Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 217 records · Page 12Linked to original sources

bioRxiv2025

High-resolution single-cell RNA sequencing using canFam4 reveals novel immune subsets and checkpoint programs in healthy dogs

Single-cell RNA sequencing (scRNA-seq) enables high-resolution profiling of immune heterogeneity. Although previous studies have mapped the single-cell transcriptomic atlases of peripheral leukocytes in healthy dogs, the identification and functional characterization of distinct immune subsets remain incomplete. We constructed a single-cell atlas of peripheral leukocytes from six healthy small-breed dogs using the 10x Genomics platform and the updated canFam4 genome. Analysis of 30,040 high-quality transcriptomes revealed 51 distinct immune subsets, including CD14{square}CD33{square} monocytes, XCR1{square}CD1D{square} dendritic cells, CEACAM1{square}CD24{square} neutrophils, and IL32{square}BATF{square} regulatory T cells, which were underrepresented in canFam3.1-based studies. Interferon-enriched CD14{square} monocytes and CD4{square} T subsets associated with myxomatous mitral valve disease were also identified. Functional analysis revealed that PDCD1 attenuates TCR signaling, LAG3 modulates malate metabolism in CD4{square} T cells, and suppresses TBX21 in CD8{square} T cells associated with viral response. CD274 encoding PD-L1 was linked to IL-10 production in neutrophils, and CTLA4 represented an initial activation of double-negative T subsets. T cell exhaustion scores and proliferative fractions varied across cohorts, reflecting differences in environmental antigenic exposures. Our study represents the first comprehensive, gene-resolved single-cell analysis that reveals immunoregulatory checkpoint mechanisms underlying immune homeostasis in healthy dogs. Our dataset will serve as a valuable resource for future comparative and translational immunology research in dogs.

immunology↗

bioRxiv2025

The biosynthetic gene cluster landscape of the oral microbiome across health and dental caries

Specialized metabolites encoded by biosynthetic gene clusters (BGCs) in the oral microbiome remain largely unexplored in the context of oral health and disease. Previous genome-centric surveys have cataloged hundreds of uncharacterized BGCs in the oral cavity associated with health and disease, but these studies relied on reference genomes and did not capture strain-level variation or the native distribution of BGCs. Here, we assembled three independently sourced metagenomic datasets from healthy and dental caries samples, extracted BGCs, and quantified their abundance alongside expression in a metatranscriptomic dataset. We first identified that aryl polyene, ribosomally synthesized and post-translationally modified peptide (RiPP), and nonribosomal peptide (NRP) encoding BGCs were the most abundant BGC classes across all three metagenomic datasets. We then grouped these BGCs into homology-based families and found that homologous clusters were usually consistently associated with either health or dental caries, suggesting conserved community-level roles for BGCs. An elastic-net regression model further selected 45 BGCs out of >5000 that could distinguish healthy and dental caries samples in the metatranscriptomic dataset, which demonstrated that BGCs could be predictive markers of disease. This analysis emphasizes the importance of high-quality metagenomic and metatranscriptomic datasets to resolve BGC expression patterns and to guide discovery of metabolites relevant to oral health and disease.

bioinformatics↗

bioRxiv2025

Elevated surface La promotes hyperfusion and contributes to impaired resorption in osteopetrosis.

The skeleton is a living, biological tissue responding to the biomechanical demands placed upon it throughout life. The individual bones creating this physiological system are each shaped by a multinucleated cell type - the osteoclast - that sculpts each bone in collaboration with local cellular partners, which offer chemical and even tactile feedback of many sorts. Unfortunately, the perturbation of osteoclast formation and function underpins a broad range of human skeletal pathologies, including osteopetrosis - a systemic pathology characterized by impaired osteoclast resorption leading to skeletal thickening, brittle bones, frailty, and lethality. Here, we describe a molecular dysfunction observed in murine and human models of two forms of osteoclast-rich, autosomal recessive osteopetrosis, and our approach for exploiting this molecular dysfunction to correct pathologic osteoclast hyperfusion and resorptive impairment. We find that La - a manager of osteoclast fusion and subsequent resorptive activity - is greatly elevated at the surface of osteoclasts upon loss of SNX10 or OSTM1. Using inhibitory antibodies, we suppress excessive La surface function in these mutant osteoclasts, impede osteopetrotic hyperfusion and restore osteoclast resorptive function. We share these observations as proofs-of-principle that osteoclast fusion represents a viable therapeutic target for addressing osteoclast dysfunction in diseases underpinned by excessive osteoclast multinucleation and perturbed resorptive function.

cell biology↗

bioRxiv2025

Hydrophobic interactions of FG-nucleoporins are required for dilating nuclear membrane pores into selective transport channels after mitosis

Nuclear envelope (NE) reformation after mitosis is essential for daughter cell viability and requires tightly coordinated nuclear pore complex (NPC) assembly and nuclear membrane reformation. To reveal how these processes are mechanistically linked, we combined acute molecule perturbations in live cells with correlative 3D electron tomography or MINFLUX super-resolution microscopy. We show that degrading Nup62 during mitosis arrests NPC assembly at an intermediate step with smaller membrane pores and removes the whole central transport channel. Molecular dynamics simulations predicted that 32 copies of the central channel subcomplex, recruited into the previously unoccupied pore center, can self-associate via hydrophobic interactions to occupy the volume required for full pore size and exert an outward pushing force; indeed, disrupting these interactions during NPC assembly blocked pore dilation. Later in mitotic exit, perturbed cells exhibited impaired nuclear import, smaller nuclei, and looser NE spacing. Acute inhibition of nuclear import recapitulated these NE defects without affecting NPC assembly. Together, our findings reveal a new, two-step molecular mechanism linking NPC assembly and NE reformation. First, hydrophobic FG-nucleoporins dilate the assembling nuclear pore to its full width by forming the central transport channel, which then allows nuclear import-driven nuclear expansion leading to tight, regular NE membrane spacing.

cell biology↗

bioRxiv2025

Multi-omics analysis reveals genetic regulatory mechanismsof muscle traits in wild and domesticated Bactrian camels

Bactrian camels, large domesticated animals adapted to extreme environments, have evolved under natural and artificial selection to suit their living conditions and meet human needs. In arid and semi-arid regions, they provide valuable resources through economically important traits such as meat, milk, and wool production, contributing significantly to both economy and ecology. However, research on gene function, adaptive evolution, and molecular mechanisms underlying complex traits in Bactrian camels remains limited, constraining the full utilization of their breeding potential and conservation efforts.To address this gap, we performed whole-genome resequencing (WGS) on 35 domesticated Bactrian camels from the Chinese Sunite local population and integrated this data with publicly available WGS data from 112 Asian Bactrian camels. Our comprehensive analysis revealed significant genetic differences and genomic features between wild and domesticated Bactrian camels. We further integrated 27 epigenomic (ATAC-seq) and transcriptomic (RNA-seq) datasets from eight biologically important tissues of four Bactrian camels, along with skeletal muscle scRNA-seq and scATAC data. This allowed us to identify tissue-specific genes, regulatory elements, and genes under positive selection.Our integrated analysis identified target genes and their upstream regulatory elements, including potential regulatory transcription factors, with a focus on positively selected regions in Bactrian camel muscle tissue. We constructed regulatory pathways from key SNPs to regulatory elements to genes, and for the first time, identified regulatory elements in major tissues of the Bactrian camel genome. Our results also summarized the single-cell transcriptional landscape of Bactrian camel skeletal muscle, revealing cellular heterogeneity and genetic expression patterns across two developmental stages.This comprehensive regulatory element map provides a valuable resource for genetic and genomic studies in Bactrian camels. It reveals key regulatory networks, important genes, and regulatory elements influencing muscle development, as well as potentially significant functional variants affecting meat production traits. These findings will provide crucial data support for future genetic improvement and breeding efforts in Bactrian camels.

genetics↗

bioRxiv2025

Segmented poly(A) tails with microRNA target sites confer tissue-specific regulation for mRNA therapeutics

Targeted delivery and controlled expression of mRNA-LNPs are critical for the development of safe and effective mRNA medicines. However, efficient post-delivery regulation of mRNA-LNP expression remains challenging. In this study, we engineered segmented poly(A) tail variants that function as gene-specific regulatory elements for synthetic mRNAs. Specifically, we inserted microRNA target sites (MTS) for miR-122 or miR-142 at various positions of the poly(A) tail of synthesized luciferase reporter mRNA. These modifications significantly reduced luciferase expression in non-target tissues in vitro and in vivo, demonstrating position-dependent selective expression control. Furthermore, by incorporating triple-MTS sequences for miR-142, miR-126, and miR-148a in all possible combinations at the 5 end of the poly(A) tail, we identified triple-MTS arrangements that simultaneously decrease luciferase activities in three non-target hepatic cell types, while preserving robust expression in hepatocytes. The results highlighted the importance of MTS insertion order for optimal mRNA silencing. These triple-MTS modules significantly expanded the utility of single miRNA-responsive elements, enabling cell-type selective regulation for mRNA therapeutics. By complementing tissue-tropic delivery LNPs, our mRNA cargo regulatory elements have the potential to improve tissue and cell type selectivity as a novel platform for post-delivery regulation of mRNA-LNP.

bioengineering↗

bioRxiv2025

What Large Language Models Know About Plant Molecular Biology

Large language models (LLMs) are rapidly permeating scientific research, yet their capabilities in plant molecular biology remain largely uncharacterized. Here, we present MOBIPLANT, the first comprehensive benchmark for evaluating LLMs in this domain, developed by a consortium of 112 plant scientists across 19 countries. MOBIPLANT comprises 565 expert-curated multiple-choice questions and 1,075 synthetically generated questions, spanning core topics from gene regulation to plant-environment interactions. We benchmarked seven leading chat-based LLMs using both automated scoring and human evaluation of open-ended answers. Models performed well on multiple-choice tasks (exceeding 75% accuracy), although most of them exhibited a consistent bias towards option A. In contrast, expert reviews exposed persistent limitations, including factual misalignment, hallucinations, and low self-awareness. Critically, we found that model performance strongly correlated with the citation frequency of source literature, suggesting that LLM knowledge inherits the visibility distribution of the underlying scientific corpus. Consequently, models tend to be more reliable on consolidated topics and less reliable on under-cited or recently emerging ones. We also benchmarked agents equipped with web-search and additional tools in more complex tasks involving DNA sequence analysis. These agents were outperformed by domain specific models in sequence classification and regression tasks, indicating an opportunity for joint agentic systems that combine both the reasoning power of LLMs and the dedicated processing of DNA models. This understanding is key to guiding both the development of next-generation models and the informed use of current tools in the everyday work of plant researchers. MOBIPLANT is publicly available online in this link.

plant biology↗

bioRxiv2025

Evaluating Place Cell Detection Methods in Ratsand Humans: Implications for Cross-Species Spatial Coding

Place cells, first identified in the rat hippocampus as neurons that fire selectively at specific locations, are central to investigations of the neural underpinnings of spatial navigation. With recent work with human patients, identifying and characterizing place cells across species has become increasingly important for understanding the extent to which decades of rodent research generalize to humans and uncovering principles of spatial cognition. One challenge, however, is that detection methods differ: rodent studies often rely on spatial information (SI), whereas human studies employ analysis of variance (ANOVA) - based approaches. These methodological differences may affect the identified place cell population, which complicates how their properties are interpreted and cross-species comparisons. To address this, we systematically applied multiple detection pipelines to human and rat datasets, supported by simulations that vary place-field properties. Our analyses and simulations demonstrate that spatial information and ANOVA-based approaches are responsive to distinct place field properties: spatial information primarily reflects the contrast between peak and average firing rates, while ANOVA emphasizes consistency across trials. Across species, rodent place cells revealed a broad spectrum of spatial tuning, including strongly tuned neurons with high spatial information (SI) and high ANOVA values. In contrast, human place cells lacked this strongly tuned population and exhibited a narrower distribution of tuning scores, concentrated at the lower end of both spatial tuning metrics. Despite these differences, both species had an overlapping population of neurons with weaker yet consistent spatial tuning, which may support important functional roles such as generalization and mixed selectivity. Together, our study provides a roadmap showing how spatial tuning metrics shape place cell detection and interpretation, while underscoring the functional importance of weaker-tuned neurons in cross-species comparisons. Author SummaryPlace cells are neurons that become active in specific locations, and they play a critical role in how the brain supports navigation and memory. Place cells were first discovered in rats and later observed in humans, however, there has been a lack of direct comparisons between species using comparable approaches. Part of the difficulty doing so is that studies of rodent and human place cells have often relied on different analysis methods, making it difficult to determine if and how place-cell properties differ between species. To address this, in this study, we set out to understand how differences in place cell detection methods affect the identified place cell populations and interpretations of spatial coding across species. To do so, we compared the most prevalent detection methods used in rodent and human research side by side, applying them to datasets from both species and to simulations. We found that different methods emphasize different features of spatial responses, which changes which neurons are identified as place cells. Across species, rat recordings revealed a wide range of spatial responses, from neurons with sharply localized activity to those with broader but reliable patterns. Human recordings, by contrast, were more concentrated at weaker but consistent levels of tuning. Importantly, these weaker but consistent responses reflect an overlapping population of neurons found in both species, which may serve similar functional roles in supporting flexible spatial memory and generalization. By separating methodological effects from biological differences, we lay the groundwork for future cross-species studies for spatial coding. Materials Descriptions and Availability StatementsO_ST_ABSProject RepositoryC_ST_ABSThis project is openly available through an online project repository, which includes all the code used for data pre-processing and analysis. Project Repository: https://github.com/HSUPipeline/PlaceCellMethods DatasetThis project uses electrophysiological data collected from neurosurgical patients, as well as an open-access dataset of rat recordings from CRCNS.org: http://dx.doi.org/10.6080/K09G5JRZ The human data were collected as part of a previously published study and will be made available prior to publication [1]. A custom simulation framework was developed to evaluate place cell detection methods across species and will be released as part of the open-source SpikeTools repository prior to publication. SoftwareAll code used and developed for this project was written in the Python programming language. The code is openly available, licensed for reuse, and deposited in the project repository. Management of the dataset was conducted using the Human Single Unit (HSU) Pipeline: https://github.com/HSUPipeline Analyses of the single-neuron data were performed using the open-source SpikeTools toolbox: https://github.com/spiketools/spiketools Literature searches and related resources were organized using LISC, an open-source Python module for literature analysis. https://github.com/HSUPipeline/Literature

neuroscience↗

bioRxiv2025

A Spatially Resolved Atlas of Alternative Polyadenylation Across 18 Human Tissues and 76 Disease States

Alternative polyadenylation (APA) is a key regulator of gene expression and cellular dynamics, yet systematic investigations of spatially resolved APA across diverse human tissues remain limited. Here, we developed SpatialAPA (https://github.com/Omicslab-Zhang/spatialAPA), a framework that benchmarks multiple APA identification methods and integrates spatial APA data with gene expression and cellular dynamics at spatial resolution. Applying SpatialAPA to 363 spatial transcriptomic data from 56 projects across 18 human tissues and 76 diseases, we constructed a spatially resolved APA atlas comprising 346,932 APA events across 52,175 genes. This atlas reveals organ-specific APA patterns and provides new insights into how APA regulates tissue homeostasis and disease progression beyond transcriptional control. To ensure cross-sample comparability, we applied batch correction, while spatial cell deconvolution uncovered cell-type-specific dynamics and interactions. In triple-negative breast cancer, integrated spatial and single-cell analyses identified TSPAN8-positive epithelial subpopulations whose distinct APA regulation and transcriptional programs drive differentiation and malignant progression. To facilitate community access, we developed an online platform (http://www.biomedical-web.com/spatialAPAdb/home) for exploring APA, gene expression, and cellular dynamics in health and disease. Together, this study establishes the first comprehensive spatial APA atlas, providing a valuable resource and analytical framework for investigating molecular mechanisms and therapeutic targets.

bioinformatics↗

bioRxiv2025

Post-inhibitory rebound firing drives hypothalamic activation for male mating

Many behaviorally relevant limbic circuits are dominated by inhibitory connections, raising the question of how neuronal activation arises in such contexts. In male mating, both activation of mPOA and its inhibitory inputs are essential--a paradox previously ascribed to disinhibition. Here, we show that the mPOA largely lacks local inhibitory circuits, arguing against disinhibition. Instead, in vivo recordings reveal that mount-active mPOA neurons are suppressed prior to behavioral onset, and this inhibition negatively correlates with subsequent activation, consistent with post- inhibitory rebound firing (PIR). A biologically plausible conductance-based model demonstrates that synaptic inhibition interacts with T-type Ca{superscript 2} currents -- the ionic basis of PIR -- to promote mPOA neuron firing. Experimentally, bidirectional manipulations of mPOA T-type Ca{superscript 2} channels confirm this mechanism: knockdown reduces PIR and impairs male mating, while overexpression enhances mating. Together, these results identify PIR as a critical mechanism by which inhibition promotes activation in limbic circuits to drive male mating.

neuroscience↗

bioRxiv2025

Matrix metalloproteinase-3 promotes arteriovenous fistula failure by regulating FAK-AKT signaling

Objective- Surgically created upper extremity arteriovenous fistulae (AVF) are the preferred vascular access for patients requiring dialysis. It is estimated, however, that 50% of AVF fail within one year due to aggressive neointimal hyperplasia, which significantly increases morbidity and mortality. Matrix metalloproteinase-3 (MMP-3), also known as stromelysin-1, is a member of the metalloproteinase family that plays a critical role in the pathogenesis of many human disorders by degrading extracellular matrix and regulating molecular signaling pathways. The role of MMP- 3 in AVF neointimal failure has not been explored. Approach and Results- We observed that MMP-3 was induced in a time-dependent fashion by fetal bovine serum (FBS) and the growth factor PDGF-BB in cultured venous SMC. MMP-3 was also highly expressed in the neointimal SMCs of the outflow veins and the juxta-anastomotic area in an AVF mouse model, as well as in human AVF specimens. Knockdown of MMP-3 significantly suppressed venous SMC proliferation, whereas overexpression of MMP-3 facilitated cell growth in vitro. Importantly, deficiency of global and SMC-specific MMP-3 significantly reduced neointimal hyperplasia and improved patency after AVF creation. Mechanistic studies showed that MMP-3-mediated SMC proliferation and AVF neointimal hyperplasia were regulated via the FAK-AKT signaling pathway. Conclusions- These data suggest that MMP-3 is a key mediator of AVF neointimal failure. Targeting local MMP-3 activity may be a novel therapeutic strategy to prevent AVF neointimal failure and improve outcomes in patients requiring hemodialysis.

cell biology↗

bioRxiv2025

The U1 snRNP protein U1C and Helix H of U1 snRNA are critical for small molecule splicing modulator function

Risdiplam and branaplam represent two classes of small-molecule splicing modulators that promote U1 snRNP recognition of weak non-canonical GA/GU-containing 5 splice sites (ss). We demonstrated that branaplam enhanced recognition of these 5 ss by reconstituted U1 snRNP in vitro, and that this effect depended on the ZnF domain of U1C and Helix H of U1 snRNA, but not U1A or U1-70K. In cells, depletion of U1C generally reduced compound-induced exon inclusion for most cassette exons. Interestingly, a subset of cassette exons became responsive to compound only upon U1C knockdown, supporting a model in which U1C stabilizes specific conformations at the 5 ss/U1 snRNA interface in a context-dependent manner that can either facilitate or hinder compound binding. Surprisingly, risdiplam shows no effect on weak 5 ss recognition in vitro, suggesting additional cellular factors are required for its activity.

