Density Functional Theory-Inspired Design of Ir/P,S-Catalysts for Asymmetric Hydrogenation of Olefins

In silico-based optimization of Ir/P,S-catalysts for the asymmetric hydrogenation of unfunctionalized olefins using (E)-1-(but-2-en-2-yl)-4-methoxybenzene as a benchmark olefin has been carried out. DFT calculations revealed that the thioether group has a major role in directing the olefin coordination. This, together with the configuration of the biphenyl phosphite group, has an impact in maximizing the energy gap between the most stable transition states leading to opposite enantiomers. As a result, the optimized catalyst proved to be efficient in the hydrogenation of a range of alkenes with the same substitution pattern and olefin geometry as the benchmark olefin, regardless of the presence of functional groups with different coordination abilities (ee values up to 97%). Appealingly, further modifications at the thioether groups and at the biaryl phosphite moiety allowed the highly enantioselective hydrogenation of olefins with different substitution patterns (e.g., α,β-unsaturated lactones and lactams, 1,1′-disubstituted enol phosphinates, and cyclic β-enamides; ee values up to >99%).We gratefully acknowledge financial support from the Spanish Ministry of Science and Innovation (PID2019-104904GB-I00, PGC2018-100780-B-I00, and PGC2018-096616-B-I00), European Regional Development Fund (AEI/FEDER, UE), the Catalan Government (2017SGR1472), and the University of Alicante (VOGROB-316FI). M.B. also thanks the URV for generous support

MicroRNAs Clustered within the 14q32 Locus Are Associated with Endothelial Damage and Microparticle Secretion in Bicuspid Aortic Valve Disease

Background: We previously described that PECAM+ circulating endothelial microparticles (EMPs) are elevated in bicuspid aortic valve (BAV) disease as a manifestation of endothelial damage. In this study, we hypothesized that this endothelial damage, is functionally related to the secretion of a specific pattern of EMP-associated miRNAs.Methods: We used a bioinformatics approach to correlate the PECAM+ EMP levels with the miRNA expression profile in plasma in healthy individuals and BAV patients (n = 36). In addition, using the miRNAs that were significantly associated with PECAM+ EMP levels, we inferred a miRNA co-expression network using a Gaussian graphical modeling approach to identify highly co-expressed miRNAs or miRNA clusters whose expression could functionally regulate endothelial damage.Results: We identified a co-expression network composed of 131 miRNAs whose circulating expression was significantly associated with PECAM+ EMP levels. Using a topological analysis, we found that miR-494 was the most important hub within the co-expression network. Furthermore, through positional gene enrichment analysis, we identified a cluster of 19 highly co-expressed miRNAs, including miR-494, that was located in the 14q32 locus on chromosome 14 (p = 1.9 × 10−7). We evaluated the putative biological role of this miRNA cluster by determining the biological significance of the genes targeted by the cluster using functional enrichment analysis. We found that this cluster was involved in the regulation of genes with various functions, specifically the “cellular nitrogen compound metabolic process” (p = 2.34 × 10−145), “immune system process” (p = 2.57 × 10−6), and “extracellular matrix organization” (p = 8.14 × 10−5) gene ontology terms and the “TGF-β signaling pathway” KEGG term (p = 2.59 × 10−8).Conclusions: Using an integrative bioinformatics approach, we identified the circulating miRNA expression profile associated with secreted PECAM+ EMPs in BAV disease. Additionally, we identified a highly co-expressed miRNA cluster that could mediate crucial biological processes in BAV disease, including the nitrogen signaling pathway, cellular activation, and the transforming growth factor beta signaling pathway. In conclusion, EMP-associated and co-expressed miRNAs could act as molecular effectors of the intercellular communication carried out by EMPs in response to endothelial damage

Glycoprotein and Lipoprotein Profiles Assessed by 1H-NMR and Its Relation to Ascending Aortic Dilatation in Bicuspid Aortic Valve Disease

Introduction: The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. Methods: Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. Results: Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. Conclusions: Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter

Performance analysis of a STEMI network: prognostic impact of the type of first medical contact facility

Prognosis in ST-elevation myocardial infarction (STEMI) is determined by delay in primary percutaneous coronary intervention (PPCI). The impact of first medical contact (FMC) facility type on reperfusion delays and mortality remains controversial.We performed a prospective registry of primary coronary intervention (PCI)-treated STEMI patients (2010-2020) in the Codi Infart STEMI network. We analyzed 1-year all-cause mortality depending on the FMC facility type: emergency medical service (EMS), community hospital (CH), PCI hospital (PCI-H), or primary care center (PCC).We included 18?332 patients (EMS 34.3%; CH 33.5%; PCI-H 12.3%; PCC 20.0%). Patients with Killip-Kimball classes III-IV were: EMS 8.43%, CH 5.54%, PCI-H 7.51%, PCC 3.76% (P?<?.001). All comorbidities and first medical assistance complications were more frequent in the EMS and PCI-H groups (P?<?.05) and were less frequent in the PCC group (P?<?.05 for most variables). The PCI-H group had the shortest FMC-to-PCI delay (median 82?minutes); the EMS group achieved the shortest total ischemic time (median 151?minutes); CH had the longest reperfusion delays (P?<?.001). In an adjusted logistic regression model, the PCI-H and CH groups were associated with higher 1-year mortality, OR, 1.22 (95%CI, 1.00-1.48; P?=?.048), and OR, 1.17 (95%CI 1.02-1.36; P?=?.030), respectively, while the PCC group was associated with lower 1-year mortality than the EMS group, OR,?0.71 (95%CI 0.58-0.86; P?<?.001).FMC with PCI-H and CH was associated with higher adjusted 1-year mortality than FMC with EMS. The PCC group had a much lower intrinsic risk and was associated with better outcomes despite longer revascularization delays.Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved