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SummarySynergy of resistance and disease tolerance mechanisms is necessary for an effective immune response leading to survival and return to homeostasis when an organism is challenged by infection. Antibiotics are used for their resistance enhancement capabilities by decreasing pathogen load, but several classes have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here we report that tetracycline antibiotics, a class of ribosome-targeting drugs, robustly protects against sepsis by inducing disease tolerance, independently from their direct antibiotic properties. Mechanistically, we find that mitochondrial inhibition of protein synthesis perturbs the electron transfer chain and leads to improved damage repair in the lung and fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a partial and acute deletion ofCRIF1in the liver, a critical mitoribosomal component for protein synthesis, we find that mice are protected against bacterial sepsis, an observation which is phenocopied by the transient inhibition of complex I of ETC by phenformin. Together, we demonstrate that ribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a novel mechanism for the induction of disease tolerance.

Background:The Hypoxia Altitude Simulation Test (HAST) is the Gold Standard to evaluate hypoxia in response to altitude and to decide on in-flight requirements for oxygen supplementation. Several equations are available to predict PaO2 in altitude (PaO2alt), but it remains unclear whether their predictive value is equivalent. We aimed to compare the results obtained by the available methods in a population of cystic fibrosis (CF) adults.Methods:Eighty-eight adults (58 healthy controls and 30 CF patients) performed a spirometry followed by an HAST. HAST results were compared with the predicted PaO2alt made by five equations: 1st: PaO2alt= 0,410 x PaO2ground + 1,7652; 2nd: PaO2alt= 0,519 x PaO2ground + 11,855 x FEV1 (L) − 1,760; 3rd: PaO2alt= 0,453 x PaO2ground + 0,386 x FEV1 (%) + 2,44; 4th: PaO2alt= 0,88 + 0,68 x PaO2ground; 5th: PaO2alt= PaO2ground − 26,6.Results:None of the controls required in-flight oxygen neither by HAST or by the five predictive equations. Eleven CF-patients had PaO2alt < 50 mmHg, accessed by HAST. The positive predictive value was 50% (1st), 87.5% (2nd and 3rd), 77.78% (4th) and 58.33% (5th). Areas under the curve were 78.95% (1st), 84.69% (2nd), 88.04% (3rd) and 78.95% (4th and 5th). FEV1 and PaO2ground were correlated with HAST results.Conclusions:The 3rd equation gave the best predictions in comparison with results obtained by HAST. However, because the individual differences found were substantial for all equations, we still recommend performing a HAST whenever possible to confidently access in-flight hypoxia and the need for oxygen.

Acute appendicitis is the most frequent surgical abdominal emergency, but its etiology remains poorly understood. Histological examination of the appendix, following its removal due to acute appendicitis, consistently shows features in common with bronchial asthma, suggesting an allergic reaction as a candidate etiologic factor. Here we propose the concept of appendicular lavage and used it to study the levels of the Th2 cytokines IL-4, IL-5 and IL-9 in patients with a clinical diagnosis of acute appendicitis. The study group included 20 patients with a histological diagnosis of phlegmonous appendicitis, 13 patients with gangrenous appendicitis, and a control group of 8 patients with clinical diagnosis of appendicitis but with normal histology. Cytokines levels were higher in acute appendicitis. The difference was more pronounced when comparing phlegmonous appendicitis with non-pathological appendix (p=0.01) for IL-4 (48,3 vs 21,3 pg/mL), IL-5 (29,2 vs 8,0 pg/mL) and IL-9 (34,1 vs 16,6 pg/mL). This Th2 cytokine profile is compatible with the hypothesis of allergy as an etiologic factor for acute appendicitis and may have important implications for the diagnosis, prevention and treatment of this condition.

The premessenger RNA of the majority of human genes can generate various transcripts through alternative splicing, and different tissues or disease states show specific patterns of splicing variants. These patterns depend on the relative concentrations of the splicing factors present in the cell nucleus, either as a consequence of their expression levels or of post-translational modifications, such as protein phosphorylation, which are determined by signal transduction pathways. Here, we analyzed the contribution of protein kinases to the regulation of alternative splicing variant Rac1b that is overexpressed in certain tumor types. In colorectal cells, we found that depletion of AKT2, AKT3, GSK3β, and SRPK1 significantly decreased endogenous Rac1b levels. Although knockdown of AKT2 and AKT3 affected only Rac1b protein levels suggesting a post-splicing effect, the depletion of GSK3β or SRPK1 decreased Rac1b alternative splicing, an effect mediated through changes in splicing factor SRSF1. In particular, the knockdown of SRPK1 or inhibition of its catalytic activity reduced phosphorylation and subsequent translocation of SRSF1 to the nucleus, limiting its availability to promote the inclusion of alternative exon 3b into the Rac1 pre-mRNA. Altogether, the data identify SRSF1 as a prime regulator of Rac1b expression in colorectal cells and provide further mechanistic insight into how the regulation of alternative splicing events by protein kinases can contribute to sustain tumor cell survival.