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关键词： apoptosis   DNA damage   DNase   trans-kingdom effector   Type VI secretion systems (T6SSs)   Yersinia pseudotuberculosis  

摘要： The Type VI secretion system (T6SS) is a key virulence mechanism utilized by many Gram-negative bacteria to mediate the microbial competition and host pathogenesis. Despite the identification of diverse T6SS effectors targeting eukaryotic or prokaryotic cells, the trans-kingdom T6SS effectors that simultaneously target both eukaryotic and prokaryotic cells remain rarely reported. In this study, it is demonstrated that Yersinia pseudotuberculosis (Yptb) T6SS secretes a DNase effector, TkeA, which induces apoptosis in host cells. The translocation of TkeA into host cells causes nuclear DNA damage. This, in turn, activates the DNA-sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. The activation of the cGAS-STING pathway by TkeA subsequently triggers apoptosis in host cells via extrinsic pathways, with tumor necrosis factor (TNF) signaling playing a critical role. Additionally, TkeA enhances bacterial competition by targeting rival bacteria, thereby promoting host colonization. These findings reveal that the transkingdom T6SS effector TkeA executes a "one weapon, two battlefields" strategy, acting as a trans-kingdom effector that enhances interbacterial competition while inducing apoptosis in host cells through the activation of the cGAS-STING-TNF axis. This highlights a previously unrecognized dimension of bacterial virulence strategies and expands the understanding of host-pathogen interactions involving T6SS effectors.

关键词： 5-MTHF   5-methyl THF   AA   arachidonic acid   ADHD   attention-deficit hyperactivity disorder   AIMS   Abnormal Involuntary Movement Scale   ALA   α-lipoic acid   AMPK   AMP-activated protein kinase   AP   antipsychotic   ASD   autism spectrum disorder   BARS   Barnes Akathisia Rating Scale   BDNF   brain-derived neurotrophic factor   BPRS   Brief Psychiatric Rating Scale   CDSS   Calgary Depression Scale for Schizophrenia   CGI-S   Clinical Global Impression–Severity   CI   confidence interval   DHA   docosahexaenoic acid   DSHEA   Dietary Supplement Health and Education Act   EMA   European Medicines Agency   EPA   eicosapentaenoic acid   EPS   extrapyramidal symptoms   FDA   US Food and Drug Administration   FGA   first-generation antipsychotic   GAF   Global Assessment of Functioning   GSH   glutathione   HDRS   Hamilton Depression Rating Scale   IL   interleukin   LDL   low-density lipoprotein   LTP   long-term potentiation   MCCB   MATRICS Cognitive Consensus Battery   mGluR2   metabotropic glutamate receptor 2   NAC   N-Acetylcysteine   NbN   neuroscience-based nomenclature   Nf-kB   nuclear factor kappa-light-chain-enhancer   NMDA   N-methyl-D-aspartic acid   Nrf-2   nuclear factor erythroid 2-related factor   OR   odds ratio   PANSS   Positive and Negative Symptoms of Schizophrenia   PI3K   phosphatidylinositol-3 kinase   PPARγ   peroxisome proliferator-activated receptor gamma   PUFA   polyunsaturated fatty acid   UGT   UDP-glucuronosyltransferase   RCT   randomized controlled trial   SANS   Scale for the Assessment of Negative Symptoms   SAS   Simpson-Angus Scale   SCFA   short-chain fatty acids   SGA   second-generation antipsychotic   THF   tetrahydrofolate   TNF-α   tumor necrosis factor-α   UKU   Udvalg for Kliniske Undersøgelser   VDR   vitamin D receptor  

摘要： Antipsychotic (AP) medications are the primary treatment for severe mental illnesses, including schizophrenia and severe mood disorders. APs are currently categorized into typical or first-generation APs and atypical or second-generation APs. Although both first-generation and second-generation APs are considered effective in treating psychotic symptoms in severe mental disorders, they differ in their mechanisms, treatment strategies, and side effect profiles. Because of their potential motor and metabolic side effects, which often compromise patient adherence and clinical outcomes, whether and how to use APs remains controversial. The use of dietary interventions in combination with APs is emerging as a viable strategy to reduce AP adverse effects while maintaining their efficacy and enhance patient adherence to treatment. In contrast to drugs that possess a well defined molecular mechanism of action, dietary interventions act in pleiotropic ways by nature. While providing a holistic approach to patient care this pleiotropy needs to be analyzed and systematized to enhance the efficacy and safety of the combination of them with APs. Guidelines for this type of treatment are still needed. In this review, we explore the pharmacological properties, therapeutic applications, and limitations of APs, and discuss the potential benefits and limitations of those dietary interventions that are employed to improve the efficacy and counteract side effects of APs discussing also their mechanisms of action. Finally, we critically discuss the main results of clinical studies combining APs and dietary interventions and provide a view on future directions in terms of research and clinical use of these combinations. Significance Statement: Antipsychotic drugs are useful in a variety of psychiatric conditions, yet their use is hampered by issues of efficacy and safety. An important step toward therapy optimization is their use in combination with dietary interventions (ie, dietary sup

关键词： tumor immunity   T cell-based tumor epitopes   immunopeptidomics   HLA-presented ligands   cancer immunotherapy  

摘要： A fundamental principle of immunotherapy is that T cells are capable of detecting tumor epitopes presented on cancer cell surfaces. Immunopeptidomic strategies empowered by liquid chromatography-tandem mass spectrometry have transformed tumor epitopes identification and provided novel insights into tumor immunology. It enables in-depth profiling of major histocompatibility complex (MHC) presented ligands, thereby offering valuable perspectives on the molecular dialog among tumor and T cells. Here, we developed an immune-ligand identification and analysis pipeline from large-scale immunopeptidomics data. Through an extensive collection and processing of 5821 immunopeptidomic samples, which amounted to 305.7 million MS2 spectra, we identified 24 380 595 peptide-spectrum matches from these samples and further detected a total of 1 017 731 unique MHC immune ligands. These ligands were deconvolved and classified to specific HLA alleles. In total, we detected 582 852 HLA-I peptides and 434 879 HLA-II peptides that can bind to 292 HLA alleles, thereby greatly expanding the cancer immunopeptidome. Additionally, we identified and annotated 372 720 tumor-associated post-translational modification (PTM) peptides, revealing the comprehensive landscape of PTM antigens. All ligands and annotations were aggregated into *** Atlas, a comprehensive repository dedicated to tumor-derived HLA-presented ligands across 26 major human cancers (54 subtypes). Overall, our study uniquely integrates batch-effect correction, leverages the optimized software with novel deconvolution approach for immunopeptidomics analysis and ligand identification, and provides a public web portal with a comprehensive HLA ligand repository. *** Atlas functions as an invaluable resource, offering crucial understandings into immunology investigations. It will accelerate the advancement of cancer vaccines and immunotherapies. *** Atlas is available at http://***/***-Atlas/.

关键词： 2-AG   2-arachidonoylglycerol   2-MAGs   2-mono-acyl-glycerols   2-OG   2-oleoylglycerol   AA   arachidonic acid   AA-5-HT   N-arachidonoyl-serotonin   AA-Ser   N-arachidonoyl-serine   ABHD   alpha/beta hydrolase domain-containing enzyme   AD   Alzheimer disease   AEA   anandamide (N-arachidonoylethanolamine)   ALS   amyotrophic lateral sclerosis   AMP   adenosine monophosphate   Aβ   amyloid-beta   BPC-157   body protective compound-157   BK channel   big potassium (K+) channels   BPA   bisphenol A   BMI   body mass index   cAMP   cyclic adenosine monophosphate   CBD   cannabidiol   CB1   cannabinoid receptor type 1   CB2   cannabinoid receptor type 2   CBDV   cannabidivarin   CFA   complete Freund’s adjuvant   CNS   central nervous system   COX-2   cyclooxygenase-2   CP55,940   a nonselective cannabinoid agonist   DAG   diacylglycerol   DAGL   diacylglycerol lipase   DHA-DA   N-docosahexaenoyl dopamine   eCB   endocannabinoid   eCBome   endocannabinoidome   EPA   eicosapentaenoic acid   EPSCs   excitatory postsynaptic currents   FAAH   fatty acid amide hydrolase   FAAH-2   fatty acid amide hydrolase 2   FABP5   fatty acid-binding protein 5   FADS2   fatty acid desaturase 2   FAE   fatty acid ethanolamide   FMT   fecal microbiota transplant   Gi/o   G-protein–coupled receptor subtypes (inhibitory)   GLP-1   glucagon-like peptide-1   GPCRs   G-protein–coupled receptors   GP-NAE   glycerophospho-N-acylethanolamine   Gq/11   G-protein–coupled receptor subtype (activates phospholipase C)   Gs   G-protein–coupled receptor subtype (stimulating)   HEK293   human embryonic kidney 293 cells   HD   Huntington disease   HPA   hypothalamic-pituitary-adrenal (axis)   IBD   inflammatory bowel disease   IEM   inherited erythromelalgia   IL   interleukin   IPSCs   inhibitory postsynaptic currents   Kv   voltage-gated potassium channels   Kv3.1   voltage-gated potassium channel subtype 3.1   Kv4.3   voltage-gated potassium channel subtype 4.3   Kv1.1   voltage-gated potassium channel subtype 1.1   Kv7.1-7.5   voltage-gated potassium channel subtypes 1-5 (also known as KCNQ1-KCNQ5)   LEAN   linoleoylethanolamine   LOX   lipoxygenase   LPA   lysophosphatidic acid   LPI   lysophosphatidylinositol   M1   pro-inflammatory macrophage phenotype 1   M2   anti-inflammatory macro  

摘要： The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s. It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol;their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels;and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCBlike signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome). This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer. The importance of other "eCBomes" in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being. Significance Statement: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across

关键词： Bronchoalveolar lavage   COPD   IL-26   lung function   bronchoalveolar pathology   nasal lavage   nasal cavity  

