Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that ...nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Cardiovascular disease (CVD) is the leading cause of mortality in the world, with most CVD-related deaths resulting from myocardial infarction or stroke. The main underlying cause of thrombosis and ...cardiovascular events is atherosclerosis, an inflammatory disease that can remain asymptomatic for long periods. There is an urgent need for therapeutic and diagnostic options in this area. Atherosclerotic plaques contain autoantibodies
, and there is a connection between atherosclerosis and autoimmunity
. However, the immunogenic trigger and the effects of the autoantibody response during atherosclerosis are not well understood
. Here we performed high-throughput single-cell analysis of the atherosclerosis-associated antibody repertoire. Antibody gene sequencing of more than 1,700 B cells from atherogenic Ldlr
and control mice identified 56 antibodies expressed by in-vivo-expanded clones of B lymphocytes in the context of atherosclerosis. One-third of the expanded antibodies were reactive against atherosclerotic plaques, indicating that various antigens in the lesion can trigger antibody responses. Deep proteomics analysis identified ALDH4A1, a mitochondrial dehydrogenase involved in proline metabolism, as a target antigen of one of these autoantibodies, A12. ALDH4A1 distribution is altered during atherosclerosis, and circulating ALDH4A1 is increased in mice and humans with atherosclerosis, supporting the potential use of ALDH4A1 as a disease biomarker. Infusion of A12 antibodies into Ldlr
mice delayed plaque formation and reduced circulating free cholesterol and LDL, suggesting that anti-ALDH4A1 antibodies can protect against atherosclerosis progression and might have therapeutic potential in CVD.
This paper shows some results of the analysis of wall construction with adobe bricks, carried out in a pilot building in Villa Clara, Cuba. Our main objective was to obtain some construction ...recommendations to avoid the humidity due to capillarity. The recommendations deal with uprising speed of construction, adequate wall longitude, binding mortar between adobe bricks, adobe protection from weathering, etc.
En el presente artículo se estudian las condiciones en las que deben ser levantados los muros de adobe en construcciones de tierra. Para ello, se construye una edificación piloto en Villa Clara, ...Cuba, que ha servido de base para probar distintas soluciones constructivas. Como resultado de esta investigación se dan recomendaciones para evitar el ascenso de la humedad por capilaridad, sobre la velocidad de levantamiento, la longitud de muro adecuada, el mortero de unión tanto de adobes entre sí como de adobe con otro material, el cerramento, los dinteles, la protección de vanos así como para el revestimiento adecuado para la protección del muro de adobe del intemperismo.
(
) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key
virulence factor hydrolyzes urea, facilitating bacterial survival ...in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for
urease (
U). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel
U inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.
Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, ...facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.
RESUMEN La rápida propagación del SARS-CoV-2 ha ocasionado grandes desafíos, algunos de ellos relacionados con la gestión y la visibilidad de la información. Los profesionales de las instituciones de ...información enfrentaron el reto de tener que reorganizar sus servicios en un breve tiempo, con un componente tecnológico esencial para lograr la virtualidad ante el imperativo indiscutible del distanciamiento físico. Como parte del Plan de enfrentamiento desplegado por Cuba durante esta crisis sanitaria, el Centro Nacional de Información de Ciencias Médicas (CNICM/Infomed) desempeña un rol fundamental, al actuar como proveedor y facilitador de las fuentes, herramientas y servicios de información científica especializada, además de garantizar la plataforma tecnológica para todo el sistema nacional de salud y la población. El presente documento se propone describir el flujo de trabajo concebido por esta institución, los espacios y modos empleados para la producción y difusión de la información científica durante la epidemia, así como los aportes realizados (elaboración de productos y desarrollo e implementación de herramientas y servicios( para apoyar las investigaciones científicas y la toma de decisiones en salud durante la pandemia de la COVID-19.
RESUMEN Los procesos de docencia e investigación constituyen un soporte esencial en la sociedad actual, donde prevalece una cultura de aprendizaje a lo largo de la vida y el progreso hacia una ...investigación más social y abierta. Para dar respuesta a este reto es primordial estudiar los activos intangibles existentes en un momento y tiempo determinados en una institución o departamento docente, con el propósito de definir estrategias orientadas a elevar la capacidad de los profesores e investigadores. El presente estudio tuvo como objetivo auditar el conocimiento organizacional de los trabajadores del Departamento de Docencia e Investigación del Centro Nacional de Información de Ciencias Médicas de Cuba, como parte de un estudio general que se realizó en los segmentos técnicos de la institución. Para esto se realizó una investigación cualitativa de tipo descriptiva entre mayo y junio del año 2018. Se aplicó una encuesta ajustada a las características de las actividades docentes e investigativas y se realizaron encuentros con todos los trabajadores. Se identificaron los elementos que caracterizan la gestión del conocimiento de los miembros del departamento, como son los conocimientos, las habilidades y las actitudes para conducir los procesos en los que están involucrados, y que habitualmente socializan tanto en la organización como en el entorno nacional e internacional. Se identifica como barrera la poca visibilidad en las redes sociales profesionales. Se requiere trazar estrategias para crear capacidades en el desarrollo de los procesos docentes e investigativos del Centro Nacional de Información de Ciencias Médicas.
Obex® may be helpful in reducing body weight and fat. The current study was carried out to evaluate the efficacy and safety of Obex® in the treatment of overweight and obese subjects.
A double-blind, ...randomised, controlled phase III clinical trial was conducted involving 160 overweight and obese subjects (BMI ≥ 25.0 and < 40 kg/m
) aged 20 to 60 years, who received Obex® (n = 80) and placebo (n = 80) plus non-pharmacological treatment (physical activity and nutritional counseling). One sachet of Obex® or placebo were administered before the two main meals each day for 6 months. In addition to anthropometric measurements and blood pressure, fasting plasma and 2 h glucose levels during the oral glucose tolerance test, lipid profile, insulin, liver enzymes, creatinine, and uric acid (UA) were determined, insulin resistance (HOMA-IR) beta-cell function (HOMA-β) were assessed and insulin sensitivity (IS) was calculated with three indirect indexes.
After 3 months of Obex®, 48.3% of the participants (28/58) achieved complete success in reducing both weight and waist circumference by greater than or equal to 5% from baseline, as opposed to 26.0% (13/50) of individuals receiving placebo (p = 0.022). Compared to baseline, at 6 months no differences were found between the groups concerning anthropometric and biochemical measurements, except for high-density lipoprotein cholesterol (HDL-c) levels, which were higher in subjects receiving Obex® compared to those receiving placebo (p = 0.030). After 6 months of treatment, both groups showed reduced cholesterol and triglyceride levels (p < 0.012) compared to baseline value. However, only those intake Obex® showed reduced insulin concentrations and HOMA-IR, improved IS (p < 0.05), and decreased creatinine and UA levels (p < 0.005).
The consumption of Obex® together with lifestyle changes increased HDL-c, contributed to a rapid reduction of weight and waist circumference, as well as improved insulin homeostasis, which did not occur in the placebo group, and appears to be safe as an adjunct at conventional obesity treatment.
Clinical trial protocol was registered in the Cuban public registry of clinical trials under code RPCEC00000267 on 17/04/2018 and also registered in the international registry of clinical trials, ClinicalTrials.gov, under code: NCT03541005 on 30/05/2018.
RESUMEN Introducción: La gestión de la comunicación interna en las organizaciones de salud representa una herramienta sistémica y organizativa que impacta en el nivel de satisfacción y compromiso de ...los trabajadores con la organización y se extiende hasta beneficiar a los pacientes como usuarios de los servicios. Su implementación constituye una política de la Administración Central del Estado Cubano que la dirección del Ministerio de Salud Pública prioriza, al considerarla imprescindible para el logro de los objetivos de trabajo. Esto condujo a diseñar un procedimiento que permitiera gestionar la comunicación interna en la institución. Objetivo: Exponer los métodos, las técnicas y los procedimientos empleados para diseñar un procedimiento para la gestión de la comunicación interna en el Ministerio de Salud Pública de Cuba. Resultados: Se plantea una investigación de desarrollo tecnológico, de tipo mixta, aplicada en dos fases y desarrolladas con técnicas cuantitativas y cualitativas. Conclusiones: El empleo de técnicas cuantitativas y cualitativas permitió identificar los elementos que componen un procedimiento para gestionar la comunicación interna en el Ministerio de Salud Pública. El procesamiento de los datos obtenidos desde el nivel individual hasta el colectivo facilitó la integración de conocimientos para organizar el diseño del procedimiento por etapas. La metodología empleada permitió obtener un procedimiento actualizado y válido por expertos y el público interno.
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