ABSTRACT
Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2- γδ T cells, with equivalent representation of Vδ1+ and Vδ1- cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2- T cells can express the transcriptional program of exhausted αß CD8+ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2- γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2- γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2- T-cell receptors. Human tumor-derived Vδ2- γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2- T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2- γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.
Subject(s)
CD8-Positive T-Lymphocytes , Kidney Neoplasms , Humans , CD8-Positive T-Lymphocytes/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Programmed Cell Death 1 Receptor/metabolism , Kidney Neoplasms/metabolism , T-Lymphocyte Subsets , Tumor MicroenvironmentABSTRACT
The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.
ABSTRACT
Homo sapiens was present in northern Asia by around 40,000 years ago, having replaced archaic populations across Eurasia after episodes of earlier population expansions and interbreeding1-4. Cultural adaptations of the last Neanderthals, the Denisovans and the incoming populations of H. sapiens into Asia remain unknown1,5-7. Here we describe Xiamabei, a well-preserved, approximately 40,000-year-old archaeological site in northern China, which includes the earliest known ochre-processing feature in east Asia, a distinctive miniaturized lithic assemblage with bladelet-like tools bearing traces of hafting, and a bone tool. The cultural assembly of traits at Xiamabei is unique for Eastern Asia and does not correspond with those found at other archaeological site assemblages inhabited by archaic populations or those generally associated with the expansion of H. sapiens, such as the Initial Upper Palaeolithic8-10. The record of northern Asia supports a process of technological innovations and cultural diversification emerging in a period of hominin hybridization and admixture2,3,6,11.
Subject(s)
Archaeology , Hominidae , Tool Use Behavior , Animals , Bone and Bones , China , History, Ancient , Humans , NeanderthalsABSTRACT
The development of targeted drugs allows precision medicine in cancer treatment and optimal targeted therapies. Accurate identification of cancer druggable genes helps strengthen the understanding of targeted cancer therapy and promotes precise cancer treatment. However, rare cancer-druggable genes have been found due to the multi-omics data's diversity and complexity. This study proposes deep forest for cancer druggable genes discovery (DF-CAGE), a novel machine learning-based method for cancer-druggable gene discovery. DF-CAGE integrated the somatic mutations, copy number variants, DNA methylation and RNA-Seq data across Ë10 000 TCGA profiles to identify the landscape of the cancer-druggable genes. We found that DF-CAGE discovers the commonalities of currently known cancer-druggable genes from the perspective of multi-omics data and achieved excellent performance on OncoKB, Target and Drugbank data sets. Among the Ë20 000 protein-coding genes, DF-CAGE pinpointed 465 potential cancer-druggable genes. We found that the candidate cancer druggable genes (CDG) are clinically meaningful and divided the CDG into known, reliable and potential gene sets. Finally, we analyzed the omics data's contribution to identifying druggable genes. We found that DF-CAGE reports druggable genes mainly based on the copy number variations (CNVs) data, the gene rearrangements and the mutation rates in the population. These findings may enlighten the future study and development of new drugs.
Subject(s)
Genomics , Neoplasms , Humans , Genomics/methods , Multiomics , DNA Copy Number Variations , Neoplasms/drug therapy , Neoplasms/genetics , Machine Learning , Genetic Association StudiesABSTRACT
Cancer driver genes are critical in driving tumor cell growth, and precisely identifying these genes is crucial in advancing our understanding of cancer pathogenesis and developing targeted cancer drugs. Despite the current methods for discovering cancer driver genes that mainly rely on integrating multi-omics data, many existing models are overly complex, and it is difficult to interpret the results accurately. This study aims to address this issue by introducing InDEP, an interpretable machine learning framework based on cascade forests. InDEP is designed with easy-to-interpret features, cascade forests based on decision trees and a KernelSHAP module that enables fine-grained post-hoc interpretation. Integrating multi-omics data, InDEP can identify essential features of classified driver genes at both the gene and cancer-type levels. The framework accurately identifies driver genes, discovers new patterns that make genes as driver genes and refines the cancer driver gene catalog. In comparison with state-of-the-art methods, InDEP proved to be more accurate on the test set and identified reliable candidate driver genes. Mutational features were the primary drivers for InDEP's identifying driver genes, with other omics features also contributing. At the gene level, the framework concluded that substitution-type mutations were the main reason most genes were identified as driver genes. InDEP's ability to identify reliable candidate driver genes opens up new avenues for precision oncology and discovering new biomedical knowledge. This framework can help advance cancer research by providing an interpretable method for identifying cancer driver genes and their contribution to cancer pathogenesis, facilitating the development of targeted cancer drugs.
Subject(s)
Neoplasms , Humans , Neoplasms/genetics , Multiomics , Precision Medicine , Oncogenes , Machine LearningABSTRACT
Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury-induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.
Subject(s)
Kidney Diseases , Lymphatic Vessels , Humans , Intestines , Lymphatic SystemABSTRACT
A steady stream of material transport based on carriers and channels in living systems plays an extremely important role in normal life activities. Inspired by nature, researchers have extensively applied supramolecular cages in cargo transport because of their unique three-dimensional structures and excellent physicochemical properties. In this review, we will focus on the development of supramolecular cages as carriers and channels for cargo transport in abiotic and biological systems over the past fifteen years. In addition, we will discuss future challenges and potential applications of supramolecular cages in substance transport.
ABSTRACT
The formation of a protein corona gives nanomedicines a distinct biological identity, profoundly influencing their fate in the body. Nonspecific nanoparticle-protein interactions are typically highly heterogeneous, which can lead to unique biological behaviors and in vivo fates for individual nanoparticles that remain underexplored. To address this, we have established an in situ approach that allows quantitative examination of nanoparticle-protein adsorption at the individual nanoparticle level. This method integrates dual fluorescence quantification techniques, wherein the nanoparticles are first individually analyzed via nanoflow cytometry to detect fluorescent signals from adsorbed proteins. The obtained fluorescence intensity is then translated into protein quantities through calibration with microplate reader quantification. Consequently, this approach enables analysis of interparticle heterogeneity of nano-protein interactions, as well as in situ monitoring of protein adsorption kinetics and nanoparticle aggregation status in blood serum, preconditioning for a comprehensive understanding of nano-bio interactions, and predicting in vivo fate of nanomedicines.
Subject(s)
Blood Proteins , Nanoparticles , Adsorption , Nanoparticles/chemistry , Blood Proteins/chemistry , Blood Proteins/analysis , Humans , Protein Corona/chemistry , Fluorescence , KineticsABSTRACT
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and worldwide. Proteinuria is a major marker of the severity of injury. Dipeptidyl peptidase-4 inhibitor (DPP-4I) increases incretin-related insulin production and is, therefore, used to treat diabetes. We investigated whether DPP4I could have direct effect on kidney independent of its hypoglycemic activity. We, therefore, tested the effects of DPP4I with or without angiotensin-converting enzyme inhibitor (ACEI) on the progression of diabetic nephropathy and albuminuria in a murine model of DKD. eNOS-/-db/db mice were randomized to the following groups at age 10 weeks and treated until sacrifice: baseline (sacrificed at week 10), untreated control, ACEI, DPP4I, and combination of DPP4I and ACEI (Combo, sacrificed at week 18). Systemic parameters and urine albumin-creatinine ratio were assessed at baseline, weeks 14, and 18. Kidney morphology, glomerular filtration rate (GFR), WT-1, a marker for differentiated podocytes, podoplanin, a marker of foot process integrity, glomerular collagen IV, and alpha-smooth muscle actin were assessed at the end of the study. All mice had hyperglycemia and proteinuria at study entry at week 10. Untreated control mice had increased albuminuria, progression of glomerular injury, and reduced GFR at week 18 compared with baseline. DPP4I alone reduced blood glucose and kidney DPP-4 activity but failed to protect against kidney injury compared with untreated control. ACEI alone and combination groups showed significantly reduced albuminuria and glomerular injury, and maintained GFR and WT-1+ cells. Only the combination group had significantly less glomerular collagen IV deposition and more podoplanin preservation than the untreated control. DPP-4I alone does not decrease the progression of kidney injury in the eNOS-/-db/db mouse model, suggesting that targeting only hyperglycemia is not an optimal treatment strategy for DKD. Combined DPP-4I with ACEI added more benefit to reducing the glomerular matrix.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Dipeptidyl-Peptidase IV Inhibitors , Hyperglycemia , Mice , Animals , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/etiology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Albuminuria/drug therapy , Albuminuria/complications , Kidney , Hypoglycemic Agents/pharmacology , Mice, Inbred Strains , Collagen , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/pharmacology , Dipeptidyl Peptidase 4ABSTRACT
Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). However, the molecular mechanisms underlying these phenomena remain poorly understood. YAP (Yes-associated protein) is an important transcriptional coactivator that binds with various other transcription factors, including the TEAD family members (nuclear effectors of the Hippo pathway), that regulate cell proliferation, differentiation, and apoptosis. The present study found an increase in YAP phosphorylation at S127 of YAP and a reduction of nuclear YAP localization in podocytes of diabetic mouse and human kidneys, suggesting dysregulation of YAP may play a role in diabetic podocyte injury. Tamoxifen-inducible podocyte-specific Yap gene knockout mice (YappodKO) exhibited accelerated and worsened diabetic kidney injury. YAP inactivation decreased transcription factor WT1 expression with subsequent reduction of Tead1 and other well-known targets of WT1 in diabetic podocytes. Thus, our study not only sheds light on the pathophysiological roles of the Hippo pathway in diabetic podocyte injury but may also lead to the development of new therapeutic strategies to prevent and/or treat DN by targeting the Hippo signaling pathway.
Subject(s)
Adaptor Proteins, Signal Transducing , Diabetes Mellitus, Experimental , Diabetic Nephropathies , Mice, Knockout , Phosphoproteins , Podocytes , Signal Transduction , Transcription Factors , WT1 Proteins , YAP-Signaling Proteins , Podocytes/metabolism , Podocytes/pathology , Animals , WT1 Proteins/metabolism , WT1 Proteins/genetics , YAP-Signaling Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Diabetic Nephropathies/pathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/etiology , Diabetic Nephropathies/genetics , Humans , Phosphorylation , Transcription Factors/metabolism , Transcription Factors/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Phosphoproteins/metabolism , Phosphoproteins/genetics , TEA Domain Transcription Factors/metabolism , Hippo Signaling Pathway , Mice , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Male , Mice, Inbred C57BL , Tamoxifen/pharmacology , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Nuclear Proteins/metabolism , Nuclear Proteins/geneticsABSTRACT
BACKGROUND & AIMS: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. METHODS: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. RESULTS: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ-resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. CONCLUSIONS: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC.
Subject(s)
Colitis , Colorectal Neoplasms , Humans , Mice , Animals , Glycosylation , Colorectal Neoplasms/pathology , Interferon-gamma , Immunotherapy , Colitis/pathology , TretinoinABSTRACT
Neoadjuvant chemotherapy (NACT) is a viable therapeutic option for women diagnosed locally advanced cervical cancer (LACC). However, the factors influencing pathological response are still controversial. We collected pair specimens of 185 LACC patients before and after receiving NACT and conducted histological evaluation. 8 fresh tissues pre-treatment were selected from the entire cohort to conducted immune gene expression profiling. A novel pathological grading system was established by comprehensively assessing the percentages of viable tumor, inflammatory stroma, fibrotic stroma, and necrosis in the tumor bed. Then, 185 patients were categorized into either the good pathological response (GPR) group or the poor pathological response (PPR) group post-NACT, with 134 patients (72.4%, 134/185) achieving GPR. Increasing tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating lymphocytes volume (TILV) pre-treatment were correlated with GPR, with TILV emerging as an independent predictive factor for GPR. Additionally, CIBERSORT analysis revealed noteworthy differences in the expression of immune makers between cPR and non-cPR group. Furthermore, a significantly heightened density of CD8 + T cells and a reduced density of FOXP3 + T cells were observed in GPR than PPR. Importantly, patients exhibiting GPR or inflammatory type demonstrated improved overall survival and disease-free survival. Notably, stromal type was an independent prognostic factor in multivariate analysis. Our study indicates the elevated TILV in pre-treatment specimens may predict a favorable response to NACT, while identifying stromal type in post-treatment specimens as an independent prognostic factor. Moreover, we proposed this pathological grading system in NACT patients, which may offer a more comprehensive understanding of treatment response and prognosis.
Subject(s)
Lymphocytes, Tumor-Infiltrating , Neoadjuvant Therapy , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/drug therapy , Middle Aged , Lymphocytes, Tumor-Infiltrating/immunology , Adult , Treatment Outcome , Aged , Disease-Free SurvivalABSTRACT
BACKGROUND: Severe heart failure (HF) has a higher mortality during vulnerable period while targeted predictive tools, especially based on drug exposures, to accurately assess its prognoses remain largely unexplored. Therefore, this study aimed to utilize drug information as the main predictor to develop and validate survival models for severe HF patients during this period. METHODS: We extracted severe HF patients from the MIMIC-IV database (as training and internal validation cohorts) as well as from the MIMIC-III database and local hospital (as external validation cohorts). Three algorithms, including Cox proportional hazards model (CoxPH), random survival forest (RSF), and deep learning survival prediction (DeepSurv), were applied to incorporate the parameters (partial hospitalization information and exposure durations of drugs) for constructing survival prediction models. The model performance was assessed mainly using area under the receiver operator characteristic curve (AUC), brier score (BS), and decision curve analysis (DCA). The model interpretability was determined by the permutation importance and Shapley additive explanations values. RESULTS: A total of 11,590 patients were included in this study. Among the 3 models, the CoxPH model ultimately included 10 variables, while RSF and DeepSurv models incorporated 24 variables, respectively. All of the 3 models achieved respectable performance metrics while the DeepSurv model exhibited the highest AUC values and relatively lower BS among these models. The DCA also verified that the DeepSurv model had the best clinical practicality. CONCLUSIONS: The survival prediction tools established in this study can be applied to severe HF patients during vulnerable period by mainly inputting drug treatment duration, thus contributing to optimal clinical decisions prospectively.
Subject(s)
Heart Failure , Proportional Hazards Models , Humans , Heart Failure/mortality , Heart Failure/drug therapy , Female , Male , Aged , Reproducibility of Results , Prognosis , Survival Analysis , Middle Aged , ROC Curve , Algorithms , Area Under Curve , Databases, Factual , Deep Learning , Severity of Illness IndexABSTRACT
Vinylidene ortho-quinone methides (VQMs) have been proven to be versatile and crucial intermediates in the catalytic asymmetric reaction in last decade, and thus have drawn considerable concentrations on account of the practical application in the construction of enantiomerically pure functional organic molecules. However, in comparison to the well established chiral Brønsted base-catalyzed asymmetric reaction via VQMs, chiral Brønsted acid-catalyzed reaction is rarely studied and there is no systematic summary to date. In this review, we summarize the recent advances in the chiral Brønsted acid-catalyzed asymmetric reaction via VQMs according to three types of reactions: a) intermolecular asymmetric nucleophilic addition to VQMs; b) intermolecular asymmetric cycloaddition of VQMs; c) intramolecular asymmetric cyclization of VQMs. Finally, we put forward the remained challenges and opportunities for potential breakthroughs in this area.
ABSTRACT
BACKGROUND: The gut microbiota plays a crucial role in coronary artery disease (CAD) development, but limited attention has been given to the role of the microbiota in preventing this disease. This study aimed to identify key biomarkers using metagenomics and untargeted metabolomics and verify their associations with atherosclerosis. METHODS: A total of 371 participants, including individuals with various CAD types and CAD-free controls, were enrolled. Subsequently, significant markers were identified in the stool samples through gut metagenomic sequencing and untargeted metabolomics. In vivo and in vitro experiments were performed to investigate the mechanisms underlying the association between these markers and atherosclerosis. RESULTS: Faecal omics sequencing revealed that individuals with a substantial presence of Faecalibacterium prausnitzii had the lowest incidence of CAD across diverse CAD groups and control subjects. A random forest model confirmed the significant relationship between F. prausnitzii and CAD incidence. Notably, F. prausnitzii emerged as a robust, independent CAD predictor. Furthermore, our findings indicated the potential of the gut microbiota and gut metabolites to predict CAD occurrence and progression, potentially impacting amino acid and vitamin metabolism. F. prausnitzii mitigated inflammation and exhibited an antiatherosclerotic effect on ApoE-/- mice after gavage. This effect was attributed to reduced intestinal LPS synthesis and reinforced mechanical and mucosal barriers, leading to decreased plasma LPS levels and an antiatherosclerotic outcome. CONCLUSIONS: Sequencing of the samples revealed a previously unknown link between specific gut microbiota and atherosclerosis. Treatment with F. prausnitzii may help prevent CAD by inhibiting atherosclerosis.
Subject(s)
Atherosclerosis , Gastrointestinal Microbiome , Humans , Animals , Mice , Faecalibacterium prausnitzii/metabolism , LipopolysaccharidesABSTRACT
Keratin and lipid structures in the stratum corneum (SC) are closely related to the SC barrier function. The application of penetration enhancers (PEs) disrupts the structure of SC, thereby promoting infiltration. To quantify these PE-induced structural changes in SC, we used confocal Raman imaging (CRI) and polarized Raman imaging (PRI) to explore the integrity and continuity of keratin and lipid structures in SC. The results showed that water is the safest PE and that oleic acid (OA), sodium dodecyl sulfate (SDS), and low molecular weight protamine (LMWP) disrupted the ordered structure of keratin, while azone and liposomes had less of an effect on keratin. Azone, OA, and SDS also led to significant changes in lipid structure, while LMWP and liposomes had less of an effect. Establishing this non-invasive and efficient strategy will provide new insights into transdermal drug delivery and skin health management.
Subject(s)
Liposomes , Skin , Liposomes/pharmacology , Epidermis , Oleic Acid/pharmacology , KeratinsABSTRACT
OBJECTIVE: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. METHODS: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. RESULTS: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. CONCLUSIONS: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice.
Subject(s)
Carbazoles , DNA, Z-Form , Neoplasms , Mice , Animals , Lipopolysaccharides/pharmacology , Apoptosis , PyroptosisABSTRACT
PURPOSE: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-ß-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. CONCLUSION: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.
Subject(s)
Anti-Bacterial Agents , Azabicyclo Compounds , Aztreonam , Drug Resistance, Multiple, Bacterial , Drug Synergism , Escherichia coli , Metabolomics , Aztreonam/pharmacology , Azabicyclo Compounds/pharmacology , Escherichia coli/drug effects , Escherichia coli/metabolism , Escherichia coli/genetics , Anti-Bacterial Agents/pharmacology , Humans , Microbial Sensitivity Tests , Escherichia coli Infections/microbiology , Escherichia coli Infections/drug therapy , Metabolome/drug effectsABSTRACT
Although organic-inorganic hybrid Mn2+ halides have advanced significantly, achieving high stability and narrow-band emission remains enormously challenging owing to the weak ionic nature and soft crystal lattice of the halide structure. To address these issues, we proposed a cationic engineering strategy of long-range cation π···π stacking and C-H···π interactions to simultaneously improve the crystal structural stability and rigidity. Herein, two organic zero-dimensional (0D) manganese halide hybrids of (BACQ)2MnX4 [BACQ = 4-(butylamino)-7-chloroquinolin-1-ium; X = Cl and Br] were synthesized. (BACQ)2MnX4 display strong green-light emissions with the narrowest full width at half-maximum (fwhm) of 39 nm, which is significantly smaller than those of commercial green phosphor ß-SiAlON:Eu2+ and most of reported manganese halides. Detailed Hirshfeld surface analyses demonstrate the rigid environment around the [MnX4]2- units originating from the interactions between [BACQ]+. The rigid crystal structure weakens the electron-phonon coupling and renders narrow fwhm of these manganese halides, which is further confirmed by temperature-dependent emission spectra. Remarkably, (BACQ)2MnX4 realizes outstanding structural and luminescence stabilities in various extreme environments. Benefiting from the excellent performance, these Mn2+ halides are used to assemble light-emitting diodes with a wide color gamut of 105% of the National Television System Committee 1931 standard, showcasing the advanced applications in liquid-crystal-display backlighting.
ABSTRACT
Condensation of 3,3'-diamino-2,2'-ethylene-bridged azobenzene with 1,2,4,5-tetrakis-(4-formylphenyl) benzene produces a visible light responsive porous 2D covalent organic framework, COF-bAzo-TFPB, with a large surface area, good crystallinity, and thermal and chemical stability. The results demonstrate that the elaborated designed linker can make azo unit on the COF-bAzo-TFPB skeleton undergo reversible photoisomerization. This work expands the application scope of covalent organic frameworks in photo-controlled release, uptake of guest molecules, dynamic photoswitching, and UV-sensitive functions.