Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity

Conexión inteligente para la gestión turística desde el aula al destino (CIGTAD – II)

Para reducir la brecha digital existente en la sociedad actual es necesario situar la innovación en el núcleo de la toma de decisiones. Este proyecto camina hacia la plena inclusión de todos los colectivos de la comunidad universitaria en el uso de las nuevas tecnologías, y gracias a ellas, poder generar una mayor conciencia social y medioambiental. Desarrollaremos soluciones para la mejora de la accesibilidad a la información que se genera, tanto formal como informal, para los grupos implicados y en cuyos contenidos se introducirá la conceptualización de los ODS y su implicación en sectores tan importantes como el Comercio y el Turismo. Se trabajará con tecnología actual y futura de los destinos turísticos, lo que mejorará, a su vez, la empleabilidad de los egresados en la facultad. El proyecto impulsa la implementación de las tecnologías que se están utilizando en los planes estratégicos de Destinos Turísticos Inteligentes. De este modo, los estudiantes del Grado en Turismo y el Doble Grado en Turismo y Comercio, así como del Máster en Planificación y Gestión de Destinos Turísticos podrán experimentar la inmersión en el uso de este tipo de herramientas. El proyecto estará dividido en 3 fases como son: el análisis, el desarrollo de contenidos y la implementación de las herramientas en el que participarán diferentes colectivos tales como PDI, PAS y Estudiantes de diferentes niveles y Alumni de la Facultad de Comercio y Turismo, así como la participación de una trabajadora social experta en trabajar con colectivos juveniles. El proyecto está alineado para trabajar por mejorar la sostenibilidad de la facultad e incrementar el nivel de compromiso de los colectivos con los objetivos de la Agenda 2030

Essential Role of TGF-β/Smad Pathway on Statin Dependent Vascular Smooth Muscle Cell Regulation

BACKGROUND: The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (also called statins) exert proven beneficial effects on cardiovascular diseases. Recent data suggest a protective role for Transforming Growth Factor-beta (TGF-beta) in atherosclerosis by regulating the balance between inflammation and extracellular matrix accumulation. However, there are no studies about the effect of statins on TGF-beta/Smad pathway in atherosclerosis and vascular cells. METHODOLOGY: In cultured vascular smooth muscle cells (VSMCs) statins enhanced Smad pathway activation caused by TGF-beta. In addition, statins upregulated TGF-beta receptor type II (TRII), and increased TGF-beta synthesis and TGF-beta/Smad-dependent actions. In this sense, statins, through Smad activation, render VSMCs more susceptible to TGF-beta induced apoptosis and increased TGF-beta-mediated ECM production. It is well documented that high doses of statins induce apoptosis in cultured VSMC in the presence of serum; however the precise mechanism of this effect remains to be elucidated. We have found that statins-induced apoptosis was mediated by TGF-beta/Smad pathway. Finally, we have described that RhoA inhibition is a common intracellular mechanisms involved in statins effects. The in vivo relevance of these findings was assessed in an experimental model of atherosclerosis in apolipoprotein E deficient mice: Treatment with Atorvastatin increased Smad3 phosphorylation and TRII overexpression, associated to elevated ECM deposition in the VSMCs within atheroma plaques, while apoptosis was not detected. CONCLUSIONS: Statins enhance TGF-beta/Smad pathway, regulating ligand levels, receptor, main signaling pathway and cellular responses of VSMC, including apoptosis and ECM accumulation. Our findings show that TGF-beta/Smad pathway is essential for statins-dependent actions in VSMCs

Incidencia y pronóstico del ictus minor y ataque isquémico transitorio de alto riesgo en Nordictus: estudio IMMINENT

