Biology subjects

Yang, Q.

Publications and source records attributed to Yang, Q..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

NeuroDISK: An AI Approach to Automate Continuous Inquiry-Driven Discoveries in Neuroimaging Genetics

Collaborative and multi-site neuroimaging studies have greatly accelerated the rate at which new and existing data can be aggregated to answer a neuroscientific question. New research initiatives are continuously collecting more data, allowing opportunities to refine previous published findings through continuous and dynamic updates. Yet, we lack a practical framework for researchers to systematically, automatically, and continuously update published findings. We developed NeuroDISK, an automated artificial intelligence based framework that: 1) performs automated and inquiry-driven analyses, and 2) continuously updates these analyses as new data becomes available. NeuroDISK was evaluated using published results from the ENIGMA consortiums work on the genetic architecture of the cerebral cortex. We incorporate both meta-analysis and meta-regression options to showcase our framework on the effect of specific genotypes and moderators on select brain regions. Initial NeuroDISK meta-analysis results replicate the original publication, and we show result updates after adding new data. The NeuroDISK framework can be generalized for users to define question(s), run corresponding workflow(s) and access results interactively and continuously.

bioinformatics↗

bioRxiv2025

Comparative molecular landscapes of immature neurons in the mammalian dentate gyrus across species reveal special features in humans

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity, learning and memory, but their evolutionary changes across species and specialized features in humans remain poorly understood. Here we performed machine learning-augmented analysis of published single-cell RNA-sequencing datasets and identified macaque imGCs with transcriptome-wide immature neuronal characteristics. Our cross-species comparisons among humans, monkeys, pigs, and mice showed few shared (such as DPYSL5), but mostly species-specific gene expression in imGCs that converged onto common biological processes regulating neuronal development. We further identified human-specific transcriptomic features of imGCs and demonstrated functional roles of human imGC-enriched expression of a family of proton-transporting vacuolar-type ATPase subtypes in development of imGCs derived from human pluripotent stem cells. Our study reveals divergent gene expression patterns but convergent biological processes in the molecular characteristics of imGCs across species, highlighting the importance of conducting independent molecular and functional analyses for adult neurogenesis in different species.

neuroscience↗

bioRxiv2025

Unprecedented Number of Recurrent Mutations Drive the Rapid Evolution of Pesticide Resistance in a Notorious Pest

The genetic basis of pesticide resistance has been widely studied, but the exact nature of this evolutionary process in the field is often unclear, particularly when a limited number of populations is considered and when there is a lag between the evolutionary event and its investigation. We showed that an unprecedented number of recurrently evolved mutations in an arthropod pest, the two-spotted spider mite Tetranychus urticae, drive the rapid evolution of resistance to a recently commercialized acaricide, cyetpyrafen. We first observed high levels of resistance that appeared and became widespread within three years. Genome scans revealed genetic heterogeneity of resistance among populations and identified 15 target mutations, including six mutations on five amino acid residues of subunit sdhB, and nine mutations on three amino acid residues of subunit sdhD of the pesticide target succinate dehydrogenase, with as many as five substitutions on one residue. No mutations were present in 2666 screened historical specimens, suggesting that mutations arose rapidly through de novo substitutions or from very rare segregating mutations. Identical mutations recurrently appeared in different genetic backgrounds, increasing the likelihood of resistance evolution. The high number of mutational options available for the evolution of target site resistance in this pest challenges resistance management practices.

evolutionary biology↗

bioRxiv2025

A maize near-isogenic line population designed for gene discovery and characterization of allelic effects

In this study we characterized a panel of 1,264 maize near-isogenic lines (NILs), developed from crosses between 18 diverse inbred lines and the recurrent parent B73, referred to as nested NILs (nNILs). 884 of the nNILs were genotyped using genotyping-by-sequencing (GBS). Subsequently, 24 of these nNILs, and all the parental lines, were re-genotyped using a high-density SNP chip. A novel pipeline for calling introgressions, which does not rely on knowing the donor parent of each nNIL, was developed based on a hidden Markov model (HMM) algorithm. By comparing the introgressions detected using GBS data with those identified using chip data, we optimized the HMM parameters for analyzing the entire nNIL population. A total of 2,972 introgressions were identified across the 884 nNILs. Individual introgression blocks ranged from 21 bp to 204 Mbp, with an average size of 17 Mbp. By comparing SNP genotypes within introgressed segments to the known genotypes of the donor lines we determined that in about one third of the lines, the identity of the donors did not match expectation based on their pedigrees. We characterized the entire nNIL population for three foliar diseases. Using these data, we mapped a number of quantitative trait loci (QTL) for disease resistance in the nNIL population and observed extensive variation in effects among the alleles from different donor parents at most QTL identified. This population will be of significant utility for dissecting complex agronomic traits and allelic series in maize. Significance StatementThe study reports the characterization of a publicly available population of 1,264 maize near-isogenic lines largely derived from a single recurrent parent and 18 donor lines. This population is likely to be of significant utility for the characterization of allelic series at loci of interest.

plant biology↗

bioRxiv2025

Preventing large deletions and chromosome loss in engineered human primary T cells by CasPlus with optimized guide RNAs

Genetically engineered T-cell therapies rely heavily on genome editing tools, such as the CRISPR/Cas9 system. However, unintended on-target chromosomal alterations, including large deletions and chromosome loss can occur and pose significant risks including tumorigenesis. Here we combined CasPlus and optimized guide RNAs to reduce these issues in CRISPR/Cas9 engineering human primary T cells. CasPlus, which integrates an engineered T4 DNA polymerase with Cas9 nuclease and guide RNA, promotes favorable small insertions (1-2 bp) while reducing large deletions and chromosome loss in T cells. Our optimized guide RNAs favoring small insertions reduced large deletions and chromosome loss by two- to five-fold versus those favoring small deletions. Moreover, combining optimized guide RNA with T4 DNA polymerase further synergistically reduced large deletions and chromosome loss by additional two-fold. Notably, replacing currently used guide RNA pairs in clinically applications with optimized pairs biased towards small insertions, along with CasPlus instead of Cas9, for editing greatly reduced large deletions and chromosome loss in gene-edited human primary T cells. These findings demonstrated that pre-selecting target sites favoring small insertions via guide RNA optimization coupled with CasPlus editing is a safer and more effective strategy to improve genome stability in T-cell engineering and other gene-editing applications.

bioengineering↗

bioRxiv2025

SMTdb: A comprehensive spatial meta-transcriptome resource in cancer

Microbes have been found in various tumors and the research of tumor microbiome has been garnering increased attention. However, it remains challenge to investigate the microbiome in cancer at spatial resolution. The rapid advent of spatially resolved transcriptomics techniques has given rise to map transcripts at single-cell resolution in various types of cancer. Here, we constructed a comprehensive spatial meta-transcriptome resource by manually curating 203 fresh frozen (FF) slices from 20 cancers encompassing 334,253 spots and 1,908,646 cells. SMTdb (http://bio-bigdata.hrbmu.edu.cn/SMTdb/) was constructed to provide comprehensive insights into the abundance, distribution and enriched TME regions of 1218 microbiota in spatial tissue slices. SMTdb enables vast interactive data exploration of spatial distribution and expression of microbiota, host gene modules associated with certain microbiota and co-occurrence between microbiota and immune cells within tumor microenvironment. The atlas resource serves as a one-stop and time-effective platform to investigate the interactions among microbial ecosystems and hosts in cancer.

bioinformatics↗

bioRxiv2025

High-speed mapping of whole-mouse peripheral nerves at subcellular resolution

In contrast to the rapid advancements in mesoscale connectomic mapping of the mammalian brain, similar mapping the peripheral nervous system has remained challenging due to the bodys size and complexity. Here, we present a high-speed blockface volumetric imaging system with an optimized workflow of whole-body clearing, capable of imaging the entire adult mouse at micrometer resolution within 40 hours. Three-dimensional reconstruction of individual spinal fibers in Thy1-EGFP mice reveals distinct morphological features of sensory and motor projections along the ventral and dorsal rami. Immunostaining facilitates body-wide mapping of sympathetic nerves and their branches, highlighting their perivascular patterns in limb muscles, bones, and most visceral organs. Viral tracing elucidates the fine architecture of vagus nerves and individual vagal fibers, revealing unexpected projection routes to various organs. Our approach offers an effective means to achieve a holistic understanding of cellular-level interactions among different systems that underlie body physiology and disease. HighlightsO_LIImaging of whole adult mouse at uniform subcellular resolution within 40 hours C_LIO_LIReconstruction of 191 thoracic spinal neuron projections for Thy1-EGFP mice C_LIO_LIMapping of immunolabeled sympathetic projections and their perivascular patterns C_LIO_LIResolving virus-labeled architecture of vagus nerves and complex single-fiber routes C_LI

neuroscience↗

bioRxiv2025

Cell heterogeneity and fate bistability drive tissue patterning during intestinal regeneration

Tissue regeneration relies on the ability of cells to undergo de novo patterning. While tissue patterning has been viewed as the transition from initially identical un-patterned cells to an arrangement of different cell types, recent evidence suggests that initial heterogeneities between cells modulate tissue-scale pattern formation. Yet, how such heterogeneities arise and, thereafter, regulate cell type emergence in a population of cells is poorly understood. Using in vivo and in vitro mouse regenerative systems, we identify a critical tissue density that is required to induce heterogeneous inactivation of the mechanosensor YAP1. Experimental and biophysical approaches demonstrate that YAP1 cell-to-cell heterogeneity pre-patterns the first cell fate decision, via both chromatin remodelling and a supracellular feedback between FOXA1 and Delta-Notch signalling. This feedback motif induces cell fate bistability endowing memory to the system and the maintenance of patterns during homeostasis. These findings reveal a generalisable framework in which transient cell-to-cell heterogeneity, regulated by tissue-scale properties, serves as a critical control parameter for the emergence of cell fate and stable patterning during regeneration.

cell biology↗

bioRxiv2025

Activity dependent Clustering of Neuronal L-Type Calcium Channels by CaMKII

Neuronal depolarization activates L-type voltage-gated Ca{superscript 2} channels (LTCCs), increasing local Ca{superscript 2} concentrations to initiate excitation-transcription (E-T) coupling. We show that depolarization enhances clustering of CaV1.2 and CaV1.3 LTCCs in cultured hippocampal neurons, coinciding with increased nuclear CREB phosphorylation. LTCC clustering and LTCC-dependent CREB phosphorylation are selectively disrupted by 1,6-hexanediol, implicating biomolecular condensation. Activated CaMKII holoenzymes assemble complexes containing multiple CaV1.2 and/or CaV1.3 1 subunits. Complex assembly is facilitated by co-expression of CaMKII-binding {beta}2a subunits and Shank3 and selectively disrupted by 1,6-hexanediol. In HEK293 cells, pharmacological LTCC activation enhances clustering only when wild-type CaMKII is co-expressed. A CaMKII mutant that cannot bind LTCC N-terminal domains fails to support LTCC subunit complex formation in vitro and LTCC clustering in HEK293 cells. In neurons, the knockdown of CaMKII expression disrupts depolarization-induced (co-)clustering of CaV1.2 and CaV1.3. Together, these findings indicate that CaMKII-dependent clustering of plasma membrane LTCCs via biomolecular condensation is essential for initiating long-range signaling to activate gene expression following neuronal depolarization.

neuroscience↗

bioRxiv2025

MAIT cell deficiency exacerbates neuroinflammation in P301S human tau transgenic mice

The role of immune cells in neurodegeneration remains incompletely understood. Our recent study revealed the presence of mucosal-associated invariant T (MAIT) cells in the meninges, where they express antioxidant molecules to maintain meningeal barrier integrity. Accumulation of misfolded tau proteins are a hallmark of neurodegenerative diseases. The role of MAIT cells in tau-related neuroinflammation and neurodegeneration, however, remains unclear. Here we report that the meninges of P301 mutant human tau transgenic mice had increased numbers of MAIT cells, which retained their expression of antioxidant molecules. Mr1-/-P301S mice that lacked MAIT cells exhibited increased tau pathology and hippocampus atrophy compared to control Mr1+/+ P301S mice. Adoptive transfer of MAIT cells reduced tau pathology and hippocampus atrophy in Mr1-/- P301S mice. Meningeal barrier integrity was compromised in Mr/-/-P301S mice, but not in control Mr1+/+ P301S mice. A distinctive microglia subset with proinflammatory gene expression profile (M-inflammatory) was enriched in the hippocampus of Mr1-/- P301S mice. The transcriptomes of the remaining microglia in these mice also shifted towards a proinflammatory state, with increased expression of inflammatory cytokines, chemokines, and genes related with ribosome biogenesis and immune responses to toxic substances. The transfer of MAIT cells restored meningeal barrier integrity and suppressed microglial inflammation in the Mr1-/- P301S mice. Together, our data indicate an important role for MAIT cells in regulating tau-pathology-related neuroinflammation and neurodegeneration.

immunology↗

bioRxiv2025

LCORL and STC2 variants increase body size and growth rate in cattle and other animals

Using ancestral recombination graphs, we investigated recent selection signatures in European beef cattle breeds, pinpointing sweep-driving variants in the LCORL and STC2 loci with notable effects on body size and growth rate. The ACT-to-A frameshift mutation in LCORL occurs mainly in central-European cattle, and stimulates growth. Remarkably, convergent truncating mutations were also found in commercial breeds of sheep, goats, pigs, horses, dogs, rabbits, and chickens. In the STC2 gene, we identified a missense mutation (A60P) located within the conserved region across vertebrates. We validated the two natural mutations in gene-edited mouse models, where both variants in homozygous carriers increase the average weight by 11%. Our findings provide insights into a seemingly recurring gene target of body size enhancing truncating mutations across domesticated species, and offer valuable targets for gene editing-based breeding in animals.

genetics↗

bioRxiv2024

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

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

bioinformatics↗

bioRxiv2024

scRepertoire 2: Enhanced and Efficient Toolkit for Single-Cell Immune Profiling

Single-cell adaptive immune receptor repertoire sequencing (scAIRR-seq) and single-cell RNA sequencing (scRNA-seq) provide a transformative approach to profiling immune responses at unprecedented resolution across diverse pathophysiologic contexts. This work presents scRepertoire 2, a substantial update to our R package for analyzing and visualizing single-cell immune receptor data. This new version introduces an array of features designed to enhance both the depth and breadth of immune receptor analysis, including improved workflows for clonotype tracking, repertoire diversity metrics, and novel visualization modules that facilitate longitudinal and comparative studies. Additionally, scRepertoire 2 offers seamless integration with contemporary single-cell analysis frameworks like Seurat and SingleCellExperiment, allowing users to conduct end-to-end immune profiling with transcriptomic data. Performance optimizations in scRepertoire 2 substantially reduce computational time and memory usage, addressing the demands of the ever-increasing size and scale of single-cell studies. This release marks an advancement in single-cell immunogenomics, equipping researchers with a robust toolset to uncover immune dynamics in health and disease.

immunology↗

bioRxiv2024

Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina

Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the rapid advancements in deep-learning techniques, we developed sequence-based predictors to interpret non-coding risk variants of retina diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases, and provides a resource for studying the gene regulatory programs of the human retina and relevant diseases.

genomics↗

bioRxiv2024

Mechanistic origins of temperature scaling in the early embryonic cell cycle

Temperature profoundly impacts organismal physiology and ecological dynamics, particularly affecting ectothermic species and making them especially vulnerable to climate changes. Although complex physiological processes usually involve dozens of enzymes, empirically it is found that the rates of these processes often obey the Arrhenius equation, which was originally proposed for individual chemical reactions. Here we have examined the temperature scaling of the early embryonic cell cycle, with the goal of understanding why the Arrhenius equation approximately holds and why it breaks down at temperature extremes. Using experimental data from Xenopus laevis, Xenopus tropicalis, and Danio rerio, plus published data from Caenorhabditis elegans, Caenorhabditis briggsae, and Drosophila melanogaster, we find that the apparent activation energies (Ea values) for the early embryonic cell cycle for diverse ectotherms are all similar, 75 {+/-} 7 kJ/mol (mean {+/-} std.dev., n = 6), which corresponds to a Q10 value at 20{degrees}C of 2.8 {+/-} 0.2 (mean {+/-} std.dev., n = 6). Using computational models, we find that the approximate Arrhenius scaling and the deviations from it at high and low temperatures can be accounted for by biphasic temperature scaling in critical individual components of the cell cycle oscillator circuit, by imbalances in the Ea values for different partially rate-determining enzymes, or by a combination of both. Experimental studies of cycling Xenopus extracts indicate that both of these mechanisms contribute to the general scaling of temperature, and in vitro studies of individual cell cycle regulators confirm that there is in fact a substantial imbalance in their Ea values. These findings provide mechanistic insights into the dynamic interplay between temperature and complex biochemical processes, and into why biological systems fail at extreme temperatures.

systems biology↗

bioRxiv2024

PPARδ restrains the suppression function of intra-tumoral Tregs by limiting CIITA-MHC II expression

