siRNA screen of microglia to identify neuroprotective drug targets in Parkinson´s disease

The uploaded accepted version corresponds to pages E183-E184 of the publication "GLIA Bilbao 2015: Abstracts Oral Presentations, Posters, Indexes" available at https://doi.org/10.1002/glia.22870.Question: Neuroinflammation is a fundamental process contributing to the death of dopaminergic neurons in Parkinson´s Disease (PD). During this process, activated microglia secrete cytotoxic substances which lead to neuronal death. Therefore, we are looking for the molecular mechanism that reverses the inflammatory activation of microglia, since this knowledge would be essential to protect from neurodegeneration. Methods and Results: Very interestingly our previous data (Neubrand et al., 2014) indicate that adipose derived mesenchymal stem cells (ASCs) exert important anti-inflammatory actions on microglia. We observed that microglia exposed to ASCs or their secreted factors (conditioned medium, CM) underwent a dramatic cell shape change into a highly elongated morphology (Fig 1A), similar to the phenotype of microglia observed in a healthy brain. The elongation induced by ASCs was associated with a decrease of the pro-inflammatory cytokine TNFalpha (Fig 1B) as well as with an upregulation of neurotrophic factors. Thus, ASC stimulated microglia represent an ideal tool to study the intracellular events necessary for the transition from inflammatory activated to non-inflammatory neuroprotective microglia. In this way we have already identified the small RhoGTPases Rac1 and Cdc42, which are important regulators of the actin cytoskeleton, as essential molecules in this transition (Fig 1C). Since these molecules represent possible drug targets to induce the reversion of neurotoxic microglia to neuroprotective ones, we are currently performing an siRNA screen to identify the molecular players of this ASC-induced reversion. Because this transition is easily detectable by light microscopy (see Figs 1A and C) and changes in the cell shape are intrinsically related to changes of the cytoskeleton, we are carrying out a microscopy-based screen of the major cytoskeletal regulators. In addition, we are including in the screen the regulators of microglia-specific activation/inflammatory pathways as siRNA targets. Conclusion: Our project is the first siRNA screen performed in primary microglia and we aim to identify a list of molecules that are specifically implicated in the reversion from activated to neuroprotective microglia. Since positive hits would represent potential neuroprotective drug targets, the outcome of this screen opens up a variety of novel investigation lines and therapies in PD or other neurodegenerative diseases

Placental transfer of NMDAR antibodies causes reversible alterations in mice

Objective: To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies. Methods: Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects. Results: In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood. Conclusions: In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy

L'entesa entre la PIME i la banca: una aproximació a la negociació financera

La gestió del finançament de les petites i mitjanes empreses mai ha estat fàcil. L’òptima administració dels recursos porta a una inexorable necessitat d’entesa entre l’empresari i la banca, que sol ser fluïda en èpoques de bonança econòmica i extremadament complicada en temps de crisi. En moments de dificultat com l’actual, la posició de les entitats financeres sol ser hermètica, però no es pot deixar de considerar l’exigència de generar negoci rendible a la que el banc es veu sotmès. La solució a les necessitats financeres de les empreses depèn de diverses situacions, però no hi ha dubte que és molt important la bona comunicació que mantenen amb els bancs. Quan més entenedora és la problemàtica de l’empresa per part del banc, més fàcil és la negociació. Per circumstàncies del seu perfil professional, l’empresari no disposa sovint dels coneixements imprescindibles per elaborar una presentació adequada de la necessitats de finançament de l’empresa. També és freqüent que en la relació amb el banc es contempli sols la seva conveniència, sense tenir en compte els interessos de risc i negoci de l’altra part. Per aconseguir l’objectiu cal disposar d’una estratègia de negociació, documentada amb una clara descripció de les necessitats i possibilitats de l’empresa, amb una informació acurada sobre el seu posicionament financer i sobre les seves previsions de futur. L’experiència de diversos professionals de la gestió financera de l’empresa i de la banca, membres de la Comissió d’Economia Financera de la seu de Tarragona del Col•legi d’Economistes de Catalunya, ha permès l’elaboració d’aquest document de treball, amb la pretensió de facilitar les relacions entre les PIMEs i les entitats financeres. Aquest treball vol ser un manual per a un millor coneixement de la realitat financera pròpia i per a l’anàlisi de les possibles solucions, així com una guia de negociació per a obtenir solucions amb garantia d’èxit.Postprint (published version

