Dinámica molecular con múltiples moléculas: Inhibición alostérica de las proteínas antiapoptóticas Mcl-1 y Bcl-xL.

Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2020, Tutor: Jaime Rubio MartínezThe purpose of the present work is the study and selection of allosteric inhibitors of the Mcl-1 and Bcl-xL, Bcl-2 protein family members, involved in the regulation of the programmed cell death called apoptosis. Given that the over-expression of these antiapoptotic proteins is related to the development of some types of cancer, both proteins are considered potential therapeutic targets for the development of effective cancer treatment. However, the similarity of the Mcl-1 and Bcl-xL active sites leads to undesirable side effects of cancer treatment. Due to the lack of selectivity in compounds that targets the active site of these proteins, the aim of this work is the selection of two drug candidate fragments capable of selectively regulate the apoptotic mechanism of the proteins Mcl-1 and Bcl-xL by means of their selective inhibition. For this purpose, six different fragments have been studied in order to predict their binding affinity and selectivity towards both proteins. To accomplish this purpose, four independent Gaussian accelerated Molecular Dynamics and their respective trajectory analysis have been performed for each studied system. Through the evaluation of the obtained results, the identification of the different allosteric binding sites for both proteins has been possible. As the knowledge of the binding poses is important to determine the correct growth of the fragments, a first proposal of the binding mode has been made. To correctly discern the binding site of each selected fragment, it has been suggested the necessity of extending the study of their binding modes by an increase of the Molecular Dynamics simulation time. Therefore, more precise and reliable results will be obtained to develop larger ligands in further studies

Supporting information Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 Mpro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation

PDF file contains: Tables S1-S6 and Figures S1-S5Peer reviewe

Smoking cessation opportunities in severe mental illness (tobacco intensive motivational and estimate risk — TIMER—): study protocol for a randomized controlled trial

There is an increased risk of premature death in people with severe mental illness (SMI). Respiratory disorders and cardiovascular disease are leading causes of increased mortality rates in these patients, and tobacco consumption remains the most preventable risk factor involved. Developing new tools to motivate patients towards cessation of smoking is a high priority. Information on the motivational value of giving the lung age and prevention opportunities is unknown in this high-risk population. In the context of community care, screening and early detection of lung damage could potentially be used, together with mobile technology, in order to produce a prevention message, which may provide patients with SMI with a better chance of quitting smoking.This study receives funding by the Spanish Ministry of Economy, Industry and Competitiveness, Instituto Carlos III (FIS PI16/00802)

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Towards the creation of a teaching learning community in the area of ​​Statistics and Operational Research

El objetivo del presente proyecto ha sido crear un espacio de reflexión y evaluación de estrategias didácticas aplicadas en asignaturas de Estadística e Investigación Operativa facilitando la creación de una comunidad docente de aprendizaje en el área,Depto. de Estadística e Investigación OperativaFac. de Ciencias MatemáticasFALSEsubmitte

ERC, 10 años de excelencia en la ciencia

Datos técnicos: 8 minutos, color, español. Ficha técnica: Gabinete de Presidencia CSIC y Departamento de ComunicaciónEl Consejo Europeo de Investigación (ERC, por sus siglas en inglés) cumplió 10 años el 24 de marzo de 2017. A lo largo de esta década de vida, se ha financiado a unos 7.000 investigadores, permitiendo la publicación de cerca de 100.000 artículos en revistas científicas internacionales. En España, cerca de 400 investigadores han recibido un total de 650 millones de euros y el Consejo Superior de Investigaciones Científicas (CSIC) destaca por ser la institución española con mayor número de ayudas, por delante de la Universidad Pompeu Fabra, el Instituto de Ciencias Fotónicas, la Universidad de Barcelona y el Centro de Regulación Genómica. Entre los más de 400 proyectos que han obtenido una ayuda del Consejo Europeo de Investigación en España, más de un centenar han recaído en el CSIC.N

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved