Rituales virtuales como una nueva forma de habitar el espacio público

Los ritos se han dado desde la propia constitución social, mas no han desaparecido. Del mismo modo que la sociedad ha cambiado, los ritos se han transformado, han trasmutado y han reglado el juego comunicacional. Hoy, los jóvenes habitan el espacio virtual ritualizando acciones para identificarse con un “nosotros”. La cosmovisión de los jóvenes, un proceso social concreto y virtual en el cual se trazan líneas conductoras de existencia para ser en el mundo, muestran el orden y el sentido dado por los significados y los valores que le otorgan a las relaciones virtuales sociales. Así se (re)construye una concepción de espacio público que no puede ser considerada como correcta o inexacta, simplemente es coherente y lógica para el grupo que la concibe y la re significa. Exponerse en el espacio público de una sociedad virtual, recrear un mundo prescrito, donde la efectividad de las creencias, los ritos y todas las prácticas derivan del universo habitado, es lo que comunican los jóvenes en su presencia virtual.The rituals have taken place since the social constitution. Just as society has changed, the rituals have changed, have transmuted and have ruled the game communication. Today, young people inhabit the virtual space, in which they ritualized actions to identify with an ‘us’. Young people´s worldview, a concrete and virtual social process in which conducting lines are drawn there for being in the world, shows the order and direction given by the meanings and values to virtual social relationships. Thus, it (re)constructs a conception of public space that can not be regarded as correct or inaccurate, merely is coherent and logical for the group that conceived and resignifies. Be exposed in the public space of a virtual society, to recreate a prescribed world, where the effectiveness of the beliefs, rituals and all practices derive from the inhabited universe, is what young people communicate in their virtual presence.Facultad de Periodismo y Comunicación Socia

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA

Defective chaperone-mediated autophagy is a hallmark of joint disease in patients with knee osteoarthritis

[Abstract] Objective: Defects in autophagy contribute to joint aging and Osteoarthritis (OA). Identifying specific autophagy types could be useful for developing novel treatments for OA. Design: An autophagy-related gene array was performed in blood from non-OA and knee OA subjects from the Prospective Cohort of A Coruña (PROCOAC). The differential expression of candidate genes was confirmed in blood and knee cartilage and a regression analysis was performed adjusting for age and BMI. HSP90A, a chaperone mediated autophagy (CMA) marker was validated in human knee joint tissues, as well as, in mice with aging-related and surgically-induced OA. The consequences of HSP90AA1 deficiency were evaluated on OA pathogenesis. Finally, the contribution of CMA to homeostasis was studied by assessing the capacity to restore proteostasis upon ATG5-mediated macroautophagy deficiency and genetic HSP90AA1 overexpression. Results: 16 autophagy-related genes were significantly down-regulated in blood from knee OA subjects. Validation studies showed that HSP90AA1 was down-regulated in blood and human OA cartilage and correlated with risk incidence of OA. Moreover, HSP90A was reduced in human OA joints tissues and with aging and OA in mice. HSP90AA1 knockdown was linked to defective macroautophagy, inflammation, oxidative stress, senescence and apoptosis. However, macroautophagy deficiency increased CMA, highlighting the CMA-macroautophagy crosstalk. Remarkably, CMA activation was sufficient to protect chondrocytes from damage. Conclusions: We show that HSP90A is a key chaperone for chondrocyte homeostasis, while defective CMA contributes to joint damage. We propose that CMA deficiency is a relevant disease mechanism and could represent a therapeutic target for OA.Instituto de Salud Carlos III; PI17/02059Instituto de Salud Carlos III; PI20/0064

Reduced Levels of H₂S in Diabetes-Associated Osteoarthritis Are Linked to Hyperglycaemia, Nrf-2/HO-1 Signalling Downregulation and Chondrocyte Dysfunction

[Abstract] Different findings indicate that type 2 diabetes is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Changes in the balance of hydrogen sulphide (H₂S) are thought to play an important role in the pathogenesis of diabetes and its complications, although its role is still controversial. In this study, we examined the modulation of H₂S levels in serum and chondrocytes from OA diabetic (DB) and non-diabetic (non-DB) patients and in cells under glucose stress, in order to elucidate whether impairment in H₂S-mediated signalling could participate in the onset of DB-related OA. Here, we identified a reduction in H₂S synthesis in the cartilage from OA-DB patients and in cells under glucose stress, which is associated with hyperglycaemia-mediated dysregulation of chondrocyte metabolism. In addition, our results indicate that H₂S is an inductor of the Nrf-2/HO-1 signalling pathway in cartilage, but is also a downstream target of Nrf-2 transcriptional activity. Thereby, impairment of the H₂S/Nrf-2 axis under glucose stress or DB triggers chondrocyte catabolic responses, favouring the disruption of cartilage homeostasis that characterizes OA pathology. Finally, our findings highlight the benefits of the use of exogeneous sources of H₂S in the treatment of DB-OA patients, and warrant future clinical studies.This research was funded by grant PI19/01206 from the Fondo de Investigación Sanitaria, integrated in the National Plan for Scientific Program, Development, and Technological Innovation 2013–2016 and funded by the Instituto de Salud Carlos III (ISCIII)-General Subdirection of Assessment and Promotion of Research-European Regional Development Fund (FEDER) “A way of making Europe”, and also by grants ED431B 2020/55 (Grupos con Potencial de Crecemento 2020) and IN607A 2021/7 (Grupos de Referencia Competitiva) from Xunta de Galicia. The study was also supported by the Biomedical Research Network Centre (CIBER), an initiative of ISCIII. C.V.-G. thanks Xunta de Galicia for his postdoctoral contract (grant number ED481D 2017/023)Xunta de Galicia; ED431B 2020/55Xunta de Galicia; IN607A 2021/7Xunta de Galicia; ED481D 2017/02

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Research paper[Abstract] Background. Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy. Methods. Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-β-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration. Findings. Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Interpretation. These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment.Instituto de Salud Carlos III; PI14/01324Instituto de Salud Carlos III; PI17/02059Ministerio de Economía y Competitividad; P01 AG043376Ministerio de Economía y Competitividad; U19 AG05627

KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain

The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. Here, we show that the combined elimination of both proteins in forebrain excitatory neurons of adult mice resulted in a rapidly progressing neurological phenotype associated with severe ataxia, dendritic retraction and reduced electrical activity. At the molecular level, we observed the downregulation of neuronal genes, as well as decreased H3K27 acetylation and pro-neural transcription factor binding at the promoters and enhancers of canonical neuronal genes. The combined deletion of CBP and p300 in hippocampal neurons resulted in the rapid loss of neuronal molecular identity without de- or transdifferentiation. Restoring CBP expression or lysine acetylation rescued neuronal-specific transcription in cultured neurons. Together, these experiments show that KAT3 proteins maintain the excitatory neuron identity through the regulation of histone acetylation at cell type-specific promoter and enhancer regions.M.L. is recipient of a Santiago Grisolia fellowship given by the Generalitat Valenciana, J.M.C. is recipient of a fellowship from the Spanish Ministry of Education, Culture and Sport (MECD), J.F.-A. and C.M.N. are recipients of fellowships from the Spanish Ministry of Science and Innovation (MICINN). The ultrastructure research was supported by the Polish National Science Center Grant UMO-2014/15/N/NZ3/04468 and by the European Regional Development Fund POIG 01.01.02-00-008/08. J.P.L.-A. research is supported by Grants RYC-2015-18056 and RTI2018-102260-B-I00 from MICINN co-financed by ERDF. A.B. research is supported by Grants SAF2017-87928-R, PCIN-2015-192-C02-01, and SEV-2017-0723 from MICINN co-financed by ERDF, PROMETEO/2016/026 from the Generalitat Valenciana, and RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO). The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa”.Peer reviewe

El Ciclo Ándico de Groeber en la cuenca Neuquina, una revisión y actualización.

A state of the knowledge of the Andean cycle is presented, mainly based on our recent works, butalso on highlights of recent research of many colleagues. This synthesis allowed us to update thegeochronology of its different units. New absolute ages through U-Pb analysis in zircons by differentmethods complement those previously carried out and made possible to accurately limit the ageof these units. We have been able to define the boundary between the Tordillo and Vaca MuertaFormations very precisely between 147 and 146 Ma; the age of the Agrio Formation between 132 and126 Ma, and to present the first absolute ages of the Huitrín Formation. All these data are screenedthrough precise biostratigraphy, sequence stratigraphy and astrochronology. The Troncoso Memberof the Huitrín Formation yielded an age of 123 Ma that placed it in the Barremian. This is partiallycorroborated by the finding of fossils in the La Tosca Member with trigonioids and foraminifera ofundoubted marine origin, dated with nannofossils of early Barremian age indicating the permanence ofcommunication with the Pacific during the deposition of the Huitrín Formation