Effect of OAS genes on SARS-CoV-2 infection and the induction of innate immune responses

Resumen del trabajo presentado en el 8th European Congress of Virology, celebrado en Gdańsk (Polonia), del 4 al 7 de mayo de 2023Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) infections cause different clinical symptoms ranging from asymptomatic patients to patients suffering severe respiratory disease leading to death in some of them. Genetic and functional studies have shown inborn-errors of interferon (IFN)-related genes in severe COVID-19 patients explaining why some young patients devoid of co-morbidities succumbed to infection. In addition, very large genomic studies identified common genetic variants affecting the expression and splicing of IFN-stimulated genes (ISGs) of the 2",5"- oligoadenylate (2-5A) synthetase (OAS) family associated with COVID-19 severity. We have sequenced the whole genome of 274 patients who required hospitalization after SARS-CoV-2 infection, finding ultrarare mutations in OAS1 and OAS3 genes. Upon double-stranded (ds)RNA binding, the OAS1, OAS2, and OAS3 proteins synthetize 2¿- 5¿olygoadenylates which activate the endonuclease RNAseL. This endonuclease degrades viral and cellular RNAs, inhibiting viral replication. We have analyzed the effect of OAS1 and OAS3 genetic variants identified in our patients, and found that some of them impair the RNAseL activation. In addition, by using OAS3 knock-out cells generated in our laboratory and performing overexpression experiments, we have shown that OAS3 negatively modulates proinflammatory responses induced by immune challenges, and that the activation of the RNAseL activity seems necessary for this function. In addition, by using OAS3 knock-out mice infected with SARS-CoV-2 or treated with the double-stranded RNA analog poly(I:C), we have shown that OAS3 deficiency leads to a higher mouse susceptibility to SARS-CoV-2 infection and that OAS3 counteracts the induction of innate immune responses in the mouse infectedlungs, leading to a higher inflammatory response in OAS3 knock-out mice, compared to the parental mice. Given the contribution of exacerbated inflammatory responses to COVID-19 disease severity, our results suggest that OAS1/OAS3 could play a role limiting the severity of the clinical symptoms after SARS-CoV-2 infection

The role of emotions on consumers’ satisfaction within the fitness context

Previous studies have suggested that consumption-related emotions are important to understand post-purchase reactions. This study examines the relationship between fitness consumers’ emotions and overall satisfaction. After an initial step of free-thought listing and content validity, followed by a pre-test, a survey was conducted among consumers of five different fitness centers (n=786). The questionnaire included measures to assess positive and negative emotions, as well as overall satisfaction with the fitness center. The results gathered through a structural equation model provide evidence that negative emotion experienced by consumers impacts negatively overall satisfaction, while positive emotion have a positive effect on overall satisfaction. These findings suggest managerial implications, such as the need to collect consumers’ perceptions of both tangible and intangible aspects of the services, listen costumers’ opinions in a regular basis, and provide regular training to staff members, in order to identify the triggers of positive emotions and contribute to increased levels of overall satisfaction. Guidelines for future research within the fitness context are also suggested.Estudos precedentes sugerem que as emoções relacionadas com o consumo são importantes para compreender as reações dos consumidores após a compra. Este estudo analisa a relação entre as emoções dos consumidores de fitness e satisfação global. Depois de uma etapa inicial de listagem de pensamento-livre e validade de conteúdo, seguido de um pré-teste, foi realizada uma pesquisa entre os consumidores de cinco centros de fitness diferentes (n = 786). O questionário incluiu medidas para avaliar as emoções positivas e negativas, bem como a satisfação global com o centro de fitness. Os resultados obtidos através de um modelo de equações estruturais forneceram evidências de que as emoções negativas vivenciadas pelos consumidores impactam negativamente a satisfação global, enquanto as emoções positivas têm um efeito positivo sobre a satisfação global. Estes resultados sugerem implicações para os gestores, tais como a necessidade de recolher informação sobre a perceção dos consumidores dos aspetos tangíveis e intangíveis dos serviços, ouvir regularmente as opiniões dos consumidores e facultar formação regular aos colaboradores. Isto permitirá identificar os aspetos que desencadeiam emoções positivas e contribuir para o aumento dos níveis de satisfação global. Orientações para futuras pesquisas no contexto de fitness também são sugeridas.Sin financiación0.185 SJR (2015) Q3, 1090/1779 Medicine (miscellaneous); Q4, 177/229 Health (social science), 112/128 Sports scienceUE

Computational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2

Background: Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. Methodology/Principal Findings: The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDAapproved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the antiinflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses

Effects on short term outcome of non-invasive ventilation use in the emergency department to treat patients with acute heart failure: A propensity score-based analysis of the EAHFE Registry

Objective: To assess the effects of non-invasive ventilation (NIV) in emergency department (ED) patients with acute heart failure (AHF) on short term outcomes. Methods: Patients from the EAHFE Registry (a multicenter, observational, multipurpose, cohort-designed database including consecutive AHF patients in 41 Spanish EDs) were grouped based on NIV treatment (NIV+ and NIV–groups). Using propensity score (PS) methodology, we identified two subgroups of patients matched by 38 covariates and compared regarding 30-day survival (primary outcome). Interaction was investigated for age, sex, ischemic cardiomyopathy, chronic obstructive pulmonary disease, AHF precipitated by an acute coronary syndrome (ACS), AHF classified as hypertensive or acute pulmonary edema (APE), and systolic blood pressure (SBP). Secondary outcomes were intensive care unit (ICU) admission; mechanical ventilation; in-hospital, 3-day and 7-day mortality; and prolonged hospitalization (>7 days). Results: Of 11, 152 patients from the EAHFE (age (SD): 80 (10) years; 55.5% women), 718 (6.4%) were NIV+ and had a higher 30-day mortality (HR = 2.229; 95%CI = 1.861–2.670) (p 85 years, p < 0.001), AHF associated with ACS (p = 0.045), and SBP < 100 mmHg (p < 0.001). No significant differences were found in the secondary endpoints except for more prolonged hospitalizations in NIV+ patients (OR = 1.445; 95%CI = 1.122–1.862) (p = 0.004). Conclusion: The use of NIV to treat AHF in ED is not associated with improved mortality outcomes and should be cautious in old patients and those with ACS and hypotension

Probiotic Bacteria Produce Conjugated Linoleic Acid Locally in the Gut That Targets Macrophage PPAR γ to Suppress Colitis

Inflammatory bowel disease (IBD) therapies are modestly successful and associated with significant side effects. Thus, the investigation of novel approaches to prevent colitis is important. Probiotic bacteria can produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anti-inflammatory effects. This study aimed to investigate the cellular and molecular mechanisms underlying the anti-inflammatory efficacy of probiotic bacteria using a mouse model of colitis. The immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in a mouse model of DSS colitis. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen, blood and colonic lamina propria cells were phenotypically and functionally characterized. Fecal samples and colonic contents were collected to determine the effect of VSL#3 and CLA on gut microbial diversity and CLA production. CLA and VSL#3 treatment ameliorated colitis and decreased colonic bacterial diversity, a finding that correlated with decreased gut pathology. Colonic CLA concentrations were increased in response to probiotic bacterial treatment, but without systemic distribution in blood. VSL#3 and CLA decreased macrophage accumulation in the MLN of mice with DSS colitis. The loss of PPAR γ in myeloid cells abrogated the protective effect of probiotic bacteria and CLA in mice with DSS colitis. Probiotic bacteria modulate gut microbial diversity and favor local production of CLA in the colon that targets myeloid cell PPAR γ to suppress colitis

Clinical phenotypes of acute heart failure based on signs and symptoms of perfusion and congestion at emergency department presentation and their relationship with patient management and outcomes

Objective To compare the clinical characteristics and outcomes of patients with acute heart failure (AHF) according to clinical profiles based on congestion and perfusion determined in the emergency department (ED). Methods and results Overall, 11 261 unselected AHF patients from 41 Spanish EDs were classified according to perfusion (normoperfusion = warm; hypoperfusion = cold) and congestion (not = dry; yes = wet). Baseline and decompensation characteristics were recorded as were the main wards to which patients were admitted. The primary outcome was 1-year all-cause mortality; secondary outcomes were need for hospitalisation during the index AHF event, in-hospital all-cause mortality, prolonged hospitalisation, 7-day post-discharge ED revisit for AHF and 30-day post-discharge rehospitalisation for AHF. A total of 8558 patients (76.0%) were warm+ wet, 1929 (17.1%) cold+ wet, 675 (6.0%) warm+ dry, and 99 (0.9%) cold+ dry; hypoperfused (cold) patients were more frequently admitted to intensive care units and geriatrics departments, and warm+ wet patients were discharged home without admission. The four phenotypes differed in most of the baseline and decompensation characteristics. The 1-year mortality was 30.8%, and compared to warm+ dry, the adjusted hazard ratios were significantly increased for cold+ wet (1.660; 95% confidence interval 1.400-1.968) and cold+ dry (1.672; 95% confidence interval 1.189-2.351). Hypoperfused (cold) phenotypes also showed higher rates of index episode hospitalisation and in-hospital mortality, while congestive (wet) phenotypes had a higher risk of prolonged hospitalisation but decreased risk of rehospitalisation. No differences were observed among phenotypes in ED revisit risk. Conclusions Bedside clinical evaluation of congestion and perfusion of AHF patients upon ED arrival and classification according to phenotypic profiles proposed by the latest European Society of Cardiology guidelines provide useful complementary information and help to rapidly predict patient outcomes shortly after ED patient arrival