Nuevas estrategias para el tratamiento de la senescencia celular

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica, leída el 08/11/2019Cellular senescence is a biological irreversible process that appears after cellular stress and stops the proliferation of dysfunctional or damaged cells. Senescent cells are accumulated in our body with aging, so the regulation of this process could have an important effect in health span and aging. Towards this end, in the present work we propose two different approaches. In the first one (Chapter A), the objective is the development of inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) enzyme for targeting progeria as a model of accelerated aging. In the second approach (Chapter B), and taking into account the possible influence that metabolites of the human microbiota can have in aging, we propose an innovative strategy for the identification of microbiota metabolites in the framework of a broader project aimed at the phenotypic study of the identified metabolites in senescence...La senescencia celular es un proceso biológico irreversible que aparece después de una etapa de estrés celular y detiene la proliferación de células disfuncionales o dañadas. Las células senescentes se acumulan en nuestro cuerpo con la edad, por lo que la regulación de este proceso podría tener un efecto importante en la esperanza de vida y el envejecimiento. Con este fin, en el presente trabajo proponemos dos enfoques diferentes para abordar el proceso de senescencia celular. En el primero de ellos (Capítulo A), el objetivo es el desarrollo de inhibidores de la enzima isoprenilcisteína carboxil metiltransferasa (ICMT) para el tratamiento de la progeria como un modelo de envejecimiento acelerado. En la segunda aproximación (Capítulo B), teniendo en cuenta la posible influencia que los metabolitos de la microbiota humana pueden tener en el envejecimiento, proponemos una nueva estrategia para la identificación de los metabolitos de la microbiota. En particular, se pretende la puesta a punto de dicha metodología para poder abordar un proyecto más amplio que permita el estudio fenotípico en senescencia de los metabolitos identificados...Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEunpu

Aplicación de la síntesis de Torgov enantioselectiva en la preparación de esteroides no naturales

En el presente trabajo se ha estudiado la ciclación estereoselectiva de 3-metoxi-8,14-seco-1,3,5(10)-9-estrapentaeno-14,17-diona catalizada por diferentes ácidos de Brönsted quirales. Esta metodología constituye una nueva vía en la síntesis estereoselectiva de Torgov de esteroides no naturales, de entre los que se puede destacar: gestodeno, levonorgestrel y desogestrel. Estos productos tienen un elevado interés comercial debido a su alta actividad farmacológica. Durante este trabajo se ha preparado y ensayado varios ácidos fosfóricos derivados de ácido tartárico y S-Binol como catalizadores del proceso de ciclación. La reacción de ciclación transcurre con buenos rendimientos químicos, pero baja relación de estereoisómeros.Grado en Químic

Intervención en habilidades sociales para Educación Primaria

Las habilidades sociales hacen referencia a la interacción positiva con los demás centradas en las relaciones interpersonales como clave para el funcionamiento adecuado. Existe una amplia experiencia en la utilización de programas para el desarrollo de las habilidades sociales en la etapa escolar. También se ha puesto de manifiesto su importancia para el desarrollo integral de la infancia y adolescencia. El objetivo fue estudiar el aprendizaje de las habilidades sociales en Educación Primaria teniendo en cuenta la edad y el género. Los participantes fueron 137 alumnos/as (48.9% chicas) de dos colegios de la población de Alcàsser (Valencia), con edades comprendidas entre los 6 y los 12 años (M=9.0; DT=2.07). La distribución fue homogénea en los distintos cursos: 1º de primaria (n=40), 4º de primaria (n=47) y 6º de primaria(n=50). La evaluación se realizó en horario escolar, mediante el instrumento Cuestionario de Habilidades de Interacción Social (CHIS). Tras la administración del cuestionario se informó a los padres sobre el desarrollo del programa y se solicitó su colaboración en casa, reforzando las conductas practicadas en clase. Posteriormente, se aplicó el programa de intervención. Cada curso se entrena en dos áreas de habilidades sociales, con un total de diez habilidades por curso. Los resultados señalan que los alumnos de 4º de primaria poseen más habilidades sociales que los demás cursos, antes de aplicar el programa. La aplicación del programa de intervención ha sido efectiva en los cursos 1º y 4º de primaria. Pero, no se han observado diferencias significativas en 6º de primaria. Como conclusión, la intervención ha mejorado las habilidades sociales de los alumnos/as sólo en algunos cursos, por lo que son necesarios nuevos estudios sobre la eficacia de la intervención. Además, la presencia del profesor durante la intervención se muestra como una variable decisiva para el aprendizaje de dichas habilidades en estos cursos.Social skills refer to the positive interaction with others, focusing on interpersonal relationships as the key to proper functioning. There is extensive experience in the use of programs to develop social skills at school age. They have also been shown to play an important role in the overall development of children and adolescents. The aim is to study the learning of social skills at primary school taking into account age and gender. The participants were 137 randomly selected Spanish children between 6-12 years old (M= 9.0; DT = 2.07) of both sexes (48.9% girls). The distribution was homogeneous in the different years: 1ert year (n=40), 4th year (n=47), and 6th year of primary (n = 50). The evaluation of social skills was conducted during school hours with the Interaction Skills Questionnaire (CHIS). After the administration of the questionnaire, parents were informed about the program and were asked to collaborate at home. After that, we applied the intervention program. Each year was trained in two areas of social skills, with a total of ten skills. The results show that it is the 4th year primary school students who have the most social skills. The implementation of the intervention program has been effective in courses 1st and 4th years of primary education, whereas no significant differences were observed in the 6th year of primary education. Furthermore, the presence of the teacher during the social skills intervention is a critical variable in learning.peerReviewe

Surveillance on ESBL-Escherichia coli and Indicator ARG in Wastewater and Reclaimed Water of Four Regions of Spain: Impact of Different Disinfection Treatments

[EN] In the present study, the occurrence of indicator antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) both in the influent and the effluent of four Spanish wastewater treatment plants (WWTPs) was monitored for 12 months, and the susceptibility profiles of 89 recovered extended spectrum β-lactamase (ESBL)-producing Escherichia coli isolates were obtained against a wide range of antimicrobials. The aim of the study was to better understand whether the current wastewater treatment practices allow us to obtain safe reclaimed water mitigating the spread of ARB and ARGs to the environment. Results showed high concentrations of ESBL-producing E. coli as well as a high prevalence of a range of ARGs in the influent samples. The reclamation treatments implemented in the WWTPs were effective in reducing both the occurrence of ESBL E. coli and ARGs, although significant differences were observed among WWTPs. Despite these reductions in occurrence observed upon wastewater treatment, our findings suggest that WWTP effluents may represent an important source of ARGs, which could be transferred among environmental bacteria and disseminate antimicrobial resistance through the food chain. Remarkably, no major differences were observed in the susceptibility profiles of the ESBL E. coli isolated from influent and effluent waters, indicating that water treatments do not give rise to the emergence of new resistance phenotypesSIThis research was funded by the Spanish Ministry of Science and Innovation (TED2021- 131427B-C21 and TED2021-131427B-C22

Isoprenylcysteine Carboxylmethyltransferase-Based Therapy for Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is a rare genetic disease characterized by premature aging and death in childhood for which there were no approved drugs for its treatment until last November, when lonafarnib obtained long-sought FDA approval. However, the benefits of lonafarnib in patients are limited, highlighting the need for new therapeutic strategies. Here, we validate the enzyme isoprenylcysteine carboxylmethyltransferase (ICMT) as a new therapeutic target for progeria with the development of a new series of potent inhibitors of this enzyme that exhibit an excellent antiprogeroid profile. Among them, compound UCM-13207 significantly improved the main hallmarks of progeria. Specifically, treatment of fibroblasts from progeroid mice with UCM-13207 delocalized progerin from the nuclear membrane, diminished its total protein levels, resulting in decreased DNA damage, and increased cellular viability. Importantly, these effects were also observed in patient-derived cells. Using the Lmna G609G/G609G progeroid mouse model, UCM-13207 showed an excellent in vivo efficacy by increasing body weight, enhancing grip strength, extending lifespan by 20%, and decreasing tissue senescence in multiple organs. Furthermore, UCM-13207 treatment led to an improvement of key cardiovascular hallmarks such as reduced progerin levels in aortic and endocardial tissue and increased number of vascular smooth muscle cells (VSMCs). The beneficial effects go well beyond the effects induced by other therapeutic strategies previously reported in the field, thus supporting the use of UCM-13207 as a new treatment for progeria.This work was supported by grants from The Progeria Research Foundation (PRF 2016-65) and the Spanish MINECO (PID2019-106279RB-I00, PID2019-108489RBI00). The authors thank Fundación La Caixa (A.G.), CEI Moncloa (N.I.M.-R.), MINECO (F.J.O.-N. and M.B.) and Ministerio de Ciencia, Innovación y Universidades (N.K.-F.) for predoctoral fellowships. The authors thank C. López-Otín for kindly donating LmnaG609G/G609G progeroid and their corresponding wild-type fibroblasts and UCM’s CAIs Cytometry and Fluorescence Microscopy, Genomics, NMR, and Mass Spectrometry, for their assistance. The CNIC is supported by the Ministerio de Ciencia e Innovación, the Instituto de Salud Carlos III, and the pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant SEV-2015- 0505). The generation of the antiprogerin antibody was funded by the Wellcome Trust (098291/Z/12/Z to S.N.).S

Viruses Previously Identified in Brazil as Belonging to HIV-1 CRF72_BF1 Represent Two Closely Related Circulating Recombinant Forms, One of Which, Designated CRF122_BF1, Is Also Circulating in Spain

Circulating recombinant forms (CRFs) are important components of the HIV-1 pandemic. Those derived from recombination between subtype B and subsubtype F1, with 18 reported, most of them of South American origin, are among the most diverse. In this study, we identified a HIV-1 BF1 recombinant cluster that is expanding in Spain, transmitted mainly via heterosexual contact, which, analyzed in near full-length genomes in four viruses, exhibited a coincident BF1 mosaic structure, with 12 breakpoints, that fully coincided with that of two viruses (10BR_MG003 and 10BR_MG005) from Brazil, previously classified as CRF72_BF1. The three remaining Brazilian viruses (10BR_MG002, 10BR_MG004, and 10BR_MG008) previously identified as CRF72_BF1 exhibited mosaic structures highly similar, but not identical, to that of the Spanish viruses and to 10BR_MG003 and 10BR_MG005, with discrepant subtypes in two short genome segments, located in pol and gp120env. Based on these results, we propose that the five viruses from Brazil previously identified as CRF72_BF1 actually belong to two closely related CRFs, one comprising 10BR_MG002, 10BR_MG004, and 10BR_MG008, which keep their CRF72_BF1 designation, and the other, designated CRF122_BF1, comprising 10BR_MG003, 10BR_MG005, and the viruses of the identified Spanish cluster. Three other BF1 recombinant genomes, two from Brazil and one from Italy, previously identified as unique recombinant forms, were classified as CRF72_BF1. CRF122_BF1, but not CRF72_BF1, was associated with protease L89M substitution, which was reported to contribute to antiretroviral drug resistance. Phylodynamic analyses estimate the emergence of CRF122_BF1 in Brazil around 1987. Given their close phylogenetic relationship and similar structures, the grouping of CRF72_BF1 and CRF122_BF1 in a CRF family is proposed.This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, projects “Estudios Sobre Vigilancia Epidemiológica Molecular del VIH-1 en España”, PI16CIII/00033, and “Epidemiología Molecular del VIH-1 en España y su Utilidad Para Investigaciones Biológicas y en Vacunas“, PI19CIII/00042, and through scientific agreement with Consellería de Sanidade, Government of Galicia (MVI 1004/16).S

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: A nationwide study in Spain

Objective To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. Settings The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. Participants This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. Interventions An exploratory factorial analysis was performed to select the most relevant variables of the sample. Primary and secondary outcome measures Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. Results Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/10 5 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade =3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/10 5 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. Conclusions Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/10 5 people/week) was a statistically independent predictor of mortality. Trial registration number CEIM 20/217

I Congreso - Convergencias y divergencias. Hacia educaciones y desarrollo otros.

