Regioselective mono and dihalogenations of amino, hydroxy and methoxy pyridines (2-, 3-, and 4-substituted) as well as 2,6-dimethoxy pyridine with N-bromosuccinimide in different solvents have been studied. Reactivity of the substrates decreases in the order amino>hydroxy>methoxy and regioselectivity depends on the position of the substituent (2-substituted > 3-substituted). In most of the cases we obtained monobrominated derivatives regioselectively and in high yields. Hydroxy and amino pyridines can also be dibrominated in almost quantitative yield with 2 equivalents of NBS.Polyfunctional pyridines are very useful compounds which have found applications as precursors of pharmacological compounds, 1 in the synthesis of liquid crystals 2 and polymers, 3 as well as ligands for different transition metal cations. 4 The wide range of halopyridines, 5,6 which are able to undergo metal-halogen exchange with n-BuLi, nucleophilic substitutions and oxidative additions with Pd(0) allowing the introduction of many functional groups to the pyridine ring, means they are of great interest from a synthetic point of view. Moreover, halopyridines are themselves important final products as herbicides, 7 insecticides 8 and fungicides. 9 As a consequence of these features the regioselective synthesis of halopyridines is a matter of great interest.Data published in the literature up to 1970 showed that bromination of activated pyridines must be carried out with bromine in polar protic solvents, such as water or ethanol. 10 Several years later, it was reported the bromination of aminopyridines and N-oxides 11 with bromine in mixtures of CH 3 CN/CH 2 Cl 2 , while bromination of methoxypyridines 10,12 was carried out in acetic acid. Also tetrabromocyclohexa-2,5-dienone 10 has been used for the bromination of 3-aminopyridine. In most of these papers, the formation of mixtures of monohalo and dihalo derivatives is reported but their relative proportions as well as their 1 H NMR characterisation is omitted. Recently, Br 2 / NaOH has successfully been employed by Schnatterer et al. 13 for the highly regioselective bromination of 3-hydroxypyridine to yield exclusively 2-bromo-3-hydroxypyridine but, to our knowledge, the authors have not extended this study to other pyridine derivatives.N-Halosuccinimides have previously been reported as reagents for the nuclear bromination of 8-quinolinol and its copper (II) chelate 14 but they have scarcely been used on pyridines bearing activating groups. 15 By contrast, radical brominations at lateral chains of alkylpyridines with NBS in the presence of radical initiators have been widely documented. 16 The good results obtained by our group in the regioselective bromination of methoxybenzenes and methoxynaphtalenes, 17 as well as phenols and napthols 18 under very mild conditions with NBS, prompted us to investigate the behaviour of activated pyridines. In this paper we report a systematic study of the bromination with NBS of pyridines bearing OH, NH 2 , and OMe groups at different positions and under ...

Aims Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. Methods and results Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. Conclusion The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.

El presente trabajo se inscribe en la línea de Feminismos en las redes sociales. El objetivo es estudiar el desarrollo y configuración del escrache, como una estrategia feminista para enfrentar la violencia de género hacia las mujeres. Para ello se retoma a la organización la Red No Están Solas (REDNES), quien ha llevado a cabo este tipo de acciones de manera recurrente a lo largo de su trayectoria política feminista en la universidad. Dicha agrupación se caracteriza por su forma de movilización y de organización en el espacio público físico y digital. Por ello utilizo una metodología que analiza los datos digitales de la fanpage de la REDNES, la cual se articula con entrevistas semiestructuradas a las integrantes de la organización, con el fin de dar cuenta de su acción colectiva híbrida.

1,3-Dipolar reactions of thiazolium azomethine ylides to enantiopure cyclic and acyclic vinyl sulfoxides provide an efficient access to polyfunctionalized pyrrolo[2,1-b][1,3]thiazoles in a highly regio- and stereoselective manner. Regioselectivity can be inverted by modifying the position of the sulfinyl group at the double bond of the sulfinylfuranones. The sulfoxide is the main controller of the endo selectivity of these processes as well as of the pi-facial selectivity in reactions of (Z)-3-p-tolylsulfinylacrylonitriles. In contrast, the pi-facial selectivity in reactions of 5-alkoxy-3-p-tolylsulfinyl furan-2(5H)-ones is mainly controlled by the configuration at C-5, affording the anti adducts with respect to the alkoxy group as the major or exclusive adducts.

RESUMENEn el presente artículo abordaremos la importancia que tiene la presencia del docente en entornos virtuales de aprendizaje desde un punto de vista de la construcción de aprendizajes. Se resumirá la evolución de los entornos virtuales de aprendizaje, es decir, del eLearning, así como el papel que tiene el docente en dichos entornos. Del mismo modo repasaremos qué entendemos por Presencia Docente, para centrarnos posteriormente en algunos factores que favorecen el desarrollo de la construcción de conocimientos. Para ello, nos referiremos a parte de los resultados obtenidos por la autora en la tesis doctoral del mismo título, centrándonos específicamente en los datos obtenidos en uno de los casos analizados, escogido por su relevancia para este artículo. PALABRAS CLAVE:Presencia docente -eLearning -innovación -motivación -aprendizaje. ABSTRACTIn this article we will discuss the importance of the Teaching Presence in virtual learning environments from a learning construction point of view. We will summarized the evolution of virtual learning environments, that is, of eLearning, as well as the role of the teacher in such environments. In the same way we will review what we mean by Teaching Presence, to focus later on some factors that favor the development of the construction of knowledge. We will reference part of the results obtained by the author in the doctoral thesis of the same title, focusing specifically on the data obtained in one of the cases analyzed, chosen because of its relevance to this article.

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BACKGROUND AND AIMS Peritoneal dialysis (PD) is a renal replacement technique that requires repeated contact of the peritoneum with hyperosmolar fluids. Unfortunately, it generates metabolic and biomechanical insults that promote structural and functional alterations of the peritoneal membrane (PM). PM is lined by a mesothelial cells (MCs) monolayer that is in direct contact with the PD fluids (PDFs). Repeated PDF exposure causes a mesothelial–mesenchymal transition (MMT) of the MCs, as well as an inflammatory response, angiogenesis and fibrosis of the peritoneal tissue. For decades, glucose (Gl) has been the most commonly used osmotic agent, and Gl itself is responsible for the aforementioned changes. Furthermore, Gl degradation products (GDPs) contribute to deleterious effects on the PM [1]. Therefore, there is an unmet need for more biocompatible osmotic agents able to better maintain the structure and function of the PM. Here we evaluated the biocompatibility of Stevia (STV), a compound of natural origin with a mixture of glycosides. STV has a molecular weight close to the theoretical ideal weight for an osmotic agent in PD [2] and it was used instead of Gl for PDF. METHODS The osmotic capacity of STV-containing fluids was analysed using an in vitro device with artificial membranes and compared to Gl-based fluids. In order to investigate the STV biocompatibility, human omental peritoneal mesothelial cells (HOMCs) were cultured in the presence of different types of Gl-based PDFs (Conventional 4.25% Gl solution with a high GDP level and biocompatible 2.3% Gl solution with low GDPs level), STV-based fluids or TGF-b for 48 h. Mice submitted to surgery of an intraperitoneal catheter insertion were treated for 40 days with STV- or Gl-based PDFs. Peritoneal tissues were collected to determine thickness, MMT, angiogenesis and inflammatory markers, as well as effluents to analyse infiltrating cells. RESULTS Experimentally, using artificial membranes we demonstrated that 1, 0.75 and 0.5% STV-based fluids have a maintained and prolonged osmotic capacity similar to commercial PDFs containing Gl concentrations between 1.5 and 2.3%. Moreover, 1.5% STV-based fluid showed an osmotic capacity higher than a PDF with Gl 2.3% and reached values similar to Gl 4.25% at longer time points. In addition, HOMCs exposed to STV-based fluids showed higher viability and did not induce MMT. Gl-based fluids induced upregulation of mesenchymal markers (VEGF, fibronectin, snail) and also downregulation of the epithelial marker E-cadherin in the case of the highest concentration of Gl (4.25%). None of these markers were significantly affected by STV treatment. In vivo, STV-based fluids preserved MCs monolayer and induced less PM thickness (Figure 1), angiogenesis, leukocyte infiltration and MMT than Gl-based fluids. Furthermore, STV solutions did not promote the release of pro-inflammatory cytokines by HOMCs nor by cells present in mice parietal peritoneal tissue in contrast to Gl-based PDFs. CONCLUSIONS STV-based fluids showed better biocompatibility than Gl-based PDFs in vivo and ex vivo since STV did not induce PM thickness, MMT, angiogenesis or the release of pro-inflammatory cytokines.