Biology subjects

Wang, Q.

Publications and source records attributed to Wang, Q..

At least 325 records · Page 18Linked to original sources

bioRxiv2024

Neuropeptide Y co-opts neuronal ensembles for memory lability and stability

Memory engrams are formed by activity-dependent recruitment of distinct subsets of excitatory principal neurons (or neuronal ensembles) whereas inhibitory neurons pivot memory lability and stability1-5. However, the molecular logic for memory engrams to preferentially recruit specific type of interneurons over other subtypes remains enigmatic. Using activity-dependent single-cell transcriptomic profiling6-8 in mice with training of cued fear memory and extinction, we discovered that neuropeptide Y (NPY)-expressing (NPY+) GABAergic interneurons in the ventral hippocampal CA1 (vCA1) region exert fast GABAergic inhibition to facilitate the acquisition of memory, but bifurcate NPY-mediated slow peptidergic inhibition onto distinct sub-ensembles underlying the extinction of single memory trace. Genetically encoded calcium and NPY sensors revealed that both calcium dynamics of NPY+ neurons and their NPY release in vCA1 ramp up as extinction learning progresses while behavioral state switches from "fear-on" to "fear-off". Bidirectional manipulations of NPY+ neurons or NPY itself demonstrated NPY is both necessary and sufficient to control the rate and degree of memory extinction by acting on two physically non-overlapping sub-ensembles composed of NPY1R- and NPY2R-expressing neurons. CRISPR/Cas9-mediated knockout of NPY2R or NPY1R further unravels that NPY co-opts its actions on these two sub-ensembles to gate early fast and late slow stages of extinction. These findings exemplify the intricate spatiotemporal orchestration of slow peptidergic inhibitions from single subtype of GABAergic interneurons to fine-tune engram lability verse stability of memory.

neuroscience↗

bioRxiv2024

STECode: an automated virulence barcode generator to aid clinical and public health risk assessment of Shiga toxin-producing Escherichia coli

Shiga Toxin (Stx) producing Escherichia coli (STEC) is a subset of pathogenic E. coli that can produce two types of Stx, Stx1 and Stx2, which can be further subtyped into four and 15 subtypes respectively. Not all subtypes, however, are equal in virulence potential, and the risk of severe disease including haemolytic uraemic syndrome has been linked to certain Stx2 subtypes e.g. Stx2a, Stx2d, highlighting the importance to survey stx subtypes. Previously, we developed a STEC virulence barcode to capture pertinent information on virulence genes to infer pathogenic potential. However, the process required multiple manual curation steps to determine the barcode. Here we introduce STECode, a bioinformatic tool to automate the STEC virulence barcode generation from sequencing reads or genomic assemblies. The development, and validation of STECode is described using a set of publicly available completed STEC genomes, along with their corresponding short reads. STECode was applied to interrogate the virulence landscape and molecular epidemiology of human STEC isolated during the period of the international border closures related to COVID-19 in the state of New South Wales, Australia. Impact statementWhole genome sequencing has been used to great effect in the genomic surveillance of STEC for public health purposes via the tracking of outbreaks. With STECode, we present a method to generate a STEC virulence barcode which captures pertinent subtyping information, useful for genomic inference of pathogenic potential. A key blind spot generated in short-read sequencing is the inability to detect the presence of multiple, isogenic stx copies in STEC. STECode mitigates this by inferring and reporting on the possibility of this occurrence. We envisage that this tool will value-add current genomic surveillance workflows through the ability to infer pathogenic potential.

microbiology↗

bioRxiv2024

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

neuroscience↗

bioRxiv2024

Functional dissection of complex and molecular trait variants at single nucleotide resolution

Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.

genetics↗

bioRxiv2024

Dopaminergic inhibition of the inwardly rectifying potassium current in direct pathway medium spiny neurons in normal and parkinsonian striatum

Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that also profoundly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Here we show that in normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently strongly increasing D1-MSN spike firing that is behavior-promoting; this DA excitation of D1-MSNs is stronger when the DA depletion is more severe. The DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl2). In behaving parkinsonian mice, BaCl2 microinjection into the dorsal striatum stimulates movement but occludes the motor stimulation of D1R agonism. Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates D1R agonistic behavioral stimulation in normal and parkinsonian animals.

neuroscience↗

bioRxiv2024

The ANTsX Ecosystem for Mapping the Mouse Brain

Precision mapping techniques coupled with high resolution image acquisition of the mouse brain permit the study of the spatial organization of gene expression and their mutual interaction for a comprehensive view of salient structural/functional relationships. Such research is facilitated by standardized anatomical coordinate systems, such as the well-known Allen Common Coordinate Framework (AllenCCFv3), and the ability to spatially map to such standardized spaces. The Advanced Normalization Tools Ecosystem is a comprehensive open-source software toolkit for generalized quantitative imaging with applicability to multiple organ systems, modalities, and animal species. Herein, we illustrate the utility of ANTsX for generating precision spatial mappings of the mouse brain and potential subsequent quantitation. We describe ANTsX-based workflows for mapping domain-specific image data to AllenCCFv3 accounting for common artefacts and other confounds. Novel contributions include ANTsX functionality for velocity flow-based mapping spanning the spatiotemporal domain of a longitudinal trajectory which we apply to the Developmental Common Coordinate Framework. Additionally, we present an automated structural morphological pipeline for determining volumetric and cortical thickness measurements analogous to the well-utilized ANTsX pipeline for human neuroanatomical structural morphology which illustrates a general open-source framework for tailored brain parcellations.

neuroscience↗

bioRxiv2024

Potent neutralization by a receptor binding domain monoclonal antibody with broad specificity for SARS-CoV-2 JN.1 and other variants

SARS-CoV-2 continues to be a public health burden, driven in-part by its continued antigenic diversification and resulting emergence of new variants. While increasing herd immunity, current vaccines, and therapeutics have improved outcomes for some; prophylactic and treatment interventions that are not compromised by viral evolution of the Spike protein are still needed. Using a rationally designed SARS-CoV-2 Receptor Binding Domain (RBD) - ACE2 fusion protein and differential selection process with native Omicron RBD protein, we developed a recombinant human monoclonal antibody (hmAb) from a convalescent individual following SARS-CoV-2 Omicron infection. The resulting hmAb, 1301B7 potently neutralized a wide range of SARS-CoV-2 variants including the original Wuhan and more recent Omicron JN.1 strain, as well as SARS-CoV. Structure determination of the SARS-CoV-2 EG5.1 Spike/1301B7 Fab complex by cryo-electron microscopy at 3.1[A] resolution demonstrates 1301B7 contacts the ACE2 binding site of RBD exclusively through its VH1-69 heavy chain, making contacts using CDRs1-3, as well as framework region 3 (FR3). Broad specificity is achieved through 1301B7 binding to many conserved residues of Omicron variants including Y501 and H505. Consistent with its extensive binding epitope, 1301B7 is able to potently diminish viral burden in the upper and lower respiratory tract and protect mice from challenge with Omicron XBB1.5 and Omicron JN.1 viruses. These results suggest 1301B7 has broad potential to prevent or treat clinical SARS-CoV-2 infections and to guide development of RBD-based universal SARS-CoV-2 prophylactic vaccines and therapeutic approaches.

immunology↗

bioRxiv2024

Native proteomics by capillary zone electrophoresis-mass spectrometry

Native proteomics measures endogenous proteoforms and protein complexes under a near physiological condition using native mass spectrometry (nMS) coupled with liquid-phase separations. Native proteomics should provide the most accurate birds-eye view of proteome dynamics within cells, which is fundamental for understanding almost all biological processes. nMS has been widely employed to characterize well-purified protein complexes. However, there are only very few trials of utilizing nMS to measure proteoforms and protein complexes in a complex sample (i.e., a whole cell lysate). Here, we pioneer the native proteomics measurement of large proteoforms or protein complexes up to 400 kDa from a complex proteome via online coupling of native capillary zone electrophoresis (nCZE) to an ultra-high mass range (UHMR) Orbitrap mass spectrometer. The nCZE-MS technique enabled the measurement of a 115-kDa standard protein complex while consuming only about 0.1 ng of protein material. nCZE-MS analysis of an E.coli cell lysate detected 72 proteoforms or protein complexes in a mass range of 30-400 kDa in a single run while consuming only 50-ng protein material. The mass distribution of detected proteoforms or protein complexes agreed well with that from mass photometry measurement. This work represents a technical breakthrough in native proteomics for measuring complex proteomes.

systems biology↗

bioRxiv2024

Design of antigens to present a tumor-specific cryptic epitope

In many cancers, the epidermal growth factor receptor (EGFR) gene is amplified, mutated, or both. The monoclonal antibody mAb806 binds selectively to cancer cells that overexpress EGFR or express the truncated mutant EGFRvIII, but not to normal cells. This suggests that a promising avenue for developing cancer vaccines may be to design antigens that elicit mAb806-like antibodies. In this study, we designed antigens that present the mAb806-binding epitope in the same conformation as in overexpressed or truncated EGFR. We first used molecular dynamics simulations to identify conformations of EGFR in which the residues of the mAb806-binding epitope are accessible. We then designed antigens by substituting that epitope in place of a structurally similar loop in a different protein and generating mutants that could potentially stabilize the mAb806-binding conformation in this new context. Two mutants in which the epitope remained stable in subsequent simulations were chosen for evaluation in vitro. Binding kinetics experiments with these designed antigens provided strong evidence that the epitope was successfully stabilized in the mAb806-binding conformation, suggesting that they could potentially form the basis of vaccines that elicit cancer-selective antibodies.

biophysics↗

bioRxiv2024

Release the Krakencoder: A unified brain connectome translation and fusion tool

Brain connectivity can be estimated in many ways, depending on modality and processing strategy. Here we present the Krakencoder, a joint connectome mapping tool that simultaneously, bidirectionally translates between structural (SC) and functional connectivity (FC), and across different atlases and processing choices via a common latent representation. These mappings demonstrate unprecedented accuracy and individual-level identifiability; the mapping between SC and FC has identifiability 42-54% higher than existing models. The Krakencoder combines all connectome flavors via a shared low-dimensional latent space. This "fusion" representation i) better reflects familial relatedness, ii) preserves age- and sex-relevant information and iii) enhances cognition-relevant information. The Krakencoder can be applied without retraining to new, out-of-age-distribution data while still preserving inter-individual differences in the connectome predictions and familial relationships in the latent representations. The Krakencoder is a significant leap forward in capturing the relationship between multi-modal brain connectomes in an individualized, behaviorally- and demographically-relevant way.

neuroscience↗

bioRxiv2024

Flynotyper 2.0: A tool for rapid quantitative assessment of Drosophila eye phenotypes

About two-thirds of the genes in the Drosophila melanogaster genome are also involved in its eye development, making the Drosophila eye an ideal system for genetic studies. We previously developed Flynotyper, a software that uses image processing operations to identify and quantify the degree of roughness by measuring disorderliness of ommatidial arrangement in the fly eye. This software has enabled researchers to quantify morphological defects of thousands of eye images caused by genetic perturbations. Here, we present Flynotyper 2.0, a software that has an updated computer vision library, improved performance, and a streamlined pipeline for high-throughput analysis of multiple eye images. We also tested several batches of Drosophila eye images to ensure robustness and reproducibility of the updated Flynotyper 2.0 software. Availability and implementationThe source code for Flynotyper 2.0 can be downloaded and installed from https://github.com/girirajanlab/flynotyper-desktop-application.

bioinformatics↗

bioRxiv2024

Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Our study showed expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (IntL-Piezo1-/-) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKK{beta}/CaMKIV-mTORC1 signaling pathway under normal chow diet or high fed diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKK{beta}/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These findings suggest a previously undiscovered mechano-regulation of GLP-1 production in L cells, which may shed new light on the treatments of diabetes.

physiology↗

bioRxiv2024

Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas CD4_CTL precursors were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift-myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model, PHARE (https://xiazlab.org/phare/), which applies to both scRNA-seq and bulk RNA-seq data. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

immunology↗

bioRxiv2024

GABAAR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation in CLN1 disease

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). To identify depalmitoylation substrate of PPT1 is crucial to understand CLN1 disease. In this study, we found that PPT1 depalmitoylates GABAAR 1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR 1 subunit binding site result in enhanced inhibitory synaptic transmission, strengthened and oscillation but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in PPT1 induced diseases.

neuroscience↗

bioRxiv2024

NPRL2 gene therapy induces effective antitumor immunity in KRAS/STK11 mutant anti-PD1 resistant metastatic non-small cell lung cancer (NSCLC) in a humanized mouse model

NPRL2/TUSC4 is a tumor suppressor gene whose expression is reduced in many cancers including NSCLC. Restoration of NPRL2 expression in cancer cells induces DNA damage which leads to cell cycle arrest and apoptosis. We investigated the antitumor immune responses to NPRL2 gene therapy in aPD1R/ KRAS/STK11mt NSCLC in a humanized mouse model. Humanized mice were generated by transplanting fresh human cord blood derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung metastases were developed from KRAS/STK11mt/aPD1R A549 cells in humanized mice and treated with NPRL2 gene-loaded cationic lipid nanoparticles (DOTAP-NPRL2) with or without pembrolizumab (aPD1). NPRL2 treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. The antitumor effect was greater in humanized than non-humanized mice suggesting that an immune response contributed to antitumor activity. NPRL2 combined with pembrolizumab was not synergistic in the KRAS/STK11mt/aPD1R tumors but was synergistic in the KRASwt/aPD1S H1299 tumors. Consistent with the A549 humanized mouse model, NPRL2 showed a significantly strong antitumor effect on KRASmt/aPD1R LLC2 syngeneic tumors, whereas aPD1 was ineffective. The antitumor effect of NPRL2 was correlated with increased infiltration of human cytotoxic immune cells and Ag-presenting HLA-DR+ DC, CD11c DC, and downregulation of myeloid and regulatory T cells in the TME. The antitumor effect of NPRL2 was significantly abolished upon in-vivo depletion of CD8 T, macrophages, and CD4 T cells. However, the antitumor effect remained unaffected upon in-vivo depletion of NK cells. A distinct pattern of gene expression profile was found in lung met after NPRL2 treatment in humanized mice. The expression of genes associated with T cell functions, including IFN{gamma}, CD8b, CD7, TNFSF18, ITGA1, GATA3, and TBX21 was significantly increased, whereas the expression of genes associated with negative regulation of T cell functions, including FOXP3, TGFB1, TGFB2, and IL-10RA were strongly inhibited upon NPRL2 treatment. NPRL2 downregulated the expression of T cell co-inhibitory molecules, including CTLA4, ICOS, LAG3, PDCD1, CD274, IDO1, PDCD1LG2, CD47, and KLRB1. Tumors established from NPRL2 stably expressing cells in humanized mice exhibited significantly slower growth compared to controls. TME analysis showed an increased presence of human CD45+, CD3+ T, CD8+ T cells, and HLA-DR+ dendritic cells and a decreased percentage of Treg, CD3+PD1+T cells, MDSC, and CD163+ TAM in NPRL2-expressing tumors. In-vitro, NPRL2 stably expressing cells showed a substantial increase in colony formation inhibition and heightened sensitivity to carboplatin in colony formation, apoptosis, and PARP cleavage assays. Stable expression of NPRL2 resulted in the downregulation of MAPK and AKT-mTOR growth signaling through inhibition of pAKT, pmTOR, pPRAS40, p4E-BP1, and pS6 expression. Taken together, these data suggest that NPRL2 gene therapy induces antitumor activity on KRAS/STK11mt/aPD1R tumors through DC-mediated antigen presentation and cytotoxic immune cell activation.

cancer biology↗

bioRxiv2024

Development of a high-throughput, quantitative platform using human cerebral organoids to study virus-induced neuroinflammation in Alzheimer's disease

Neuroinflammation is a central process in the pathogenesis of several neurodegenerative diseases such as Alzheimers disease (AD), and there are active efforts to target pathways involved in neuroinflammation for molecular biomarker discovery and therapeutic development in neurodegenerative diseases. It was also proposed that there may be an infectious etiology in AD that is associated with viruses such as herpes simplex virus (HSV-1) and influenza A virus (IAV), leading to neuroinflammation-induced AD pathogenesis or disease progression. We sought to develop high-throughput, quantitative molecular biomarker assays using dissociated cells from human cerebral organoids (dcOrgs), that can used for screening compounds to reverse AD-associated neuroinflammation. We found that HSV-1 infection, but not IAV infection, in dcOrgs led to increased intracellular A{beta}42 and phosphorylated Tau-Thr212 (pTau-212) expression, lower ratios of secreted A{beta}42/40, as well as neuronal loss, and increased proportions of astrocytes and microglia, which are hallmarks of AD. Among the glia cell-type markers, Iba1 (microglia) and GFAP (astrocyte) expression were most strongly correlated with HSV-1 expression, which further supported that these biomarkers are perturbed by glia-mediated neuroinflammation. By performing large-scale RNA sequencing, we observed that differentially expressed transcripts in HSV-1 infected dcOrgs were specifically enriched for AD-associated GWAS genes, but not for genes associated with other common neurodegenerative, neuropsychiatric or autoimmune diseases. Immediate treatment of HSV-1 infected dcOrgs with anti-herpetic drug acyclovir (ACV) rescued most of the cellular and transcriptomic biomarkers in a dosage-dependent manner, indicating that it is possible to use our high-throughput platform to identify compounds or target genes that can reverse these neuroinflammation-induced biomarkers associated with AD.

genomics↗

bioRxiv2024

Delineating the Role of ITGAM in Macrophage Dynamics and Cardiac Modulation during Sepsis-Induced Cardiomyopathy

BackgroundSepsis-induced cardiomyopathy (SIC) represents a critical complication of sepsis, characterized by reversible myocardial dysfunction and alterations. Despite extensive research, the molecular mechanisms underlying SIC remain poorly understood. MethodsUtilizing bioinformatics analysis of RNA-seq and scRNA-seq data from the GEO database, we identified key immune cell populations and molecular markers associated with SIC. Our in vitro and in vivo studies focused on the roles of ITGAM and ICAM-1 in macrophage recruitment and transformation as well as the impact of these changes on cardiac function. ResultsBioinformatics analysis revealed significant alterations in gene expression and immune cell composition in cardiac tissue during SIC, with macrophages being the predominant immune cell type. ITGAM was identified as crucial molecule in this process. In vitro experiments demonstrated an upregulation of ITGAM in macrophages and ICAM-1 in endothelial cells following LPS stimulation, indicating their roles in immune cell recruitment and interaction. Furthermore, the use of ITGAM-neutralizing antibodies led to reduced macrophages infiltration and initially improved cardiac function in SIC mice, but resulted in increased mortality in later stages. These findings highlight the dual role of ITGAM in SIC, facilitating early-stage inflammation and later-stage cardiac recovery. ConclusionThis study elucidates the complex dynamics of immune cells in SIC, with a particular emphasis on the role of ITGAM in macrophage modulation. The findings provide new insights into the reversible nature of myocardial dysfunction in SIC and underscore the importance of targeted therapeutic strategies for effective sepsis management. HighlightsIdentifies ITGAM as a key modulator in macrophage dynamics during sepsis-induced cardiomyopathy (SIC). Elucidates the impact of ITGAM on cardiac function in SIC. Reveals new insights into the immune-cellular mechanisms in SIC pathology.

genomics↗

bioRxiv2024

Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing

Both circular RNAs (circRNA) and microRNAs (miRNA) have emerged to play important roles in health and disease. To understand their function in tissue repair, we profiled circRNA, linear RNA, and miRNA expression dynamics in human wound-edge keratinocytes across the wound healing process. Our investigation spotlighted circASH1L(4,5) and its engagement with miR-129-5p, both of which levels were increased with wound repair. Unlike conventional miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting this miRNA from target-directed miRNA degradation (TDMD) triggered by NR6A1 mRNA. TGF-{beta} signaling, pivotal in wound healing, fostered circASH1L expression while suppressing NR6A1, thus enhancing the miR-129 abundance at the post-transcriptional level. Functionally, circASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds. Collectively, our study uncovers circRNAs novel role as shields for miRNAs and sheds light on the physiological importance of regulated miRNA degradation in human skin wound healing.

molecular biology↗