摘要： Background: Novel specific therapy in chronic obstructive pulmonary disease (COPD) will require accessible targets for endotyping to identify responsive patients. It is therefore of interest that IL-26 in the bronchoalveolar space is enhanced and associates with bronchoalveolar pathology among long-term smokers (LTS) with and without COPD. Objective: We determined whether IL-26 in the nasal cavity can be produced by T cells and associates with bronchoalveolar pathology and clinical symptoms in LTS with and without COPD. Methods: We characterized LTS with and without COPD plus healthy nonsmokers by radiology, spirometry, modified Medical Research Council scale, and St George Respiratory Questionnaire. We determined extracellular IL-26 concentrations (via ELISA) in nasal (NAL) and bronchoalveolar lavage (BAL) samples, BAL neutrophil counts, and NAL IL-26+ T-cell expression (via flow cytometry). Results: The NAL IL-26 concentrations were higher in LTS with COPD than in healthy nonsmokers. These enhanced IL-26 concentrations displayed a positive correlation with forced expiratory volume in 1 second/forced vital capacity ratio. The IL-26 protein was expressed in CD4+ and CD8+ T cells, but only a small portion of these cells coexpressed IL-15, IL-17A, or IL-22 in LTS with COPD. In this group, IL-26+ CD3+ T cells displayed a negative correlation with forced expiratory volume in 1 second, as did with extracellular NAL IL-26 concentrations. The relative mean fluorescence intensity for CD8+ T cells displayed a negative correlation with modified Medical Research Council and St George Respiratory Questionnaire score. Conclusion: In the nasal cavity, IL-26 can be produced by local cells. This IL-26 reflects bronchoalveolar pathology and clinical symptoms, thereby constituting an accessible target with potential for clinically relevant endotyping in COPD. (J Allergy Clin Immunol 2025;156:118-28.)

关键词： Preformed DSA   Imlifidase   Kidney transplantation   Highly sensitized patients   HLA delisting   Pretransplant desensitization  

摘要： Highly sensitized patients awaiting kidney transplantation face substantial challenges due to the presence of potential donor-specific anti-HLA antibodies (DSA). These antibodies increase the risk of antibody-mediated rejection (ABMR), but also complicate their access to HLA compatible transplantation. Although advancements in allocation priority programs, such as the Spanish Program for the Access of Highly Sensitized Patients to Kidney Transplantation (PATHI), have introduced virtual crossmatching (v-XM) to streamline compatibility assessments, patients with >99,5 % virtual panel reactive antibodies (vPRA) often remain on waiting lists for extended periods with minimal chances of receiving a transplant. This article summarizes Spanish guidelines for a harmonized and comprehensive framework for the management of highly sensitized patients. These guidelines focus on strategies to facilitate transplantation in the presence of DSA, including a stepwise approach to delist HLA antigens, prioritizing those recognized as "less deleterious" antibodies, to expand transplant options while minimizing immunological risks. Conventional desensitization techniques are discussed, alongside the innovative use of imlifidase to enable transplants in particularly complex cases. Post-transplant monitoring protocols are also exposed, with a focus on early detection of antibody rebound and effective management of ABMR. Ultimately, this resource offers clinicians a structured framework to navigate the intricate challenges of kidney transplantation in high-risk populations, aiming to enhance access to life-saving procedures and improve patient outcomes.

关键词： DSAE   Distal splenic artery embolization   LDLT   living donor liver transplant   PASE   Proximal splenic artery embolization   SASS   splenic artery steal syndrome   SAM   splenic artery modulation   TNF   tumor necrosis factor  

摘要： Indications with Preferred Techniques for Splenic Artery Embolization. Splenic artery embolization S. No Indication Preferred technique (PSAE or DSAE/parenchymal embolization) 1. Splenic trauma PSAE, DSAE done in case of active bleed/extravasation...

关键词： cholesterolized liposome   combination therapy   IL-1 beta   immunotherapy   inflammasome   oxidized mitochondrial DNA   radiotherapy   TLR7 agonist  

摘要： BackgroundRadiotherapy (RT) is a key treatment modality in cancer therapy, utilizing high-energy radiation to directly kill tumor cells. Recent research has increasingly highlighted RT's potential to indirectly enhance antitumor immunity. However, this immune activation alone often fails to generate sustained systemic antitumor responses. In this study, we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7 (TLR7) agonist liposomes, specifically 1V209-Cho-Lip, with *** tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were utilized to investigate changes in function and the activated pathways through RNA sequencing. Additionally, we explored the role of oxidized mitochondrial DNA (ox-mtDNA) released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses. The involvement of interleukin-1 beta (IL-1 beta) and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1 beta-/- and cysteinyl aspartate specific proteinase 1 knockout (Casp1-/-) mouse *** combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models. This combination therapy enhanced maturation, antigen presentation and IL-1 beta secretion of dendritic cells (DCs) in vitro. Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs. The antitumor effect of the combined therapy was significantly reduced in Il-1 beta-/- and Casp1-/- *** study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.