[Abstract] Background. Our primary aim was to investigate the incidence of non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA) and to identify predictors of stroke recurrence/death and severe bleeding. We also evaluated the rates of TIA, major vascular events, therapeutic management and predictors of poor functional outcome at 3 months in these patients. Methods. We retrospectively reviewed data from all stroke patients evaluated at the emergency department of 19 hospitals belonging to the NORDICTUS stroke network between July and December 2019. Consecutive patients with non-cardioembolic minor AIS (NIHSS ≤5) and high-risk TIA (ABCD2 ≥6 or ipsilateral stenosis ≥50%) were included. We recorded clinical, neuroimaging and therapeutic variables. Follow-up was performed at 30 and 90 days. Functional prognosis was assessed with the modified Rankin scale score (mRS). Results. Of 8275 patients, 1679 (20%) fulfilled IMMINENT criteria (1524 AIS/155 TIA), resulting in a global incidence of 48/100,000 inhabitants per-year. Recurrent stroke/death occurred in 73 (4.3%) patients. Extracranial ipsilateral stenosis (>50%): HR 1.999 (95% CI: 1.115–3.585, p = 0.020) and lack of hyperacute cerebral arterial assessment: HR 1.631 (95% CI: 1.009–2.636, p = 0.046) were associated with recurrent stroke/death at 90 days. Intracranial stenosis was associated with poor prognosis (p = 0.044). Reperfusion therapy was given to 147 (9%) and urgent double antiplatelet therapy (DAPT) to 320 (21%) patients. Conclusion. Twenty percent of our stroke patients presented as non-cardioembolic high-risk TIA or minor AIS. Extracranial ipsilateral stenosis and lack of hyperacute cerebral arterial assessment were predictors of stroke recurrence/death; intracranial stenosis was associated with poor outcome. Despite current recommendations there was a low penetrance of DAPT.[Resumen] Introducción. Nuestro objetivo principal fue investigar la incidencia de ictus minor no cardioembólico y ataque isquémico transitorio (AIT) de alto riesgo, además de identificar predictores de recurrencia de ictus/muerte y sangrado grave. Evaluamos los porcentajes de AIT, eventos vasculares mayores, manejo terapéutico y predictores de mal pronóstico funcional. Métodos. Estudio retrospectivo de todos los pacientes con ictus evaluados en urgencias de 19 hospitales de la RED NORDICTUS entre julio-diciembre de 2019. Se incluyeron pacientes consecutivos con ictus minor no cardioembólico (National Institute of Health Stroke Scale [NIHSS] ≤ 5) y AIT de alto riesgo (ABCD2 ≥ 6 o estenosis ipsilateral ≥ 50%). Registramos variables clínicas, de neuroimagen y terapéuticas. Se realizó seguimiento a los 30 y 90 días. El pronóstico funcional se determinó mediante la escala de Rankin modificada (mRS). Resultados. De 8.275 pacientes, 1.679 (20%) cumplieron criterios del estudio IMMINENT (1.524 ictus/155 AIT), la incidencia global fue 48/100.000 h habitantes-año. Hubo recurrencias de ictus/muerte en 73 (4,3%) pacientes. La estenosis extracraneal ipsilateral (>50%): HR 1.999 (IC 95%: 1.115-3.585); p = 0,020 y la ausencia de estudio cerebrovascular hiperagudo: HR 1.631 (IC 95%: 1.009-2.636); p = 0.046, fueron predictores de ictus/muerte a 90 días. La estenosis intracraneal se asoció a mal pronóstico (p = 0,044). Se administró terapia de reperfusión a 147 (9%) y doble antiagregación a 320 (21%) pacientes. Conclusión. Un 20% de los pacientes se presentó como ictus minor o AIT de alto riesgo. La estenosis extracraneal ipsilateral y la ausencia de estudio neurovascular hiperagudo fueron predictores de ictus/muerte; la estenosis intracraneal se asoció con mal pronóstico. A pesar de las recomendaciones actuales hay baja penetrancia de doble antiagregación.This study was sponsored by AstraZeneca, funder had no involvement in the analysis or interpretation of the data, or the writing of the manuscript. MER-A was funded by the Instituto de Salud Carlos III (ISCIII) JR19/00020, co-funded by ERDF/ESF, “A way to make Europe”/“Investing in your future”). Investigators of this study belong to the RETICS-RICORS ICTUS financed by ISCIII (RD21/0006/0005-RD21/0006/0016-RD21/0006/0017-RD21/0006/0020-RD21/0006/0022).Instituto de Salud Carlos III; JR19/0002

Xarxes de biblioteques públiques municipals

The article analyzes the lack of urban networks of libraries in Spain, and it analyzes the situation of the urban networks in the cities of Barcelona (Catalonia - Spain), Valladolid (Castille and Leon - Spain), Torrent and Elx (Valencian Community - Spain)

Anticuerpo anti-Dectin-1 humano, hibridoma productor de dicho anticuerpo y sus aplicaciones

