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Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-inflammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct inflammatory disease models. GSTO1-1 deficiency ameliorates the inflammatory response stimulated by LPS and attenuates the inflammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 deficient mice show a more severe inflammatory response and increased escape of bacteria from the colon into the lymphatic system in a dextran sodium sulfate mediated model of inflammatory bowel disease. These responses are similar to those of TLR4 and MyD88 deficient mice in these models and confirm that GSTO1-1 is critical for a TLR4-like pro-inflammatory response in vivo . In wild-type mice, we show that a small molecule inhibitor that covalently binds in the active site of GSTO1-1 can be used to ameliorate the inflammatory response to LPS. Our findings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of inflammation and suggest their possible application in the treatment of a range of inflammatory conditions.

Multivariate time series anomaly detection (MTSAD) can effectively identify and analyze anomalous behavior in complex systems, which is particularly important in fields such as financial monitoring, industrial equipment fault detection, and cybersecurity. MTSAD requires simultaneously analyze temporal dependencies and inter-variable relationships have prompted researchers to develop specialized deep learning models to detect anomalous patterns. In this paper, we conducted a structured and comprehensive overview of the latest techniques in deep learning for multivariate time series anomaly detection methods. Firstly, we proposed a taxonomy for the anomaly detection strategies from the perspectives of learning paradigms and deep learning models, and then provide a systematic review that emphasizes their advantages and drawbacks. We also organized the public datasets for time series anomaly detection along with their respective application domains. Finally, open issues for future research on MTSAD were identified.

NAC family genes encode plant-specific transcription factors involved in diverse biological processes. In this study, the Arabidopsis NAC gene ATAF1 was found to be induced by drought, high-salinity, abscisic acid （ABA）, methyl jasmonate, mechanical wounding, and Botrytis cinerea infection. Significant induction of ATAF1 was found in an ABA-deficient mutant aba2 subjected to drought or high salinity, revealing an ABA-independent mechanism of expression. Arabidopsis ATAFl-overexpression lines displayed many altered phenotypes, including dwarfism and short primary roots. Furthermore, in vivo experiments indicate that ATAF1 is a bonafide regulator modulating plant responses to many abiotic stresses and necrotrophic-pathogen infection. Overexpression of ATAF1 in Arabidopsis increased plant sensitivity to ABA, salt, and oxidative stresses. Especially, ATAF1 overexpression plants, but not mutant lines, showed remarkably enhanced plant tolerance to drought. Additionally, ATAF1 overexpression enhanced plant susceptibility to the necrotrophic pathogen B. cinerea, but did not alter disease symptoms caused by avirulent or virulent strains of P. syringae pv tomato DC3000. Transgenic plants overexpressing ATAF1 were hypersensitive to oxidative stress, suggesting that reactive oxygen intermediates may be related to ATAFl-mediated signaling in response to both pathogen and abiotic stresses.

Plants have evolved intricate immune mechanisms to combat pathogen infection. Upon perception of pathogen-derived signals, plants accumulate defense hormones such as ethylene (ET), jasmonate, salicylate, and damage-associated molecular patterns to amplify immune responses. In particular, the Arabidopsis peptide Pep1 and its family members are thought to be damage-associated molecular patterns that trigger immunity through Pep1 receptor kinases PEPR1 and PEPR2. Here we show that PEPR1 specifically interacts with receptor-like cytoplasmic kinases botrytis-induced kinase 1 (BIK1) and PBS1-like 1 (PBL1) to mediate Pep1-induced defenses. In vitro and in vivo studies suggested that PEPR1, and likely PEPR2, directly phosphorylates BIK1 in response to Pep1 treatment. Surprisingly, the pepr1/pepr2 double-mutant seedlings displayed reduced in sensitivity to ET, as indicated by the elongated hypocotyls. ET-induced expression of defense genes and resistance to Botrytis cinérea were compromised in pepr1/pepr2 and bik1 mutants, reenforcing an important role of PEPRs and BIK1 in ET-mediated defense signaling. Pep treatment partially mimicked ETinduced seedling growth inhibition in a PEPR-and BIK1-dependent manner. Furthermore, both ET and Pep1 treatments induced BIK1 phosphorylation in a PEPR-dependent manner. However, the Peplinduced BIK1 phosphorylation, seedling growth inhibition, and defense gene expression were independent of canonical ET signaling components. Together our results illustrate a mechanism by which ET and PEPR signaling pathways act in concert to amplify immune responses.

Plant responses to cold stress are mediated by a transcriptional cascade, in which the transcription factor ICE1 and possibly related proteins activate the expression of C-repeat (CRT)-binding factors (CBFs), leading to the transcription of downstream effector genes. The variant RING finger protein high expression of osmotically responsive gene (HOS)1 was identified genetically as a negative regulator of cold responses. We present evidence here that HOS1 is an E3 ligase required for the ubiquitination of ICE1. HOS1 physically interacts with ICE1 and mediates the ubiquitination of ICE1 both in vitro and in vivo. We found that cold induces the degradation of ICE1 in plants, and this degradation requires HOS1. Consistent with enhanced cold-responsive gene expression in loss-of-function hos1 mutant plants, overexpression of HOS1 represses the expression of CBFs and their downstream genes and confers increased sensitivity to freezing stress. Our results indicate that cold stress responses in Arabidopsis are attenuated by a ubiquitination/proteasome pathway in which HOS1 mediates the degradation of the ICE1 protein.

T lymphocytes, which are essential for cell-mediated immunity in vertebrates, rely on thymic seeding of lymphoid progenitors for commitment, differentiation and maturation. However, the epigenetic programming of lymphoid-primed progenitor migration and differentiation is incompletely understood. Here, we show that zebrafish embryos lacking the epigenetic modulator Atf7ip or Setdb1 methyltransferase exhibit decreased thymic homing and differentiation of lymphoid progenitor cells. We show that Atf7ip regulates T cell progenitor homing and differentiation via Setdb1-triggered H3K9 trimethylation. Atf7ip interacts with Setdb1 to catalyze H3K9me3 modification of the key immune regulator bach2b to derepress the expression of ccr9a and irf4a , thereby promoting lymphoid progenitor homing and intrathymic differentiation. In the absence of Atf7ip or Setdb1, replenishing irf4a or diminishing bach2b restores the thymic trafficking and differentiation of lymphoid progenitor cells. Notably, depletion of ATF7IP by two complementary cre-recombinase alleles in mice ( CAG-CreERT2 and Mx1-iCre ) impedes the migration of hematopoietic progenitors to the thymus, resulting in declined T lymphopoiesis. These findings establish the role of ATF7IP/SETDB1-mediated epigenetic programming in governing T lymphoid progenitor trafficking and differentiation, with implications for understanding the pathogenesis of human T lymphoid diseases. Here they show that ATF7IP/SETDB1-mediated epigenetic programming governs T lymphoid progenitor trafficking and differentiation, providing important insights into the pathogenesis of human T lymphoid diseases.

BackgroundCentral venous catheter (CVC) insertion complications are a prevalent and important problem in the intensive care unit (ICU), and source control by immediate catheter removal is considered urgent in patients with septic shock suspected to be caused by catheter-related bloodstream infection (CRBSI). We sought to determine the impact of immediate reinsertion of a new catheter (IRINC) on mortality among patients after CVC removal for suspected CRBSI.MethodsA propensity score-matched cohort of patients with suspected CRBSI who underwent IRINC or no IRINC in a 32-bed ICU in a university hospital in China from January 2009 through April 2021. Catheter tip culture and clinical symptoms were used to identify patients with suspected CRBSI. The Kaplan–Meier method was used to analyse 30-day mortality before and after propensity score matching, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality in the matched cohort were estimated with Cox proportional hazards models.ResultsIn total, 1,238 patients who had a CVC removed due to suspected CRBSI were identified. Among these patients, 877 (70.8%) underwent IRINC, and 361 (29.2%) did not. Among 682 propensity score-matched patients, IRINC was associated with an increased risk of 30-day mortality (HR, 1.481; 95% CI, 1.028 to 2.134) after multivariable, multilevel adjustment. Kaplan–Meier analysis found that IRINC was associated with the risk of mortality both before matching (P = 0.00096) and after matching (P = 0.018). A competing risk analysis confirmed the results of the propensity score-matched analysis. The attributable risk associated with bloodstream infection was not significantly different (HR, 1.081; 95% CI 0.964 to 1.213) among patients with suspected CRBSI in terms of 30-day mortality compared with that associated with other infections.ConclusionsIn this cohort study, IRINC was associated with higher 30-day mortality compared to delayed CVC or no CVC among patients with suspected CRBSI. A large-sample randomized controlled trial is needed to define the best management for CVC in cases of suspected CRBSI because IRINC may also be associated with noninfectious complications.Trial registration This study was registered with the China Clinical Trials Registry (URL: http://www.chictr.org.cn/index.aspx) under the following registration number: ChiCTR1900022175.