La presente colección, en su primera publicación, recoge la experiencia del I Congreso Internacional de Educación para el Desarrollo en Perspectiva Latinoamericana- EpDl “Convergencias y divergencias. Hacia educaciones y desarrollos otros.” organizado por el Centro de Educación para el Desarrollo-CED de UNIMINUTO, específicamente en relación con las ponencias, libros e iniciativas fotográficas presentadas en las seis líneas temáticas de este evento académico, a saber: (a) experiencias y prácticas pedagógicas; (b) acciones colectivas, movimientos y redes sociales; (c) perspectivas críticas al desarrollo; (d) producción de conocimiento; (e) diferencias, identidades y ciudadanía; (f) cuerpos, emociones y espiritualidades; a partir de éstas propuestas y en el marco de estas líneas, se reflexionó sobre las dinámicas y problemáticas derivadas del desarrollo hegemónico, así como sobre la posibilidad de diálogo entre saberes y conocimientos construidos de forma contextualizada, que permitan agenciar apuestas y proyectos alternativos disidentes en la búsqueda de “desarrollos y educaciones otras” desde América Latina

Diverse Large HIV-1 Non-subtype B Clusters Are Spreading Among Men Who Have Sex With Men in Spain

In Western Europe, the HIV-1 epidemic among men who have sex with men (MSM) is dominated by subtype B. However, recently, other genetic forms have been reported to circulate in this population, as evidenced by their grouping in clusters predominantly comprising European individuals. Here we describe four large HIV-1 non-subtype B clusters spreading among MSM in Spain. Samples were collected in 9 regions. A pol fragment was amplified from plasma RNA or blood-extracted DNA. Phylogenetic analyses were performed via maximum likelihood, including database sequences of the same genetic forms as the identified clusters. Times and locations of the most recent common ancestors (MRCA) of clusters were estimated with a Bayesian method. Five large non-subtype B clusters associated with MSM were identified. The largest one, of F1 subtype, was reported previously. The other four were of CRF02_AG (CRF02_1; n = 115) and subtypes A1 (A1_1; n = 66), F1 (F1_3; n = 36), and C (C_7; n = 17). Most individuals belonging to them had been diagnosed of HIV-1 infection in the last 10 years. Each cluster comprised viruses from 3 to 8 Spanish regions and also comprised or was related to viruses from other countries: CRF02_1 comprised a Japanese subcluster and viruses from 8 other countries from Western Europe, Asia, and South America; A1_1 comprised viruses from Portugal, United Kingom, and United States, and was related to the A1 strain circulating in Greece, Albania and Cyprus; F1_3 was related to viruses from Romania; and C_7 comprised viruses from Portugal and was related to a virus from Mozambique. A subcluster within CRF02_1 was associated with heterosexual transmission. Near full-length genomes of each cluster were of uniform genetic form. Times of MRCAs of CRF02_1, A1_1, F1_3, and C_7 were estimated around 1986, 1989, 2013, and 1983, respectively. MRCA locations for CRF02_1 and A1_1 were uncertain (however initial expansions in Spain in Madrid and Vigo, respectively, were estimated) and were most probable in Bilbao, Spain, for F1_3 and Portugal for C_7. These results show that the HIV-1 epidemic among MSM in Spain is becoming increasingly diverse through the expansion of diverse non-subtype B clusters, comprising or related to viruses circulating in other countries