Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes ...and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.
Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid ...synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage-dependent pathogenic mechanisms is unknown.
Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis.
In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria-associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD.
Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.
El Teatro Romano de Cádiz (España) es parte de la herencia romana que ha permanecido oculta durante siglos bajo el casco histórico de la ciudad. Se trata del teatro romano más antiguo y de mayores ...dimensiones localizado en España. En el año 2010, se inició una intervención con el fin de descubrirlo. La intervención consiste en la construcción de una serie de bóvedas de hormigón bajo los edificios construidos sobre el teatro aplicando la técnica de la inyección armada. El control de esta intervención se está realizando por medio de dos técnicas: control topográfico y Análisis Modal Operacional. La metodología seguida para el control de la intervención en el área del teatro romano y los resultados obtenidos de la misma son los principales objetivos del presente artículo.
Introduction
Despite being widely used as a screening tool, a rigorous scientific evaluation of infrared thermography for the diagnosis of minimally symptomatic patients suspected of having COVID‐19 ...infection has not been performed.
Methods
A consecutive sample of 60 adult individuals with a history of close contact with COVID‐19 infected individuals and mild respiratory symptoms for less than 7 days and 20 confirmed COVID‐19 negative healthy volunteers were enrolled in the study. Infrared thermograms of the face were obtained with a mobile camera, and RT‐PCR was used as the reference standard test to diagnose COVID‐19 infection. Temperature values and distribution of the face of healthy volunteers and patients with and without COVID‐19 infection were then compared.
Results
Thirty‐four patients had an RT‐PCR confirmed diagnosis of COVID‐19 and 26 had negative test results. The temperature asymmetry between the lacrimal caruncles and the forehead was significantly higher in COVID‐19 positive individuals. Through a random forest analysis, a cut‐off value of 0.55°C was found to discriminate with an 82% accuracy between patients with and without COVID‐19 confirmed infection.
Conclusions
Among adults with a history of COVID‐19 exposure and mild respiratory symptoms, a temperature asymmetry of ≥ 0.55°C between the lacrimal caruncle and the forehead is highly suggestive of COVID‐19 infection. This finding questions the widespread use of the measurement of absolute temperature values of the forehead as a COVID‐19 screening tool.
Immune aging is a multi-faceted process that manifests as reduced competence to fight infections and malignant cells, as well as diminished tissue repair, unprovoked inflammation, and increased ...autoreactivity. The aging adaptive immune system, with its high complexity in functional cell subpopulations and diversity of B- and T-cell receptors, has to cope with the challenge of maintaining homeostasis while responding to exogenous stimuli and compensating for reduced generative capacity. With thymic involution, naïve T cells begin to function as quasi-stem cells and maintain the compartment through peripheral homeostatic proliferation that shapes the T-cell repertoire through peripheral selection and the activation of differentiation pathways. Similarly, reduced generation of early B-cell progenitors alters the composition of the peripheral B-cell compartment with the emergence of a unique, auto-inflammatory B-cell subset, termed age-associated B cells (ABCs). These changes in T- and B-cell composition and function are core manifestations of immune aging.
La Iglesia de San Dionisio es una de las más importantes desde el punto de vista histórico y patrimonial de Jerez de la Frontera (Cádiz). Al inicio del siglo XXI, varios pilares de la estructura ...comenzaron a presentar síntomas de agotamiento a compresión, hecho que condujo al cierre del templo. En 2005 se inició la investigación para identificar las causas del deterioro estructural y establecer una estrategia de reparación adecuada. El método aplicado para la reparación de la estructura fue la inyección con tubo-manguito. Frente a otros métodos de inyección previamente documentados en fábrica, la inyección con tubo-manguito permite aplicar presiones de inyección significativamente superiores, consiguiendo así una mayor homogeneización y mejora de las propiedades resistentes del material inyectado. Este artículo aborda la investigación llevada a cabo para caracterizar el origen de los daños, la descripción del procedimiento de reparación de la estructura y la evaluación de su efectividad.
The exocytosis of phosphonate modified mesoporous silica nanoparticles (P‐MSNs) is demonstrated and lysosomal exocytosis is identified as the mechanism responsible for this event. Regulation of P‐MSN ...exocytosis can be achieved by inhibiting or accelerating lysosomal exocytosis. Slowing down P‐MSN exocytosis enhances the drug delivery effect of CPT‐loaded P‐MSNs by improving cell killing.
Mitochondrial diseases are a clinically heterogenous group of disorders caused by respiratory chain dysfunction and associated with progressive, multi-systemic phenotype. There is no effective ...treatment or cure, and no FDA-approved drug for treating mitochondrial disease. To identify and characterize potential therapeutic compounds, we developed an in vitro screening assay and identified a group of direct AMP-activated protein kinase (AMPK) activators originally developed for the treatment of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as AICAR, these compounds allosterically activate AMPK in an AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. The direct AMPK activator PT1 significantly improved mitochondrial function in assays of cellular respiration, energy status, and cellular redox. PT1 also protected against retinal degeneration in a mouse model of photoreceptor degeneration associated with mitochondrial dysfunction and oxidative stress, further supporting the therapeutic potential of AMP-independent AMPK agonists in the treatment of mitochondrial disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Los felinos silvestres son especies vulnerables a los motores de pérdida de biodiversidad. De las 41 especies existentes en el mundo, siete se encuentran en el país (17% de las especies), que ...desafortunadamente comparten serias amenazas como la pérdida y transformación del hábitat, la cacería retaliativa por ataques a animales domésticos y la fragmentación de sus poblaciones por carreteras y centros poblados. Entre 2012 y 2015 se conocieron cinco casos de apariciones de felinos silvestres en el área urbana, correspondiente a cuatro especies. Esta información se obtuvo de notas periodísticas locales y regionales.
Ionic substances with melting points at or close to room temperature are referred to as ionic liquids. Interest in ionic liquids for their potential in different chemical processes is increasing, ...because they are environmentally benign and are good solvents for a wide range of both organic and inorganic materials. In this study, a capillary electrophoretic method for resolving phenolic compounds found in grape seed extracts is reported. The method, in which 1-alkyl-3-methylimidazolium-based ionic liquids are used as the running electrolytes, is simple and reproducible. The separation mechanism seems to involve association between the imidazolium cations and the polyphenols. The role of the alkyl substituents on the imidazolium cations was investigated and will be discussed.
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