biochemistry↗

bioRxiv2025

CerS2 is a druggable target in triple-negative breast cancer

Triple-negative breast cancer (TNBC) remains a significant clinical challenge due to its aggressive nature and lack of effective targeted therapies. The enzyme ceramide synthase 2 (CerS2), which synthesizes pro-apoptotic very long-chain ceramides (VLCCs), represents a promising therapeutic target. Here, we identify and characterize DH20931, a novel, first-in-class small-molecule agonist of CerS2. We demonstrate that DH20931 directly activates CerS2 with nanomolar potency, leading to significant VLCC accumulation in breast cancer cells. This lipotoxic event induces endoplasmic reticulum (ER) stress and triggers apoptosis via the canonical ATF4/CHOP/PUMA signaling pathway. Mechanistically, we uncover a novel interaction between CerS2 and the ER calcium channel, Inositol 1,4,5-trisphosphate receptor 1 (IP3R1). We demonstrate that DH20931 promotes this interaction, enhancing ER-mitochondria proximity and facilitating a CerS2-dependent flux of calcium (Ca{superscript 2}) from the ER into mitochondria. This subsequent mitochondrial Ca{superscript 2} overload serves as a critical trigger for apoptosis. In preclinical evaluations, DH20931 potently inhibited the growth of TNBC cells in 2D and 3D cultures and significantly suppressed tumor progression in orthotopic and patient-derived xenograft (PDX) models, all while exhibiting a favorable safety profile. Our findings validate CerS2 as a druggable target in TNBC and establish a novel therapeutic strategy that leverages a coordinated attack on cancer cells through ER stress and calcium-mediated mitochondrial dysfunction. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/670525v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@2db377org.highwire.dtl.DTLVardef@6175d4org.highwire.dtl.DTLVardef@7edb8corg.highwire.dtl.DTLVardef@80042e_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDH20931 is a first-in-class, potent agonist of Ceramide Synthase 2 (CerS2). C_LIO_LICerS2 activation induces ER stress and engages the ATF4/CHOP/PUMA apoptotic pathway. C_LIO_LIDH20931 promotes a novel CerS2-IP3R1 interaction, causing lethal mitochondrial calcium overload. C_LIO_LITargeting CerS2 shows significant preclinical efficacy against triple-negative breast cancer. C_LI

cancer biology↗

bioRxiv2025

Preservation and Clonal Behavior of Extrachromosomal DNA in Patient-Derived Xenograft Models of Childhood Cancers

Extrachromosomal DNA (ecDNA) is a powerful oncogenic driver linked to poor prognosis in pediatric cancers. Whole-genome sequencing of 338 patient-derived xenograft (PDX) samples and 127 matched primary tumors across multiple childhood cancer types was used to compare ecDNA prevalence, sequence conservation, and clonal dynamics. ecDNA in PDX models frequently mirrored oncogene amplifications observed in patient tumors (e.g., MYCN, MYC, MDM2) and showed high sequence conservation. Medulloblastoma and neuroblastoma PDXs exhibited significantly higher ecDNA prevalence, consistent with strong selection or de novo formation during tumor propagation. Although ecDNA copy numbers were generally preserved, some neuroblastoma PDXs displayed marked MYCN copy gains. Single-cell multiome profiling revealed that ecDNA-positive clones either persisted or expanded dramatically in PDXs, in one case growing from a minor subpopulation to nearly all tumor cells. These findings establish PDX models as valuable systems for ecDNA research and underscore the selective growth advantage conferred by ecDNA during tumor evolution.

genomics↗

bioRxiv2025

BioScientist Agent: Designing LLM-Biomedical Agents with KG-Augmented RL Reasoning Modules for Drug Repurposing and Mechanistic of Action Elucidation

Drug discovery is protracted, resource-intensive, and afflicted by attrition rates exceeding 90 %, which leaves most diseases, particularly rare or neglected indications, without effective therapies. Drug repurposing offers a cost effective alternative, yet systematic identification of novel drug indication pairs and mechanistic rationales remains hindered by the scale and heterogeneity of biomedical knowledge. We present BioScientist Agent, an end to end framework that unifies a billion-fact biomedical knowledge graph with (i) a variational graph auto-encoder for representation learning and link prediction driven drug repurposing, (ii) a reinforcement learning module that traverses the graph to recover biologically plausible mechanistic paths, and (iii) A large language model (LLM) multi-agent layer that orchestrates these components, enabling inference of target pathways for a drug disease pair, and automatic generation of coherent causal reports. In all downstream tasks, the BioScientist Agent surpasses existing state of the art baseline models across various metrics and provides mechanistic explanations consistent with the literature. Its open and modular design accelerates hypothesis generation and reduces experimental overhead in early stage discovery.

