ABSTRACT
Obesity is associated with an increased risk of severe Covid-19. However, the effectiveness of SARS-CoV-2 vaccines in people with obesity is unknown. Here we studied the relationship between body mass index (BMI), hospitalization and mortality due to Covid-19 amongst 3.5 million people in Scotland. Vaccinated people with severe obesity (BMI>40 kg/m2) were significantly more likely to experience hospitalization or death from Covid-19. Excess risk increased with time since vaccination. To investigate the underlying mechanisms, we conducted a prospective longitudinal study of the immune response in a clinical cohort of vaccinated people with severe obesity. Compared with normal weight people, six months after their second vaccine dose, significantly more people with severe obesity had unquantifiable titres of neutralizing antibody against authentic SARS-CoV-2 virus, reduced frequencies of antigen-experienced SARS-CoV-2 Spike-binding B cells, and a dissociation between anti-Spike antibody levels and neutralizing capacity. Neutralizing capacity was restored by a third dose of vaccine, but again declined more rapidly in people with severe obesity. We demonstrate that waning of SARS-CoV-2 vaccine-induced humoral immunity is accelerated in people with severe obesity and associated with increased hospitalization and mortality from breakthrough infections. Given the prevalence of obesity, our findings have significant implications for global public health.
ABSTRACT
Opiate addiction has a high rate of relapse. The accumulating evidence shows that electroacupuncture (EA) may be effective for the treatment of opiate relapse. However, the change of expression of CB1-Rs and CB2-Rs involve in 2Hz EA anti-relapse pathway is still unclear. To explore the changes of expression of CB1-Rs and CB2-Rs, heroin self-administration (SA) model rats were adopted and treated using 2Hz EA. The expressions of CB1-Rs and CB2-Rs were observed using immunohistochemistry method. The results showed that, compared with the control group, active pokes in the heroin-addicted group increased, while the active pokes decreased significantly in 2Hz EA group compared with heroin-addicted group. Correspondingly, the expression of CB1-Rs in prefrontal cortex (PFC), hippocampus (Hip), nucleus accumbens (NAc) and ventral tegmental area (VTA) all increased significantly while the expression of CB2-Rs in those relapse-relevant brain regions decreased obviously in heroin-addicted group when compared with the control group. In addition, the expression of CB1-Rs obviously decreased in the 2Hz EA group while the expression of CB2-Rs in those relapse-relevant brain regions increased significantly when compared with the heroin-addicted group. It indicated that 2Hz EA could attenuate the heroin-evoked seeking behaviors effectively. The anti-relapse effects of 2Hz EA might be related to the decrease of CB1-Rs and increase of CB2-Rs expression in relapse-relevant brain regions of heroin SA rats.
Subject(s)
Behavior, Animal/drug effects , Brain/drug effects , Drug-Seeking Behavior/drug effects , Electroacupuncture , Heroin Dependence/therapy , Heroin/administration & dosage , Narcotic Antagonists/administration & dosage , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Animals , Brain/metabolism , Brain/physiopathology , Disease Models, Animal , Extinction, Psychological/drug effects , Heroin Dependence/metabolism , Heroin Dependence/physiopathology , Heroin Dependence/psychology , Locomotion/drug effects , Male , Rats, Sprague-Dawley , Recurrence , Self Administration , Signal TransductionABSTRACT
OBJECTIVE: MiR-155-5p has various biological cellular functions in diverse pathology, including cardiovascular disease. Nevertheless, the role of miR-155-5p in atherosclerosis is still not well known. PATIENTS AND METHODS: The levels of miR-155-5p and AKT Serine/Threonine Kinase 1 (AKT1) in plasma samples from patients with atherosclerotic CAD were detected using quantitative Real-time PCR (qRT-PCR). Cell counting kit-8 (CCK-8) assay was used to analyze the proliferation of vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) in vitro. The migration of VSMCs and HUVECs was detected using wound healing assay. The invasion of VSMCs and HUVECs using was determined using the transwell invasion assay. The expression of AKT1 was measured using immunofluorescence staining analysis. RESULTS: MiR-155-5p was down-regulated in patients with atherosclerotic CAD. Up-regulation of miR-155-5p inhibited the proliferation, migration and invasion of VSMCs and HUVECs. Bioinformatics analysis and luciferase reporter assay indicated that AKT1 was the direct target of miR-155-5p and miR-155-5p bound to the 3'-untranslated region (3'-UTR) of AKT1. The expression of AKT1 was reduced in cell that was transfected with miR-155-5p. Up-regulation of AKT1 rescued the suppressive effect of miR-155-5p on the growth, migration and invasion of VSMCs and HUVECs. Down-expression of AKT1 partially neutralized the impacts of miR-155-5p on the growth, invasion and migration of VSMCs and HUVECs. Finally, we found that AKT1 was over-regulated in plasma samples of patients with atherosclerotic CAD and its level was negative with the level of miR-155-5p. CONCLUSIONS: Our study demonstrates that miR-155-5p suppresses the proliferation, migration and invasion of VSMCs and HUVECs through regulating AKT1, which provides the new insights into the precise role of miR-155-5p in atherosclerosis.
Subject(s)
Atherosclerosis/complications , Coronary Artery Disease/genetics , Human Umbilical Vein Endothelial Cells/cytology , MicroRNAs/genetics , Muscle, Smooth, Vascular/cytology , Proto-Oncogene Proteins c-akt/genetics , 3' Untranslated Regions , Atherosclerosis/genetics , Atherosclerosis/metabolism , Cell Movement , Cell Proliferation , Cells, Cultured , Coronary Artery Disease/etiology , Coronary Artery Disease/metabolism , Down-Regulation , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/metabolism , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
Current approaches for the ablation of atrial fibrillation are often effective, but only partially rooted in mechanistic understanding. Accordingly, they are unable to predict whether a given patient will or will not do well, or which lesions sets should or should not be performed - in any given patient. This goal would require clearer mechanistic definition of what sustains AF after it has been triggered (i.e. electrophysiological substrates). There are two schools of thought. The first proposes disorganized activity that self-sustains with no 'driver', and the second describes drivers that then cause disorganization. Interestingly, these mechanisms can be separated in human studies by mapping approach - proponents of the disorganized hypothesis studying small atrial areas at high resolution, and proponents of the driver model studying wide fields-of-view at varying resolutions. Focal impulse and rotor modulation (FIRM) mapping combines a wide field of view with physiologically based signal filtering and phase analysis, and has revealed that human AF is often sustained by rotors. In the CONFIRM Trial, targeting stable AF rotors/sources for ablation improved the single-procedure efficacy for paroxysmal and persistent AF over conventional ablation alone, as now confirmed by independent laboratories. FIRM mapping gives a mechanistic foundation to predict whether any selected lesions should intersect AF sources in any given patient and which mechanisms may cause recurrence. Rotors of varying characteristics have now been shown by many groups. These insights have reinvigorated interest in AF mapping, and rationalizing these findings will likely translate into improved therapy for our patients.
