Experiencia piloto en la asignatura de Derecho Civil I

El método tradicional o clásico de enseñanza, ha variado notablemente en los últimos tiempos. En la actualidad, con el fin de preparar a los alumnos para asumir los retos y roles en un mundo cambiante, los profesores universitarios nos enfrentamos cada vez con más frecuencia la “presión” de reducir el uso de la exposición como método de instrucción, y generar en cambio un ambiente de trabajo más interactivo, en el que el alumno participe más activamente en las enseñanzas

Experiencia piloto en la asignatura de Derecho Civil I

El método tradicional o clásico de enseñanza, ha variado notablemente en los últimos tiempos. En la actualidad, con el fin de preparar a los alumnos para asumir los retos y roles en un mundo cambiante, los profesores universitarios nos enfrentamos cada vez con más frecuencia la “presión” de reducir el uso de la exposición como método de instrucción, y generar en cambio un ambiente de trabajo más interactivo, en el que el alumno participe más activamente en las enseñanzas. A lo largo de estas líneas pretendemos describir la experiencia que nosotros estamos llevando a cabo en la Asignatura Derecho Civil I, Parte General y Derecho de la Persona

Immunosenescence in multiple sclerosis: the identification of new therapeutic targets

Autoimmunitat; Immunosenescència; Esclerosi múltipleAutoinmunidad; Inmunosenescencia; Esclerosis múltipleAutoimmunity; Immunosenescence; Multiple sclerosisThe number of elderly multiple sclerosis (MS) patients is growing, mainly due to the increase in the life expectancy of the general population and the availability of effective disease-modifying treatments. However, current treatments reduce the frequency of relapses and slow the progression of the disease, but they cannot stop the disability accumulation associated with disease progression. One possible explanation is the impact of immunosenescence, which is associated with the accumulation of unusual immune cell subsets that are thought to have a role in the development of an early ageing process in autoimmunity. Here, we provide a recent overview of how senescence affects immune cell function and how it is involved in the pathogenesis of autoimmune diseases, particularly MS. Numerous studies have demonstrated age-related immune changes in experimental autoimmune encephalomyelitis models, and the premature onset of immunosenescence has been demonstrated in MS patients. Therefore, potential therapeutic strategies based on rejuvenating the immune system have been proposed. Senolytics and regenerative strategies using haematopoietic stem cells, therapies based on rejuvenating oligodendrocyte precursor cells, microglia and monocytes, thymus cells and senescent B and T cells are capable of reversing the process of immunosenescence and could have a beneficial impact on the progression of MS.This work was supported by the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III , and co-funded by the European Union ( European Regional Development Fund / European Social Fund ), “A way to build Europe”, under Grant PI18/01146 and RD16/0015/004 and the “ Agència de Gestió d'Ajuts Universitaris i de Recerca ” (AGAUR; Generalitat de Catalunya ) under Grant 2017SGR527

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Immunitat adaptativa; Envelliment; Esclerosi múltipleInmunidad adaptativa; Envejecimiento; Esclerosis múltipleAdaptive immunity; Aging; Multiple sclerosisPatients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.This work was supported by grants FIS-PI15/00513, FIS-PI18/00572 and RD16/0015/0001 from the Instituto de Salud Carlos III. Ministerio de Ciencia e Innovación, Spain and FEDER: "Una manera de hacer Europa"

Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis

Soluble receptor; Multiple sclerosisReceptor soluble; Esclerosis múltipleReceptor soluble; Esclerosi múltipleThe pathogenic role of the interleukin 21 (IL-21) in different autoimmune diseases, such as multiple sclerosis (MS), has been extensively studied. However, its pleiotropic nature makes it a cytokine that may exhibit different activity depending on the immunological stage of the disease. In this study, we developed a gene therapy strategy to block the interaction between IL-21 and its receptor (IL-21R) by using adeno-associated vectors (AAV) encoding a new soluble cytokine receptor (sIL21R) protein. We tested this strategy in a murine model of experimental autoimmune encephalomyelitis (EAE), obtaining different clinical effects depending on the time at which the treatment was applied. Although the administration of the treatment during the development of the immune response was counterproductive, the preventive administration of the therapeutic vectors showed a protective effect by reducing the number of animals that developed the disease, as well as an improvement at the histopathological level and a modification of the immunological profile of the animals treated with the AAV8.sIL21R. The beneficial effect of the treatment was also observed when inducing the expression of the therapeutic molecule once the first neurological signs were established in a therapeutic approach with a doxycyline (Dox)-inducible expression system. All these clinical results highlight the pleiotropicity of this cytokine in the different clinical stages and its key role in the EAE immunopathogenesis.Open Access Funding provided by Universitat Autonoma de Barcelona. This project was supported by the Ministerio Ciencia Innovación, retos Sociedad (PI15/0271). A.E was a recipient of a VHIR fellowship

N-aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: Design, synthesis, computational studies, and antitumor effect

Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment

Semiconducting pi-extended discotic liquid-crystalline triindoles: studying their FET vs. SCLC mobilities

The field of organic electronics has experienced a vast development in the last few years, having the first generation of devices based in this technology already reached the market. Advances achieved in this field have been associated with the research of organic semiconductors able to transport charge carriers with a high mobility. However, finding organic semiconductors with the right balance between mobility and processability is still a challenge in the area. In this context, discotic liquid crystals, constituted by an aromatic central core surrounded by flexible alkyl tails, are among the most promising new candidates. Triindoles have been widely studied as a π-conjugated platforms in the construction of high mobility semiconducting liquid crystals. Three-fold oxidative cyclodehydrogenation of hexaphenyltriindole renders the significantly enlarged aromatic core, with structural characteristics of both triphenylene moieties and triindole. In this π-extended discotic core, the attachment of three flexible alkyl chains to the nitrogen atoms is sufficient to induce mesomorphism. The ratio of conducting versus isolating fraction is impressively enhanced when comparing to triindole liquid crystals, not only by enlarging the size of the central core but also by reducing the amount of isolating peripheral chains. In this presentation the electrical properties of the aforementioned semiconductor have been analyzed by applying two different methods: space-charge limited current (SCLC) measurements in a diode-like structure and field effect mobility measurements in a thin film transistor device. The mobility found on a diode type device is higher than that determined on thin film transistors, which can be understood by the high tendency of large π-conjugated molecules to deposit on surfaces with their extended core parallel to the substrate. This is demonstrated with a full analysis of the active layer of the thin film transistor, in order to analyze the molecular orientation in the semiconductor-dielectric interface, via Surface Enhanced Raman Spectroscopy (SERS). The observation of field effect behavior in a discotic liquid crystal processed by simple drop-casing suggests an increased dimensionality of charge transport by facilitating hopping between neighboring columns as a result of the large conducting/isolating ratio found in this discotic platform. Density Functional Theory (DFT) calculations have been performed in order to enlighten with more detail the charge-transport parameters at a molecular level.Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tec

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.Funding: This study has been supported: (i) by MICINN (SAF2009-11847 and SAF2015-68580-C2-1-R), CIBERNED (CB06/05/0089) and “Fundación Eugenio Rodríguez Pascual”, to JFR; (ii) by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin, to CJH; and (iii) by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014) and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), to PM. Carmen Rodríguez-Cueto was a predoctoral fellow supported by FPI Program-Ministry of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio