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The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene–disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases.

Las aplicaciones móviles basadas en la atención plena son un medio que puede ayudar a lograr los numerosos beneficios psicológicos y físicos de las prácticas del mindfulness. Este estudio tiene el objetivo de plantear un prototipo de aplicación mindfulness para móviles. Para ello, realizaremos una revisión sistemática de las aplicaciones móviles de mindfulness de Android y iPhone para analizar sus características, su calidad y su adecuación para contextos educativos mediante rúbricas como la Mobile App Rating Scale (MARS). Para realizar un análisis sobre las aplicaciones que existen hoy en día en el mercado, se realizó una búsqueda tanto en el buscador de Android “Play Store” como en el buscador del IOS “Apple Store”. En total se obtuvieron 9 aplicaciones que superan el puntaje mínimo de aceptabilidad (3.0), de las cuales solo tres superan el cuatro de media. Se concluye que son pocas las aplicaciones de mindfulness destinadas a la educación secundaria, ya que la mayoría va destinada a educación infantil y primaria, lo cual abre un campo de mejora en esta área.

Many drug discovery projects are started, but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the freetext reasons for 28,842 clinical trials that stopped before their endpoints were met. We then evaluated these classes in the light of the underlying evidence for the therapeutic hypothesis and target properties. We show that trials are more likely to stop due to lack of efficacy in the absence of strong genetic evidence from human populations or genetically-modified animal models. Furthermore, trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is not selectively expressed. These results support the growing use of human genetics to evaluate targets for drug discovery programmes.

Distal pancreatectomy with celiac axis resection (DP-CAR) is a surgical procedure with high morbidity and mortality performed in patients with locally advanced pancreatic cancer. Preoperative embolization of hepatic artery (PHAE) has been postulated as a technical option to increase resection rate.comparison of morbidity and mortality at 90 days, operative time, hospital stay and survival between patients that performed DP-CAR with and without PHAE.Observational retrospective multicentre study.patient operated in Spanish centers with DP-CAR for pancreatic cancer from April 2004 until 23 June 2018. Preoperative (PHAE, neodjuvant treatment), intraoperative (operative time and blood loss) and postoperative data (morbidity, hospital stay, R0 and survival) were studied. Complications were measured with Clavien classification at 90 days. Specific pancreatic complications were measured using ISGPS classifications. Data were analyzed using R version 3.1.3 (http://www.r-project.org). Level of significance was set at 0.05.41 patients were studied. 26 patients were not embolized (NO-PHAE group) and 15 patients received PHAE. Preoperative BMI and percentage of neoadjuvant chemotherapy were the only preoperative variables different between both groups. The operative time in the PHAE group was shorter (343 min) than in the non-PHAE group (411 min) (p 0.06). Major morbidity (Clavien IIIa) and mortality at 90 days were higher in the PHAE group than in the non-PHAE group (60% vs 23% and 26.6% vs 11.6% respectively) (p 0.004). No statistical difference in overall survival was observed between both groups (p = 0.14).In our study PHAE is not related with less postoperative morbidity. Even more, major morbidity (Clavien III-IV) and mortality was higher in PHAE group.

International audience; Introduction: To explore the prevalence of dysphonia in European patients with mild-to-moderate COVID-19 and the clinical features of dysphonic patients.Methods: The clinical and epidemiological data of 702 patients with mild-to-moderate COVID-19 were collected from 19 European Hospitals. The following data were extracted: age, sex, ethnicity, tobacco consumption, comorbidities, general, and otolaryngological symptoms. Dysphonia and otolaryngological symptoms were self-assessed through a 4-point scale. The prevalence of dysphonia, as part of the COVID-19 symptoms, was assessed. The outcomes were compared between dysphonic and nondysphonic patients. The association between dysphonia severity and outcomes was studied through Bayesian analysis.Results: A total of 188 patients were dysphonic, accounting for 26.8% of cases. Females developed more frequently dysphonia than males (P = 0.022). The proportion of smokers was significantly higher in the dysphonic group (P = 0.042). The prevalence of the following symptoms was higher in dysphonic patients compared with nondysphonic patients: cough, chest pain, sticky sputum, arthralgia, diarrhea, headache, fatigue, nausea, and vomiting. The severity of dyspnea, dysphagia, ear pain, face pain, throat pain, and nasal obstruction was higher in dysphonic group compared with nondysphonic group. There were significant associations between the severity of dysphonia, dysphagia, and cough.Conclusion: Dysphonia may be encountered in a quarter of patients with mild-to-moderate COVID-19 and should be considered as a symptom list of the infection. Dysphonic COVID-19 patients are more symptomatic than nondysphonic individuals. Future studies are needed to investigate the relevance of dysphonia in the COVID-19 clinical presentation.

This study examines the mediator role of cognitive fusion between depressive symptoms, activity avoidance and excessive persistence at different levels of pain acceptance (moderator) among fibromyalgia patients (FM). Using a sample of 231 women, multiple and moderate mediation analyses were conducted with PROCESS. Results showed that depression was positively associated with activity avoidance and excessive persistence. Furthermore, cognitive fusion and pain acceptance were found to mediate the effect of depression in both patterns. Additionally, pain acceptance was found to play a contextual role in cognitive fusion, as a moderator, between depressive symptoms and maladaptive patterns. Specifically, FM patients with high acceptance levels and low levels of depression presented the strongest associations between depression and cognitive fusion. Techniques aimed at reducing cognitive fusion, could be especially beneficial to FM women with high pain acceptance.

BACKGROUND: Impaired mineral ion metabolism is a hallmark of CKD-metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR. METHODS: To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox ). RESULTS: Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D 3), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice. CONCLUSIONS: These results suggest that, in addition to CaSR's established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.

Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses1,2,3,4,5. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors5,6,7. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses is unclear. Here we show that activation of mouse astroglial type-1 cannabinoid receptors associated with mitochondrial membranes (mtCB1) hampers the metabolism of glucose and the production of lactate in the brain, resulting in altered neuronal functions and, in turn, impaired behavioural responses in social interaction assays. Specifically, activation of astroglial mtCB1 receptors reduces the phosphorylation of the mitochondrial complex I subunit NDUFS4, which decreases the stability and activity of complex I. This leads to a reduction in the generation of reactive oxygen species by astrocytes and affects the glycolytic production of lactate through the hypoxia-inducible factor 1 pathway, eventually resulting in neuronal redox stress and impairment of behavioural responses in social interaction assays. Genetic and pharmacological correction of each of these effects abolishes the effect of cannabinoid treatment on the observed behaviour. These findings suggest that mtCB1 receptor signalling can directly regulate astroglial glucose metabolism to fine-tune neuronal activity and behaviour in mice., This work was funded by: INSERM, the European Research Council (Endofood, ERC–2010–StG–260515 and CannaPreg, ERC-2014-PoC-640923, MiCaBra, ERC-2017-AdG-786467), Fondation pour la Recherche Medicale (FRM, DRM20101220445), the Human Frontiers Science Program, Region Nouvelle Aquitaine and Agence Nationale de la Recherche (ANR; NeuroNutriSens ANR-13-BSV4-0006, CaCoVi ANR 18-CE16-0001-02, MitObesity ANR 18-CE14-0029-01, ORUPS ANR-16-CE37-0010-01 and BRAIN ANR-10-LABX-0043) (to G.M.); NIH/NIDA (1R21DA037678-01), Spanish Ministry of Science, Innovation and Universities (MCINU/FEDER; grants SAF2016-78114-R and RED2018-102576-T), Instituto de Salud Carlos III (CB16/10/00282), an EU BATCure grant (666918), Junta de Castilla y León (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA and Fundación Ramón Areces (to J.P.B.); Instituto de Salud Carlos III (PI18/00285; RD16/0019/0018), the European Regional Development Fund, the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement 686009), Junta de Castilla y León (IES007P17) and Fundación Ramón Areces to (A.A.); French State/ANR/IdEx (ANR-10-IDEX-03-02), Eu-Fp7 (FP7-PEOPLE-2013-IEF-623638) and Ramon y Cajal Investigator Program (RYC-2017-21776) (to A.B.-G.); FRM (SPF20121226369) (to R.S.); FRM (ARF20140129235) (to L.B.); Spanish Ministry of Science, Innovation and Universities (MCINU/FEDER; grants SAF2015-64945-R and RTI2018-095311-B-I00) (to M.G.); Canada Research Chair, Alzheimer Society of Canada—Brain Canada (17-09), Natural Sciences and Engineering Research Council (RGPIN-2015-05880), Canadian Breast Cancer Foundation (2015-317342), Canadian Health Research Institute (CIHR, 388808), New Brunswick Innovation Foundation, New Brunswick Health Research Foundation and Université de Moncton (to E.H.-C.); Basque Government (IT1230-19), Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III), European Regional Development Funds-European Union (ERDF-EU; RD16/0017/0012) and MINECO/FEDER, UE (SAF2015-65034-R) (to P.G.); University of the Basque Country PhD contract (PIF 16/251) (to S.A.); POP contract (BES-2016-076766, BES-C-2016-0051) (to I.B.-D.R.); French State/ANR (ANR-10-IDEX and TRAIL ANR-10-LABX-57); French-Swiss ANR-FNS (ANR-15- CE37-0012) (to A.-K.B.-S.); SFB/TRR 58 ‘Fear, anxiety, anxiety disorders’ (subproject A04); and CRC 1193 ‘Neurobiology of resilience’ (subproject B04) (to B.L.).

Although positive psychology interventions increase well-being and reduce depression, little is known about whether they facilitate a reorganization of the connections between psychological element...

Circulating platelet microparticles (PMP) are the most abundant in bloodstream, are highly procoagulant and contribute to cross-talk with inflammatory cells. The aim of the present study was to investigate the interactions of PMP with platelets and explore the involvement of toll-like receptor 4 (TLR-4).PMP were separated by ultracentrifugation of expired platelet concentrates and added to: i) washed platelets, to confirm uptake, by flow cytometry and confocal and transmission electron microscopy, ii) platelet rich plasma (PRP), to assess changes in platelet function due to uptake by aggregometry in response to ADP; and iii) whole blood, to evaluate heterotypic aggregate (HA) formation by flow cytometry. Moreover, whole blood previously enriched with platelets with internalized PMP was used to explore modifications in thromboelastometry parameters (ROTEM). The inhibitory action of anti-TLR-4 was investigated.Confocal and ultrastructural microscopy studies revealed PMP internalization by platelets. Flow cytometry showed PMP-platelet association (p 0.01 vs controls, at different PMP dilutions). PMP, at 1/20 dilution, increased HA (p 0.05 vs controls), the percentage of maximal platelet aggregation to ADP (p 0.05 vs controls), and accelerated clotting and clot formation times (p 0.05 vs controls). Incubation of platelets with anti-TLR-4 prior to exposure to PMP reduced PMP-platelet association (p 0.05 vs absence of the antibody), prevented HA formation, reduced maximal platelet aggregation and normalized ROTEM parameters.Platelets exhibit internalization ability towards their own PMP, a process that potentiates their thrombogenicity and is partially mediated by the innate immunity receptor TLR-4.

La influencia indiscutible de La Celestina en La Lozana andaluza no se limita a su estructura, contenido y función (Botta 2002; Checa 2005; Imperiale 1991; Márquez Villanueva 2006), sino que abarca también el simbolismo animal empleado en la configuración del personaje de la puta alcahueta (Shipley 2020; López-Rodríguez 2018; Miaja de la Peña 2017; Snow 2021). Celestina y Lozana son melosas y laboriosas como las abejas, putas y maternales como las gallinas, locuaces y libres como las aves, tentadoras y pecaminosas cuales sierpes, libidinosas y obstinadas como las asnas e incluso mansas e indefensas como las ovejas. En efecto, existe una suerte de bestiario en la creación de las figuras de las proxenetas, cuyo físico y personalidad, vivienda, oficios, creencias y función social están marcados con rasgos animales. Aparte de recalcar el mundo instintivo animal del sexo con el que se ganan la vida estas dos rameras, la iconografía bestial sirve para esbozar la naturaleza polifacética de Celestina y Lozana. A fin de cuentas, su supervivencia, cual animal, depende de su adaptación al medio, porque, en palabras del personaje de Francisco Delicado, «¿Qué me tengo que mantener […] como camaleón?» (179).

Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent‐conjugated bacterial toxins to label Gb3 to develop a cell‐based high content imaging (HCI) screening assay for the repurposing of FDA‐approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient‐derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease., The neuronal ceroid lipofuscinoses (NCL), commonly known as Batten disease (BD), are a group of recessively inherited fatal diseases of the nervous system that typically arise in childhood. There is neither cure nor drugs to revert the course of these diseases.

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable energetic substrate for neurons and as a signalling molecule. Astrocytes and neurons also differ in the regulation of glycolytic enzymes and in the organization of their mitochondrial respiratory chain. Unlike neurons, astrocytes rely on glycolysis for energy generation and, as a consequence, have a loosely assembled mitochondrial respiratory chain that is associated with a higher generation of mitochondrial reactive oxygen species (ROS). However, whether this abundant natural source of mitochondrial ROS in astrocytes fulfils a specific physiological role is unknown. Here we show that astrocytic mitochondrial ROS are physiological regulators of brain metabolism and neuronal function. We generated mice that inducibly overexpress mitochondrial-tagged catalase in astrocytes and show that this overexpression decreases mitochondrial ROS production in these cells during adulthood. Transcriptomic, metabolomic, biochemical, immunohistochemical and behavioural analysis of these mice revealed alterations in brain redox, carbohydrate, lipid and amino acid metabolic pathways associated with altered neuronal function and mouse behaviour. We found that astrocytic mitochondrial ROS regulate glucose utilization via the pentose-phosphate pathway and glutathione metabolism, which modulates the redox status and potentially the survival of neurons. Our data provide further molecular insight into the metabolic cooperation between astrocytes and neurons and demonstrate that mitochondrial ROS are important regulators of organismal physiology in vivo., This work was funded by MINECO (SAF2016-78114-R to J.P.B.), H2020 European Commission (BatCure grant 666918 to J.P.B.) and Fundación BBVA (to J.P.B.). A.A. is funded by H2020 European Commission (PANA grant 686009), Instituto de Salud Carlos III (PI15/00473 and RD16/0019/0018), Junta de Castilla y León (IES007P17) and Fundación Ramón Areces. J.A.E. is funded by MINECO (SAF2015-65633-R). The CNIC is supported by MINECO and Pro-CNIC Foundation, and is a SO-MINECO (award SEV-2015-0505). We thank the viral vector facility headed by A. Bemelmans for producing AAVs at MIRCen. This work was cofunded by FEDER. J.P.B. and J.A.E. are funded by CIBERFES (CB16/10/00282).

Cells naturally produce mitochondrial reactive oxygen species (mROS), but the in vivo pathophysiological significance has long remained controversial. Within the brain, astrocyte-derived mROS physiologically regulate behaviour and are produced at one order of magnitude faster than in neurons. However, whether neuronal mROS abundance differentially impacts on behaviour is unknown. To address this, we engineered genetically modified mice to down modulate mROS levels in neurons in vivo. Whilst no alterations in motor coordination were observed by down modulating mROS in neurons under healthy conditions, it prevented the motor dis- coordination caused by the pro-oxidant neurotoxin, 3-nitropropionic acid (3-NP). In contrast, abrogation of mROS in astrocytes showed no beneficial effect against the 3-NP insult. These data indicate that the impact of modifying mROS production on mouse behaviour critically depends on the specific cell-type where they are generated., J.P.B. is funded by the Agencia Estatal de Investigación (SAF2016-78114-R, PID2019-105699RB-I00/AEI/10.13039/501100011033 and RED2018-102576-T), Plan Nacional sobre Drogas (2020I028), ISCIII (CB16/10/00282), Junta de Castilla y León (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigación Bio-medicina 2017 Fundación BBVA and Fundación Ramón Areces. A.A. is unded by the ISCIII (PI18/00265, RD16/0019/0018), AEI (PI18/00265, RD16/0019/0018) and European Union’s Horizon 2020 Research and Innovation Program (Grant Agreement 686009). J.P.B. and A.A. are fundedby the grant CSI151P20 from the Junta de Castilla y Leon.

Trabajo presentado al 20th Biennial Meeting of The Society for Free Radical Research International (SFRR-I) del 15 al 18 de marzo de forma virtual, Neuronal ceroid lipofuscinoses (NCLs), known as Batten disease, are the most common of the rare neurodegenerative disorders in children. These disorders are grouped together based on clinical similarities and uniform neuropathological features, including accumulation of lipofuscin in lysosomes and widespread gliosis. CLN7 disease is one of these NCLs that present in late infancy and is caused by mutations in the CLN7/MFSD8 gene, which encodes a lysosomal membrane glycoprotein of unknown function, hence the biochemical processes affected by CLN7-loss of function are not understood. Here, we found in the Cln7Δex2 mouse model of CLN7 disease that failure in the autophagy-lysosomal pathway causes aberrant accumulation of reactive oxygen species (ROS)-producing brain mitochondria. Metabolic profile analysis of Cln7Δex2 neurons revealed a decrease in the basal oxygen consumption rate (OCR), ATP-linked and maximal OCR and proton leak, indicating bioenergetically impaired mitochondria. To assess the impact of ROS on CLN7 disease progression, Cln7Δex2 mice were crossed with mice expressing a mitochondrial-tagged form of catalase (mCAT) governed by a neuron-specific promoter (Cln7Δex2-CAMKIIaCre-mCAT). The increased mROS observed in Cln7Δex2 neurons was abolished in Cln7Δex2- CAMKIIaCre-mCAT neurons, verifying the efficacy of this approach. The brain mitochondrial swelling and mitochondrial cristae profile widening observed in Cln7Δex2 mice were abolished in Cln7Δex2-CAMKIIaCre-mCAT mice. Notably, Cln7Δex2 brain accumulation of subunit C-ATPase and lysosomal lipofuscin, as well as gliosis, which are hallmarks of the disease, were ameliorated in Cln7Δex2- CAMKIIaCre-mCAT mice. Altogether, these findings indicate that the generation of ROS by bioenergetically-impaired mitochondria in Cln7Δex2 neurons contributes to the histopathological symptoms of CLN7 disease.

En el territorio nacional hay una gran cantidad de estructuras palaciales construidas entre los siglos XVI y XVIII, muchas de ellas se encuentran en estado de ruina y olvido. La reutilización es un elemento clave de las actuaciones de rehabilitación arquitectónica en las que se busca siempre la posibilidad de una gestión y mantenimiento sostenibles, con beneficiosas repercusiones socioeconómicas en el entorno. Para ello, se realiza un estudio de casos de palacios españoles reutilizados, analizando sus características histórico-artísticas y extrayendo los principales riesgos y ventajas de cada uso dado. Posteriormente se aplican las conclusiones de forma hipotética para plantear los usos idóneos en un caso concreto, que se estudia histórica y arquitectónicamente, el palacio ubicado en Corpa. Al mismo tiempo, se fundamenta también la necesidad de la documentación histórica precisa antes de las intervenciones y reutilizaciones del patrimonio palacial., In Spain there are a large number of palaces built during the 16th and 18th centuries. There are numerous examples of crumbling and forgotten palaces. Then the re-use of ancient buildings becomes a key issue concerning architectural rehabilitation, as well as sustainable management and socioeconomic benefits for the environment. To this end, a case study is made focusing on Spanish palaces that are being re-used. In such manner the main dangers and advantages caused by each use can be identified as well as the primary historic and artistic characteristics. Finally, such uses can be hypothetically applied on the case of the palace located in Corpa. The palace’s history and architecture are also studied establishing the need of collecting historic data before the architectural interventions and re-uses of heritage palaces.