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Li, W.

Publications and source records attributed to Li, W..

At least 91 records · Page 5Linked to original sources

A Diploid Panax Genome Reveals Ginsenoside Diversity Driven by UGT Diversification and Network Rewiring, Rather Than Gene Family Expansion

The medicinal herb Panax notoginseng produces a structurally diverse array of triterpene saponins (ginsenosides), yet the genetic basis of this chemical complexity remains unclear. Here we present a high-quality chromosome-level genome of diploid P. notoginseng and integrate comparative genomics with multi-tissue, multi-year metabolomics and transcriptomics. Surprisingly, unlike tetraploid Panax species, P. notoginseng shows no general expansion of core saponin biosynthetic gene families. Instead, lineage-specific diversification of UDP-glycosyltransferase (UGT) families, a recent burst of LTR retrotransposons, and enrichment of species-specific genes in metabolic modification pathways point to an alternative evolutionary route. Saponin accumulation follows strict spatiotemporal compartmentalisation, and co-expression network analysis reveals that the biosynthetic machinery is not static but continuously rewired during development-from a basic synthesis module in the first year to a modular pattern supporting both broad accumulation and branch-specific modification by the third year. Seventeen differentially expressed UGTs show clear tissue preferences and saponin-branch correlations. As a representative example, PnUGT33 is tightly linked to the PPD-type saponin branch; structural modelling, molecular docking and 100 ns molecular dynamics simulations demonstrate its differential recognition of diverse triterpene skeletons. Collectively, our findings establish that ginsenoside diversity in diploid P. notoginseng arises primarily from UGT lineage diversification, developmentally rewired regulatory networks and UGT mediated branch selective post-modification, rather than from expansion of core pathway genes. This work provides a new paradigm for understanding how plants achieve metabolic complexity without whole genome duplication or massive gene amplification.

genomics↗

Selective vulnerability of excitatory cortical neurons to ZMYND11 loss reveals cell-type-specific mechanisms of neurodevelopmental disorder risk

Excitation/inhibition (E:I) imbalance is a convergent mechanism in neurodevelopmental disorders (NDDs), yet whether NDD risk genes disrupt excitatory and inhibitory neurons through shared or distinct molecular programs remains poorly understood. Using human pluripotent stem cell-derived cortical projection and medial ganglionic eminence-like inhibitory neurons, we show that loss-of-function mutations in the chromatin reader ZMYND11 produce cell-type-selective vulnerability in cortical excitatory neurons. ZMYND11-deficient excitatory neurons exhibit hyperexcitability accompanied by de-repression of BMP signaling, dysregulation of glutamate receptor expression, and a shift toward non-brain splicing isoforms, whereas these molecular signatures are largely absent in ZMYND11-deficient inhibitory neurons. This cell-type selectivity is associated with differential upregulation of RBFOX family splicing regulators. Structure-function analysis reveals that MYND domain is required for normal progenitor dynamics and neuronal excitability. Together, these findings indicate that E:I imbalance in ZMYND11-associated NDD arises primarily from cell-type-selective vulnerability of excitatory cortical projection neurons and identify MYND domain as a critical determinant of neuronal function. HighlightsO_LIZMYND11-deficient excitatory neurons (ExNs) show hyperexcitability. C_LIO_LIAltered BMP signaling & glutamate receptor levels are implicated in mutant ExNs. C_LIO_LIInhibitory neurons show attenuated response to ZMYND11 loss. C_LIO_LIThe MYND domain in ZMYND11 is a critical regulator of neuronal excitability. C_LI

neuroscience↗

The metastasis susceptibility gene RRP1B is a stress-responsive regulator of nuclear RNA processing and splicing in breast cancer

The tumor microenvironment exposes cancer cells to mechanical, thermal, hypoxic, and acidic stresses, yet how cells integrate these signals to remodel RNA processing remains poorly understood. Here, we show that ribosomal RNA Processing 1B (RRP1B), previously characterized as a nucleolar ribosome biogenesis factor and metastasis modifier, functions as a broad-spectrum stress sensor that dynamically repositions among the nuclear envelope, nucleolus, and nuclear speckles (NS). Relocalization is governed by multi-site phosphorylation within intrinsically disordered regions (IDRs): phosphomimetic substitutions promote NS-proximal condensate formation in an RNA-dependent manner, while unphosphorylatable substitutions confine RRP1B to the nucleolus. Under stress, the RRP1B interactome shifts globally, with ribosomal processing partners replaced by pre-mRNA splicing components enriched for NS-resident proteins. RNA immunoprecipitation sequencing (RIP-seq) demonstrates that under basal conditions RRP1B associates with long, intron-rich, nuclear periphery-proximal transcripts, whereas heat shock redirects binding toward shorter, exon-dense transcripts enriched for motifs of serine/arginine-rich (SR) proteins near the NS. RRP1B overexpression nearly abolishes cytoplasmic retained intron accumulation and drives preferential export of specific transcript isoforms in a compartment- and temperature-dependent manner, establishing RRP1B as a regulator of RNA localization fidelity rather than transcriptional output. An RRP1B overexpression signature is most highly activated in basal-like and claudin-low breast tumors, and the RRP1B-associated retained intron splicing program correlates with reduced survival in a tumor-grade-dependent manner. These findings reframe RRP1B as a microenvironmentally sensitive regulator of nuclear RNA processing with direct implications for aggressive breast cancer biology.

Cancer Biology↗

Systematic evaluation of Cyanidioschyzon merolae across photobioreactor systems: Linking reactor design to biomass production and biochemical composition

Extremophilic red microalgae are promising platforms for sustainable biotechnology, combining robust growth under selective thermoacidophilic conditions with production of thermostable phycobiliproteins and carbon-rich biomass. However, reactor-dependent effects on growth, product formation and biomass composition remain insufficiently resolved. Here, we systematically evaluated the extremophilic red microalga Cyanidioschyzon merolae across cultivation scales and reactor formats and benchmarked its performance against the well-established Galdieria javensis and Limnospira platensis. In small-scale multi-cultivator photobioreactors and microfluidic growth chambers, C. merolae showed superior growth, reaching a maximum growth rate of 0.034 {+/-} 0.001 h-1 and 8.3 {+/-} 0.3 g l-1 cell dry weight. Microfluidic cultivation enabled growth analysis at single-cell resolution and matched growth rates obtained in photobioreactors. To identify scalable production strategies, C. merolae was further cultivated in a flat-panel photobioreactor and a custom-designed internally illuminated photobioreactor. The custom-designed photobioreactor delivered the highest biomass concentration and productivity, yielding 11.5 {+/-} 0.6 g l-1 cell dry weight and 1.07 {+/-} 0.06 g l-1 d-1, and comparable yields with regard to R-phycocyanin and R-allophycocyanin. Biomass analysis revealed substantial carbon and nitrogen contents, starch accumulation up to > 20 % of cell dry weight, and fatty acids dominated by palmitic, linoleic and oleic acids. Despite its reduced cell wall fraction, C. merolae contained structurally diverse, cultivation-dependent polysaccharides. These results establish C. merolae as a versatile chassis for thermostable pigment production and renewable feedstock generation, highlighting photobioreactor design as a key determinant of productivity and biomass quality.

microbiology↗

The HUSH Complex Dictates EBV-transformed B cell Sensitivity to NK Cell Surveillance Through Repression of NKG2A Ligand γ-Proto-cadherin

Natural Killer (NK) cells control Epstein-Barr virus (EBV), though how EBV+ B-cells escape NK surveillance to form tumors remains unknown. To gain insights, we performed a human genome-wide CRISPR-Cas9 screen in EBV-transformed lymphoblastoid cell lines (LCL). This revealed that the HUSH complex maintains LCL sensitivity to NK. HUSH knockout (KO) de-repressed LCL protocadherin gamma (PCDHG), typically expressed by neurons. PCDHG expression protected LCLs from NK and was necessary for HUSH KO-driven NK resistance. CRISPR analyses revealed NKG2A/CD94 as the PCDHG NK inhibitory counter-receptor, and NKG2A KO restored NK lysis of HUSH KO LCLs. HUSH perturbation impaired NK control of murine LCL xenografts in vivo. A subset of follicular lymphoma (FL) upregulate PCDHG, and PCDHG KO enhanced FL lysis by NK. Therefore, HUSH plays dual roles in foreign DNA surveillance and in support of NK, potentially as a neuronal dont kill me signal that can be exploited by transformed cells.

immunology↗

Gonadal PIP-seq reveals genes involved in germ cell development and sexual differentiation in sea lamprey ( Petromyzon marinus )

Vertebrate sex determination is highly diverse, with distinct mechanisms that have evolved repeatedly and independently across phylogeny. The sea lamprey (Petromyzon marinus) is an extant jawless vertebrate that remains sexually labile during its larval stage that lasts around 3-20 years. Their gonad contains bipotential, female, and male germ cells before metamorphosis. To examine the genetic programs in germ cells at different developmental stages, we profiled transcriptomes of dissociated gonadal cells from larvae and recently metamorphosed juvenile (transformers, sex-determined) using fluorescence-activated cell sorting (BD FACS Aria IIu) and PIPseqTM (Fluent BioSciences/Illumina). 66,676 cells were sequenced and classified into 19 cell clusters according to their gene expression profiles. Primordial germ cells differentially expressed genes encoding various heat-shock proteins, hormones, growth factors, and their receptors, and proteins sensitive to iron, nitrogen starvation, sugar and lipid metabolisms, and oxidative stress, providing possible links between environmental factors, cellular functions, and cell fate determinants. Germ cells in larvae had enriched expression of genes involved in DNA replication, transcription, translation, apoptosis, autophagy, cell cycle, cell differentiation, cell adhesion and migration, cell survival, chromatin remodeling, and proliferation. Specifically, female germ cells differentially expressed various transcript isoforms of AEP1, CUZD1, S100A1, and ZP genes, whereas male germ cells differentially expressed BOLL and PIWIL1. Pseudotime trajectory and Gene Ontology (GO) analysis revealed that genes with changing expressions along the female differentiation pathway were involved in binding of sperm to zona pellucida, egg coat formation, prevention of polyspermy and positive regulation of acrosome reaction. On the other hand, genes with changing expressions along the male differentiation pathway were involved in ribosome assembly and translation. Several WNT5 transcripts were differentially expressed in germ cells or somatic cells. Our results suggest that sea lamprey sex determination and sexual differentiation likely involve the coordinated action of numerous genes that interact with various environmental factors and regulate germ cell specification and development.

Developmental Biology↗

Structural basis for loop-dependent inhibition by AcrIIC1 anti-CRISPR proteins

Most known anti-CRISPR proteins exert inhibition via solitary functional pathways, and few natural Acr homologs have been reported to possess coupled inhibitory mechanisms. Here, we demonstrate that AcrIIC1Boe represses Nme1Cas9 activity through loop-coupled inhibitory effects. Beyond canonical occlusion of the HNH catalytic site, the unique extended loop of AcrIIC1Boe further perturbs sgRNA binding and restricts R-loop maturation to reinforce inhibition. Strikingly, loop deletion completely abrogated this layered inhibitory capacity, confirming that the loop is indispensable for full anti-CRISPR function. Consistently, transplantation of this functional loop into the weakly active AcrIIC1Nme1 markedly upgraded its inhibitory performance. Our findings reveal an unprecedented loop-governed coupled inhibition mode, clarify the structural basis for functional divergence within the AcrIIC1 family, and provide a modular engineering strategy for the rational design and optimization of high-potency anti-CRISPR proteins.

