La suplementación de larga duración con atenolol convierte la insaturación de las membranas mitocondriales de músculo esquelético y de corazón de ratón en la característica de mamíferos de supervivencia diez veces mayor. Efectos sobre la longevidad

The long-term effects of atenolol in drinking water throughout the whole lifespan (3.3 years) of a mammal (128 C57BL/6 male mice-SPF) were studied for the first time. We observed beneficial aging-related changes: decreases in the degree of unsaturation of mitochondrial membranes and of the 22:6n-3 fatty acid, an increase in oleic acid, as well as decreases in protein oxidation, glycoxidation and lipoxidation and oxidative damage in mtDNA in heart and skeletal muscle mitochondria. However, a secondary effect of the drug only in old animals was detected that agrees with recent meta-analyses in human patients.Se estudia por primera vez el efecto a largo plazo del atenolol en el agua de bebida durante toda la vida (3,3 años) de un mamífero (128 ratones C57BL/6 macho-SPF). Observamos cambios beneficiosos relacionados con el envejecimiento: descenso en el grado de insaturación de las membranas mitocondriales y del ácido graso 22:6n-3, un incremento del ácido oleico, y descenso de la oxidación, glicoxidación y lipoxidación de proteínas y daño oxidativo al ADNmt en mitocondrias de corazón y músculo esquelético. Sin embargo, detectamos un efecto secundario del fármaco sólo en animales viejos que coincide con meta-análisis recientes en pacientes humanos

ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

Mucociliary epithelia provide a first line of defense against pathogens. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/beta-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive, and studies yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway Basal cells, we characterize the evolutionarily conserved roles of Wnt/beta-catenin signaling in vertebrates. In multiciliated cells, Wnt is required for cilia formation during differentiation. In Basal cells, Wnt prevents specification of epithelial cell types by activating Delta N-TP63, a master transcription factor, which is necessary and sufficient to mediate the Wnt-induced inhibition of specification and is required to retain Basal cells during development. Chronic Wnt activation leads to remodeling and Basal cell hyperplasia, which are reversible in vivo and in vitro, suggesting Wnt inhibition as a treatment option in chronic lung diseases. Our work provides important insights into mucociliary signaling, development, and disease

Reducción en el índice de peroxidizabilidad de la membrana mitocondrial y niveles de lipoxidación proteícos en el corazón de la rata después de la interrupción de la señalización del receptor betaadrenérgico con el betabloqueante atenolol

A new mammalian longevity model based on ß-adrenergic signaling interruption at the level of adenylyl cyclase has reported decreased bone and heart aging and mean and maximum longevity increases in AC5KO mice (1). We decided to mimic this model in male Wistar rats treated with the ß-blocker atenolol in the drinking water and to check if an oxidative stress decrease could be involved. Atenolol treatment did not modify heart mitROS generation rate and mitDNA oxidative damage but significantly decreased global peroxidizability index of mitochondrial membranes, as well as protein lipoxidation, probably mediated by changes in elongases and desaturases activities.Un nuevo modelo de longevidad en mamíferos basado en la interrupción de la vía de señalización beta-adrenérgica a nivel de la adenilato ciclasa ha revelado una ralentización del envejecimiento del corazón y el hueso de ratones AC5KO y un incremento de su longevidad media y máxima [1]. Decidimos mimetizar este modelo en ratas Wistar utilizando atenolol en el agua de bebida para comprobar si un descenso de estrés oxidativo podría estar implicado. El tratamiento no modificó la tasa de generación de radicales y el daño oxidativo al ADN del corazón, pero si redujo el índice de peroxidizabilidad y la lipoxidación proteica de las membranas mitocondriales, probablemente debido a cambios en las actividades elongasas y desaturasas

A systematic review of clinical practice guidelines and recommendations for the management of pain, sedation, delirium and iatrogenic withdrawal syndrome in pediatric intensive care

IntroductionThis systematic review aimed to evaluate the quality of clinical practice guidelines (CPGs) and recommendations for managing pain, sedation, delirium, and iatrogenic withdrawal syndrome in pediatric intensive care (PICU). The objectives included evaluating the quality of recommendations, synthesizing recommendations, harmonizing the strength of the recommendation (SoR) and the certainty of evidence (CoE), and assessing the relevance of supporting evidence.MethodsA comprehensive search in four electronic databases (Medline, Embase.com, CINAHL and JBI EBP Database), 9 guideline repositories, and 13 professional societies was conducted to identify CPGs published from January 2010 to the end of May 2023 in any language. The quality of CPGs and recommendations was assessed using the AGREE II and AGREE-REX instruments. Thematic analysis was used to synthesize recommendations, and the GRADE SoR and CoE harmonization method was used to interpret the credibility of summary recommendations.ResultsA total of 18 CPGs and 170 recommendations were identified. Most CPGs were of medium-quality, and three were classified as high. A total of 30 summary recommendations were synthesized across each condition, focused on common management approaches. There was inconsistency in the SoRs and CoE for summary recommendations, those for assessment showed the highest consistency, the remaining were conditional, inconsistent, inconclusive, and lacked support from evidence.ConclusionThis systematic review provides an overview of the quality of CPGs for these four conditions in the PICU. While three CPGs achieved high-quality ratings, the overall findings reveal gaps in the evidence base of recommendations, patient and family involvement, and resources for implementation. The findings highlight the need for more rigorous and evidence-based approaches in the development and reporting of CPGs to enhance their trustworthiness. Further research is necessary to enhance the quality of recommendations for this setting. The results of this review can provide a valuable foundation for future CPG development.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=274364, PROSPERO (CRD42021274364)

The Genome of a Pathogenic Rhodococcus: Cooptive Virulence Underpinned by Key Gene Acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi

Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadHuman tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion.Health Department PERIS-project of the Catalan Government (Generalitat de Catalunya) AGAUR of the Catalan Government (Generalitat de Catalunya) Instituto de Salud Carlos III Ministerio de Economia y Competitividad (MINECO) European Union (EU) Foundation CELLEX La Caixa Foundatio

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Reducción en el índice de peroxidizabilidad de la membrana mitocondrial y niveles de lipoxidación proteícos en el corazón de la rata después de la interrupción de la señalización del receptor betaadrenérgico con el betabloqueante atenolol

Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity

Rationale: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional coactivator Yes-associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood. Objective: To investigate the role of alpha-catenins in the heart using cardiac-specific alpha E- and alpha T-catenin double knockout mice. Methods and Results: We used 2 cardiac-specific Cre transgenes to delete both alpha E-catenin (Ctnna1) and alpha T-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of alpha-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the alpha-catenin double knockout hearts. Fetal genes were increased in the alpha-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of alpha-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of alpha-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction. Conclusions: These studies demonstrate that alpha-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting alpha-catenins might be a useful strategy to promote myocardial regeneration after injury