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BackgroundPatients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates of these deficits remain unclear. Here, we studied the participation of the expanded endocannabinoid system (ECS), which is known to be affected by alcohol in other life periods, and it is involved in memory impairments of neurodevelopmental disorders.MethodsC57BL/6 female mice were exposed to a time-limited access to either water or alcohol to model prenatal and lactation alcohol exposure (PLAE). The expanded ECS was analyzed in the prefrontal cortex and the hippocampus of the offspring at post-partum day (PD) 25 and 70. Then, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase N-acylethanolamines (NAEs), and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist; ii) pioglitazone, a PPAR-γ agonist. Finally, we used a viral approach to upregulate astrocytic PPAR-γ in the hippocampus to restore memory deficits.ResultsWe report that PLAE causes a hippocampal reduction of NAEs and PPAR-γ at PD25. Moreover, URB597 suppresses PLAE-induced memory deficits through PPAR-γ, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, we demonstrate that the upregulation of PPAR-γ in hippocampal astrocytes is sufficient to rescue PLAE-induced memory deficits.ConclusionOur data reveal a bidirectional link between memory deficits and expanded ECS alterations in the context of early alcohol exposure. Furthermore, we proved that PPAR-γ in hippocampal astrocytes represents a specific therapeutic target for memory deficits in FASD.

[EN] Digital transformation must be addressed strategically in every organization, as it generates complex challenges of improvement and innovation in people, processes, systems and technologies. It is not just a matter of technological investment; it is a matter of considering improved ways of implementing the organization's mission, rethinking its main functions in order to benefit from the digital. For this reason, it is important to approach this transformation from a strategic perspective, avoiding isolated actions and maximizing the institution's support with wellfounded digital projects. What has been said so far applies to all organizations, but even more so to institutions of special purpose and complexity, such as museums, especially Natural History Museums. During the last decades museums have also bet on digital innovation, although it seems that at a slower pace than other sectors, so that today many museums are still far from reaching digital maturity. The perception of the heritage sector is that Natural History Museums have a certain digital advantage over other museum themes, due to the great complexity and volume of their collections. In such circumstances, the strategic planning of their digital transformation, and the right leadership in the deployment of digital projects, are crucial to establish guidelines, objectives and strategic projects that support the achievement of their mission and enhance their relevance in today's society. Although the relative scarcity of resources and staff availability may hinder digital transformation in many museums, such limitations can be better addressed with the right institutional leadership and through the use of guidelines and methods specially adapted to the museum reality; allowing to plan and address digital transformation with a strategic, methodical, systematic, cross-cutting approach that minimizes the associated risks and maximizes the opportunities for success. In order to explore such a strategic approach, the Natural Science Museum of Barcelona and the Polytechnic University of Catalunya are cooperating in an applied research project, approved and funded by the Industrial Doctorate Program of the Generalitat de Catalunya, resulting in a method for the strategic planning of digital transformation initiatives in Natural History Museums, as well as a first digital transformation plan for this museum., [ES] La transformación digital debe abordarse estratégicamente en toda organización, pues genera retos complejos de mejora e innovación en las personas, los procesos, los sistemas y las tecnologías. No se trata únicamente de inversión tecnológica, se trata de plantear formas mejoradas de implementar la misión de la organización, repensando sus funciones principales para beneficiarse de lo digital. Por eso, conviene abordar dicha transformación desde el planteamiento estratégico, evitando las actuaciones aisladas y maximizando el apoyo de la institución con proyectos digitales bien fundamentados. La transformación digital constituye un proceso complicado que exige gran compromiso, el desarrollo de nuevas capacidades, posibles reestructuraciones organizativas, la superación de inercias y la gestión del cambio. Lo dicho hasta aquí sirve para el común de las organizaciones, pero aún más para instituciones de especial propósito y complejidad, como es el caso de los museos, especialmente los museos de historia natural. Durante las últimas décadas los museos también han apostado por la innovación digital, aunque parece que con un ritmo más lento que otros sectores, por lo que hoy todavía muchos museos están lejos de alcanzar la madurez digital. La percepción del sector patrimonial es que los museos de historia natural llevan cierta ventaja digital sobre otras temáticas museísticas, motivada por la gran complejidad y volumen de sus colecciones. En tales circunstancias, la planificación estratégica de su transformación digital, y el correcto liderazgo en el despliegue de los proyectos digitales, resultan cruciales para establecer pautas, objetivos y proyectos estratégicos, que apoyen el logro de su misión y potencien su relevancia en la sociedad actual. Aunque la relativa escasez de recursos y disponibilidad del personal puedan dificultar la transformación digital en muchos museos, dichas limitaciones se pueden encajar mejor con el correcto liderazgo institucional y mediante el uso de pautas y métodos adaptados especialmente a la realidad museística; que permitan planificar y abordar la transformación digital con un enfoque estratégico, metódico, sistemático, transversal, que minimice los riesgos asociados y maximice las oportunidades de éxito. Con objeto de explorar dicho enfoque estratégico, el Museo de Ciencias Naturales de Barcelona y la Universidad Politécnica de Cataluña están cooperando en un proyecto de investigación aplicada, aprobado y financiado por el Programa de Doctorados Industriales de la Generalitat de Catalunya, del que resulte un método para la planificación estratégica de iniciativas de transformación digital en museos de historia natural, así como un primer plan de transformación digital para dicho museo.

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS. Ministerio de Ciencia, Innovacion y Universidades FPU13/01867 Alba Navarro-Romero Ministerio de Ciencia e Innovacion BES-2016-077950 Lorena Galera-Lopez Ministerio de Ciencia e Innovacion RTI2018-099282-B-I00 Andres Ozaita Ministerio de Ciencia e Innovacion SAF2017-84060-R Rafael Maldonado Generalitat de Catalunya 2017SGR-669 Rafael Maldonado Ministerio de Ciencia e Innovacion SAF2016-78508-R Victoria Campuzano Basque Country Government IT1454-22 Rafael Rodriguez-Puertas Instituto de Salud Carlos III PI20/00153, co-funded by the European Union (ERDF "A way to make Europe") Rafael Rodriguez-Puertas Institucio Catalana de Recerca i Estudis Avancats Rafael Maldonado Ministerio de Economia y Competitividad #MDM-2014-0370 Alba Navarro-Romero Ministerio de Economia y Competitividad #MDM-2014-0370 Eduardo Eyras Ministerio de Ciencia e Innovacion PRE2019-087644 Lucia de los Reyes-Ramirez Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Andres Ozaita Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Rafael Maldonado Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Victoria Campuzano Ministerio de Economia y Competitividad FEDER Alba Navarro-Romero Ministerio de Economia y Competitividad FEDER Eduardo Eyras Ministerio de Economia y Competitividad IPEP MdM-2017 Eduardo Eyras Ministerio de Ciencia e Innovacion UE Andres Ozaita Ministerio de Ciencia e Innovacion UE Rafael Maldonado Ministerio de Economia y Competitividad UE Alba Navarro-Romero Ministerio de Ciencia e Innovacion UE Victoria Campuzano Ministerio de Economia y Competitividad EU Eduardo Eyras FRAXA Research Foundation Lorena Galera-Lopez The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Aberrant endocannabinoid signaling accompanies several neurodegenerative disorders, including multiple sclerosis. Here, we report altered endocannabinoid signaling in X-linked adrenoleukodystrophy (X-ALD), a rare neurometabolic demyelinating syndrome caused by malfunction of the peroxisomal ABCD1 transporter, resulting in the accumulation of very long-chain fatty acids (VLCFAs). We found abnormal levels of cannabinoid receptor 2 (CB2r) and related endocannabinoid enzymes in the brain and peripheral blood mononuclear cells (PBMCs) of X-ALD patients and in the spinal cord of a murine model of X-ALD. Preclinical treatment with a selective agonist of CB2r (JWH133) halted axonal degeneration and associated locomotor deficits, along with normalization of microgliosis. Moreover, the drug improved the main metabolic disturbances underlying this model, particularly in redox and lipid homeostatic pathways, including increased lipid droplets in motor neurons, through the modulation of the GSK-3β/NRF2 axis. JWH133 inhibited Reactive Oxygen Species elicited by excess VLCFAs in primary microglial cultures of Abcd1-null mice. Furthermore, we uncovered intertwined redox and CB2r signaling in the murine spinal cords and in patient PBMC samples obtained from a phase II clinical trial with antioxidants (NCT01495260). These findings highlight CB2r signaling as a potential therapeutic target for X-ALD and perhaps other neurodegenerative disorders that present with dysregulated redox and lipid homeostasis., This study was funded by the Institute of Health Carlos III through projects [PI19/01008] to SF and [PI20/00759] to AP (co-funded by the European Regional Development Fund, ERDF, a way to build Europe), Miguel Servet program [CPII16/00016] to SF and [PFIS, FI18/00141] to LPS (co-funded by the European Social Fund, ESF investing in your future). This study was also funded by grants from the Spanish Ministry of Health, Social Services and Equality (EC10-137), the Autonomous Government of Catalonia [2017SGR1206], the Hesperia Foundation, CERTIS Obres i Serveis, and the Crowd funding Campaign Arnau’97 to AP. JP was a predoctoral fellow of IDIBELL. The Center for Biomedical Research on Rare Diseases (CIBERER), an initiative of the Institute of Health Carlos III, funded the position of MR. Locomotor experiments were performed by the SEFALer unit F5 led by AP, which belongs to the CIBERER structure. We thank the CERCA Program/Generalitat de Catalunya for institutional support.

Endocannabinoids are well poised to regulate crosstalk between energy sensing of hunger and satiety and reward-driven motivation. Here, we aimed to unravel associations between plasma endocannabinoids and brain connectivity in homeostatic and reward circuits across hunger and satiety states. Fifteen participants (7 females) underwent two counter-balanced resting-state functional magnetic resonance imaging scans, one after overnight fasting and one after consumption of a standardized filling meal (satiety). Before each scan, we drew blood to measure plasma endocannabinoid concentrations (anandamide [AEA], anandamide-derived POEA, and 2-arachidonoylglycerol [2-AG]), analyzed with liquid chromatography tandem mass spectrometry. We found that AEA levels were associated with increased connectivity between the lateral hypothalamus and the ventral striatum during satiety. Furthermore, fasting AEA levels correlated with connectivity between the ventral striatum and the anterior cingulate cortex and the insula. Altogether, results suggest that peripheral AEA concentrations are sensitive to homeostatic changes and linked to neural communication in reward and salience networks. Findings may have significant implications for understanding normal and abnormal interactions between homeostatic input and reward valuation.

Background: Neuropathic pain is a complex condition characterized by sensory, cognitive and affective symptoms that magnify the perception of pain. The underlying pathogenic mechanisms are largely unknown and there is an urgent need for the development of novel medications. The endocannabinoid system modulates pain perception and drugs targeting the cannabinoid receptor type 2 (CB2) devoid of psychoactive side effects could emerge as novel analgesics. An interesting model to evaluate the mechanisms underlying resistance to pain is the fragile X mental retardation protein knockout mouse (Fmr1KO), a model of fragile X syndrome that exhibits nociceptive deficits and fails to develop neuropathic pain. Methods: A partial sciatic nerve ligation was performed to wild-type (WT) and Fmr1KO mice having (HzCB2 and Fmr1KO-HzCB2, respectively) or not (WT and Fmr1KO mice) a partial deletion of CB2 to investigate the participation of the endocannabinoid system on the pain-resistant phenotype of Fmr1KO mice. Results: Nerve injury induced canonical hypersensitivity in WT and HzCB2 mice, whereas this increased pain sensitivity was absent in Fmr1KO mice. Interestingly, Fmr1KO mice partially lacking CB2 lost this protection against neuropathic pain. Similarly, pain-induced depressive-like behaviour was observed in WT, HzCB2 and Fmr1KO-HzCB2 mice, but not in Fmr1KO littermates. Nerve injury evoked different alterations in WT and Fmr1KO mice at spinal and supra-spinal levels that correlated with these nociceptive and emotional alterations. Conclusions: This work shows that CB2 is necessary for the protection against neuropathic pain observed in Fmr1KO mice, raising the interest in targeting this receptor for the treatment of neuropathic pain. Significance: Neuropathic pain is a complex chronic pain condition and current treatments are limited by the lack of efficacy and the incidence of important side effects. Our findings show that the pain-resistant phenotype of Fmr1KO mice against nociceptive and emotional manifestations triggered by persistent nerve damage requires the participation of the cannabinoid receptor CB2, raising the interest in targeting this receptor for neuropathic pain treatment. Additional multidisciplinary studies more closely related to human pain experience should be conducted to explore the potential use of cannabinoids as adequate analgesic tools. This work was supported by research grants from the Spanish Ministry of Science and Innovation (#SAF2017-84060-R-AEI/FEDER-UE), the European Commission-DG Research (PainFact, #H2020-SC1-2019-2-RTD-848099), the Instituto de Salud Carlos III-RETICS (RTA, #RD16/0017/0020), the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad-Plan Nacional Sobre Drogas (#PNSD-2017I068) to RM; and the Catalan Government-AGAUR (#SGR2017-669 and ICREA Academia Award 2015 to RM and SGR2017-138 to RdlT). AR-L is the recipient of a FI predoctoral fellowship (Generalitat de Catalunya-AGAUR).

BACKGROUND AND PURPOSE Protective mechanisms of the endogenous cannabinoid system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB1 and CB2 receptors in liver fibrogenesis and inflammation. EXPERIMENTAL APPROACH The 2-arachidonoylglycerol (2-AG)-related signalling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg·kg-1 ·day-1 ) of paracetamol (acetaminophen), previously treated with selective CB1 (ACEA) and CB2 (JWH015) agonists (10 mg·kg-1 ), or lacking CB1 and CB2 receptors. KEY RESULTS Acute paracetamol increased the expression of CB2 , ABHD6 and COX-2, while repeated paracetamol increased that of CB1 and COX-2 and decreased that of DAGLβ. Both acute paracetamol and repeated paracetamol decreased the liver content of acylglycerols (2-AG, 2-LG and 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB1 and CB2 increments. Acute paracetamol-exposed CB2 KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB1 deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-α, the chemokine CCL2 and the circulating γ-glutamyltransferase (γGT). Although JWH015 reduced the expression of αSMA and TNF-α in acute paracetamol, ACEA increased the expression of cleaved caspase 3 and CCL2 in repeated paracetamol. CONCLUSION AND IMPLICATIONS The differential role of CB1 versus CB2 receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.

Context Because of its anabolic and lipolytic properties, growth hormone (GH) use is prohibited in sport. Two methods based on population-derived decision limits are currently used to detect human GH (hGH) abuse: the hGH Biomarkers Test and the Isoforms Differential Immunoassay. Objective We tested the hypothesis that longitudinal profiling of hGH biomarkers through application of the Athlete Biological Passport (ABP) has the potential to flag hGH abuse. Methods Insulin-like growth factor 1 (IGF-1) and procollagen III peptide (P-III-NP) distributions were obtained from 7 years of anti-doping data in elite athletes (n = 11 455) and applied as priors to analyze individual profiles from an hGH administration study in recreational athletes (n = 35). An open-label, randomized, single-site, placebo-controlled administration study was carried out with individuals randomly assigned to 4 arms: placebo, or 3 different doses of recombinant hGH. Serum samples were analyzed for IGF-1, P-III-NP, and hGH isoforms and the performance of a longitudinal, ABP-based approach was evaluated. Results An ABP-based approach set at a 99% specificity level flagged 20/27 individuals receiving hGH treatment, including 17/27 individuals after cessation of the treatment. ABP sensitivity ranged from 12.5% to 71.4% across the hGH concentrations tested following 7 days of treatment, peaking at 57.1% to 100% after 21 days of treatment, and was maintained between 37.5% and 71.4% for the low and high dose groups 1 week after cessation of treatment. Conclusion These findings demonstrate that longitudinal profiling of hGH biomarkers can provide suitable performance characteristics for use in anti-doping programs.

Segmentation of clients is a strategy widely used by companies and marketing units to sell their process. However, this concept is not so well established and widespread in public agencies supporting SME innovation. What are the benefits of designing advanced segmentation strategies for development agencies? Economic development practitioners agree that it’s necessary to provide customised innovation services to companies to get a greater impact. This paper presents how nine development agencies from seven European countries carry out their segmentation strategies to provide tailored initiatives of SMEs’ innovation support. The analysis also identifies common challenges RDA face, and how introducing Big Data Analysis can help them enhance innovation support in their regions.

Objective Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete’s sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse. Methods Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomly assigned to 4 groups, receiving 1 of 3 different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting 4 weeks before treatment, during 3 weeks of treatment, and at 6 weeks’ follow-up. A total of 749 serum samples were analyzed for 1305 protein markers using the SOMAscan proteomics platform. Results We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (eg, protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism. Conclusion Our analysis suggests that hGH administration affects biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH-associated proteins in the etiology of hGH-related diseases and may indicate new risks that may be associated with hGH misuse.