Recent genomic and genetic analyses based on Arabidopsis suggest that ubiquitination plays crucial roles in the plant response to abiotic stress and the phytohormone abscisic acid (ABA). However, few such studies have been reported in rice as a monocotyledonous model plant. Taking advantage of strategies in biochemistry, molecular cell biology and genetics, the RING-finger containing E3 ligase OsSDIR1 ( Oryza sativa SALT-AND DROUGHT-INDUCED RING FINGER 1) was found to be a candidate drought tolerance gene for engineering of crop plants. The expression of OsSDIR1 was detected in all tissues of rice and up-regulated by drought and NaCl, but not by ABA. In vitro ubiquitination assays demonstrated that OsSDIR1 is a functional E3 ubiquitin ligase and that the RING finger region is required for its activity. OsSDIR1 could complement the drought sensitive phenotype of the sdir1 mutant and overexpressing transgenic Arabidopsis were more sensitive to ABA, indicating that the OsSDIR1 gene is a functional ortholog of SDIR1 . Upon drought treatment, the OsSDIR1 -transgenic rice showed strong drought tolerance compared to control plants. Analysis of the stomata aperture revealed that there were more closed stomatal pores in transgenic plants than those of control plants. This result was also confirmed by the water loss assay and leaf related water content (RWC) measurements during drought treatment. Thus, we demonstrated that monocot- and dicot- SDIR1s are conserved yet have diverse functions.

T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune evasion resulting in poor therapeutic efficacy. The introduction of ferroptosis-targeted inducers offers a potential solution, as they empower T cells to induce ferroptosis and exert influence over the tumor microenvironment. Atovaquone (ATO) stands as a prospective pharmaceutical candidate with the potential to target ferroptosis, effectively provoking an excessive generation and accumulation of reactive oxygen species (ROS). In this study, we evaluated the effectiveness of a combination therapy comprising ATO and TCR-T cells against hepatocellular carcinoma (HCC), both in vitro and in vivo. The results of lactate dehydrogenase and cytokine assays demonstrated that ATO enhanced cytotoxicity mediated by AFP-specific TCR-T cells and promoted the release of IFN-γ in vitro. Additionally, in an established HCC xenograft mouse model, the combined therapy with low-dose ATO and TCR-T cells exhibited heightened efficacy in suppressing tumor growth, with no apparent adverse effects, comparable to the results achieved through monotherapy. The RNA-seq data unveiled a significant activation of the ferroptosis-related pathway in the combination therapy group in comparison to the TCR-T cells group. Mechanistically, the synergy between ATO and TCR-T cells augmented the release of IFN-γ by TCR-T cells, while concurrently elevating the intracellular and mitochondrial levels of ROS, expanding the labile iron pool, and impairing the integrity of the mitochondrial membrane in HepG2 cells. This multifaceted interaction culminated in the potentiation of ferroptosis within the tumor, primarily induced by an excess of ROS. In summary, the co-administration of ATO and TCR-T cells in HCC exhibited heightened vulnerability to ferroptosis. This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.

Ubiquitination plays important roles in plant hormone signal transduction. We show that the RING finger E3 ligase, Arabidopsis thaliana SALT- AND DROUGHT-INDUCED RING FINGER1 (SDIR1), is involved in abscisic acid (ABA)-related stress signal transduction. SDIR1 is expressed in all tissues of Arabidopsis and is upregulated by drought and salt stress, but not by ABA. Plants expressing the ProSDIR1-β-glucuronidase (GUS) reporter construct confirmed strong induction of GUS expression in stomatal guard cells and leaf mesophyll cells under drought stress. The green fluorescent protein-SDIR1 fusion protein is colocalized with intracellular membranes. We demonstrate that SDIR1 is an E3 ubiquitin ligase and that the RING finger conservation region is required for its activity. Overexpression of SDIR1 leads to ABA hypersensitivity and ABA-associated phenotypes, such as salt hypersensitivity in germination, enhanced ABA-induced stomatal closing, and enhanced drought tolerance. The expression levels of a number of key ABA and stress marker genes are altered both in SDIR1 overexpression and sdir1-1 mutant plants. Cross-complementation experiments showed that the ABA-INSENSITIVE5 (ABI5), ABRE BINDING FACTOR3 (ABF3), and ABF4 genes can rescue the ABA-insensitive phenotype of the sdir1-1 mutant, whereas SDIR1 could not rescue the abi5-1 mutant. This suggests that SDIR1 acts upstream of those basic leucine zipper family genes. Our results indicate that SDIR1 is a positive regulator of ABA signaling.