Clima y salud en la Argentina: diagnóstico de situación 2018

Fil: Domínguez, Diana Analía. Servicio Meteorológico Nacional. Dirección Nacional de Ciencia e Innovación en Productos y Servicios. Dirección Central de Monitoreo del Clima; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; Argentina.El presente diagnóstico de situación sobre Clima y Salud en Argentina fue realizado por la Mesa de Trabajo sobre Cambio Climático de la Secretaría de Gobierno de Salud. Se realizó un estudio de tipo descriptivo, en el cual se presenta por un lado el comportamiento de las variables meteorológicas y por otro, algunos eventos seleccionados en salud. Asimismo, se desarrolla el estado del conocimiento sobre la relación entre el clima y la salud en Argentina en el período comprendido entre los años 2005 y 2017. La descripción climática fue realizada por el Departamento de Climatología del Servicio Meteorológico Nacional (SMN). Las estadísticas se basan en valores medios (promedio) del periodo 1981-2010. Los efectos del clima sobre la salud humana fueron estudiados a partir de su clasificación en efectos directos e indirectos, entendiendo como efectos directos aquellos ocurridos a raíz de la ocurrencia de eventos meteorológicos extremos tales como olas de frío y calor, inundaciones, sequías y vientos fuertes. Para el análisis de estos eventos se realizó el análisis de la frecuencia y distribución espacial de los eventos extremos para el período 2005-2017. Para el estudio de las patologías sensible al clima se priorizaron las patologías más relevantes para ser descriptas en base a la evidencia científica. Se realizó una descripción de la evolución temporal de los casos entre 2005 y 2017, a partir de los datos obtenidos de la vigilancia clínica (a través del módulo C2 del SNVS). Por último se presentan las tendencias y retos que afrontará el sistema sanitario debido al cambio climático

Structure-Guided Identification of a Small Molecule That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria

The anaerobic gut microbial pathway that converts choline into trimethylamine (TMA) is broadly linked to human disease. Here, we describe the discovery that betaine aldehyde inhibits TMA production from choline by human gut bacterial isolates and a complex gut community. In vitro assays and a crystal structure suggest betaine aldehyde targets the gut microbial enzyme choline TMA-lyase (CutC). In our system, we do not observe activity for the previously reported CutC inhibitor 3,3-dimethylbutanol (DMB). The workflow we establish for identifying and characterizing betaine aldehyde provides a framework for developing additional inhibitors of gut microbial choline metabolism, including therapeutic candidates

<i>O</i>‑GlcNAc Transferase Recognizes Protein Substrates Using an Asparagine Ladder in the Tetratricopeptide Repeat (TPR) Superhelix

The essential mammalian enzyme <i>O</i>-GlcNAc Transferase (OGT) is uniquely responsible for transferring <i>N</i>-acetyl­glucosamine to over a thousand nuclear and cytoplasmic proteins, yet there is no known consensus sequence and it remains unclear how OGT recognizes its substrates. To address this question, we developed a protein microarray assay that chemoenzymatically labels <i>de novo</i> sites of glycosylation with biotin, allowing us to simultaneously assess OGT activity across >6000 human proteins. With this assay we examined the contribution to substrate selection of a conserved asparagine ladder within the lumen of OGT’s superhelical tetratrico­peptide repeat (TPR) domain. When five asparagines were mutated, OGT retained significant activity against short peptides, but showed limited limited glycosylation of protein substrates on the microarray. <i>O</i>-GlcNAcylation of protein substrates in cell extracts was also greatly attenuated. We conclude that OGT recognizes the majority of its substrates by binding them to the asparagine ladder in the TPR lumen proximal to the catalytic domain

Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models

Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes

Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models

Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited cell death in cellular models of Huntington’s disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; Fer-1 inhibited lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. We developed a mechanistic model to explain the activity of Fer-1, which guided the development of ferrostatins with improved properties. These studies suggest numerous therapeutic uses for ferrostatins, and that lipid peroxidation mediates diverse disease phenotypes

A Small Molecule That Inhibits OGT Activity in Cells

<i>O</i>-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of <i>O</i>-linked <i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) residues to nuclear and cytoplasmic proteins. Its targets include kinases, phosphatases, transcription factors, histones, and many other intracellular proteins. The biology of <i>O</i>-GlcNAc modification is still not well understood, and cell-permeable inhibitors of OGT are needed both as research tools and for validating OGT as a therapeutic target. Here, we report a small molecule OGT inhibitor, OSMI-1, developed from a high-throughput screening hit. It is cell-permeable and inhibits protein <i>O</i>-GlcNAcylation in several mammalian cell lines without qualitatively altering cell surface <i>N</i>- or <i>O</i>-linked glycans. The development of this molecule validates high-throughput screening approaches for the discovery of glycosyltransferase inhibitors, and further optimization of this scaffold may lead to yet more potent OGT inhibitors useful for studying OGT in animal models

Experimental and Computational Mechanistic Investigation of Chlorocarbene Additions to Bridgehead Carbene–Anti-Bredt Systems: Noradamantylcarbene–Adamantene and Adamantylcarbene–Homoadamantene

Cophotolysis of noradamantyldiazirine with the phenanthride precursor of dichlorocarbene or phenylchloro­diazirine in pentane at room temperature produces noradamantylethylenes in 11% yield with slight diastereoselectivity. Cophotolysis of adamantyldiazirine with phenylchlorodiazirine in pentane at room temperature generates adamantylethylenes in 6% yield with no diastereoselectivity. ¹H NMR showed the reaction of noradamantyldiazirine + phenylchlorodiazirine to be independent of solvent, and the rate of noradamantyldiazirine consumption correlated with the rate of ethylene formation. Laser flash photolysis showed that reaction of phenylchlorocarbene + adamantene was independent of adamantene concentration. The reaction of phenylchlorocarbene + homoadamantene produces the ethylene products with <i>k</i> = 9.6 × 10⁵ M^–1 s^–1. Calculations at the UB3LYP/6-31+G­(d,p) and UM062X/6-31+G­(d,p)//UB3LYP/6-31+G­(d,p) levels show the formation of exocyclic ethylenes to proceed (a) on the singlet surface via stepwise addition of phenylchlorocarbene (PhCCl) to bridgehead alkenes adamantene and homoadamantene, respectively, producing an intermediate singlet diradical in each case, or (b) via addition of PhCCl to the diazo analogues of noradamantyl- and adamantyldiazirine. Preliminary direct dynamics calculations on adamantene + PhCCl show a high degree of recrossing (68%), indicative of a flat transition state surface. Overall, 9% of the total trajectories formed noradamantylethylene product, each proceeding via the computed singlet diradical

Upregulation of nuclear factor-related kappa B suggests a disorder of transcriptional regulation in minimal change nephrotic syndrome.

Immune mechanisms underlying the pathophysiology of idiopathic nephrotic syndrome, the most frequent glomerular disease in children, are believed to involve a systemic disorder of T cell function and cell mediated immunity. How these perturbations take place remains unclear. We report here that NFRKB, a member of the chromatin remodeling complex, is upregulated in MCNS relapse, mainly in CD4+T cells and B cells and undergo post-translational modifications including sumoylation. We showed that NFRKB was highly expressed in nuclear compartment during the relapse, while it was restricted to cytoplasm in remission. NFRKB induced the activation of AP1 signaling pathway by upregulating the expression of c-jun. We showed that NFRKB promotes hypomethylation of genomic DNA, suggesting its implication in regulation of gene expression by enhancing the binding of transcription factors through chromatin remodeling. These results suggest for the first time that NFRKB may be involved in the disorders of transcriptional regulation commonly observed in MCNS relapse