Molecular Biology↗

Lineage-specific chromatin poising enforced by ETS-IRF composite elements determines the divergent interferon responses of plasmacytoid dendritic cells and epithelial cells

Plasmacytoid dendritic cells (pDCs) produce robust type I interferons (IFN-I) within hours of viral sensing, while epithelial cells at mucosal surfaces mount a delayed response dominated by type III interferons (IFN-III). Both cell types express pattern recognition receptors that activate similar downstream transcription factors, yet they produce distinct subsets of IFNs. The mechanisms underlying these differences have remained unclear. Here, using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) in primary human pDCs and intestinal epithelial cells, we show that IFN-I and IFN-III gene loci carry opposing, constitutively established chromatin accessibility landscapes that determine cell-type-specific interferon induction. The IFN-I locus is broadly open in pDCs and constitutively closed in epithelial cells, while the IFN-III locus displays the reciprocal pattern. Motif enrichment analysis of accessible regions at the IFN-I locus in pDCs revealed unexpected and significant enrichment of ETS family binding motifs alongside IRF motifs, which determines the cell-type-specific locus accessibility. The ETS factor PU.1 and IRF8 bind IFN-I promoters, at composite ETS-IRF elements positioned at the Positive Regulatory Domain IV (PRDIV) site of IFNB1 promoter and adjacent to the TATA-proximal IRF motif of IFNA promoters. IFNL gene promoters lack ETS recognition sequences. PU.1-IRF8 composite factor binding extends across intergenic regions of the IFN-I locus, where candidate enhancer elements marked by H3K4me1, H3K27ac, and RNA Pol II occupancy were identified. We propose that this network of ETS-IRF composite-element-anchored enhancers maintains the IFN-I locus in a constitutively poised state in pDCs, licensing the rapid and robust IFN-I response that defines pDCs. In epithelial cells, the absence of PU.1 and IRF8 renders the IFN-I locus epigenetically silent, while the IFN-III locus is constitutively open. Despite this, the delayed IFN-III gene expression in epithelial cells is due to intrinsically weaker promoter activity relative to IFN-I. These findings reveal that the divergent IFN induction of pDCs and epithelial cells is determined by the chromatin architecture prior to infection. Overall, these observations show that lineage-specific ETS-IRF regulatory factors and promoter strength determine the cell-type-specific IFN activation.

immunology↗

Host genetic regulation of fermentation-related cecal microbial taxa is associated with loin muscle deposition in meat rabbits

Loin muscle weight is an important indicator of carcass yield in meat rabbit production, but the host genetic and intestinal microbial factors associated with its variation remain poorly understood. Because the cecum is the primary site of hindgut fermentation in rabbits, we integrated whole-genome resequencing, cecal transcriptome profiling, and cecal and rectal 16S rRNA sequencing data from 321 Kangda meat rabbits, with rectal microbiome data used as a downstream comparative reference. Compared with the rectum, the cecum contained a richer microbial community, with more ASVs and genera and significantly higher microbial diversity, whereas predicted metabolic functions were largely conserved between the two segments. Loin muscle weight showed moderate SNP-based heritability (h{superscript 2} = 0.39), and the cecal microbiome explained a smaller but detectable proportion of phenotypic variation (m{superscript 2} = 0.13). Multi-strategy microbial screening identified 19 candidate cecal genera associated with loin muscle weight, with Methanosphaera showing the strongest negative association. Host GWAS prioritized candidate loci near MEX3C and TCF4 on chromosome 10, and integration of cecal cis-eQTL and GWAS summary statistics further prioritized GJB3 as a candidate gene associated with loin muscle weight. Consistent with the cecum-centered model, host genetic relatedness was weakly but significantly correlated with cecal microbial similarity, whereas no such global association was observed for the rectal microbiome. Microbial GWAS and SMR analyses further prioritized a cecal MRAP2-Methanobrevibacter association as the main host-regulated microbial signal, while rectal analyses identified distinct segment-specific signals, including SULF1-Roseburia. These findings suggest that host genetic variation may be linked to loin muscle deposition partly through cecal gene expression and fermentation-related cecal microbial taxa, with the rectal microbiome providing comparative evidence for hindgut segment specificity. This study provides candidate host and microbial targets for future functional validation and microbiome-informed nutritional strategies to improve carcass traits in meat rabbits.

genetics↗

Spatiotemporal unfolding of prefrontal neural response divergence in adolescent depression during naturalistic experience

Depression alters how emotional experience is interpreted and regulated, yet how depression-related neural divergence unfolds during ongoing experience remains poorly understood, leaving unresolved whether such divergence reflects stable trait-like abnormalities or state-dependent responses that emerge only at particular moments. This question is especially consequential in adolescence, when depression often emerges amid heightened social sensitivity and continuing maturation of prefrontal regulatory systems. Here, we used naturalistic film watching fMRI data of 36 adolescents with depression and 36 matched controls to map where, how, and when neural responses diverge between diagnostic groups. Neural polarization analysis localized group-level divergence to two prefrontal hubs, the dmPFC-rACC and left dlPFC, where individual similarity to the depression-group response pattern was associated with depressive symptom severity across the cohort. These local divergence sites were not spatially isolated. Seed-based inter-subject functional connectivity showed that they were embedded within distributed stimulus-locked coupling patterns spanning prefrontal control, salience, and subcortical reward circuits. Time-resolved phase synchrony further revealed that this divergence was not continuous, but arose at specific narrative moments, with the dmPFC-rACC diverging during socio-emotional events and the left dlPFC during cognitively demanding ones. Together, these findings move beyond static localization to reveal depression-related neural divergence as a spatially organized, network-embedded, and temporally gated response pattern shaped by the unfolding content of naturalistic experience.

neuroscience↗

Salivary microRNA Profiling of Long COVID Subjects Reveals Host-Encoded Regulators of Inflammation and Viral Persistence

Periodontal disease and COVID-19 are linked by convergent immunoinflammatory pathways, yet the molecular basis of their interaction remains poorly defined. Here, we present a comprehensive salivary microRNA profile from individuals with prior SARS-CoV-2 infection, sampled approximately 3-6 months after diagnosis and meeting criteria for long COVID, providing new insight into the post-viral oral microenvironment. Salivary miRNA sequencing revealed widespread repression in patients with PD, consistent with persistent immune dysregulation. Relative to COVID-19-negative/PD-negative controls, thirty-two miRNAs were differentially expressed in COVID-19-positive/PD-positive individuals, all significantly downregulated. A similar signature was observed in a post-vaccination cohort for the selected dysregulated miRNAs. Integrative pathway analyses identified these miRNAs as regulators of core inflammatory circuits, including Ras, MAPK, and NF{kappa}B signaling, converging on IL-1{beta}- and TNF-centered networks relevant to both PD and COVID-19. Mechanistically, restoration of three downregulated miRNAs, miR- miR-30e-3p 106-3p-3p, and miR-652-3p attenuated NF{kappa}B activation and cytokine release in TLR-stimulated human oral keratinocytes, while their functional suppression using inhibitors potentiates inflammation. These miRNAs were also predicted to target SARS-CoV-2 spike and nucleocapsid transcripts, an interaction validated by dual-luciferase reporter assays. Their overexpression further reduced spike and nucleocapsid expression in Beta- and Omicron-infected epithelial cells, as measured by flow cytometry and RT-qPCR confirming host miRNAs as potent endogenous SARS-CoV-2 restriction factor. Together, these findings identify salivary host miRNAs as mechanistic regulators of oral inflammatory tone and viral persistence, establishing a molecular link between periodontal inflammation and post-COVID oral pathology.

immunology↗

Metabolic Intervention with Dimethyl Malonate Impairs Phagocytic Clearance but Fails to Protect Neurons

Secondary degeneration following optic nerve crush (ONC) is driven in part by mitochondrial dysfunction and microglial activation. Inspired by hibernation, where reduced succinate oxidation limits reactive oxygen species (ROS) production, we tested whether pharmacological inhibition of this pathway confers neuroprotection. Using in vivo ONC models and in vitro microglial assays, we evaluated the effects of dimethyl malonate (DMM), an inhibitor of succinate dehydrogenase, and a cell-permeable succinate analog (succinate-NV). Succinate-NV increased pro-inflammatory cytokine expression (IL-1{beta}) and reduced anti-inflammatory IL-10, whereas non-permeable succinate had no effect, indicating that intracellular succinate can drive microglial activation. In hibernating animals, succinate-NV disrupted neuroprotection and reduced retinal ganglion cell (RGC) survival following optic nerve injury. Although DMM partially reduced select inflammatory cytokines, it failed to normalize IL-1{beta} or IL-10 and suppressed microglial phagocytosis while exhibiting cytotoxic effects. In vivo, DMM-treated animals showed reduced IBA1{square} microglia but increased CD68{square} activation and accumulation of DAPI{square} cells at 7 days post-injury at the crush site. RGC somas persisted but were Caspase3+ consistent with impaired clearance. Astrocyte reactivity increased at lesion borders, while reduced and fragmented GFAP at the lesion site indicated localized astrocyte loss. Collectively, these findings demonstrate that inhibition of succinate oxidation alone is insufficient for neuroprotection and underscore the need for coordinated metabolic and immune regulation that cannot be achieved through single-pathway pharmacological intervention.

cell biology↗

BRCA1 promotes homologous recombination through separable DNA and RAD51 binding activities within its disordered region.

The breast and ovarian tumor suppressor BRCA1 heterodimerizes with BARD1 to promote DNA double-strand break repair by homologous recombination (HR) and to protect stressed DNA replication forks against nuclease attack. The large, intrinsically disordered central region of BRCA1 harbors binding sites for DNA and multiple repair factors, but its lack of stable structure has hindered mechanistic dissection of these activities. Using biochemical mapping and NMR spectroscopy, we delineate the DNA binding and RAD51 interaction interfaces within this region and construct separation-of-function mutants that selectively ablate each activity. Both DNA binding and RAD51 interaction are required for BRCA1-BARD1 to promote RAD51-mediated DNA strand invasion, and DNA binding also contributes to BLM-DNA2 end resection. These findings provide mechanistic insights into how individual ligand binding activities within BRCA1 contribute to genome maintenance.

biochemistry↗

The Regional Vulnerability Index (RVI) as a Neuroimaging-Based Biomarker for Autism: Associations with Likelihood, Cognition, and Longitudinal Social Outcomes

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with symptoms spanning cognitive, social and behavioral domains and leading to lifelong challenges. Autism is heritable but specific genetic and environmental factors that shape its early neurodevelopmental trajectory remain unknown. Despite the clinical variability, neuroimaging findings from Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA)-ASD consortium identified stable and replicable patterns of cortical and subcortical differences that were consistent with those reported by an independent consortium, the Cognitive Genetics Collaborative Research Organization (COCORO) in Japan. Here we developed and evaluated a regional vulnerability index (RVI), a similarity metric that quantifies how closely a persons brain resembles the specific pattern of an individual with autism. RVI-ASD is based on combining the regional effect sizes for regional brain measurements published by the ENIGMA-ASD group with microstructural white matter integrity differences reported by COCORO. RVI-ASD showed significantly higher effect size for case-control differences relative to any individual brain measure (d=0.30 vs. d=0.01-0.21) in individuals with autism, particularly in the adolescent-to-adult sample (N=2,577; Mean age = 16.1; SD=5.0). We next calculated RVI-ASD in the baseline and follow-up (ages 10 and 12) data from normally developing participants of the ABCD study (N=4,201). We tested the longitudinal stability, heritability, genotype-by-age interaction and sensitivity of RVI-ASD to known factors and cognitive measurements. RVI-ASD were stable on the 2-year follow up (ICC=0.76-0.92); showed significant heritability (h{superscript 2}=0.55-0.83, p<10-16) but was not affected by gene-by-age interaction. RVI-ASD showed significant positive correlation with paternal age, while correlation with maternal age was non-significant. Baseline and follow-up RVI-ASD were negatively correlated with cognitive measures including total, fluid and crystallized intelligence (r=-0.09 to -0.11, p<10-6). RVI-ASD scores tracked with core autism phenotypes including poor eye contact and rigid routines (p < .01). In a sub-sample of children with symptoms of autism (N=20), we found that earlier age of symptom onset was strongly correlated with higher White Matter RVI (r = -0.61), linking early behavioral emergence to the neuroanatomical signature. Longitudinal changes in subcortical RVI-ASD are significantly correlated with change in social functioning. The RVI-ASD is a neuroimaging-based biomarker linked to stable and reproducible brain patterns in autism. RVI-ASD allows researchers to study associations with factors associated with the likelihood for autism and cognition across large and inclusive non-clinical samples, thus moving beyond simple case-control models to understand the biological pathways of autism.

neuroscience↗

Integrated optimization of experimental and computational workflows improves genome recovery in long-read gut metagenomics

Short-read metagenomic sequencing has been widely applied in microbial research due to its high quality and decreasing cost. However, short reads are inherently fragmented, which limits assembly contiguity and the recovery of complete microbial genomes. In contrast, long-read sequencing, with significantly longer read lengths, helps overcome these limitations. Achieving complete and accurate genome recovery is the core goal of metagenomics. To address this challenge, we systematically evaluated and optimized the long-read metagenomic workflow, from sample processing to computational assembly, using the CycloneSEQ platform.

bioinformatics↗

MeCP2 is Necessary in Cerebellar Purkinje Cells for Precise Network Dynamics During Associative Motor Learning

Loss-of-function variants of MECP2 cause Rett syndrome; however, their impact on cerebellar computations for learning remains poorly understood. Here, we show that Mecp2 deletion specifically in Purkinje cells does not broadly disrupt cerebellar-dependent behaviors but selectively compromises those that require precise timing, coordination, and associative updating in the cerebellar cortex. Mecp2 loss altered the emergence of learning-related Purkinje cell activity in vivo and disrupted their intrinsic and synaptic properties that support adaptive cerebellar output. These findings identify MeCP2 as a critical player in Purkinje cell function to regulate cerebellar learning signals and suggest that Rett syndrome-related motor dysfunction reflects impaired adaptive computation rather than a generalized loss of motor capacity.

neuroscience↗

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

Wheat MYB transcription factor TaMYB83-7B regulates seed dormancy by influencing the balance between abscisic acid and gibberellin

In wheat, weak seed dormancy (SD) is related to an increased tendency for pre-harvest sprouting (PHS), which reduces yield and quality. However, the molecular mechanism underlying SD remains elusive. Here, we identified a wheat R2R3-MYB transcription factor (TaMYB83-7B) related to SD. Expression analysis showed that TaMYB83-7B was highly expressed in wheat seeds, and was more highly expressed in strong-dormancy varieties than in weak-dormancy varieties. Sequence and association analysis indicated that T/C mutations at -907 bp and -1133 bp in the TaMYB83-7B promoter were significantly associated with wheat SD, with C at both sites related to strong dormancy. Dual-luciferase reporter assays demonstrated that the transcriptional activity of the TaMYB83-7B promoter was significantly higher in strong-dormancy varieties than in weak-dormancy varieties. Further analyses indicated that TaMYB83-7B functions as a transcriptional inhibitor. Germination experiments revealed that overexpression of TaMYB83-7B significantly enhanced SD, while its loss-of-function reduced SD. Finally, TaMYB83-7B was found to regulate SD by influencing the balance between abscisic acid (ABA) and gibberellin (GA) in wheat seeds. Overall, the results of this study enhance our understanding of the complex regulatory mechanism underlying SD, and provide gene targets and molecular markers for the genetic improvement of PHS resistance in wheat.

molecular biology↗