The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline

EMA Fault Detection Using Fuzzy Inference Tools

Acoustic emission (AE) is one of the most important non-destructive testing (NDT) methods for materials, constructions and machines. Acoustic emission is defined as the transient elastic energy that is spontaneously released when materials undergo deformation, fracture, or both. This interdisciplinary book consists of 17 chapters, which widely discuss the most important applications of AE method as machinery and civil structures condition assessment, fatigue and fracture materials research, detection of material defects and deformations, diagnostics of cutting tools and machine cutting process, monitoring of stress and ageing in materials, research, chemical reactions and phase transitions research, and earthquake prediction.Peer ReviewedPostprint (published version

Star cluster evolution in barred disc galaxies. I. Planar periodic orbits

The dynamical evolution of stellar clusters is driven to a large extent by their environment. Several studies so far have considered the effect of tidal fields and their variations, such as, e.g., from giant molecular clouds, galactic discs, or spiral arms. In this paper we will concentrate on a tidal field whose effects on star clusters have not yet been studied, namely that of bars. We present a set of direct N-body simulations of star clusters moving in an analytic potential representing a barred galaxy. We compare the evolution of the clusters moving both on different planar periodic orbits in the barred potential and on circular orbits in a potential obtained by axisymmetrising its mass distribution. We show that both the shape of the underlying orbit and its stability have strong impact on the cluster evolution as well as the morphology and orientation of the tidal tails and the sub-structures therein. We find that the dissolution time-scale of the cluster in our simulations is mainly determined by the tidal forcing along the orbit and, for a given tidal forcing, only very little by the exact shape of the gravitational potential in which the cluster is moving.Comment: 15 pages, 17 figures, 5 tables; accepted for publication in MNRAS. Complementary movies can be be found at this http URL http://lam.oamp.fr/research/dynamique-des-galaxies/scientific-results/star-cluster-evolution

Short-term effects of impurities in the CO2 stream injected into fractured carbonates.

After the Paris Agreement in which 195 countries are involved, the Carbon Capture and Storage (CCS) is now an accepted technology in the United Nations Framework Convention on Climate Change (UNFCCC). In Spain, Fundación Ciudad de la Energía (CIUDEN) has successfully completed the full CCS chain, being CO2 captured in the Technology Development Centre in Cubillos del Sil (León, Spain) whereas that it is geologically stored in a deep saline aquifer, formed by fractured carbonates with poor matrix porosity, located in the Technology Development Plant (TDP) at Hontomín (Burgos, Spain). The results of the field tests, in which up to 150 tons of CO2 and synthetic air (5 %v of N2 and O2) were co-injected on site, are analyzed in this paper comparing the operational parameters gained during the injection of impure CO2 (pressures, temperatures and flow ranges) with its corresponding baseline previously determined (i.e. 1,500 tons of pure CO2 were injected during the reservoir hydraulic characterization). Besides that, the geochemical reactivity analysis of impure CO2 injected in this saline aquifer and its correlation with the results from laboratory tests were assessed. As main conclusions from laboratory scale results, a porosity diminution was measured after the injection of CO2 with 5 %v of SO2; apart from that, without SO2, the effluent pH was in the range of 7-8 whereas in case of CO2 and SO2, a pH of 1-2 was obtained. Otherwise and focused on field scale tests, a density decrease was detected comparing the base case (pure CO2) with the CO2 injection containing 5.1 %v of synthetic air. On the other hand, Ca2+, SO42-, Mg2+ and K+ migration effects in the rock were also detected and analyzed

Group 10 Metal Benzene-1,2-dithiolate Derivatives in the Synthesis of Coordination Polymers Containing Potassium Countercations

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/abs/10.1021/acs.inorgchem.7b01775The use of theoretical calculations has allowed us to predict the coordination behavior of dithiolene [M(SC6H4S)2]2- (M = Ni, Pd, Pt) entities, giving rise to the first organometallic polymers {[K2(μ-H2O)2][Ni(SC6H4S)2]}n and {[K2(μ-H2O)2(thf)]2[K2(μ-H2O)2(thf)2][Pd3(SC6H4S)6]}n by one-pot reactions of the corresponding d10 metal salts, 1,2-benzenedithiolene, and KOH. The polymers are based on σ,π interactions between potassium atoms and [M(SC6H4S)2]2- (M = Ni, Pd) entities. In contrast, only σ interactions are observed when the analogous platinum derivative is used instead, yielding the coordination polymer {[K2(μ-thf)2][Pt(SC6H4S)2]}nThis work was supported in part by the MICINN (grants MAT2016-77608-C3-1-P and MAT2016-75883-C2-1-P), Generalitat Valenciana (PrometeoII/2014/076), and ISIC. J.I.M. acknowledges financial support by the “Ramon y Cajal ́ ” Program of MINECO (RYC-2015-17730

Registration system of professional performances defendants in Community Pharmacy.

INTRODUCCION El diseño de una herramienta o sistema de registro de todas las actuaciones profesionales (AP) que demanda el usuario en la farmacia comunitaria, en el mostrador, donde el farmacéutico realiza la mayor parte de su labor, es imprescindible para entender la barrera de falta de “tiempo” para implantar o desarrollar servicios cognitivos en la farmacia comunitaria. MATERIAL Y METODO El equipo investigador del estudio diseñó la herramienta de registro utilizando como soporte informático el sistema de gestión disponible en las farmacias participantes en el estudio (FARMATCR). Después de un pilotaje de 15 días y de los ajustes necesarios se creó la herramienta definitiva. Los requisitos básicos que se persiguieron para el diseño de la herramienta, fueron: Registrar todas las AP demandadas en el mostrador de la farmacia comunitaria. Recopilar la máxima información para cada una de las AP. Mantener la agilidad en la resolución de las mismas. Se decide hacer un control de calidad de la herramienta para saber si satisface las necesidades para lo que se ha diseñado. RESULTADO: herramienta FINAL La herramienta consiste en la introducción en el sistema informático (FARMATCR,) de una serie de códigos de trabajo nuevos (artículos, aportaciones y desplegables). DISCUSION Es difícil encontrar un equilibrio entre agilidad y rigor del registro. La herramienta es capaz de cuantificar las AP que se realizan en el mostrador, pero con limitaciones.INTRODUCTION Designing a tool or registration system for all professional activities requested by all user over the counter in the community pharmacy, where the pharmacist conducts most of its work, is essential to enable the understanding of the barrier of “lack of time” in order to establish or develop cognitive services in the community pharmacy . METHOD The research team working on this survey, designed the registered tool using the management system available in all pharmacies participants in the survey, as a computerized record (FARMATICR) The ultimate tool was created after 15 days of pile work and needed adjustments. The basic requirements pursued for the design of the tool were: The recording of all professional activities requested at the counter in pharmacies. The compiling of all information for each of the professional activities To maintain the flexibility in the resolutions of these. It was decided to have constant feedback of the quality of the tool to see if it met the requirements for its designed purpose. RESULTS The tool is the introduction into the computer system (FARMATICR,) of a series of new labor codes (articles, transfers and leaflets). DISCUSSION. It is difficult to find a balance between the speed and the inflexibility of the record. The tool is able to quantify the professional activities carried out in the pharmacy counter, but with its limitations

Proyecto eMadrid: metodologías educativas, ludificación y calidad

Esta comunicación presenta un conjunto de trabajos de investigación sobre metodologías docentes, ludificación y calidad realizados en el seno del proyecto eMadrid, de la Comunidad Autónoma de Madrid. En primer lugar se resumen los trabajos realizados en los dos primeros años del proyecto. Posteriormente se presentan las líneas de trabajo previstas para los dos años restantesEstos trabajos se han financiado parcialmente por el proyecto eMadrid (S2013/ICE-2715) de la Comunidad de Madrid, los proyectos FLEXOR (TIN2014-52129-R), RESET (TIN2014-53199-C3-1-R) e iProg (TIN2015-66731-C2-1-R) del Ministerio de Economía y Competitividad, y el proyecto “Adaptación de la metodología PhyMEL a la formación clínica mediante el uso de simuladores” financiado por la empresa Medical Simulato