Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration

UK Biobank is a major prospective epidemiological study, including multimodal brain imaging, genetics and ongoing health outcomes. Previously, we published genome-wide associations of 3,144 brain imaging-derived phenotypes, with a discovery sample of 8,428 individuals. Here we present a new open resource of genome-wide association study summary statistics, using the 2020 data release, almost tripling the discovery sample size. We now include the X chromosome and new classes of imaging-derived phenotypes (subcortical volumes and tissue contrast). Previously, we found 148 replicated clusters of associations between genetic variants and imaging phenotypes; in this study, we found 692, including 12 on the X chromosome. We describe some of the newly found associations, focusing on the X chromosome and autosomal associations involving the new classes of imaging-derived phenotypes. Our novel associations implicate, for example, pathways involved in the rare X-linked STAR (syndactyly, telecant

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.

Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the

Kawasaki disease (KD) has become the most common cause of acquired heart disease in children and is also a risk factor for ischemic heart disease in adults. However, Kawasaki disease lacks specific laboratory diagnostic indices. Thus, this study analyzed the T cell activation profiles of Kawasaki disease and assessed their value in the diagnosis of Kawasaki disease and the prediction of intravenous immunoglobulin (IVIG) sensitivity. We analyzed human leukocyte antigen-DR (HLA-DR), CD69 and CD25 expression on peripheral blood CD4+ and CD8+ T cells during the acute phase of KD. We compared the percentages of HLA-DR+/CD69+/CD25+ T cells in the CD4+ and CD8+ T cell populations of IVIG-effective and IVIG-resistant groups. Receiver operating characteristic curves were used to assess the diagnostic value of the above parameters. The median percentage of CD8+HLA-DR+ T cells and the median ratio of CD8+HLA-DR+ T cells/CD8+CD25+ T cells were significantly elevated in the patient group compared w

OBJECTIVE: To analyze the fluorine-18 fludeoxyglucose PET/computed tomography (18F-FDG PET/CT) findings of retroperitoneal leiomyosarcoma (RLMS) and the role of this method in differentiating between benign and malignant masses and classifying the malignant degree to improve the understanding of this rare disease. METHODS: Eight leiomyomas (A group), 13 RLMSs (B group), and 20 postoperative recurrence/metastasis RLMSs (C group) were enrolled. PET/CT features of B group were analyzed. The differences of metabolic parameters between three groups were compared, receiver operating characteristic (ROC) curve analysis was performed to group A and B, and correlation analysis was performed to subgroup B. RESULTS: (1) The RLMS patients were more likely to be female, and PET/CT showed a high degree of heterogeneous metabolism in the soft tissue mass. (2) The standardized uptake value (SUV) of RLMS were significantly higher than those of benign leiomyomas (P < 0.05). The area under the ROC curve

In the interest of the trend towards miniaturization of electronic gadgets, this study demonstrates a high-density data storage device with a very simple three-stacking layer consisting of only one charge trapping layer. A simple solution-processed technique has been used to fabricate the tristable non-volatile memory. The three-stacking layer was constructed in between two metals to form a two-terminal metal-insulator-metal structure. The fabricated device showed a large multilevel memory hysteresis window with a measured ON/OFF current ratio of 107 that might be attributed to the high charge trapped in molybdenum disulphide (MoS2) flakes-graphene quantum dots (GQDs) heterostructure. Transmission electron microscopy was performed to examine the orientation of MoS2-GQD and mixture dispersion preparation method. The obtained electrical data was used further to speculate the possible transport mechanisms through the fabricated device by a curve fitting technique. Also, endurance cycle an

BACKGROUND: Hands are the most common vehicle for the transmission of pathogens within the healthcare environment. Hand hygiene is the leading measure for reducing healthcare-associated infections (HCAIs) and preventing the spread of antimicrobial resistance. OBJECTIVE: An interventional study was carried out to evaluate the knowledge, attitude and practices of hand hygiene among third semester medical students. MATERIALS AND METHODS: A total of 152 medical students were evaluated using a pretest self-structured questionnaire to assess the knowledge, attitude and practices regarding hand hygiene. The students were trained by faculty of microbiology vigorously with the help of a lecture and demonstration on hand hygiene followed by hands-on training. The same group of students were then distributed the post-training questionnaire. The pre-training and post training data was analyzed and compared. RESULT: There was a significant improvement in knowledge, attitude and practice towards han

This studystudy focuses on the effect of radiation treatment and hydrogen peroxide (H2O2) on the toxicity of anticancer methotrexate. For cytotoxicity, different bioassays such as Allium cepa, hemolytic, brine shrimp were employed. The Ames test was used for mutagenicity analysis. The solutions having concentrations 5, 10 and 15 ppm were irradiated with UV radiation exposure time 15, 30, 45, 60, 75 and 90 min and gamma radiation absorbed doses 0.3, 0.6, 0.9, 1.2, 2, 3 and 4 kGy in combination with with H2O2. There was a clear difference observed for aqueous solution before and after treatment with reference to cytotoxicity and mutagenicity. In Allium cepa test, a 47.07, 44.36 and 38.23% increase in root length (RL), root count (RC) and mitotic index (MI) was observed, respectively, for UV/H2O2 treatment and in the case of gamma/H2O2 treatment, the RL, RC and MI were increased up to 49.39, 52.63 and 52.38%, respectively. Brine shrimp test has shown 85.95 and 91.30% decrease in toxicity

Sodium-glucose cotransporter-2 (SGLT2) is selectively expressed in the human kidney, where it executes reabsorption of filtered glucose with a high capacity; it may be overactive in patients with diabetes, especially in the early, hyperfiltering stage of the disease. As a therapeutic target, SGLT2 has been successfully engaged by orally active, selective agents. Initially developed as antihyperglycemic drugs, SGLT2 inhibitors have deployed a range of in vivo actions. Consequences of their primary effect, i.e., profuse glycosuria and natriuresis, involve hemodynamic (plasma volume and blood pressure reduction) and metabolic pathways (increase in lipid oxidation and ketogenesis at the expense of carbohydrate utilization); the hormonal mediation extends to insulin, glucagon, and gastrointestinal peptides. Their initial trial in high-risk patients with diabetes has provided evidence for marked reduction of cardiovascular risk. This review focuses on the quantitative pharmacology of SGLT2 i

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an i

BACKGROUND: The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a signalling hub associated with the pathogenesis of neuroinflammatory conditions such as multiple sclerosis (MS). NLRP3 inflammasome activation requires interplay between pathogen-/damage-associated molecular patterns and other soluble factors, which initiates inflammation to promote the secretion of the cytokine, interleukin (IL)-1β. OBJECTIVE: To determine if the expression of NLRP3 inflammasome signalling components is altered in the brain and in immune cells in MS. METHODS: Using post-mortem brain tissue from 21 cases, including 8 non-MS control, 7 primary progressive (PP) MS and 6 secondary progressive (SP) MS cases, alongside peripheral blood mononuclear cells (PBMCs) isolated from 45 subjects including healthy controls (n = 23), and people with (pw) a relapsing remitting (RR) (n = 15), SP (n = 5) or PP (n = 2) form of MS, we profiled the expression of

Monocytes are innate immune cells that release inflammatory factors upon detection of infectious and injurious stimuli. CD16+ monocytes, a subset of the total monocyte population, are associated with acute and chronic inflammation in human immunodeficiency virus-associated neurocognitive disorder and rheumatoid arthritis. Given the role monocytes play in regulating the host immune response, this investigation explored the effects of cannabinoids on the monocyte secretome for potential therapeutic applications. Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are major cannabis-derived compounds established to have immune-modulating properties. Despite a rise in medical cannabis use, the specific mechanism by which THC and CBD modulate the inflammatory response, including by human monocytes remains poorly understood. We hypothesized that THC and CBD suppress toll-like receptor (TLR) 7- or TLR8-induced inflammatory profiles by CD16+ and CD16- monocytes, specifically interleukin (IL) 1

In the interest of the trend towards miniaturization of electronic gadgets, this study demonstrates a high-density data storage device with a very simple three-stacking layer consisting of only one charge trapping layer. A simple solution-processed technique has been used to fabricate the tristable non-volatile memory. The three-stacking layer was constructed in between two metals to form a two-terminal metal-insulator-metal structure. The fabricated device showed a large multilevel memory hysteresis window with a measured ON/OFF current ratio of 107 that might be attributed to the high charge trapped in molybdenum disulphide (MoS2) flakes-graphene quantum dots (GQDs) heterostructure. Transmission electron microscopy was performed to examine the orientation of MoS2-GQD and mixture dispersion preparation method. The obtained electrical data was used further to speculate the possible transport mechanisms through the fabricated device by a curve fitting technique. Also, endurance cycle an

COVID-19 vaccination programmes are ongoing worldwide. Neutralizing antibodies are thought to be key for host protection against COVID-19; however, strategies that focus only on neutralizing antibodies may not be sufficient to cope with the pandemic in the longer term owing to the decay of antibody titres and the emergence of antibody-escape variants of SARS-CoV-2. Here, we describe the protective roles of T cells in COVID-19 and the conservation of T cell epitopes in SARS-CoV-2 variants of concern, and discuss the potential contribution of T cell-oriented strategies to controlling the COVID-19 pandemic. This Comment article proposes that T cell-oriented vaccine strategies should be considered to control the COVID-19 pandemic in the longer term, given declining levels of neutralizing antibodies with time after vaccination or infection and the emergence of viral escape variants.

BACKGROUND AND PURPOSE: Increasing evidence suggests systemic inflammation-caused skeletal muscle atrophy as a major clinical feature of cachexia. Triptolide obtained from Tripterygium wilfordii Hook F possesses potent anti-inflammatory and immunosuppressive effects. The present study aims to evaluate the protective effects and molecular mechanisms of triptolide on inflammation-induced skeletal muscle atrophy. EXPERIMENTAL APPROACH: The effects of triptolide on skeletal muscle atrophy were investigated in LPS-treated C2C12 myotubes and C57BL/6 mice. Protein expressions and mRNA levels were analysed by western blot and qPCR, respectively. Skeletal muscle mass, volume and strength were measured by histological analysis, micro-CT and grip strength, respectively. Locomotor activity was measured using the open field test. KEY RESULTS: Triptolide (10-100 fM) up-regulated protein synthesis signals (IGF-1/p-IGF-1R/IRS-1/p-Akt/p-mTOR) and down-regulated protein degradation signal atrogin-1 in C2C12 myotubes. In LPS (100 ng·ml-1 )-treated C2C12 myotubes, triptolide up-regulated MyHC, IGF-1, p-IGF-1R, IRS-1 and p-Akt. Triptolide also down-regulated ubiquitin-proteasome molecules (n-FoxO3a/atrogin-1/MuRF1), proteasome activity, autophagy-lysosomal molecules (LC3-II/LC3-I and Bnip3) and inflammatory mediators (NF-κB, Cox-2, NLRP3, IL-1β and TNF-α). However, AG1024, an IGF-1R inhibitor, suppressed triptolide-mediated effects on MyHC, myotube diameter, MuRF1 and p62 in LPS-treated C2C12 myo

BACKGROUND: Glaucoma, the major cause of irreversible blindness worldwide, is characterized by progressive degeneration of retinal ganglion cells (RGCs). Current treatments for glaucoma only slow or partially prevent the disease progression, failing to prevent RGCs death and visual field defects completely. Glutamate excitotoxicity via N-methyl-D-aspartic acid (NMDA) receptors plays a vital role in RGCs death in glaucoma, which is often accompanied by oxidative stress and NLRP3 inflammasome activation. However, the exact mechanisms remain unclear. METHODS: The glutamate-induced R28 cell excitotoxicity model and NMDA-induced mouse glaucoma model were established in this study. Cell counting kit-8, Hoechst 33342/PI dual staining and lactate dehydrogenase release assay were performed to evaluate cell viability. Annexin V-FITC/PI double staining was used to detect apoptosis and necrosis rate. Reactive oxygen species (ROS) and glutathione (GSH) were used to detect oxidative stress in R28 cells. Levels of proinflammatory cytokines were measured by qRT-PCR. Transmission electron microscopy (TEM) was used to detect necroptotic morphological changes in RGCs. Retinal RGCs numbers were detected by immunofluorescence. Hematoxylin and eosin staining was used to detect retinal morphological changes. The expression levels of RIP1, RIP3, MLKL and NLRP3 inflammasome-related proteins were measured by immunofluorescence and western blotting. RESULTS: We found that glutamate excitotoxicity induc