PIMEs i finançament: necessitats i alternatives

Postprint (published version

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis

Anti-N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumor if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analog of 24(S)-hydroxycholesterol, which is a potent, and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients' NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patients' CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients' or controls' CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location (NOL) test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation [LTP]) were examined in the hippocampus on day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patients' CSF antibodies, but not those infused with controls' CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of LTP. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, LTP) were prevented in the animals that were treated with SGE-301, despite that this compound did not antagonize antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (1) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel, and (2) it significantly decreased the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar modulators of NMDAR, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations

Kinetics of immune responses elicited after three mRNA COVID-19 vaccine doses in predominantly antibody-deficient individuals

Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n = 9), common variable immunodeficiency (CVID, n = 12), combined immunodeficiency (CID, n = 1), and thymoma with immunodeficiency (TID, n = 1). unPAD patients and healthy controls (HCs, n = 10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Of interest, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+T cells. CID and TID patients developed cellular but not humoral responses. Although the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.info:eu-repo/semantics/publishedVersio

A pediatric regimen for adolescents and young adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia: Results of the ALLRE08 PETHEMA trial

Background: Pediatric-based or -inspired trials have improved the prognosis of adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL). Methods: This study reports the results of treatment of the ALLRE08 trial, a full pediatric trial for AYA aged 15-30 years with standard-risk (SR) ALL. Results: From 2008 to 2018, 89 patients (38 adolescents [15-18 years] and 51 young adults [YA, 19-30 years], median age: 20 [15-29] years) were enrolled in the ALLRE08 trial. The complete response (CR) was 95%. Twenty-two patients were transferred to a high-risk (HR) protocol because of poor marrow response on day 14 (n = 20) or high-level of end-induction minimal residual response (MRD ≥ 0.25%, n = 2). Cumulative incidence of relapse (CIR) at 5 years was 35% (95%CI: 23%-47%), with significant differences between adolescents and YA: 13% (4%-28%) vs 52% (34%-67%), P = .012. No treatment-related mortality was observed in 66/66 patients following the ALLRE08 trial vs 3/23 patients moved to a HR trial. The estimated 5-year overall survival (OS) was 74% (95%CI: 63%-85%), with significantly higher rates for adolescents vs YA: 87% (95%CI: 74%-100%) vs 63% (46%-80%), P = .021. Although CIR or OS were lower in patients who were transferred to a HR trial, the differences were not statistically significant (CIR: 34% [21%-47%] vs 37% [14%-61%]; OS: 78% [66%-90%] vs 61% [31%;91%]). Conclusion: A full pediatric trial is feasible and effective for AYA with Ph-neg, SR-ALL, with better results for adolescents than for YA. Outcome of patients with poor early response rescued with a HR trial was not significantly inferior

A pediatric regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia : Results of the ALLRE08 PETHEMA trial

Altres ajuts: Supported in part by grants from Fundació La Caixa and CIBERONC (JMHR and AO).Pediatric-based or -inspired trials have improved the prognosis of adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL). This study reports the results of treatment of the ALLRE08 trial, a full pediatric trial for AYA aged 15-30 years with standard-risk (SR) ALL. From 2008 to 2018, 89 patients (38 adolescents [15-18 years] and 51 young adults [YA, 19-30 years], median age: 20 [15-29] years) were enrolled in the ALLRE08 trial. The complete response (CR) was 95%. Twenty-two patients were transferred to a high-risk (HR) protocol because of poor marrow response on day 14 (n = 20) or high-level of end-induction minimal residual response (MRD ≥ 0.25%, n = 2). Cumulative incidence of relapse (CIR) at 5 years was 35% (95%CI: 23%-47%), with significant differences between adolescents and YA: 13% (4%-28%) vs 52% (34%-67%), P = .012. No treatment-related mortality was observed in 66/66 patients following the ALLRE08 trial vs 3/23 patients moved to a HR trial. The estimated 5-year overall survival (OS) was 74% (95%CI: 63%-85%), with significantly higher rates for adolescents vs YA: 87% (95%CI: 74%-100%) vs 63% (46%-80%), P = .021. Although CIR or OS were lower in patients who were transferred to a HR trial, the differences were not statistically significant (CIR: 34% [21%-47%] vs 37% [14%-61%]; OS: 78% [66%-90%] vs 61% [31%;91%]). A full pediatric trial is feasible and effective for AYA with Ph-neg, SR-ALL, with better results for adolescents than for YA. Outcome of patients with poor early response rescued with a HR trial was not significantly inferior. A full pediatric trial is feasible and effective for adolescent and young adults with acute lymphoblastic leukemia, with better results for adolescents than for young adults. The outcome of patients showing poor early response was not significantly inferior than that observed for good responders after being transferred to a high-risk trial

Museos y exposiciones de Madrid como oportunidad de trabajar conceptos clave de la sociedad y analizar la experiencia museística ampliada con herramientas tecnológicas de comunicación, en colaboración con estudiantes UCM y Erasmus+Incoming

Este proyecto se enmarca en los trabajos de nuestro grupo para enriquecer el proceso de enseñanza/aprendizaje con la utilización de recursos de los museos y exposiciones de la ciudad. Se propone el uso de los museos como una oportunidad para reflexionar sobre aspectos relevantes de la vida social y sobre la evolución de la tecnología. La actual propuesta se alinea con los trabajos que proponen experiencias museísticas como herramientas de aprendizaje en la educación superior. Se han desarrollado acciones de mejora en el proceso de enseñanza-aprendizaje mediante visitas a los museos de la ciudad adaptándose a las características del visitante universitario. La evaluación se ha realizado mediante un grupo focalizado y un cuestionario de elaboración propia. Además, se utilizan los resultados descritos en el texto “Nuevas herramientas de comunicación de los museos como recurso docente para acercar la cultura a los universitarios” publicado como capítulo del libro “Innovación e investigación docente en educación: experiencias prácticas” (Carcelén García, Narros González, Galmés González, & Díaz Bustamante Ventisca, 2021). Se han presentado resultados derivados de estos trabajos en los siguientes Congresos: INNTED (Congreso Internacional de Innovación y Tendencias Educativas) con la ponencia titulada “Nuevas herramientas de comunicación de los museos como recurso docente para acercar la cultura a los universitarios” y CINDU (Congreso Internacional de Docencia Universitaria) con la ponencia titulada: “Utilización de nuevas tecnologías de la comunicación para atraer a los jóvenes hacia la cultura. Aplicación empírica en museos”.Unidad Dptal. de Organización de Empresas y MarketingFac. de Ciencias de la InformaciónFALSEsubmitte

re-habitar El Carmen : Un proyecto sobre patrimonio contemporáneo

El proyecto _re-HABITAR suponía para el propio proceder de la institución un avance más allá del reconocimiento, registro, inventario o protección patrimonial de la arquitectura del siglo XX y del Movimiento Moderno para posicionarse en la acción preventiva y conservativa de ese legado contemporáneo. Para ello, la praxis patrimonial se aferraba a un modelo: el de la vivienda social en España en la segunda mitad del siglo XX; a un caso concreto: el de la barriada de Nuestra Señora del Carmen (Recasens Méndez-Queipo de Llano, 1958); y a un requisito fundamental: analizar un objeto vivo y en uso, aún con la presencia de quienes lo vivieron y usaron desde su origen