Regulatory T cells (Treg cells) play a critical role in suppressing anti-tumor immunity, often resulting in unfavorable clinical outcomes across numerous cancers. However, systemic Treg depletion, while augmenting anti-tumor responses, also triggers detrimental autoimmune disorders. Thus, dissecting the mechanisms by which Treg cells navigate and exert their functions within the tumor microenvironment (TME) is pivotal for devising innovative Treg-centric cancer therapies. Our study highlights the role of peroxisome proliferator-activated receptor {beta}/{delta} (PPAR{delta}), a nuclear hormone receptor involved in fatty acid metabolism. Remarkably, PPAR{delta} ablation in Treg escalated tumor growth and augmented the immunosuppressive characteristics of the TME. This absence of PPAR{delta} spurred an increased expression of genes central to antigen presentation, notably CIITA and MHC II. Our results showcase a novel association where the absence of CIITA in PPAR{delta}-deficient Treg bolsters anti-tumor responses, casting CIITA as a pivotal downstream regulator of PPAR{delta} within Treg. In vitro assays demonstrated that elevated CIITA levels enhance the suppressive capacity of Treg, facilitated by an antigen-independent interaction between Treg-MHC II and Tconv-TCR/CD4/Lag3. A significant revelation was the role of type 1 interferon as a TME signal that promotes the genesis of MHC II+ Treg; PPAR{delta} deficiency intensifies this phenomenon by amplifying type 1 interferon signaling, mediated by a notable upsurge in JAK3 transcription and an increase of pSTAT1-Y701. In conclusion, the co-regulation between TME cues and PPAR{delta} signaling shapes the adaptive and suppressive roles of Treg cells through the CIITA-MHC II pathway. Strategically targeting the potent MHC II+ Treg population could open a new avenue for cancer therapies by boosting anti-tumor defenses while curbing autoimmune threats. HighlightsO_LIPPAR{delta} Treg conditional knockout mice show accelerated tumor growth due to increased expression of CIITA-MHC II. C_LIO_LIType I interferon signal regulates Treg CIITA-MHC II axis in vitro and in vivo. C_LIO_LIPPAR{delta} attenuates Type I interferon response and restrains CIITA-MHC II expression in Treg cells. C_LIO_LITreg suppressive function is enhanced by Treg MHC IIs direct interaction with TCR/CD4/Lag3 on Teff cells. C_LI

immunology↗

bioRxiv2024

Spread of a single superclone drives insecticide resistance in Acyrthosiphon kondoi across an invasive range

Populations under similar selection pressures may adapt via parallel evolution or dispersal of advantageous alleles. Here, we investigated insecticide resistance in the invasive blue-green aphid, Acyrthosiphon kondoi, which reproduces clonally in Australia and has rapidly developed resistance across geographic locations. Using genomic, transcriptomic, and experimental approaches, we explored the evolutionary origins and molecular mechanisms of resistance. We developed the first nuclear genome assembly for A. kondoi (443.8 Mb, 28,405 annotated genes, BUSCO score 97.5%) and a partial mitochondrial assembly (11,598 bp). All resistant strains shared a common ancestor, supporting the spread of a resistant superclone lineage that is distinct from susceptible strains. Resistance was associated with over-expression of an esterase gene that was homologous to E4/FE4 esterases in other aphid pests that are linked to resistance. Functional experiments in Drosophila melanogaster confirmed a causal role of this E4- like esterase in resistance to organophosphates, carbamates, and pyrethroids. These findings highlight how clonal dispersal and insecticide overuse can transform local adaptation into a widespread pest management issue. Our results suggest a parallel macroevolutionary response to insecticide selection in A. kondoi and other aphid species at the gene family level, but with a distinct regulatory mechanism in A. kondoi. Given the rapid spread of the resistant superclone, alternative management strategies, including expanded chemical control options and enhanced biological control, are urgently needed to mitigate this growing pest problem.

evolutionary biology↗

bioRxiv2024

Asymmetric Activation of Retinal ON and OFF Pathways by AOSLO Raster-Scanned Visual Stimuli

Adaptive optics scanning light ophthalmoscopy (AOSLO) enables high-resolution retinal imaging, eye tracking, and stimulus delivery in the living eye. AOSLO-mediated visual stimuli are created by temporally modulating the excitation light as it scans across the retina. As a result, each location within the field of view receives a brief flash of light during each scanner cycle (every 33-40 ms). Here we used in vivo calcium imaging with AOSLO to investigate the impact of this intermittent stimulation on the retinal ON and OFF pathways. Raster-scanned backgrounds exaggerated existing ON-OFF pathway asymmetries leading to high baseline activity in ON cells and increased response rectification in OFF cells.

neuroscience↗