Biology subjects

Xue, S.

Publications and source records attributed to Xue, S..

At least 19 recordsLinked to original sources

bioRxiv2026

IFNγ-CXCL9-CXCR3 axis links T cell recruitment to skeletal muscle remodelling in human physical frailty

Introduction: Physical frailty is increasingly prevalent in our ageing society, and results in higher morbidity and healthcare costs. Yet, targeted therapeutics are lacking because underlying mechanisms are poorly defined. Human cohort studies have linked inflammation with frailty, but do not define the mechanisms by which the ageing immune system affects skeletal muscle and physical function. Defining this immune-muscle interaction is therefore crucial for identifying therapeutics for human physical frailty. Methods: We first studied two independent human ageing cohorts (discovery n=22; validation n=33). Physical frailty was quantified with age-adjusted timed-up-and-go (TUG) residuals. Peripheral blood was analysed for plasma OLINK proteomics, high-dimensional spectral immunophenotyping and in a subset, single-cell RNA-sequencing of PBMCs with paired TCR profiling. We then examined an independent human skeletal-muscle cohort (n=340) by bulk RNA-sequencing to derive our proposed immune-muscle axis. Finally, we interrogated individual steps of this axis in primary human in vitro models using IFN{gamma}-conditioned myotube-fibroblast co-cultures, PBMC transwell migration assays with CXCL9 neutralisation (anti-CXCL9) and receptor CXCR3 antagonism (AMG487). Macrophage co-cultured with CD8 were sequentially co-cultured with myotube/fibroblast co-culture, supernatant was then analysed for fibrosis mediators. We used fixed-effect meta-analysis, multivariable models and sequential mediation for analyses. Results: Physical frailty, by single-cell analyses, was associated with a compartmentalised immune-remodelling state involving inflammatory, tissue-remodelling and trafficking programmes in myeloid and T-cells. This finding was validated with plasma proteomics of the same human cohort, where physical frailty was significantly positively associated with an interferon-gamma (IFN{gamma})/CXCR3 (IL-18R1, IFN{gamma}, CXCL9) module, within which plasma CXCL9 was the strongest correlate. CD8-TEMRA and {gamma}{delta} T-cells were most responsive to CXCL9 in physical frailty. This expanded CD8-TEMRA compartment was polyclonal, consistent with bystander IFN{gamma} production rather than a shared antigen-specific response. In human muscle, CXCL9 was significantly positively associated with T-cell module, and through this, fibrosis. Conversely, fibrosis was associated with macrophages. Sequential mediation was consistent with a CXCL9-T-cell-macrophage-fibrosis pathway. Finally, in in-vitro human primary cell experiments, IFN{gamma}-conditioned myotube-fibroblast cultures produced CXCL9 and attracted CD8-TEMRA subsets. Anti-CXCL9 and CXCR3 antagonism significantly reduced this migration, indicating that recruitment of CD8-TEMRA cells was dependent on the CXCL9-CXCR3 axis. Incubating with activated CD8 cells shifted macrophages towards mixed CD163+CD86+ and pro-inflammatory CD163-CD86+ phenotypes. These CD8-co-cultured macrophages in myotube/fibroblast co-culture were associated with increased fibrosis markers transforming growth factor beta-1 and plasminogen activator inhibitor-1. Conclusion: We identified a CD8-TEMRA T-cell migration to human muscle dependent on IFN{gamma}-CXCL9-CXCR3 axis that is associated with human TUG-defined physical frailty which presents potential therapeutic avenues.

immunology↗

bioRxiv2026

Pathogenic T-bet+ memory B cells worsen multiple sclerosis through myeloid cell activation

Depletion of B cells in multiple sclerosis (MS) is beneficial yet there is no defined pathogenic B cell subset in MS. Here, we demonstrate that T-bet+ memory B cells are rare in control human brain specimens but are found in MS lesions. Transfer of murine T-bet+ memory B cells into mice with ongoing experimental autoimmune encephalomyelitis (EAE), a model of MS, worsened their disability and demyelination. Microglia/macrophage density increased in central nervous system parenchyma even though B cells mostly remained in barriers. In culture, secreted factors from T-bet+ memory B cells promoted macrophage migration. IFN-{gamma} produced by T-bet+ memory B cells activated microglia to secrete chemokines that further enabled macrophage migration. Consistent with their age-associated elevation, conditional deletion of T-bet in B cells lowered EAE severity in aged but not young mice. We define T-bet+ memory B cells as pathogenic in EAE and MS through their IFN-{gamma}-facilitated interactions with microglia/macrophages.

immunology↗

bioRxiv2026

GWAS and multi-omics uncover the SLC6A3 locus for canine stranger-directed social anxiety and implicate NRIP3 in dopaminergic network regulation

The social anxiety disorder (SAD) is one of the most common mental health disorders, often developing in adolescence. It can severely impair educational achievement, career progression, and social functioning. Certain individuals within the Chinese Kunming dog (CKD) population display spontaneous, SAD-like behaviors towards strangers, offering a valuable model for genetic investigation. Using whole-genome sequencing data, we conducted a genome-wide association study on this SAD-like behavior in 100 CKDs, identifying several genes previously linked to human psychiatric disorders. Notably, SLC6A3 reached genome-wide significance, whereas CADPS2 exceeded only the suggestive threshold and is therefore considered a network-supported candidate locus. By integrating weighted gene co-expression network analysis with public RNA-seq data from the VTA of 38 mice (after quality control), we further showed that Slc6a3 and Cadps2 are part of a co-expression network module associated with the dopamine system. These findings suggest that this specific module may play a functional role in the stranger-directed anxiety-related behaviours in CKDs. Furthermore, we identified Nrip3 as a key candidate transcriptional coregulator in this specific module. Subsequent virus-mediated overexpression and behavioural experiments showed that Nrip3 regulates gene expression within this network and induces a spectrum of behavioural alterations in mice, including social avoidance, anhedonia, and increased locomotor activity. Collectively, this study highlights the involvement of dopamine system genes in canine social anxiety and suggests Nrip3 as an upstream regulator of Slc6a3 associated with anxiety. The identification of conserved anxiety-related signatures between humans and dogs further supports the dog as a valuable translational model for psychiatric research.

genetics↗

bioRxiv2026

Featural representation and internal noise around the visual field

In human adults, visual performance varies systematically around the visual field. It is higher along the horizontal than the vertical meridian (horizontal-vertical anisotropy, HVA) and higher at the lower than the upper vertical meridian (vertical-meridian asymmetry, VMA). Although these robust performance fields have been linked to non-uniform neural resources, the system-level computations that translate neural constraints into perceptual asymmetries remain largely unexplored. Here, we used reverse correlation to characterize feature weighting and internal noise during peripheral orientation detection. Reverse correlation revealed non-ideal feature weighting in the joint orientation-spatial-frequency space, which was incorporated into a noisy-observer model jointly constrained by trial-wise detection responses and double-pass consistency. Across observers, the magnitude of the HVA in contrast sensitivity was correlated with individual asymmetries in orientation sensitivity and additive internal noise. In contrast, we found limited evidence that any tested representational or noise components reliably accounted for individual differences in VMA magnitude. Spatial-frequency tuning exhibited substantial individual variability, often peaking below the signals spatial frequency, but did not vary systematically across locations or explain performance asymmetries. These findings suggest that the HVA reflects systematic variation in the feature weighting of task-relevant orientations and internal noise, while constraining which computational components provide robust explanations of polar-angle asymmetries. Moreover, our framework provides a principled approach that links this prevalent perceptual asymmetry to the system-level computations that transform sensory information into perceptual decisions. Author summaryHuman vision is surprisingly uneven across our field of view. At the same distance from where we look, vision is better along the horizontal axis than the vertical axis, and better in the lower than the upper half of the vertical axis. These differences are well established, but little is known about their computational basis. To investigate, we combined visual detection tasks with computational modeling. By analyzing how observers detected faint patterns within noisy images, we measured how they process distinct features--like patterns with different orientations and spatial frequencies at different visual field locations. We then fit a mathematical model to separate distinct sources of internal noise. We found that differences in how the brain processes line orientations predicted the magnitude of the horizontal-vertical asymmetry across individuals, whereas distinct components of internal noise predicted these asymmetries in different ways. Our results show that visual field asymmetries are not driven by a single visual bottleneck, but rather by location-specific combinations of how the brain encodes relevant feature information and neural noise. This study helps explain why human vision is fundamentally uneven across our field of view.

neuroscience↗

bioRxiv2026

A sensitive bioassay for detecting Plasmodiophora brassicae in canola field soils

We describe a biodegradable-cup bioassay for detecting viable Plasmodiophora brassicae in soil samples. Soil samples either artificially inoculated with P. brassicae resting spores or collected from canola fields were aliquoted into biodegradable cups containing 20 g of soil per cup. Two cups representing the same soil sample or inoculum concentration were placed in each pot filled with Sunshine Mix. Six seeds of the canola cultivar Westar were sown into each cup and thinned to four seedlings per cup ten days after planting. After four weeks, roots were examined for the presence of clubroot galls. Across three independent inoculated-soil experiments, galls were observed in samples containing as few as 1 resting spore g-1 soil. In contrast, under a qPCR assay evaluated in parallel, consistent amplification across three technical replicates was obtained only at 100 resting spores g-1 soil or greater. In field samples, the bioassay produced galls from 11 qPCR-positive samples and seven of ten qPCR-negative samples. Although the bioassay is not intended for rapid diagnosis or direct quantification, it provides a practical tool for annual clubroot surveys and for studies requiring recovery, propagation, or characterization of viable P. brassicae from soil samples collected across diverse geographic regions.

microbiology↗

bioRxiv2026

Unconventional biocatalytic strategies orchestrate synthesis of the nucleoside analog sinefungin

Sinefungin is a potent nucleoside antimetabolite of S-adenosylmethionine (SAM), yet its biosynthesis has remained unclear for decades. Here we detail the identification and characterization of the complete sinefungin biosynthetic gene cluster (BGC) from Streptomyces incarnatus NRRL 8089. In vitro and in vivo analyses demonstrate that the defining carbon-carbon (C-C) bond is formed not by the long-hypothesized PLP-dependent process, but by a vitamin B12-dependent radical SAM enzyme. Using isotope-labeled cofactors and substrates, we provide evidence that the adenosyl group of sinefungin atypically originates from adenosylcobalamin via a homolytic SH2 substitution, establishing a rare instance where adenosylcobalamin is enzymatically consumed during the reaction. Furthermore, the pathway utilizes a cryptic phosphorylation-dephosphorylation strategy to control intermediate processing and substrate recognition. We also characterize two peptide aminoacyl-tRNA ligases (PEARLs) that append alanines onto the nucleoside scaffold using tRNA-activated amino acids. The PEARLs act directly on small molecules rather than macromolecular substrates, with one PEARL capable of iterative elongation. Finally, we leverage these enzymes in a reduced multi-enzyme cascade to biosynthesize sinefungin. Together, these findings redefine radical-mediated C-C bond formation and pearlin enzyme versatility, unlocking biocatalytic possibilities to produce amino acid-nucleoside conjugates. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/726688v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@10e48deorg.highwire.dtl.DTLVardef@d220ceorg.highwire.dtl.DTLVardef@167e60borg.highwire.dtl.DTLVardef@2fddec_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Protenix-v2: Broadening the Reach of Structure Prediction and Biomolecular Design

Advances in biomolecular modeling have broadened the range of problems addressable by structure prediction and design models. Here, we present results from Protenix-v2, a system spanning high-accuracy structure prediction and biomolecular design. On the structure prediction side, Protenix-v2 achieves antibody-antigen success rates with up to 13-point gains over Protenix-v1, while 5-seed performance surpasses previous 1000-seed results. On the design side, Protenix-v2 demonstrates a 100% target-level success rate in novelty-controlled VHH-Fc campaigns, reaching hit rates up to 48%. Crucially, the model enables hit discovery on difficult GPCR targets with hit rates of 16%-88% (VHH-Fc) and up to 50% (mAb) under 16-30 testing budgets per target. Resulting hits show high developability and diversity. Beyond antibody tasks, we report improved ligand-related plausibility and successful cross-variant SARS-CoV-2 spike RBD mini-binder design. These results establish Protenix-v2 as a robust and powerful model for accelerated drug discovery.

molecular biology↗

bioRxiv2026

Vagus Nerve Stimulation Ameliorates Epilepsy via a Gut Microbiota-Butyrate-Vagus Nerve-Brain Axis

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical-translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve-dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid-producing bacteria, including Akkermansia muciniphila, Prevotella, Alistipes, and Odoribacter. Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota-butyrate-vagal pathway essential for the therapeutic effects of VNS, highlighting the gut-brain axis as a target for epilepsy treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/707138v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@8243e6org.highwire.dtl.DTLVardef@37f0e6org.highwire.dtl.DTLVardef@a8b321org.highwire.dtl.DTLVardef@1887342_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIVagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. C_LIO_LIVNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila, in both humans and mice. C_LIO_LITransplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. C_LIO_LIAkkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway. C_LI

neuroscience↗

bioRxiv2026

On the sensitivity of qPCR diagnostics for the canola clubroot pathogen Plasmodiophora brassicae

Clubroot, caused by Plasmodiophora brassicae, is an important disease of canola and other Brassica crops. Polymerase chain reaction (PCR), particularly probe-based quantitative PCR (qPCR), is widely used for the detection of P. brassicae in soil samples. To improve consistency in clubroot detection while maintaining efficiency, diagnostic laboratories would benefit from adopting a single, highly efficient qPCR system for routine testing. In this study, we analyzed the primer and probe sequences of all published PCR and qPCR systems for P. brassicae detection. Based on these analyses, three independently developed probe-based qPCR systems were selected and their performance was evaluated using synthesized target DNA (gBlock). One probe-based qPCR system exhibiting superior sensitivity on gBlock was subsequently evaluated on P. brassicae genomic DNA. This system consistently detected DNA equivalent to four resting spores per reaction, corresponding to a soil sample containing 1,000 spores per g soil when the DNA extraction protocol was considered as a component of the qPCR system. The sensitivity of the system was further validated using DNA extracted from soil samples collected from multiple locations across Alberta, where P. brassicae was detected at levels below those associated with visible clubroot symptoms. Based on these results, we recommend this qPCR system for routine clubroot diagnostics in laboratories across Canada.

microbiology↗

bioRxiv2025

Microstructural functional coupling as a multimodal biomarker of emotional state transitions in bipolar disorder

Bipolar disorder (BD) is characterized by dynamic transitions between depressive and manic states, yet the neural mechanisms underlying these state shifts remain unclear. Here, we developed an integrative framework to quantify the microstructural-functional coupling (MFC) of the brain, which captures the distributional similarity between voxel-wise diffusion and functional features within each cortical region. Using multimodal MRI data from 72 BD patients and 65 matched healthy controls, we observed a global increase of MFC of BD, which indicates a de-similarity of brain microstructure and function. Partial least squares correlation (PLSC) analysis revealed that the principal latent component linking MFC to behavioral scores explained 67.2% of the variance, with the strongest contributions from the control and somatosensory networks. Mediation analysis demonstrated that regional MFC influenced anxiety indirectly through depressive symptoms, supporting a sequential affective transition from depression to anxiety. Moreover, macroscale gradient analysis showed that the principal MFC gradient was significantly correlated with neurotransmitter receptor distributions, including 4{beta}2, 5-HT1B, and H3. Together, these findings highlight MFC as a multimodal biomarker sensitive to emotional state transitions in BD and suggest its potential as a bridge between microstructural alterations, functional dynamics, and neurotransmitter systems.

neuroscience↗

bioRxiv2025

System-Level Computations Underlie Visual Field Heterogeneity

Human visual perception for basic dimensions varies with eccentricity and polar angle, influencing daily activities such as reading, searching and scene perception. We investigated whether and how system-level computations that transform visual input into perception underlie these heterogeneities. Using the equivalent noise method and perceptual template model, we estimated gain, internal noise, and nonlinearity for orientation discrimination across eccentricity (fovea, parafovea and perifovea) and around polar angle. Participants discriminated the orientation of Gabors embedded in dynamic white noise and showed the expected variations across eccentricity and around polar angle. Importantly, visual performance declined with eccentricity due to decreased gain and nonlinearity and increased internal noise. Observers with stronger eccentricity effects showed greater gain decrease. Only gain varied with polar angle--higher along the horizontal than vertical meridian, and lower than upper vertical meridian--paralleling performance asymmetries. This dissociation aligns with known variations in neuronal count and tuning, suggesting that neural correlations and neural noise contribute to these system-level computations. By revealing distinct system-level computations underlying the eccentricity effect and polar angle asymmetries, our findings link perceptual heterogeneity across the visual field and neural architecture and provide insights into how the human brain encodes information under neural constraints. Significance StatementHuman visual performance varies across eccentricity-distance from gaze-and around polar angle -circular dimension. Retinal factors and cortical surface area account for eccentricity, but only partially for polar angle variations. Here, we show that system-level computations--how signal are amplified and how noisy the system is--distinctly underlie these perceptual variations. Decline across eccentricity stems from both reduced gain and nonlinearity and elevated internal noise, whereas variation around polar angle arises solely from gain difference. This dissociation implies fundamental differences in information processing along two axes of the visual field. Our results provide a computational link between behavior and its neural bases and highlight the importance of considering both eccentricity and polar angle in modeling and understanding human perception.

neuroscience↗

bioRxiv2025

SMCHD1 compacts DNA directly in an ATP-regulated manner

Structural maintenance of chromosome (SMC) complexes play crucial roles in genome organization by DNA loop extrusion. SMCHD1 is a non-canonical SMC protein important for X-inactivation, imprinting and the silencing of specific autosomal genes. While it is known to be a repressor, little is known about its structure or mechanism of action. Here, we show that the SMCHD1 homodimer is flexible and dynamic in solution. This flexibility is conferred by its yet uncharacterized linker domain, which can alter its length by dynamically switching between compact and extended conformations. Interestingly, we observed that SMCHD1 can directly bridge and compact DNA, independently of other proteins, forming large protein-DNA clusters. SMCHD1 contains a GHKL ATPase domain and SMC hinge domain, however each domain alone is insufficient for DNA compaction. DNA compaction rate decreases when the linker domain is removed. The coiled-coil domain does not affect compaction rate but facilitates interaction with a partner protein LRIF1. Surprisingly, DNA compaction by SMCHD1 does not require ATP and paradoxically, compaction rate is reduced with the addition of ATP. Similarly, SMCHD1 forms clusters with reconstituted nucleosome arrays in the absence of ATP, and the addition of ATP results in a reduction in cluster sizes. Our data provides biophysical and mechanistic insights into the role of SMCHD1 in gene silencing and genome organization.

molecular biology↗

bioRxiv2024

Nematode-Trapping Fungus Arthrobotrys oligospora is Hungry for COQ7 to Alleviate Environmentally Triggered Iron Overload

Choosing the right and appropriate amount of substances in a changing environment is essential for the growth and survival of all species. We found that elevated oxygen levels significantly enhanced the iron-rich trapping devices of a nematode-trapping fungus (NTF), Arthrobotrys oligospora. Interestingly, genomic analysis revealed that all NTFs lacked coq7, a key gene involved in ubiquinol (UQ) biosynthesis and iron chelation. Notably, A. oligospora utilizes UQ instead of UQ for low-aerobic respiration. Transcriptional, metabolic, mutational, and phenotypic analyses revealed that A. oligospora produces a chemotaxonomic class of highly oxygenated arthrobotrins with characteristics similar to UQ skeleton, for high-aerobic respiration. Disruption of arthrobotrin biosynthesis in the {Delta}art mutant not only enhanced UQ biosynthesis, but also triggered trapping device formation and nematicidal activity under elevated oxygen conditions. The addition of UQ to both wild-type and {Delta}art mutants strongly inhibited trapping device development. Remarkably, the iron-rich trapping devices preferentially capture N2 nematodes harboring iron-chelating COQ7 with ferritin properties. Time-calibrated evolutionary analyses, combined with geological data, indicated that the NTF ancestor lost the coq7 gene after acquiring the arthrobotrin biosynthetic gene cluster during the "superoligotrophy" period, characterized by dramatic shifts in global oxygen levels and temperature changes. Our results demonstrate that oxygen is a critical factor in inducing iron overload, highlighting the origin and role of coq7 loss in the evolution of predatory behavior of NTFs. Our finding that NTFs capture nematodes for iron chelation therapy, rather than for food, explains a long standing debate about the limited carnivorous ability of trapping devices.

microbiology↗

bioRxiv2024

Inferring single-cell resolution spatial gene expression via fusing spot-based spatial transcriptomics, location and histology using GCN

Spatial transcriptomics technology allows for the detection of cellular transcriptome information while preserving the spatial location of cells. This capability enables researchers to better understand the cellular heterogeneity, spatial organization and functional interactions in complex biological systems. However, current technological methods are limited by low resolution, which reduces the accuracy of gene expression levels. Here, we propose scstGCN, a multimodal information fusion method based on Vision Transformer (ViT) and Graph Convolutional Network (GCN) that integrates histological images, spot-based spatial transcriptomics data and spatial location information to infer super-resolution gene expression profiles at single-cell level. We evaluated the accuracy of the super-resolution gene expression profiles generated on diverse tissue ST datasets with disease and healthy by scstGCN along with their performance in identifying spatial patterns, conducting functional enrichment analysis, and tissue annotation. The results show that scstGCN can predict super-resolution gene expression accurately, aid researchers in discovering biologically meaningful differentially expressed genes and pathways. Additionally, scstGCN can segment and annotate tissues at a finer granularity, with results demonstrating strong consistency with coarse manual annotations. Key PointsO_LIscstGCN combines multi-modal information including histology image, spot-based spatial transcriptomics (ST) data, and physical spatial location through deep learning methods to achieve single-cell resolution of spot-based ST data without requiring single-cell references. C_LIO_LIscstGCN employs GCN to capture complex relationships between neighboring cells, facilitating the integration of multimodal feature information based on single-cell level, and then accurately infers single-cell resolution spatial gene expression. C_LIO_LIscstGCN can infer single-cell resolution gene expression across the entire tissue region. Through transfer learning, gene expression in three-dimensional tissues can be characterized efficiently. Furthermore, it demonstrates outstanding performance in spatial patterns enhancement, functional enrichment analysis, and annotate tissues at the high-resolution. C_LI

bioinformatics↗

bioRxiv2024

Suppressing PDGFRβ Signaling Enhances Myocyte Fusion to Promote Skeletal Muscle Regeneration

Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFR{beta}) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of Pdgfr{beta} enhances muscle regeneration and increases myofiber size, whereas PDGFR{beta} activation impairs muscle repair. Inhibition of PDGFR{beta} activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFR{beta} activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFR{beta} signaling cooperates with TGF{beta} signaling to direct myocyte size and fusion. Mechanistically, PDGFR{beta} signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFR{beta} signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.

developmental biology↗

bioRxiv2024

Genome-Wide Mapping of RNA-Protein Associations via Sequencing

RNA-protein interactions are crucial for regulating gene expression and cellular functions, with their dysregulation potentially impacting disease progression. Systematically mapping these interactions is resource-intensive due to the vast number of potential RNA and protein interactions. Here, we introduce PRIM-seq (Protein-RNA Interaction Mapping by sequencing), a method for the concurrent de novo identification of RNA-binding proteins (RBPs) and the elucidation of their associated RNAs. PRIM-seq works by converting each RNA-protein pair into a unique chimeric DNA sequence, which is then decoded through DNA sequencing. Applied to two human cell types, PRIM-seq generated a comprehensive human RNA-protein association network (HuRPA), consisting of more than 350,000 RNA-proteins pairs involving approximately 7,000 RNAs and 11,000 proteins. The data revealed an enrichment of previously reported RBPs and RNA-protein interactions within HuRPA. We also identified LINC00339 as a protein-associating non-coding RNA and PHGDH as an RNA-associating protein. Notably, PHGDH interacts with BECN1 and ATF4 mRNAs, suppressing their protein expression and consequently inhibiting autophagy, apoptosis, and neurite outgrowth while promoting cell proliferation. PRIM-seq offers a powerful tool for discovering RBPs and RNA-protein associations, contributing to more comprehensive functional genome annotations.

molecular biology↗

bioRxiv2024

Unveiling Frequency-Specific Microstate Correlates of Anxiety and Depression Symptoms

Electroencephalography (EEG) microstates are canonical voltage topographies that reflect the temporal dynamics of resting-state brain networks on a millisecond time scale. Changes in microstate parameters have been described in patients with psychiatric disorders, indicating their potential as clinical biomarkers with broadband EEG signals (e.g., 1-30 Hz). Considering the distinct information provided by specific frequency bands, we hypothesized that microstates in decomposed frequency band could provide a more detailed depiction of the underlying psychological mechanism. In this study, with a large open access resting-state dataset (n = 203), we examined the properties of frequency-specific microstates and their relationship with emotional disorders. We conducted clustering on EEG topographies in decomposed frequency band (delta, theta, alpha and beta), and determined the number of clusters with a meta-criterion. Microstate parameters, including global explained variance (GEV), duration, coverage, occurrence and transition probability, were calculated for eyes-open and eyes-closed states, respectively. Their predictive power for the scores of depression and anxiety symptoms were identified by correlation and regression analysis. Distinct microstate patterns were observed across different frequency bands. Microstate parameters in the alpha band held the best predictive power for emotional symptoms. Microstates B (GEV, coverage) and parieto-central maximum microstate C (coverage, occurrence, transitions from B to C) in the alpha band exhibited significant correlations with depression and anxiety, respectively. Microstate parameters of the alpha band achieved predictive R-square of 0.100 for anxiety scores, which is much higher than those of broadband (R-square = -0.026, p < .01). These results suggested the value of frequency-specific microstates in predicting emotional symptoms.

neuroscience↗

bioRxiv2024

Cryo-EM Structure of the R388 plasmid conjugative pilus reveals a helical polymer characterised by an unusual pilin/phospholipid binary complex

Bacterial conjugation is a process by which DNA is transferred unidirectionally from a donor cell to a recipient cell. It is the main means by which antibiotics resistance genes spread among bacterial populations. It is crucially dependent upon the elaboration of an extracellular appendage, termed "pilus", by a large double-membrane spanning secretion system termed conjugative "type IV secretion system". Here we present the structure of the conjugative pilus encoded by the R388 plasmid. We demonstrate that, as opposed to all conjugative pili produced so far for cryo-EM structure determination, that encoded by the R388 plasmid is greatly stimulated by the presence of recipient cells. Comparison of its cryo-EM structure with existing conjugative pilus structures highlights a number of important differences between the R388 pilus structure and that of its homologues, the most prominent being the highly distinctive conformation of its bound lipid.

microbiology↗