Anticuerpo anti-Dectin-1 humano, hibridoma productor de dicho anticuerpo y sus aplicaciones. La presente invención consiste en el hibridoma MGD3 y el anticuerpo monocional producido por él (denominado también MGD3), que reconoce de forma especifica al receptor de membrana Decti-1 humano. El anticuerpo MGD3 es capaz de inhibir la unión de Dectin-1 a su ligando natural, los -glucanos que son componentes de la pared de los hongos. Además, bloquea específicamente la unión a Candida albicans así como la secreción de citoquinas inducidas por la misma. El anticuerpo MGD3 obtenido permite la detección in vitro, ex vivo e in vivo de la proteína humana Dectin-1. Del mismo modo, puede emplearse para detectar el nivel de expresión del receptor en leucocitos humanos y para definir el papel de este receptor en la patogenia de enfermedades autoinmunes y de condiciones caracterizadas por inflamación crónica así como para conocer el efecto terapéutico de distintos agentes anti-inflamatorios e inmunosupresores. Además, el anticuerpo MGD3 podría tener potencial terapéutico en enfermedades inflamatorias crónicas.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Fundación para la Investigación Biomédica del Hospital de La PrincesaB1 Patente con informe sobre el estado de la ténic

Anticuerpo ant-Dectin-1 humano, hibridoma productos de dicho anticuerpo y sus aplicaciones

[EN] The invention relates to hybridoma MGD3 and the monoclonal antibody produced thereby (also called MGD3), which specifically recognises the human Dectin-1 membrane receptor. Antibody MGD3 is capable of inhibiting the binding of Dectin-1 to the natural ligand thereof, the ss-glucans that are components of the fungal wall. In addition, the aforementioned antibody specifically blocks binding to Candida albicans and the secretion of cytokines induced thereby. The MGD3 antibody obtained enables in vitro, ex vivo and in vivo detection of the human protein Dectin-1. Similarly, said antibody can be used to detect the level of expression of the receptor in human leukocytes, to define the role of this receptor in the pathogenesis of autoimmune illnesses and of conditions characterised by chronic inflammation and to ascertain the therapeutic effect of different anti-inflammatory and immunosuppressor agents. In addition, the MGD3 antibody may have therapeutic potential in chronic inflammatory illnesses.[ES] La invención relaciona al hibridoma MGD3 y al anticuerpo monoclonal producido de tal modo (también llamado MGD3), que reconoce específicamente el receptor humano de la membrana Dectin-1. El anticuerpo MGD3 es capaz de inhibir el atascamiento de Dectin-1 al ligand natural de eso, los ss-glucanos los componentes de ese son de la pared fúngica. Además, del anticuerpo los bloques mencionados específicamente que ataban a la Candida albicans y la secreción de citoquinas indujeron de tal modo. El anticuerpo MGD3 obtenido posibilita in vitro, detección viva e in vivo ex de la proteína humana Dectin-1. Semejantemente, el bote dicho del anticuerpo sea utilizado detectar el nivel de expresión del receptor en leucocitos humanos, definir el papel de este receptor en la patogénesis de enfermedades autoinmunes y de las condiciones caracterizadas por la inflamación crónica y determinar el efecto terapéutico de los diferentes agentes antiinflamatorios y del immunosuppressor. Además, el anticuerpo MGD3 puede tener potencial terapéutico en enfermedades inflamatorias crónicas.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patentes con informe sobre el estado de la técnic

Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.

International audienceCandida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadherin. A role in internalization, for a non-classical stimulation of the clathrin-dependent endocytosis machinery, was recently highlighted. Based on the similarities between the C. albicans and L. monocytogenes invasion proteins, we studied the role of clathrin in the internalization of C. albicans. Using live-cell imaging and indirect immunofluorescence of epithelial cells infected with C. albicans, we observed that host E-cadherin, clathrin, dynamin and cortactin accumulated at sites of C. albicans internalization. Similarly, in endothelial cells, host N-cadherin, clathrin and cortactin accumulated at sites of fungal endocytosis. Furthermore, clathrin, dynamin or cortactin depletion strongly inhibited C. albicans internalization by epithelial cells. Finally, beads coated with Als3 were internalized in a clathrin-dependent manner. These data indicate that C. albicans, like L. monocytogenes, hijacks the clathrin-dependent endocytic machinery to invade host cells

Candida albicans β-Glucan Exposure Is Controlled by the Fungal CEK1-Mediated Mitogen-Activated Protein Kinase Pathway That Modulates Immune Responses Triggered through Dectin-1 ▿ †

Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as β-glucan seems to be a mechanism that fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall β-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IκB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in β-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target

Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase

Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore