Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

CREATE: cell-type-specific cis-regulatory elements identification via discrete embedding

Identifying cis-regulatory elements (CREs) within non-coding genomic regions--such as enhancers, silencers, promoters, and insulators--is pivotal for elucidating the intricate gene regulatory mechanisms underlying complex biological traits. The current prevalent sequence-based methods often focus on singular CRE types, limiting insights into cell-type-specific biological implications. Here, we introduce CREATE, a multimodal deep learning model based on the Vector Quantized Variational AutoEncoder framework, designed to extract discrete CRE embeddings and classify multiple CRE classes using genomic sequences, chromatin accessibility, and chromatin interaction data. CREATE excels in accurate CRE identification and exhibits strong effectiveness and robustness. We showcase CREATEs capability in generating comprehensive CRE-specific feature spectrum, offering quantitative and interpretable insights into CRE specificity. By enabling large-scale prediction of CREs in specific cell types, CREATE facilitates the recognition of disease- or phenotype-related biological variabilities of CREs, thereby expanding our understanding of gene regulation landscapes.

bioinformatics↗

bioRxiv2024

The topography of gene tree topology space in a plant genus with a legacy of recent polyploidy and introgression

The eukaryotic genome has been described as a collection of different histories; for any set of taxa one of these histories is the record of cladogenic events that together comprise the species tree. Among the other histories expected to occur are those attributable to deep coalescence/lineage sorting; to biological causes such as introgression and horizontal transfer; or to pseudo-orthology, long branch attraction, and other technical issues. Gene tree topology space is the portion of tree space occupied by the gene trees reconstructed for a particular dataset of sampled genetic loci. Because coalescent theory predicts that the species tree topology will generally be the most frequent among gene trees, a reasonable expectation is that there will be a peak in gene tree topology space at the species tree topology, with secondary peaks present due to trees tracking other histories. Gene tree topology space in the small ([~]30 species, including the cultivated soybean) legume genus, Glycine should not only have signals from the species tree and from lineage sorting, but also from a likely introgression event that created incongruence between the plastid and nuclear genomes. Additionally, Glycine is the product of a relatively recent (<13 million years) whole genome duplication, raising the possibility of pseudo-orthology. We explored this space using a set of 2389 nuclear genes and representative accessions from a 570-taxon concatenation tree, reconstructing gene trees for all nuclear loci and from complete plastid genomes and partial mitochondrial genomes. Species trees (ASTRAL) and maximum likelihood (ML) concatenation trees were congruent for a 61-taxon dataset but were incongruent with organellar genome trees. Gene tree topology space was flat: No topology was represented by more than one gene tree. This was also true for a reduced dataset of 27 taxa; only when the dataset was reduced to six ingroup taxa were multiple gene trees having the species tree topology observed, along with a topology congruent with the chloroplast genome topology, presumably representing nuclear loci introgressed along with the plastome. Clustering failed to identify any regional differentiation of gene tree topology space populated by loci with similar topologies. Pseudo-orthology did not contribute meaningfully to incongruence, in agreement with recent modeling work that minimizes concerns about this phenomenon. Clearly, different genes have different historical signals, but these signals are complex and exist at the level of clades within trees rather than as entire gene trees.

evolutionary biology↗

bioRxiv2024

A qualitative review of Oxford Nanopore Sequencing datasets for RNA modifications

There are many oxford nanopore datasets available to study methylations. Methylations and modifications occur at nucleotides such as adenine (A), cytosine (C), guanine (G) and theanine (T) or uracil (U). Among all these provided datasets, some have the most common m6A methylation and others have m5C etc. using various real organism reference sequences such as human, mouse and artificial reference sequences which are prepared in the laboratory such as curlcake and IVT. These datasets are required to be organized by the methylation types to research ONT datasets. Here we provide a summary of the read qualities, base mapping success rates etc. for these methylation types and reference genomes. We have used minimap2 base mapping and longreadsum results. We find that methylated data have lower success rates than non-methylated data and mapping quality is lower for the real reference genomes such as human and mice. This could be because they contain more than 100,000 transcriptomes whereas artificial reference sequences contain only a few transcriptomes. Datasets which contain artificially created reference sequences have a higher quality than the others, thus they are recommended to be used for methylation or modification classification tasks in the future. DatasetAll datasets used in this study are the publicly available. Dataset LicenseAll datasets used in this study are the publicly available.

bioinformatics↗

bioRxiv2024

Inositol Hexaphosphate (InsP6) Activates the HDAC1/3 Epigenetic Axis toMaintain Intestinal Barrier Function

While HDAC inhibition shows promise in cancer treatment, pan-HDAC inhibitors cause gastrointestinal issues in 48% of patients. Understanding HDAC activation mechanisms is crucial to treat diverse diseases beyond cancer. Our study reveals the essential role of inositol polyphosphate multikinase (IPMK) and inositol hexakisphosphate (InsP6 or phytic acid), enriched in vegan diets, in activating the HDAC3 epigenetic axis and maintaining intestinal barrier integrity. IPMK binds to HDAC3, driving InsP6 synthesis, which selectively activates HDAC3 at 10nM concentration by recruiting the DAD domain of its corepressor protein. IPMK deletion diminishes HDAC3 activation, leading to histone hyperacetylation and MMP gene transcription, compromising intestinal barrier integrity. InsP6 treatment is sufficient to rescue these effects. In inflammatory bowel disease, diminished IPMK levels exacerbated intestinal permeability, while oral InsP6 treatment mitigated gut permeability by restoring the HDAC3 epigenetic axis, indicating the clinical implications of the IPMK-HDAC3 epigenetic axis and therapeutic potential of phytic acid.

cell biology↗

bioRxiv2024

Discovery of novel 1,4-dicarbonylthiosemicarbazides as DNA gyrase inhibitors for the treatment of MRSA infection

Antibiotic resistance has become a serious threat to public health, thus novel antibiotics are urgently needed to combat drug-resistant bacteria including MRSA (methicillin-resistant S. aureus). The 1,4-dicarbonylthiosemicarbazide is an interesting chemotype that could exhibit antibacterial activity. However, the currently available compounds are not as potent as clinical antibiotics. Herein, we adopted the computer-aided drug design strategy, substructure search, to retrieve antibacterial 1,4-dicarbonylthiosemicarbazide derivatives, and identified compound B5 (Specs ID: AG-690/15432331) from the Specs chemical library that exhibited moderate activity (minimum inhibitory concentration (MIC): 6.25 {micro}g/mL) against S. aureus (ATCC 29213). Based on that compound, we further designed and synthesized 45 derivatives, and evaluated their antibacterial activity. Eight derivatives were more potent than or equivalent to vancomycin (MIC: 1.56 {micro}g/mL). We compared the three most potent ones for their cytotoxicity to HepG2 and HUVEC cells and selected compound 1b as our lead compound for comprehensive biological evaluation. As a result, compound 1b exhibited a bacteriostatic mode, and was active against a panel of gram-positive bacteria strains, metabolically stable, and effective to protect the mice from MRSA infection. More importantly, we applied 2D similarity calculation and reverse docking to predict potential targets of compound 1b. Through experimental validation and molecular dynamics simulation, we were able to confirm that compound 1b inhibited S. aureus DNA gyrase (IC50: 1.81 {micro}M) and DNA supercoiling, potentially by binding to the ATPase domain, where ASP81, GLU58 and GLN91 formed key hydrogen bonds. Taken together, we have discovered a new class of DNA gyrase inhibitors represented by compound 1b for the treatment of MRSA infection, through the design, synthesis, and biological evaluation of novel 1,4-dicarbonylthiosemicarbazides. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/611349v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@549dadorg.highwire.dtl.DTLVardef@13bff64org.highwire.dtl.DTLVardef@1fc2c00org.highwire.dtl.DTLVardef@acee76_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAn interesting 1,4-dicarbonylthiosemicarbazide derivative B5 with moderate antibacterial activity for S. aureus was discovered by substructure search. C_LIO_LIBased on B5, 45 new 1,4-dicarbonylthiosemicarbazides were designed, synthesized and biologically evaluated, which led to the discovery of a promising lead compound 1b. C_LIO_LICompound 1b exhibited good antibacterial activity for a panel of gram-positive bacteria strains, and was effective to protect mice from MRSA infection. C_LIO_LIThe 1,4-dicarbonylthiosemicarbazides represented by compound 1b were discovered as a new class of DNA gyrase inhibitors, by target prediction and experimental validation. C_LI

pharmacology and toxicology↗

bioRxiv2024

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG[~]MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation. Significance statementMITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.

cancer biology↗

bioRxiv2024

Survival of hepatocytes from executioner caspase activation promotes liver regeneration by enhancing JAK/STAT3 activity

Activation of executioner caspases, which is a key step in the apoptotic process, has been reported to promote tissue regeneration by sending pro-proliferation signals to the surrounding cells. However, whether executioner caspase activation (ECA) has cell-autonomous effect on tissue regeneration is not clear. Here, by generating transgenic mice carrying a lineage tracing system for cells that have experienced ECA, we demonstrate that transient ECA occurs in hepatocytes during liver regeneration after partial hepatectomy (PHx) or carbon tetrachloride (CCl4) treatment. Instead of committing apoptotic cell death, the majority of hepatocytes with ECA survive and proliferate to contribute to liver regeneration. Interestingly, inhibition of ECA in livers results in reduced hepatocyte proliferation and impaired regeneration, whereas increasing ECA to a level sufficient to kill hepatocytes also impedes regeneration, suggesting that ECA needs to be precisely controlled during liver regeneration. Mechanistic studies show that ECA promotes hepatocyte proliferation during regeneration through enhancing JAK/STAT3 activity. Our work reveals an essential role of survival of hepatocytes from ECA in liver regeneration.

developmental biology↗

bioRxiv2024

Borrelia burgdorferi Secretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts

Borrelia burgdorferi (B. burgdorferi), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including the development and severity of Lyme arthritis. However, the specific Pathogen-Associated Molecular Patterns (PAMPs) of B. burgdorferi responsible for triggering the IFN-I response are not well understood. Previous studies have identified an unknown, nuclease-resistant component in B. burgdorferi culture supernatants that significantly stimulates the IFN-I response, but its identity remains unknown. In this study, we reveal that B. burgdorferi secretes cyclic-di-adenosine monophosphate (c-di-AMP) as a key extracellular PAMP, inducing the host IFN-I response in macrophages. Using genetically manipulated B. burgdorferi strains, we demonstrate a requirement of c-di-AMP for stimulating IFN-I response by macrophages ex vivo. Additionally, infecting mice with B. burgdorferi alongside exogenous c-di-AMP resulted in a markedly increased IFN-I response in mouse tissues. Furthermore, inactivation or inhibition of the host STING signaling pathway significantly reduced the IFN-I response, indicating that c-di-AMP-induced IFN-I production is STING-dependent. Our findings identify c-di-AMP as a crucial PAMP secreted by B. burgdorferi to elicit the host IFN-I response via activation of STING signaling pathway, suggesting that targeting c-di-AMP production could represent a novel therapeutic strategy against Lyme arthritis. SUMMARYBorrelia burgdorferi, the bacteria that causes Lyme disease, induces a robust host immune response, including the production of type-I interferon (IFN-I). While this response helps combat the infection, it also contributes to complications such as Lyme arthritis. Our research aimed to identify the specific bacterial component that triggers the IFN-I response. We discovered that Borrelia burgdorferi releases a second messenger molecule, cyclic-di-adenosine monophosphate (c-di-AMP), which is recognized by host immune cells and subsequently triggers IFN-I production. This finding is significant as it advances our understanding of Lyme disease pathogenesis and offers a new strategy to tackle Lyme disease by targeting the production of c-di-AMP, in which we may be able to reduce the severity of the disease and mitigate long-term tissue damage. One sentence summaryBorrelia burgdorferi c-di-AMP induces Type I IFN response

immunology↗

bioRxiv2024

Placental and fetal microbiota in rhesus macaque: a case study using metagenomic sequencing

Recent evidence challenging the notion of a sterile intrauterine environment has sparked research into the origins and effects of fetal microbiota on immunity development during gestation. Rhesus macaques (RMs) serve as valuable non-human primate (NHP) models due to their similarities to humans in development, placental structure, and immune response. In this study, metagenomic analysis was applied to the placenta, umbilical cord, spleen, gastrointestinal (GI) tissues of an unborn RM fetus, and the maternal intestine, revealing the diversity and functionality of microbes in these tissues. We observed substantial microbial sharing between the mother and fetus, with the microbial composition of the placenta and umbilical cord more closely resembling that of the fetal organs than the maternal intestine. Notably, compared with other adult RMs, there was a clear convergence between maternal and fetal microbiota, alongside distinct differences between the microbiota of adults and the fetus, which underscores the unique microbial profiles in fetal environments. Furthermore, the fetal microbiota displayed a less developed carbohydrate metabolism capacity than adult RMs. It also shared antibiotic resistance genes (ARGs) with both maternal and adult RM microbiomes, indicating potential vertical transmission. Comparative analysis of the metagenomes between the RM fetus and a human fetus revealed significant differences in microbial composition and genes, yet also showed similarities in certain abundant microbiota. Collectively, our results contribute to a more comprehensive understanding of the intrauterine microbial environment in macaques.

microbiology↗

bioRxiv2024

A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.

cancer biology↗

bioRxiv2024

Predict metal-binding proteins and structuresthrough integration of evolutionary-scale andphysics-based modeling

Metals are essential elements in all living organisms, binding to approximately 50% of proteins. They serve to stabilize proteins, catalyze reactions, regulate activities, and fulfill various physiological and pathological functions. While there have been many advancements in determining the structures of protein-metal complexes, numerous metal-binding proteins still need to be identified through computational methods and validated through experiments. To address this need, we have developed the ESMBind workflow, which combines evolutionary scale modeling (ESM) for metal-binding prediction and physics-based protein-metal modeling. Our approach utilizes the ESM-2 and ESM-IF models to predict metal-binding probability at the residue level. In addition, we have designed a metal-placement method and energy minimization technique to generate detailed 3D structures of protein-metal complexes. Our workflow outperforms other models in terms of residue and 3D-level predictions. To demonstrate its effectiveness, we applied the workflow to 142 uncharacterized fungal pathogen proteins and predicted metal-binding proteins involved in fungal infection and virulence.

bioinformatics↗

bioRxiv2024

LongReadSum: A fast and flexible quality control and signal summarization tool for long-read sequencing data

While several well-established quality control (QC) tools are available for short reads sequencing data, there is a general paucity of computational tools that provide long read metrics in a fast and comprehensive manner across all major sequencing platforms (such as PacBio, Oxford Nanopore, Illumina Complete Long Read) and data formats (such as ONT POD5, FAST5, basecall summary files and PacBio unaligned BAM). Additionally, none of the current tools provide support for summarizing Oxford Nanopore basecall signal or comprehensive base modification (methylation) information from genomic data. Furthermore, nowadays a single PromethION flowcell on the Oxford Nanopore platform can generate terabytes of signal data, which cannot be handled by existing tools designed for small-scale flowcells. To address these challenges, here we present LongReadSum, a multi-threaded C++ tool which provides fast and comprehensive QC reports on all major aspects of sequencing data (such as read, base, base quality, alignment, and base modification metrics) and produce basecalling signal intensity information from the Oxford Nanopore platform. We demonstrate use cases to analyze cDNA sequencing, direct mRNA sequencing, reduced representation methylation sequencing (RRMS) through adaptive sequencing, as well as whole genome sequencing (WGS) data using diverse long-read platforms.

bioinformatics↗

bioRxiv2024

The study on the impact of indoleacetic acid on enhancing the ability of the rumen's original microecology to degrade aflatoxin B1.

Aflatoxin B1 (AFB1) poses a serious threat to the health of cattle and is strictly monitored in their diets. Rumen microorganisms in cattle have the ability to degrade AFB1, but this capability is limited. Enhancing the degradation capacity of the original rumen microecology for AFB1 is a novel approach. From a molecular perspective,indoleacetic-3-acid (IAA) promotes the expression of cytochromes, which can improve the degradation of AFB1. Therefore, this study aims to investigate the impact of different concentrations of IAA on the degradation of AFB1 by the rumen microecology. Experiments used rumen fluid from three adult cows as donors, and the cows were all fed the same total mixed ration. Rumen fluid was collected from these three cannulated cows before morning feeding to prepare in vitro fermentation fluid. The experiments used a completely randomized design, with each treatment repeated four times. The results showed that as the fermentation time increased, the content of AFB1 gradually decreased, with a degradation rate of up to 75.73% after 24 h. AFB1 altered the rumen fermentation pattern, with a significant reduction in the content of acetic acid (P<0.05) and a significant decrease in the acetic acid to propionic acid ratio (P<0.05). It also affected the rumen microecology, causing a significant reduction in the abundance of Ruminococcus amylophilus, Prevotella ruminicola, and Fusobacterium succinogenes (P<0.05). In addition, this study found that with the increase in the amount of IAA added, the content of AFB1 in the rumen gradually decreased. IAA enhances the degradation capacity of the original rumen microecology for AFB1, and the addition of IAA alleviates the impact of AFB1 on Ruminococcus amylophilus, Prevotella ruminicola, and Fusobacterium succinogenes in the rumen (P<0.05). Moreover, the addition of IAA can promote the stability of the rumen microecology, with significantly higher acetic acid and acetic acid to propionic acid ratios in the fermentation fluid compared to the non-added group (P<0.05). In summary, the addition of IAA can improve the degradation capacity of the rumen microecology for AFB1, providing a new solution for alleviating the impact of AFB1 on animal health.

microbiology↗

bioRxiv2024

CIB2 as a Ca2+ Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity of TMC1 in Hearing Loss

Non-syndromic sensorineural hearing loss is characterized by genetic heterogeneity, leading to potential clinical misdiagnosis. TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca2+ regulation in MET, which is essential for sound perception, remains unclear. CIB2, another MET component associated with deafness, can bind with calcium and may play a role in MET gating. Our study reveals that the TMC1-CIB2 complex undergoes a Ca2+-induced conformational change, highlighting the crucial role of Ca2+ in MET. We identified a vertebrate-specific binding site on TMC1, named CR3, that interacts with apo CIB2, with the binding interface linked to hearing loss. Using an in-vivo animal model, we demonstrated that disruption of the calcium-sensing site of CIB2 perturbs the MET channel conductivity, confirming its role as a Ca2+ sensor for MET. Additionally, after systematically analyzing the hearing-loss variants, we observed that dominant mutations of TMC1 are often located near the ion pore or at the binding interfaces with the Ca2+ sensor CIB2. This provides a detailed mechanism of the genetic heterogeneity of TMC1 in hearing loss at an atomic level.

molecular biology↗

bioRxiv2024

Trait anxiety impairs reciprocity behavior: A multi-modal and computational modeling study

Anxiety significantly impacts reciprocal behavior, crucial for positive social interactions. The neurocomputational mechanisms of anxietys effects on the core (individual propensity) and peripheral (decision context) factors shaping reciprocity remain unclear. Here, we investigated reciprocity in individuals with low and high trait anxiety using a binary trust game with gain/loss framing, combining computational modeling, eye-tracking, and event-related potentials (ERPs). Our computational model, validated by eye-tracking data, identified four psychological components driving reciprocal behavior: reward, guilt aversion, superiority aversion, and superiority attraction. Regarding the core of reciprocity, trait anxiety diminished both overall reciprocity and specific psychological components like guilt aversion and superiority attraction, irrespective of context. The reduction in guilt aversion was supported by ERP findings showing decreased P2 (selective attention) and increased LPP (emotion regulation) amplitudes in anxious individuals. Regarding the periphery of reciprocity, trait anxiety altered the contextual perception of both superiority aversion and reward. Further, trait anxiety reversed the perception of superiority aversion from gain to loss contexts, a pattern that was linked to the N2 amplitudes (cognitive control). Our findings revealed distinct effects of trait anxiety on core and peripheral factors in reciprocity, offering potential targets for interventions aimed at improving reciprocity in individuals with anxiety disorders.

neuroscience↗

bioRxiv2024

Highly quantitative measurement of differential protein-genome binding with PerCell chromatin sequencing

We report a universal strategy for 2D chromatin sequencing, to increase uniform data analyses and sharing across labs, and to facilitate highly quantitative comparisons across experimental conditions. Within our system, we provide wetlab and drylab tools for researchers to establish and analyze protein-genome binding data with PerCell ChIP-seq. Our methodology is virtually no cost and flexible, enabling rapid, quantitative, internally normalized chromatin sequencing to catalyze project development in a variety of systems, including in vivo zebrafish epigenomics and cancer cell epigenomics. While we highlight utility in these key areas, our methodology is flexible enough such that rapid comparisons of cellular spike-in versus non spike-in are possible, and generalizability to nuclease-based 2D chromatin sequencing would also be possible within the framework of our pipeline. Through the use of well-defined cellular ratios containing orthologous species chromatin, we enable cross-species comparative epigenomics and highly quantitative low-cost chromatin sequencing with utility across a range of disciplines.

genomics↗

bioRxiv2024

A VgrG2b fragment cleaved by caspase-11/4 promotes Pseudomonas aeruginosa infection through suppressing the NLRP3 inflammasome

The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammatory cytokines mediated by inflammasomes are crucial for the body to resist bacterial infections. Here we found that during the infection of P. aeruginosa, non-canonical inflammasome was activated in macrophages, but the activation of downstream NLRP3 inflammasome was inhibited. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administrating a specific peptide that inhibits the cleavage of VgrG2b by caspase-11 to mice can significantly improve their survival rate during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.

immunology↗

bioRxiv2024

Atf4 protects islet beta-cell identity and function under acute glucose-induced stress but promotes beta-cell failure in the presence of free fatty acid

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in {beta}-cell failure and type 2 diabetes (T2D) via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in {beta}-cells is dispensable for glucose homeostasis in young mice, but it is required for {beta}-cell function during aging and under obesity-related metabolic stress. Henceforth, aged Atf4-deficient {beta}-cells display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced loss-of identity and dysfunction. At molecular level, Atf4-deficient {beta}-cells down-regulate genes involved in protein translation, reducing {beta}-cell identity gene products under high glucose. They also upregulate several genes involved in lipid metabolism or signaling, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for {beta}-cell identity and function under high glucose, but this paradoxically induces {beta}-cell failure in the presence of high levels of free fatty acids. Different branches of Atf4 activity could be manipulated for protecting {beta}-cells from metabolic stress-induced failure. HighlightsO_LIAtf4 is dispensable in {beta}-cells in young mice C_LIO_LIAtf4 protects {beta}-cells under high glucose C_LIO_LIAtf4 exacerbate fatty acid-induced {beta}-cell defects C_LIO_LIAtf4 activates translation but depresses lipid-metabolism C_LI

genetics↗