Papel de FAS y p21 en la limitación de las células T de memoria y la enfermedad autoinmune

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 25-05-201

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.This work was supported by grants from the Ministry of Economy and Competitivity (MINECO/FEDER PI11/00950 and SAF2016-80803-R to DB, and SAF2013-42289-R and SAF2016-75456-R to CM-A), from the Fundación Alfonso Martin Escudero to CM-A, and from the Community of Madrid (MITIC S2011/BMD2502 to DB and CM-A).Peer reviewe

Tween 80 Improves the Acid-Fast Bacilli Quantification in the Magnetic Nanoparticle-Based Colorimetric Biosensing Assay (NCBA)

Despite its reduced sensitivity, sputum smear microscopy (SSM) remains the main diagnostic test for detecting tuberculosis in many parts of the world. A new diagnostic technique, the magnetic nanoparticle-based colorimetric biosensing assay (NCBA) was optimized by evaluating different concentrations of glycan-functionalized magnetic nanoparticles (GMNP) and Tween 80 to improve the acid-fast bacilli (AFB) count. Comparative analysis was performed on 225 sputum smears: 30 with SSM, 107 with NCBA at different GMNP concentrations, and 88 with NCBA-Tween 80 at various concentrations and incubation times. AFB quantification was performed by adding the total number of AFB in all fields per smear and classified according to standard guidelines (scanty, 1+, 2+ and 3+). Smears by NCBA with low GMNP concentrations (≤1.5 mg/mL) showed higher AFB quantification compared to SSM. Cell enrichment of sputum samples by combining NCBA-GMNP, incubated with Tween 80 (5%) for three minutes, improved capture efficiency and increased AFB detection up to 445% over SSM. NCBA with Tween 80 offers the opportunity to improve TB diagnostics, mainly in paucibacillary cases. As this method provides biosafety with a simple and inexpensive methodology that obtains results in a short time, it might be considered as a point-of-care TB diagnostic method in regions where resources are limited

Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production.

Self/non-self discrimination characterizes immunity and allows responses against pathogens but not self-antigens. Understanding the principles that govern this process is essential for designing autoimmunity treatments. p21 is thought to attenuate autoreactivity by limiting T cell expansion. Here, we provide direct evidence for a p21 role in controlling autoimmune T cell autoreactivity without affecting normal T cellresponses. We studied C57BL/6, C57BL/6/lpr and MRL/lpr mice overexpressing p21 in T cells, and showed reduced autoreactivity and lymphadenopathy in C57BL/6/lpr, and reduced mortality in MRL/lpr mice. p21 inhibited effector/memory CD4(+) CD8(+) and CD4(-)CD8(-) lpr T cell accumulation without altering defective lpr apoptosis. This was mediated by a previously non-described p21 function in limiting T cell overactivation and overproduction of IFN-γ, a key lupus cytokine. p21 did not affect normal T cell responses, revealing differential p21 requirements for autoreactive and normal T cell activity regulation. The underlying concept of these findings suggests potential treatments for lupus and autoimmune lymphoproliferative syndrome, without compromising normal immunity.This work was supported by grants from the Ministry of Economy and Competitivity (MINECO)/Instituto Carlos III (PI081835 PI11/00950) and the CAM (MITIC S2011/ BMD2502) to DB, and from the MINECO (SAF2010-21205 and PIB2010BZ-00564) and the CAM (MITIC S2011/BMD2502) to CMA.Peer reviewe

Spatial Distribution and Potential Impact of Drifted Thalli of the Invasive Alga Rugulopteryx okamurae in Circalittoral and Bathyal Habitats of the Northern Strait of Gibraltar and the Alboran Sea

The arrival of a new invasive alga, Rugulopteryx okamurae, in the Strait of Gibraltar (SoG) in 2015 marked an unprecedented milestone in the North African and, later, in the European marine ecosystems. Nowadays, it is colonising vast infralittoral areas and significantly modifying some habitats and associated communities of the southern Iberian Peninsula. In recent expeditions, a high amount of free drifted thalli of this alga has been detected in different circalittoral and bathyal habitats of the northern SoG and the Alboran Sea. The present study combines quantitative data of this alga obtained with the use of a remotely operated vehicle (ROV) and a bottom otter trawl. The coverage–entanglement level of the drifted thalli on circalittoral and bathyal benthic invertebrates (e.g., not covering, covering only the basal part, covering one-third of the invertebrate, etc.) was also annotated from picture frames taken in locations with abundant drifted thalli. In underwater images, drifted thalli were mainly detected in circalittoral and bathyal bottoms of the northern SoG and the north-western Alboran Sea, between 50 to ca. 450 m depth. Nevertheless, abundant drifted thalli were also detected in bottom otter trawl samples from circalittoral bottoms of the north-central and north-eastern Alboran Sea. Small benthic organisms (e.g., encrusting sponges, hydrozoans, etc.) generally displayed low coverage–entanglement levels of drifted thalli. Nevertheless, large sessile and colonial benthic organisms with a complex three-dimensional morphology (e.g., gorgonians, colonial scleractinians) reached high levels of R. okamurae thalli entangled in different parts of their colonies. The drifted R. okamurae thalli entangled in these colonial suspension feeding organisms may hinder their feeding capability in the long term, resulting in habitat deterioration in the near future.This study has been funded by the projects 18-ESMARES2-CIRCA (IEO and Ministerio de Transición Ecológica y Reto Demográfico—MITERD of the Spanish government for the application of the Marine Strategy Framework Directive in Spanish waters) and DEMALBORAN (Evaluación de Recursos Demersales por Métodos Directos en el Mar de Alborán, IEO and the European Maritime and Fisheries Fund).Peer reviewe

Los principios cooperativos y su incidencia en el régimen legal y fiscal de las cooperativas

Este libro constituye un verdadero tratado de Derecho cooperativo, con más de ochocientas páginas y veintinueve capítulos, elaborados por grandes especialistas en la materia que tratan desde aspectos más generales a cuestiones de detalles en el ámbito societario, tributario y fiscal de las cooperativas. La obra se se divide en cuatro grandes bloques o parte: los principios y valores cooperativos de la Alianza Cooperativa Internacional; recepción legal de los distintos principios cooperativos; nuevos principios cooperativos; y los principios cooperativos y la fiscalidad de las cooperativas. En el primero de estos bloques se aborda el origen y la evolución de los principios y valores cooperativos de la ACI y, en especial, su discutido carácter de fuente del Derecho. El bloque segundo de la obra está dedicado al Derecho positivo español, pues se trata de ver cómo nuestro ordenamiento ha acogido y desarrollado los siete principios cooperativos de la ACI: 1.º de adhesión voluntaria y abierta, 2.º de control democrático de los miembros, 3.º de participación económica, 4.º de autonomía e independencia, 5.º de educación, formación e información, 6.º de cooperación entre cooperativas y 7.º de interés por la comunidad. Este análisis se realiza teniendo en cuenta la legislación estatal y autonómica de cooperativas, con continuas referencias al derecho comparado y se abordan temas de tanto interés práctico como el ejercicio del derecho de baja voluntaria por los socios, la posibilidad del voto plural ponderado, la asamblea de delegados, las prácticas de buen gobierno corporativo en el consejo rector y en la propia asamblea general, e régimen económico y del capital social de las cooperativas y de la constitución de reservas y dotación de fondos, por poner sólo algunos ejemplos. En el bloque tercero se analizan por separado los nuevos principios que algunas leyes han reconocido recientemente en su articulado (sostenibilidad empresarial y medio ambiental, fomento del empleo estable y de calidad, igualdad de género, etc.). Por último, el bloque cuarto trata de los principios cooperativos y la fiscalidad de este tipo de entidades

Database of spatial distribution of non indigenous species in Spanish marine waters

Research in marine Spanish waters are focused on several actions to achieve an effectively management on protected areas, with the active participation of the stakeholders and research as basic tools for decision-making. Among these actions, there is one about the knowledge and control on NIS. One of its objectives is the creation of NIS factsheets, which are going to be added to the National Marine Biodiversity Geographical System (GIS) providing complementary information about taxonomic classification, common names, taxonomic synonyms, species illustrations, identification morphological characters, habitat in the native and introduced regions, biological and ecological traits, GenBank DNA sequences, world distribution, first record and evolution in the introduced areas, likely pathways of introduction, effects in the habitats and interaction with native species, and potential management measures to apply. The database will also provide data for (1) the European online platforms, (2) the environmental assessment for the Descriptor 2 (D2-NIS) of the EU Marine Strategy Framework Directive (MSFD), as well as (3) supporting decisions made by stakeholders. It is the result of extensive collaboration among scientist, manager’s and citizen science in the Spanish North-Atlantic, South-Atlantic, Gibraltar Strait-Alboran, Levantine-Balearic and Canary Islands marine divisions, providing an updated overview of the spatial distribution of relevant extended and invasive NIS of recent and established NIS introduced by maritime transport and aquaculture pathways, as well as on cryptogenic or native species in expansion due to the climatic water warming trend

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes

Purpose: The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes. Methods: This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 μg/dL (confirmed ACS if >5 μg/dL and possible ACS if 1.8–5 μg/dL) in the absence of spe cific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels. Results: The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS–PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS–PA and PA-only patients was simil ar, except for older age and larger tumor size of the adrenal lesion in the ACS–PA group. When comparing the ACS–PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64–22.32)) and cardiovascular events (OR 5.0 (2.29–11.07)) was higher in ACS–PA patients than in ACS patients. The coexistence of ACS in patien ts with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS–PA and PA-only groups. Conclusion: Co-secretion of cortisol and aldosterone affects almost one-thi rd of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS–PA and PA-only are similar

5to. Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad. Memoria académica

El V Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad, CITIS 2019, realizado del 6 al 8 de febrero de 2019 y organizado por la Universidad Politécnica Salesiana, ofreció a la comunidad académica nacional e internacional una plataforma de comunicación unificada, dirigida a cubrir los problemas teóricos y prácticos de mayor impacto en la sociedad moderna desde la ingeniería. En esta edición, dedicada a los 25 años de vida de la UPS, los ejes temáticos estuvieron relacionados con la aplicación de la ciencia, el desarrollo tecnológico y la innovación en cinco pilares fundamentales de nuestra sociedad: la industria, la movilidad, la sostenibilidad ambiental, la información y las telecomunicaciones. El comité científico estuvo conformado formado por 48 investigadores procedentes de diez países: España, Reino Unido, Italia, Bélgica, México, Venezuela, Colombia, Brasil, Estados Unidos y Ecuador. Fueron recibidas un centenar de contribuciones, de las cuales 39 fueron aprobadas en forma de ponencias y 15 en formato poster. Estas contribuciones fueron presentadas de forma oral ante toda la comunidad académica que se dio cita en el Congreso, quienes desde el aula magna, el auditorio y la sala de usos múltiples de la Universidad Politécnica Salesiana, cumplieron respetuosamente la responsabilidad de representar a toda la sociedad en la revisión, aceptación y validación del conocimiento nuevo que fue presentado en cada exposición por los investigadores. Paralelo a las sesiones técnicas, el Congreso contó con espacios de presentación de posters científicos y cinco workshops en temáticas de vanguardia que cautivaron la atención de nuestros docentes y estudiantes. También en el marco del evento se impartieron un total de ocho conferencias magistrales en temas tan actuales como la gestión del conocimiento en la universidad-ecosistema, los retos y oportunidades de la industria 4.0, los avances de la investigación básica y aplicada en mecatrónica para el estudio de robots de nueva generación, la optimización en ingeniería con técnicas multi-objetivo, el desarrollo de las redes avanzadas en Latinoamérica y los mundos, la contaminación del aire debido al tránsito vehicular, el radón y los riesgos que representa este gas radiactivo para la salud humana, entre otros