Alberto Sols Biomedical Research Institute
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La imposibilidad de bonificar las tasas por instalaciones deportivas municipales a los empadronados : Análisis de la STS de 20 de julio de 2023, rec. núm. 4638/2021
Get PDFEn este comentario se analiza críticamente la Sentencia del Tribunal Supremo de 20 de julio de
2023 (rec. núm. 4638/2021), que declara que un ayuntamiento no puede establecer diferencias
cuantitativas en una tasa por la utilización de frontones, piscinas e instalaciones polideportivas
municipales atendiendo a que los usuarios estén o no empadronados en el municipio, al no
erigirse el empadronamiento, a juicio de la sala, en un criterio razonable y objetivo a los efectos
de justificar aquellas. El análisis se centra en dos cuestiones especialmente controvertidas: por
un lado, el alcance de la reserva de ley en relación con la posibilidad de establecer beneficios
fiscales en las tasas locales y, por otro lado, la utilización del empadronamiento como criterio
para el establecimiento de diferencias en la cuota tributaria de este tipo de tasas, a la luz del
principio de igualda
Development of SOCS1 mimetics as novel approach to harmonize inflammation, oxidative stress, and fibrogenesis in metabolic dysfunction-associated steatotic liver disease
Get PDFBackground: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease, encompassing a spectrum from simple steatosis to steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. As part of metabolic syndrome, MASLD/MASH is characterized by inflammation, oxidative stress, and fibrosis, highlighting the need for targeted therapies. The dysregulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and its negative regulators the suppressors of cytokine signaling (SOCS), plays a critical role in liver function and contributes to MASLD progression. Aim: Based on a SOCS1 functional domain, we developed mimetic peptides (linear and cyclic) targeting JAK activity and assessed their hepatoprotective potential in experimental MASLD/MASH. Results: In dietary mouse models of MASLD/MASH, the administration of peptides ameliorated liver damage at both early and advanced stages, as evidenced by significant decreases in serum transaminases and hepatic content of lipids, inflammatory cells, and collagen. Treatment attenuated hepatic STAT1/3 activation and downregulated genes involved in inflammation, fibrosis, and lipid metabolism. Livers from treated mice exhibited lower levels of oxidative damage markers, reduced expression of NADPH oxidase 1 (NOX1), and upregulation of the antioxidant genes catalase and superoxide dismutase. In vitro, the peptides were safe for hepatocytes at different doses and effectively counteracted palmitate-induced cytotoxicity, superoxide anion production, and cytokine and NOX1 expression, while increasing anti-inflammatory and antioxidant genes. Conclusions: SOCS1 mimetic peptides exhibit hepatoprotective effects in experimental MASLD/MASH by modulating lipotoxicity, inflammation, redox balance and fibrogenesis. This proof-of-concept supports their potential as candidates for preclinical MASLD therapy developmentThis study was supported by MICIU/AEI/10.13039/501100011033 and “ERDF/EU” (grant PID2021-127741OB-I00 to CGG), Instituto de Salud Carlos III (grants DTS19/00093 and PI23/00119 to JE) and CIBERDEM (postdoctoral contract to IP). We thank Comunidad de Madrid and UAM for supporting MK (PIPF-2023-SAL-GL-29901) and IHR (PEJ-2023-AI_SAL-GL-28534). DM was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC; grant IG 2022, Rif. 27378). AMV is member of COMETA network (CSIC, Spain
Propiedades electrónicas de sistemas híbridos orgánico-inorgánicos: quiralidad, polarizaciónn de espín y efectos fotovoltaicos
Get PDFTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física de la Materia Condensada. Fecha de Lectura: 23-04-202
Análisis de la infección por Vaccinia virus por aproximaciones multi-ómicas: Identificación y caracterización de la Beta-2 Microglobulina como factor hospedador para la entrada viral
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina Preventiva y Salud Pública y Microbiología. Fecha de Lectura: 20-07-2023Esta tesis tiene embargado el acceso al texto completo hasta el 20-01-2025Vaccinia virus (VV), a member of the Orthopoxvirus genus and the family Poxviridae, is a large, complex, enveloped virus with a linear double-stranded DNA genome of approximately 190 kbp. It is mostly known for being used as the vaccine for the erradication of Variola virus, the causative agent of Smallpox, as a result of a campaign started in 1967.
Vaccinia virus has been extensively studied as the prototype organism for Poxvirus biology and has emerged as a promising platform for the development of novel vaccines and oncolytic therapies.
Transcriptional regulation is a crucial aspect of Vaccinia virus biology, as the virus encodes its own transcription and replication machinery, which allows it to control the transcription of its genes in a highly specific and sequential manner. The transcription of the viral genome is divided into three stages: early, intermediate, and late, allowing for precise regulation of the viral cycle.
Recent advances in single-cell RNA sequencing (scRNAseq) have enabled the profiling of the transcriptome of individual cells, providing a detailed understanding of the viral infection trajectory and its relationship with the host cell response. Using scRNAseq, we have identified heterogeneous cellular responses to VV infection, highlighting the importance of single-cell approaches to better understand the biology of this virus.
Vaccinia virus entry into cells is a complex process that has been subject to numerous studies. The size of the virus has led to the assumption that its entry into the cell cannot happen through caveolin or clathrin vesicles. Instead, several membrane proteins have been proposed to serve as VV entry receptors or co-receptors, leading to VV internalization through fluid phase endocytosis followed by membrane fusion. Surprisingly, VV entry process varies significantly between different cell lines, virus strains, and viral forms, pointing to the existence of several pathways leading to VV entry.
Genome-wide genetic screens using CRISPR/Cas gRNA libraries have become an important tool to identify factors involved in biological processes. Several high-throughput screenings using CRISPR/Cas9 technology have been performed to target cellular factors involved in viral infections, revealing many host cell factors involved in viral infection. In order to better understand the VV entry process and identify new host factors involved, we have performed genome-wide CRISPR/Cas9 screens revealing new candidates for host factors for VV infection. Among the hits detected in the screens, Beta-2 microglobulin appeared consistently in the top of the host dependencies for VV, and has not been previously described to be involved in VV infection. In this work, I have conducted an in-depth study on the requirement of 3
β-2-microglobulin and its functional implications in virus infection, detecting that its absence
negatively affects viral entry and more specifically, the internalization of the virus.
In summary, this thesis focuses on the study of VV infection using multi-omic approaches, both for the investigation of virus-cell interactions and the host cell responses to infection, as well as for the detection of novel pro-viral genes required for VV infectio
Análisis de los cuentos infantiles de George MacDonald a través de la teoría de la Literatura Fantástica
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Filosofía y Letras, Departamento de Filología Inglesa. Fecha de Lectura: 13-07-2023Esta Tesis tiene embargado el acceso al texto completo hasta el 13-01-2025George MacDonald (1824-1905), nacido en Huntley (Aberdeenshire), fue un escritor, poeta y ministro cristiano escocés victoriano. El objetivo principal de esta tesis doctoral es el de reconocer el increíble genio literario de George MacDonald para crear relatos fantásticos, así como las numerosas contribuciones que ha hecho al género moderno de la literatura fantástica tal y como la conocemos a día de hoy. Para lograr este objetivo, esta tesis ofrece un análisis detallado de tres de sus más famosos cuentos para niños: La llave de oro (1867), La princesa y el duende (1872) y Más allá del viento del norte (1871). Este estudio incluirá cuestiones sociales victorianas; la representación y el papel de los personajes femeninos, los cuales anticipan el concepto de “New Woman” del siglo XX; el papel que juegan los motivos, categorías y subgéneros típicos de la fantasía moderna en las obras de MacDonald; y la influencia del Romanticismo inglés y alemán en la concepción de la imaginación del propio autor. En conjunto, esta tesis pretende aportar abundantes pruebas para demostrar por qué George MacDonald, -a pesar de no haber sido tan conocido como otros de sus contemporáneos, como Charles Dickens, u otros autores de literatura fantástica como Lewis Carroll, William Morris o Julio Verne, durante su época – merece ser considerado como el “padre fundador” de la literatura fantástica moderna. Además, MacDonald se ha convertido claramente en una inspiración y una referencia importante para otros autores de fantasía cristianos más conocidos del siglo XX, como lo son J. R. R. Tolkien y C. S. Lewis. De este modo, las tres historias que analizo en este trabajo demuestran que la producción literaria de cuentos fantásticos para niños que ofrece MacDonald lo sitúa como uno de los autores más innovadores y completos de su época, al integrar a su vez numerosas aportaciones que pertenecen a las tradiciones míticas clásicas y celtas con su visión cristiana humanista del mund
Implicación dual de GSDMB en la biología del cáncer: desde la resistencia a la terapia anti-HER2 hasta la inducción de la muerte celular
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 14-09-2023Esta tesis tiene embargado el acceso al texto completo hasta el 14-03-202
Desarrollo de nuevos procesos redox: reacciones enantioselectivas basadas en la catálisis de Rodio Quiral y uso de sales de sulfinatos
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica. Fecha de Lectura: 14-07-2023Esta tesis tiene embargado el acceso al texto completo hasta el 14-01-2025When considering the employment of reactive radical species in organic synthesis, it is astonishing
the mildness which photo and electro reactions required to handle them. In fact, relevant toxic radical
initiators can be easily substituted by catalytic amounts of a photocatalyst or by the use of “green”
electrons. With this perspective, the last decade has evidenced the powerful of such methods by the
publication of uncountable strategies.
In this sense, the first part of this PhD thesis will focus on the design of photocatalytic protocols to
access valuable cyclic structures, as 1-pyrroline and alicyclic β amino carbonyl derivatives. Both
strategies emerge by the combination of rhodium-chiral catalysis and photoredox catalysis.
In chapter 2.1 the strategy involves the distal functionalization of acyl heterocycles through a
hydrogen-atom transfer (HAT) process and the use of tailor-made ketimines as reliable electrophilic
partners. This transformation is translated into an enantiomerically controlled radical/polar cascade
reaction in which water is produced as the sole by-product and stereoselectivity is dictated by
coordination to a chiral-at-rhodium catalyst.
In chapter 2.2 the overall reactivity relies on the performance of the substrate-catalyst complex to
assist both the enantiocontrol and the photoredox tasks. This transformation led to an
enantioselective [3 + 2] photocycloaddition between coordinated α,β-unsaturated acyl imidazoles and
cyclopropylamine derivatives.
Successively, the focus of the thesis is directed toward the design of new valuable redox
transformations based on single-electron oxidation of sulfinate salts. Their dual nature as alkylating
or sulfonylating agents is employed for the photoflow functionalisation of heteroarenes and the
electrosynthesis of allyl sulfones.
In chapter 3.4 the protocol relies on the in situ generation and further in-line use of alkyl zinc
sulfinates through a continuous-flow system. The environmentally friendly character of the protocol is
assured by the use of a green solvent mixture, the presence of a metal free oxidant and low waste
generation.
In chapter 3.5 the protocol starts with the anodic oxidation of the sodium sulfinate, then the radical
addition to the alkene is followed by the elimination of the trifluoroborate moiety, giving rise to a variety
of differently substituted allyl sulfones. The process transpires under very mild and simple reaction
conditions that can even take place using water as solvent and in absence of additional electrolytes,
which provides a general, appealing and low-cost methodology for the synthesis of allyl sulfonesLas financiaciones de este trabajo han procedido por el Gobierno Español (PID2021-122299NB-I00, TED2021-130470B-I00, TED2021-129999B-C32), de la Comunidad de Madrid y de los Fondos Estructurales y de Inversión Europeos (S2018/NMT-4367), de los proyectos sinérgicos I+D (Y2020/NMT6469), así como de la Comunidad Autónoma de Madrid (SI1/PJI/2019–00237
La lamina A/C como modulador de la respuesta inmune mieloide en el contexto de infecciones virales y enfermedad inflamatoria intestinal
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 03-10-2023Esta tesis tiene embargado el acceso al texto completo hasta el 03-04-2025A-type lamins (lamin A/C) are type V intermediate filament proteins that form the nuclear lamina (NL) along with B-type lamins. NL is in the internal part of the inner nuclear membrane and interacts with chromatin, transcription factors, and nuclear pore complexes. Lamin A/C regulates many functions, highlighting its fundamental role in the maintenance of nuclear architecture and mechanical stability.
Dendritic cells (DCs) are a complex myeloid subset that bridges innate and adaptive immune responses by acting as professional antigen presenting cells. Using a mouse model lacking lamin A/C (Lmna-/-) specifically in the myeloid compartment, we studied the role of lamin A/C in DCs. GM-CSF Lmna-/--bone marrow-derived DCs (BMDCs), differentiated in vitro, showed a diminished capacity to form conjugates with naïve CD4+ T cells and to promote CD4+ T cell activation and proliferation when matured with Lipopolysaccharide (LPS). However, the opposite results were obtained when the cells were kept in an immature state. Lamin A/C deficiency in mature DCs alters NF-κB nucleus-cytoplasm localization and NF-κB-dependent transcription. Additionally, Lmna-/--BMDCs showed lower expression of proinflammatory genes without an apparent effect on the expression of MHC-II and other co-stimulatory molecules.
In vivo, LysM-Cre Lmna-/- mice generated lower Th1 and CTL responses and less viral clearance upon Vaccinia virus infection compared to WT, when the virus was administered intraperitoneally or by skin scarification in the tail. However, when subcutaneous infection was performed, differences were observed between genotypes only at 6 days post-infection, but not at 14 days after. These results suggest that lamin A/C modulates myeloid response to Vaccinia virus, depending on the route of infection. On the other hand, when young and adult mice were infected with Influenza A virus, differences in symptomatology and weight loss between WT and LysM-Cre Lmna-/- mice were only notable in adult mice. The observed results can be explained by the fact that lamin A/C deficiency in myeloid cells leads to the loss of monocytic alveolar macrophages in the lungs. Furthermore, the absence of lamin A/C in some myeloid populations protects against the development of inflammatory bowel disease in mice as they presented a milder disease, showing less weight loss, less symptomatology, and less shortening of the colon compared to their WT counterparts. A model of colitis based on dextran sodium sulfate (DSS) administration was used. With therapeutic interest, the adoptive transfer of immature Lmna-/--BMDCs to WT mice before DSS treatment, improved colitis by reducing the percentage of IFNγ+ CD8+ T cells and increasing the proportion of Treg cells.
Here, we demonstrated that the action of lamin A/C is context-dependent, modulating myeloid cell plasticity and function. This work lays the groundwork to enhance immunotherapies based on DCs or developing new therapeutics to treat infectious or inflammatory disease
La modulación de AMPK y de JNK1 en el hipotálamo por Olanzapina controla el balance energético y la lipogénesis hepática: beneficios adicionales de la inhibición de PTP1B
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 06-10-2023Esta tesis tiene embargado el acceso al texto completo hasta el 06-04-2025Schizophrenia is a chronic psychiatric disorder which is treated with second generation antipsychotics (SGAs). However, many patients on treatment develop metabolic dysfunctions such as a body weight gain, hyperglycemia, dyslipidemia and hepatic steatosis. Among target candidates to combat metabolic diseases, protein tyrosine phosphatase-1B (PTP1B), a critical negative modulator of leptin and insulin signaling, is currently considered as a therapeutic target for obesity and type 2 diabetes. In this Thesis we have evaluated the effects of olanzapine (OLA), a widely prescribed, but highly obesogenic SGA, in male mice analyzing changes in body weight and energy balance modulated by the hypothalamus-brown/beige adipose tissue axis. We also investigated OLA effects in hepatic lipid metabolism focusing on the hypothalamus-liver interactome. Further, we explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin and insulin hypersensitivity protected against obesity and metabolic syndrome. Studies were conducted in male mice receiving OLA orally (supplemented in the diet) or injected via intraperitoneal (i.p.). Preliminary studies were conducted in females receiving OLA via i.p. Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but only WT mice gained weight. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake. In i.p. treated-mice, reduced hypothalamic AMP-dependent protein kinase (AMPK) phosphorylation concurred with elevations in Uncoupling Protein-1 (UCP-1) in brown adipose tissue (BAT) and subcutaneous white adipose tissue (iWAT) and increased energy expenditure. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutively AMPK activation in the hypothalamus. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels in the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. Additionally, we found that OLA i.p. treatment induced mild oxidative stress and inflammation in the hypothalamus in a Jun N-terminal kinase-1 (JNK1)-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve, an effect concurrent with a starvation-like molecular signature, thereby preventing steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against weight gain and hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation upon i.p. administration, strongly suggests that targeting PTP1B might be a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized mannerEsta Tesis Doctoral ha sido realizada gracias a la financiación enamarcada en el programa Horizon 2020 Marie Sklodowska-Curie Innovative Training Network de la Unión Europea (ITN-TREATMENT, acuerdo de consorcio 721236), en el proyecto PID-2021-122766OB-100 financiado por la Agencia Estatal de Investigación (MCIN/AEI/ 10.13039/501100011033 y “ERDF A way of making Europe” de la Unión Europea), y a la financión individual para el Doctorado de la Fundação para a Ciência e Tecnologia a Vítor Manuel da Silva Ferreira (2020.08388.BD
Análisis semántico-pragmático de los verbos pseudocopulativos de cambio
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Filosofía y Letras, Departamento de Filología Española. Fecha de Lectura: 14-12-2023Esta Tesis tiene embargado el acceso al texto completo hasta el 14-06-202