bioinformatics↗

bioRxiv2025

Bottlebrush Polymer Conjugates for Enhanced Antisense Oligonucleotide Therapy in Myotonic Dystrophy Type 1

Oligonucleotides are a promising genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs after systemic administration has hindered drug development, and no curative treatment exists. Additionally, DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is trapped, posing challenges after endocytosis and endosomal escape. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUGexp RNA tracts, conjugated to a bottlebrush polymer, exhibited improved muscle distribution and potent correction of DM1-associated splicing at low nanomolar doses in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugates were well tolerated after 12 weeks of weekly intravenous dosing. These results suggest that bottlebrush polymer bioconjugates may overcome key limitations of traditional antisense drugs for muscular dystrophies, with the potential as potent, durable, and cost-efficient DM1 therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/668589v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@e3961corg.highwire.dtl.DTLVardef@194225dorg.highwire.dtl.DTLVardef@5c470dorg.highwire.dtl.DTLVardef@3cc46a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Distributed control circuits across a brain-and-cord connectome

Just as genomes revolutionized molecular genetics, connectomes (maps of neurons and synapses) are transforming neuroscience. To date, the only species with complete connectomes are worms1-3 and sea squirts4 (103-104 synapses). By contrast, the fruit fly is more complex (108 synaptic connections), with a brain that supports learning and spatial memory5,6 and an intricate ventral nerve cord analogous to the vertebrate spinal cord7-11. Here we report the first densely reconstructed adult fly connectome that unites the brain and ventral nerve cord, and we leverage this resource to investigate principles of neural control. We show that effector neurons (motor neurons, endocrine cells and efferent neurons targeting the viscera) are primarily influenced by sensory neurons in the same body part, forming local feedback loops. These local loops are linked by long-range circuits involving ascending and descending neurons organized into behavior-centric modules. Single ascending and descending neurons are often positioned to influence the voluntary movements of multiple body parts, together with the endocrine cells or visceral organs that support those movements. Brain regions involved in learning and navigation supervise these circuits. These results reveal an architecture that is distributed, parallelized and embodied, reminiscent of distributed control architectures in engineered systems12,13.

neuroscience↗

bioRxiv2025

Model of leaf biomass partitioning coefficient in different leaf ranks of rapeseed (Brassica napus L.) main-stem

Leaf growth is a dynamic process, and understanding the number of main-stem leaves and the distribution of leaf biomass at different development stages can provide a theoretical basis for the development of functional-structural rapeseed model. To address the gap in research on the leaf biomass partitioning coefficient model in the crop growth model, we developed the leaf biomass partitioning coefficient model for the main-stem at different leaf ranks in rapeseed. The outdoor experiment with cultivars, Ningyou 18 (V1, conventional), Ningyou 16 (V2, conventional), and Ningza 19 (V3, hybrid), and designed treatment of cultivars x fertilizer x transplanting density in the 2012-2015 growth season. The model was fitted by calculating the ratio of leaf biomass at different leaf ranks on the main-stem to the total leaf biomass on the main-stem, and normalizing the leaf ranks into (0-1] interval. We parameterized the model variables to elucidate how cultivar and environmental conditions influence the leaf biomass partitioning coefficients for different leaf ranks. The descriptive models were validated with independent experimental data, the correlation (r) of simulation and observation values all greater than 0.9 with significant levels at p < 0.001. The absolute values of the average absolute difference (da) are all less than 0.011 g g-1. The ratio of da to the average observation (dap) for the normalized leaf rank, and leaf biomass partitioning coefficient at seedling stage, and budding and bolting stage, and blooming stage, and mature stage are 13.599%, 11.236%, 11.312%, 3.077%, and 8.661%, respectively. The RMSE values are all less than 0.032 g g-1. The models developed in this paper have good performance and reliability for predicting leaf biomass partitioning coefficient of main-stem at different leaf ranks in rapeseed. This study integrates the leaf morphology model of rapeseed with the rapeseed growth model through biomass partitioning, contributing to the development of the functional-structural rapeseed model.

bioinformatics↗