wheat inflorescence development

Wheat inflorescence architecture, particularly spikelet and floret development, is critical for grain yield. To decode the cellular transcriptional regulatory network (cTRN) underlying wheat inflorescence development, we integrated multiple single-cell omics technologies to construct a spatiotemporal atlas of transcriptional and chromatin accessibility dynamics. This comprehensive analysis identified 20 cell types, 7,211 cell type-specific genes and 152,333 cell type-specific accessible chromatin regions (csACRs) in the wheat inflorescence. Trajectory analysis identified two sub-clusters of proliferating cells as the origins of spikelet and floret formation, deviating from the traditional developmental model. Key transcription factors and hormone-related genes in the cTRN, along with the csACRs, providing new targets for modulating wheat inflorescence architecture. Our findings provide a high-resolution resource for crop inflorescence research and establish a paradigm for applying spatiotemporal single-cell omics analysis to plant biology.

plant biology↗

bioRxiv2025

Differential effect of supercoiling on bacterial transcription in topological domains

DNA supercoiling (SC), the over- and under-winding of DNA, is generated by transcription as described in the twin-domain model. Conversely, SC also impacts transcription through torsional stress. SC therefore regulates transcription independent of transcription factor binding, the classic protein-based transcription regulatory mechanism, particularly in the context of chromosomal topological domains and the actions of topoisomerases. SC-coupled transcription has inspired several computational models, but a systematic and quantitative assessment of the parameters controlling this complex interplay is missing. There is also a lack of comparison to various experimental results regarding the effects of topological variables such as topoisomerase binding rates and domain size on transcription strength and noise. In this work we developed a quantitative model to describe SC-coupled transcription. We analyzed the effects of topoisomerase activities on the transcription of a single isolated gene with varying promoter strengths and in a topological domain of varying sizes. These simulations revealed qualitatively different roles of the two topoisomerases. Topoisomerase I is specifically required for strongly expressed genes that may be hindered by stalled RNAP, whereas gyrase activity favors the expression of all genes by enhancing transcription initiation and modulating the burstiness of transcription. A new analysis of transcriptomics data in several bacterial species showed that these simulations replicate a global relationship between promoters strength and response to variations in topoisomerase activities. Our work demonstrates how SC contributes to differential gene regulation and transcriptional bursting in mechanistic details and unites computational and experimental work. Author SummaryWe are interested in understanding how bacteria regulate the expression of their genes. One mechanism by which bacteria can do so is through the over- and under-winding of their DNA, termed DNA supercoiling. Because bacteria can use enzymes called topoisomerases to regulate the supercoiling level of their DNA, these enzymes can serve as gene regulators. It is difficult, however, to understand how topoisomerases act as gene regulators through experiments alone. Currently, there is no method of measuring the supercoiling level along a stretch of DNA over an extended period of time in living cells. We therefore developed a computational model of gene transcription coupled to supercoiling dynamics. Unlike some previously existing models, we consider continuous response curves of topoisomerases activities in response to the local supercoiling level and the ability of gyrase to perform several catalytic cycles per binding event. We also perform extensive comparisons between our model and existing gene expression and transcriptomics data, which is essential to ensuring the biological relevance of computational modeling efforts. We replicate and provide detailed explanations for several experimental observations, including the connection between supercoiling and transcriptional bursts and the selective gene expression modulation by topoisomerase inhibition that is based on the promoter strength.

biophysics↗

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↗

bioRxiv2024

Spatial Transcriptomics Reveals Expression Gradients in Developing Wheat Inflorescences at Cellular Resolution

The diversity of plant inflorescence architectures is specified by gene expression patterns. In wheat (Triticum aestivum), the lanceolate-shaped inflorescence (spike) is defined by rudimentary spikelets at the base which initiate first but subsequently lag in development compared with central spikelets. While previous studies identified gene expression differences between central and basal inflorescence sections, the spatio-temporal dynamics and gradients along the apical-basal axis remain poorly resolved due to bulk tissue-level techniques. Here, using spatial transcriptomics, we profiled 200 genes across four stages of wheat inflorescence development to cellular resolution. Cell segmentation and unsupervised clustering identified 18 expression domains and their enriched genes, revealing dynamic spatio-temporal organisation along the apical-basal axis of the inflorescence. Along this axis, we uncovered distinct and spatially coordinated gene expression gradients patterning meristems prior to the visible delay in basal spikelet development. This study demonstrates the potential for spatial transcriptomics time-series to advance plant developmental biology.

plant biology↗

bioRxiv2024

Cortically-mediated muscle responses to balance perturbations increase with perturbation magnitude in older adults with and without Parkinson's disease

We lack a clear understanding of how cortical contributions to balance are altered in aging and Parkinsons disease (PD), which limits development of rehabilitation strategies. Processes like balance control are typically mediated through brainstem circuits, with higher-order circuits becoming engaged as needed. Using reactive balance recovery, we investigated how hierarchical neural mechanisms shape balance- correcting muscle activity across task difficulty in older adults (OAs) with and without PD. We hypothesize that feedback loops involving brainstem and cortical circuits contribute to balance control, and cortical engagement increases with challenge, aging, and PD. We decomposed perturbation-evoked agonist and antagonist muscle activity into hierarchical components based on latency using neuromechanical models consisting of two feedback loops with different delays to reflect different neural conduction and processing times. Agonist muscle activity was decomposed into two components that both increased with balance challenge in both groups. The first component occurred [~]120ms and the second occurred [~]210ms, consistent with the latencies of brainstem and transcortical circuits, respectively. Exploratory comparisons to young adults revealed larger transcortical components in OA and PD groups at lower balance challenge levels, consistent with increased cortical involvement with aging. Antagonist muscle activity included destabilizing and stabilizing components, with the destabilizing component correlating to balance ability in OAs but not in PD. These findings demonstrate that neuromechanical models can identify changes in the hierarchical control of balance without direct brain measurements. Identifying cortical contributions during balance control may complement clinical measures of balance ability to inform balance rehabilitation and assistive devices. NEW & NOTEWORTHYA neuromechanical model can decompose perturbation evoked muscle activity into components attributed to brainstem and higher-order sensorimotor feedback based on latency. In older adults with and without PD contributions from higher-order neural circuits increase with balance challenge and are related to clinical measures of balance ability. Interpreting the neural substrates of motor output for balance may reveal individual differences in the hierarchical control of balance, that could inform rehabilitation.

neuroscience↗

bioRxiv2024

Integrative Omics reveals genetic basis and TaMYB7-A1's function in wheat WUE and drought resilience

Improving water use efficiency (WUE) and drought resistance in wheat is critical for ensuring global food security under changing climate conditions. Here, we integrated multi-omic data, including population-scale phenotyping, transcriptomics, and genomics, to dissect the genetic and molecular mechanisms underlying WUE and drought resilience in wheat. Genome-wide association studies (GWAS) revealed 8,135 SNPs associated with WUE-related traits, identifying 258 conditional and non-conditional QTLs, many of which co-localized with known drought-resistance genes. Pan-transcriptome analysis uncovered tissue-specific expression patterns, core and unique gene functions, and dynamic sub-genomic biases in response to drought. eQTL mapping pinpointed 146,966 regulatory loci, including condition-specific hotspots enriched for genes involved in water regulation, osmoregulation, and photosynthesis. Integration of Weighted gene co-expression network analysis (WGCNA), Summary-data-based Mendelian Randomization (SMR) and GWAS, eQTLs identified 207 candidate causal genes as key regulators for WUE-related traits in wheat, such as TaMYB7-A1. Functional analyses found that TaMYB7-A1 enhances drought tolerance by promoting root growth, reducing oxidative stress, and improving osmotic regulation, enabling better water access and survival under stress. It also increases photosynthesis efficiency and WUE, boosting yield under drought without compromising performance in well-watered conditions, making it ideal target for breeding. Our findings provide a comprehensive omic framework for understanding the genetic architecture of WUE and drought resistance, offering valuable targets for breeding resilient wheat varieties.

plant biology↗

bioRxiv2024

Lineage-associated Human Divergently-Paired Genes (DPGs) Exhibit Regulatory Characteristics and Evolutionary Trends

Divergently-paired genes (DPGs) represent one of the minimal co-transcriptional units (the rest include tandemly- and convergently-paired genes) of clustered genes; the former and the latter constitute greater than 10% and 75% of the total human genes, respectively. Our previous studies have shown that vertebrate DPGs are more conserved, both organizationally and functionally than invertebrates. Three critical questions remain to be addressed: (1) what are the conserved DPGs over vertebrate lineages, especially among mammals and primates? (2) being bidirectionally transcribed, to what extent do DPGs share their promoter sequences and how mechanistically and stringently are their co-expression regulated within the shared inter-TSS (transcription start site) sequence space? and (3) based on the recently released high-quality human genome assemblies, how do human-associated DPGs distribute over selected primate lineages and what are their possible functional consequences biologically? Our study begins by identifying 1399 human DPGs (12% of all human protein-coding genes), and presents findings from this analysis. First, 1136, 1118, 925, and 830 human DPGs are shared genetically with primates, mammals, avians, and fish, respectively. DPGs are not only functionally enriched toward direct protein-DNA interactions and cell cycle synchronization but also exhibit obvious lineage association, narrow in principle toward synchronization of certain core molecular mechanisms and cellular processes. Second, their inter-TSS distances and expression variables affect both co-expression strength and disparity between the two genes. Finally, our results based on a comparison among the primate DPGs reveal that the human-associated DPGs exhibit intensive diversification in co-expression, duplication, and definite involvement in neural development. Within humans, 55 and 357 DPGs are associated to the Chinese (YAO) and the European (CHM13) assemblies, respectively. Our results offer novel insights into comprehending the structure-function selection of gene clusters over evolutionary time scales, as well as a deeper understanding of the regulatory characteristics of co-expressed neighboring genes.

genomics↗

bioRxiv2024

Natural variations of TaMYB7-A1 regulate PHS resistance and specify wheat geographic adaptation

Crop domestication tended to select against seed dormancy for uniform germination--raising risks of undesirable pre-harvest sprouting (PHS) -- but regulation of seed dormancy and PHS in wheat are grossly under-characterized. Here, we identified wheat PHS resistance loci by GWAS. TaMYB7-A1 confers PHS resistance by elevating ABA signaling and seed dormancy in grains. Three TaMYB7-A1 haplotypes (Hap-1/2/3) contrast in PHS resistance, with Gly23 and Gly92 crucial for binding to and activating TaABI5 in Hap-1/3. A MITE transposon in the TaMYB7-A1Hap-1 promoter likely recruited the TaAZF1-TaABI4 module to boost expression, resulting in strong PHS resistance. TaMYB7-A1Hap-1 originated from wild einkorn and was integrated into hexaploid wheat through introgression into wild emmer. Different haplotypes of TaMYB7-A1, in conjunction with alleles of other major PHS resistance genes, is pivotal in shaping wheats adaptability to rainfall conditions in China, US and Europe during the harvest season. Introduction of TaMYB7-A1Hap-1 into elite cultivars confers PHS resistance without yield defects. Thus, artificial and natural selection across diverse climates regions have collectively shaped wheat adaptation and enabled rational delivery of improved lines tailored to local cropping needs.

plant biology↗

bioRxiv2024

Efficient mRNA Delivery In Vitro and In Vivo Using a Polycharged Biodegradable Nanomaterial

As RNA rises as one of the most significant modalities for clinical applications and life science research, efficient tools for delivering and integrating RNA molecules into biological systems become essential. We hereby report a formulation using a polycharged biodegradable nano-carrier, N1-501, which demonstrates superior efficiency and versatility in mRNA encapsulation and delivery in both cell and animal models. N1-501 is a polymeric material designed to function through a one-step facile formulation process suitable for various research settings. Its capability for mRNA transfection is investigated across a wide range of mRNA doses and in different biological models, including 18 tested cell lines and mouse models. This study also comprehensively analyzes N1-501s application for mRNA transfection by examining factors such as buffer composition and pH, incubation condition, and media type. Additionally, N1-501s superior in vivo mRNA transfection capability ensures its potential as an efficient and consistent tool for advancing mRNA-based therapies and genetic research.

biochemistry↗

bioRxiv2024

Cryo-EM structural insights into Vγ9Vδ2 TCR activation via multiple butyrophilins

Human V{gamma}9V{delta}2 T cells detect cancerous and pathogen-infected cells through an "inside-out" mechanism wherein intracellular domains of butyrophilin (BTN) proteins recognize phosphoantigens (pAgs) to prime BTN ectodomains to engage with the T cell receptor (TCR) to activate V{gamma}9V{delta}2 T cells. Here, we present cryo-electron microscopy (cryo-EM) structures, including the full-length BTN3A1-BTN3A2-BTN2A1 complex stabilized by the pAg HMBPP and an HMBPP-primed BTN multimer complex engaged with the V{gamma}9V{delta}2 TCR. The HMBPP-primed BTN3A1-BTN3A2-BTN2A1 complex confirms that this pAg bridges the intracellular B30.2 domains of BTN3A1 and BTN2A1, while also revealing an association of the ectodomains of BTN3A2 and BTN2A1. Upon TCR engagement, the TCR undergoes a substantial conformational change and BTN3A2-BTN2A1 ectodomain interaction dissociates, allowing BTN2A1 to bind to the lateral surface of the V{gamma}9 chain, while BTN3A2 binds to the apical surface of the V{delta}2 chain. Beyond demonstrating that BTN3A2 as a bona fide TCR ligand, this dissociation/binding sequence suggests a "pliers-like gripping" mechanism for TCR activation. We also obtained cryo-EM structures of BTN proteins in complex with functional antibodies, further elucidating the overall V{gamma}9V{delta}2 T cell activation process. Thus, our structural insights into how BTN proteins sense antigens and drive TCR activation lay the groundwork for developing targeted {gamma}{delta} T cell immunotherapies.

immunology↗