The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Mecanismes de resposta adaptativa davant estrès oxidatiu mediats per Grx3 i Grx4 en Saccharomyces cerevisiae: regulació de l'homeòstasi del ferro i de la via d'integritat cel.lular.

El llevat S.cerevisiae és un dels models eucariotes més adequats per l'estudi dels diversos mecanismes implicats en la supervivència cel.lular en resposta a estrès oxidatiu. Les espècies reactives d'oxigen (ROS) com els radicals hidroxil, l'anió superòxid o el peròxid d'hidrogen generen estrès oxidatiu, causant important danys intracel.lulars davant els quals la cèl.lula a desenvolupat una sèrie de mecanisme per fer-hi front. Grx3 i Grx4 són dues glutaredoxines monotiòliques de S.cerevisisae que formen part dels sistemes enzimàtics que regulen l'estat redox de les proteïnes en resposta a estrès oxidatiu. No obstant, fins ara es desconeixen els mecanismes amb els quals Grx3 i Grx4 participen en la detoxificació d'aquestes ROS i en l'adaptació cel.lular en condicions oxidatives. En el primer Capítol es caracteritza el paper funcional de Grx3 i Grx4 en la regulació de l'homeòstasi del ferro intracel.lular mitjançant la regulació del factor transcripcional Aft1, encarregat de regular la transcripció de gens que formen part del sistema d'alta afinitat de captació de ferro. A més a més, es caracteritza el paper funcional dels dominis glutaredoxina (GRX) de Grx3 i Grx4 en l'exportació nuclear d'Aft1, com a mecanisme regulador de l'estrès oxidatiu generat per un augment en els nivells de ferro intracel.lulars. En el segon Capítol hem aconseguit donar una funció específica per Grx3 i Grx4 en la regulació de la via d'integritat cel.lular o la via PKC1- MAP quinasa en resposta a estrès oxidatiu. A més a més, demostrem que són els dominis tioredoxina (TRX) de Grx3 i Grx4 qui dessarrollen el paper protagonista en l'activació de la quinasa Slt2 en resposta a estrès oxidatiu i en la repolarització del citoesquelet d'actina en condicions normals i en resposta a estrès oxidatiu. També demostrem que Grx3, Grx4 i Slt2 estàn relacionades genètica i funcionalment amb els procesos implicats en l'organització del citoesquelet d'actina en resposta a estrès oxidatiu i en la biogènesi vacuolar en condicions normals.La levadura S.cerevisiae es uno de los modelos eucariotas más adecuados para el estudio de los diferentes mecanismos implicados en la supervivencia celular en respuesta a estrés oxidativo. Las especies reactivas de oxígeno (ROS) como los radicales hidroxilo, el anión superóxido o el peróxido de hidrógeno generan estrés oxidativo, induciendo importantes daños intracelulares frente a los cuales la célula tiene que desarrollar una serie de mecanismos para hacerles frente. Grx3 i Grx4 son dos glutaredoxinas monotiólicas de S.cerevisiae que forman parte de los sistemas enzimáticos que regulan el estado redox de las proteínas en respuesta a estrés oxidativo. No obstante, hasta hoy se desconocen los mecanismos mediante los cuales Grx3 i Grx4 participan en la detoxificación de estos ROS y en la adaptación celular frente a condiciones oxidativas. En el primer Capítulo se caracteriza el papel funcional para Grx3 y Grx4 en la regulación de la homeóstasis del hierro intracelular mediante el factor transcripcional Aft1, el cual se encarga de regular la transcripción de genes que forman parte del sistema de alta afinidad de captación de hierro. Además, se caracteriza el papel funcional de los dominios GRX de Grx3 y Grx4 en la exportación nuclear de Aft1, como mecanismo regulador del estrés oxidativo generado por un aumento en los niveles de hierro intracelulares. En el segundo Capítulo hemos logrado dar una función específica a Grx3 y Grx4 en la regulación de la vía de integridad celular o vía PKC1-MAP quinasa en respuesta a estrés oxidativo. Además, tras diseccionar los dominios glutaredoxina (GRX) y tioredoxina (TRX) de Grx3 y Grx4, hemos concluido que son los dominios TRX de ambas glutaredoxinas quienes poseen un papel protagonista en la activación de la quinasa Slt2 en respuesta a estrés oxidativo y en la reorganización del citoesqueleto de actina en condiciones normales y oxidantes. También se demuestra que Grx3, Grx4 y Slt2 están relacionados genética y funcionalmente en los procesos implicados en la organización del citoesqueleto d'actina en respuesta a estrés oxidativo y en la biogénesis vacuolar en condiciones normales.The yeast S.cerevisiae is one of the most suitable eukaryotic models to study several mechanisms involved in cell survival in the response to oxidative stress. Reactive oxygen species (ROS) such as hydroxyl radicals, superoxide anions or hydrogen peroxide provoque oxidative stress and cause important cell damage. As a consequence of that, cells need to develop a series of mechanisms in order to repair their structures. Grx3 and Grx4 are two monothiol glutaredoxins of S.cerevisiae potentially involved in enzymatic systems to regulate the redox state of proteins in front of oxidative stress. Nevertheless, actually is unknown the mechanisms where Grx3 and Grx4 participate in ROS detoxification and in the cellular adaptation to oxidative conditions. In the first chapter, we characterize a functional role for both Grx3 and Grx4 in the maintenance of iron homeostasis through the regulation of Aft1, a transcription factor involved in the transcriptional regulation of a subset of genes which integrate the high affinity iron uptake system. In addition, we have characterized the functional role for both GRX domains of Grx3 and Grx4 in the nuclear export of Aft1 as a mechanism that regulates the oxidative stress generated by high levels of intracellular iron. In the second chapter, it is characterized a specific function for Grx3 and Grx4 in the regulation of the cell integrity pathway or PKC1-MAP kinase pathway in response to oxidative stress. Moreover, we described the functional role for both TRX domains of Grx3 and Grx4 in the Slt2 activation in response to oxidative stress and in the reorganization of the actin cytoskeleton in normal and oxidant conditions. We also demonstrated the genetic and the functional relationship between Grx3, Grx4 and Slt2 in the mechanisms involved in the actin cytoskeleton organization in response to oxidative stress and in the vacuolar biogenesis in normal conditions

The Cell Wall Integrity Receptor Mtl1 Contributes to Articulate Autophagic Responses When Glucose Availability Is Compromised

Mtl1protein is a cell wall receptor belonging to the CWI pathway. Mtl1 function is related to glucose and oxidative stress signaling. In this report, we show data demonstrating that Mtl1 plays a critical role in the detection of a descent in glucose concentration, in order to activate bulk autophagy machinery as a response to nutrient deprivation and to maintain cell survival in starvation conditions. Autophagy is a tightly regulated mechanism involving several signaling pathways. The data here show that in Saccharomyces cerevisiae, Mtl1 signals glucose availability to either Ras2 or Sch9 proteins converging in Atg1 phosphorylation and autophagy induction. TORC1 complex function is not involved in autophagy induction during the diauxic shift when glucose is limited. In this context, the GCN2 gene is required to regulate autophagy activation upon amino acid starvation independent of the TORC1 complex. Mtl1 function is also involved in signaling the autophagic degradation of mitochondria during the stationary phase through both Ras2 and Sch9, in a manner dependent on either Atg33 and Atg11 proteins and independent of the Atg32 protein, the mitophagy receptor. All of the above suggest a pivotal signaling role for Mtl1 in maintaining correct cell homeostasis function in periods of glucose scarcity in budding yeast.This research was funded by Plan Nacional de I+D+I of the Spanish Ministery of Economy,Industry and Competitiveness (BIO2017-87828-C2-2-P

Coping with oxidative stress. The yeast model

Saccharomyces cerevisiae is an optimal model to study stress responses for various reasons: i) budding yeast genome presents a high degree of homology with the human genome; ii) there are many proteins that show an elevated functional homology with specific human proteins; iii) it is a system whose genetic manipulation is reasonably easy and cheaper than other models; iv) the possibility of working with an haploid state facilitates the study of multiple processes; v) databases are the most complete of all the eukaryotic models. Due to the latest information derived from proteomic and genomic analyses, the genetic, biochemical and molecular information available relative to this biological system is extraordinarily big and complete. In this review, we present an overview of the mechanisms unravelling sensing and transducing oxidative stress. TOR, RAS/PKA, CWI, SNF1, and HOG are the main pathways involved both in the oxidative response and in the correct entry in stationary phase. In general, TOR and RAS/PKA dowregulation and SNF1 and CWI upregulation favour both a correct defence against oxidative damage and the entry in the quiescent state. All of these pathways have counterparts in humans. The actin cytoskeleton plays a dual function as sensor and target of oxidation, in tight connection with the former signalling cascades. In budding yeast, progression through stationary phase and quiescence constitute an accepted current model to study some of the mechanisms that determine life span. Aging is a process associated to oxidative stress and it is in tight relationship with bulk autophagy and mitophagy, both are mechanisms belonging to the oxidative defence and promoters of life extension when correctly regulated by, among other elements, the signalling cascades. - See more at: http://www.eurekaselect.com/125474/article#sthash.AVRLn2Lq.dpu