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Polygenic scores for autism are associated with reduced neurite density in adults and children from the general population
(Nature Pub. Group, 2025-02-24) Gu, Yuangu; Stauffer, Eva María; Saashi A., Bedford; Romero García, Rafael; Grove, Jackob; Børglum, Anders D.; Martin, Hilary; Baron-Cohen, Simon; Bethlehem, Richard A. I.; Warrier, Varun; APEX Consortium; iPSYCH-Autism Consortium; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Union (UE). H2020
Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.
Pharmacological Inhibition of Microglial Proliferation Supports Blood–Brain Barrier Integrity in Experimental Autoimmune Encephalomyelitis
(MDPI, 2025-03-12) Borjini, Nozha; Fernandez, Mercedes; Giardino, Luciana; Sorokin, Lydia; Calzà, Laura; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; European Union (UE)
Blood–brain barrier dysfunction (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We have previously shown that blocking microglial proliferation using GW2580, a selective inhibitor of CSF1R (Colony stimulating factor 1 receptor), reduced disease progression and severity and prevented the relapse phase. However, whether this was due to effects of GW2580 on the functional integrity of the BBB was not determined. Therefore, here, we examine BBB properties in rats during EAE under GW2580 treatment. Our data suggest that blocking early microglial proliferation through selective targeting of CSF1R signaling has a therapeutic effect in EAE by protecting BBB integrity and reducing peripheral immune cell infiltration. Taken together, our results identify a novel mechanism underlying the effects of GW2580, which could offer a novel therapy for MS.
Uso e interpretación simbólica del espacio público: las plazas de Armas y del Carmen en San Luis Potosí durante la Procesión del Silencio
(Aranzadi, 2025) Arista Castillo, Leticia; Barrera Fernández, Daniel; Universidad de Sevilla. Departamento de Urbanística y Ordenación del Territorio
En las ciudades históricas, el espacio público sirve como un punto de encuentro para diversos grupos
sociales y culturales, mostrando la variedad y la complejidad de su pasado urbano. Estos sitios, aunque
auténticos, también están en riesgo de perder su carácter al ser utilizados para fines turísticos y
comerciales. La Procesión del Silencio en San Luis Potosí es un caso específico de cómo se entrelazan
las representaciones religiosas, el uso del espacio público, los participantes y los asistentes. En este
evento, las imágenes procesionales son fundamentales para la vivencia religiosa y para tener una
experiencia colectiva dentro de la ciudad histórica. Este análisis tiene como objetivo examinar la
Procesión del Silencio como una expresión religiosa que le da un nuevo significado al centro de San
Luis Potosí, investigando la importancia de las imágenes procesionales y la movilidad de los
participantes en la creación del discurso y la identidad urbana. La metodología implica examinar fuentes
documentales acerca de la Procesión del Silencio y su vinculación con el entorno urbano de San Luis
Potosí, además de revisar literatura sobre espacio público, representación religiosa y memoria colectiva.
El estudio se centra en los dos espacios principales para la procesión: la Plaza de Armas y la Plaza del
Carmen. Uno de los descubrimientos más importantes es cómo la procesión cambia la Plaza del Carmen
en un lugar donde se crea un nuevo mensaje y se fortalece la identidad de los que participan, presentando
una manera diferente de entender el espacio histórico de la ciudad.
Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell Features
(Springer, 2025-08-27) Sierro-Martínez, Belén; Escamilla-Gómez, Virginia; Pérez-Ortega, Laura; Guijarro-Albaladejo, Beatriz; Hernández-Díaz, Paola; Garrido, María de la Rosa; Lara-Chica, Maribel; Rodríguez Gil, Alfonso; Caballero Velázquez, Teresa; Pérez Simón, José Antonio; García-Guerrero, Estefanía; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Instituto de Salud Carlos III; European Union; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España
Purpose
CAR therapy targeting BCMA is under investigation as treatment for multiple myeloma. However, given the lack of plateau in most studies, pursuing more effective alternatives is imperative. We present the preclinical and clinical validation of a new optimized anti-BCMA CAR (CARTemis-1). In addition, we explored how the manufacturing process could impact CAR-T cell product quality and fitness.
Methods
CARTemis-1 optimizations were evaluated at the preclinical level both, in vitro and in vivo. CARTemis-1 generation was validated under GMP conditions, studying the dynamics of the immunophenotype from leukapheresis to final product. Here, we studied the impact of the manufacturing process on CAR-T cells to define optimal cell culture protocol and expansion time to increase product fitness.
Results
Two different versions of CARTemis-1 with different spacers were compared. The longer version showed increased cytotoxicity. The incorporation of the safety-gene EGFRt into the CARTemis-1 structure can be used as a monitoring marker. CARTemis-1 showed no inhibition by soluble BCMA and presents potent antitumor effects both in vitro and in vivo. Expansion with IL-2 or IL-7/IL-15 was compared, revealing greater proliferation, less differentiation, and less exhaustion with IL-7/IL-15. Three consecutive batches of CARTemis-1 were produced under GMP guidelines meeting all the required specifications. CARTemis-1 cells manufactured under GMP conditions showed increased memory subpopulations, reduced exhaustion markers and selective antitumor efficacy against MM cell lines and primary myeloma cells. The optimal release time points for obtaining the best fit product were > 6 and < 10 days (days 8–10).
Conclusions
CARTemis-1 has been rationally designed to increase antitumor efficacy, overcome sBCMA inhibition, and incorporate the expression of a safety-gene. The generation of CARTemis-1 was successfully validated under GMP standards. A phase I/II clinical trial for patients with multiple myeloma will be conducted (EuCT number 2022-503063-15-00).
Recent natural selection conferred protection against schizophrenia by non-antagonistic pleiotropy
(Nature Publishing Group; Nature Portfolio, 2023-09-19) González-Peñas, Javier; De Hoyos, Lucía; Díaz-Caneja, Covadonga M.; Andreu-Bernabeu, Álvaro; Stella, Carol; Gurriarán, Xaquín; Crespo Facorro, Benedicto; Costas, Javier; Universidad de Sevilla. Departamento de Psiquiatría; Gobierno de España; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Universidad de Sevilla. CTS1086: Psiquiatría Traslacional
Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non psychiatric phenotypes.
