GSK-3β orchestrates the inhibitory innervation of adult-born dentate granule cells in vivo

Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3β) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3β-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3β overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3β is dysregulatedPID2020-113007RB-I00, SAF-2017-82185-R, PID2020-112824GB-10

Generation of the first human in vitro model for McArdle disease based on iPSC Technology

McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.This work has been funded by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (ISCIII): PI15/00484, CP16/00046 and PI18/00151 to MEG and PI17/02052 to JA (co-funded by European Regional Development Fund “A way to make Europe”); PI21/00162 and CPII21/00011 co-funded by the European Union to MEG. MdCOC receives grant support from the ‘Ministerio de Educación, Cultura y Deporte’ (FPU16/03895), ‘Fundación para la Investigación Biomédica Hospital 12 de Octubre’ (2022/0065, i+12-AY20220114-1) and EMBO Grant 8917. CL and MD were recipient of a fellowship from the French Ministry of Education. The work in FM’s laboratory was funded by “Association Française contre les Myopathies” (AFM; TRIM-RD and MoThARD) and from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir programme” AMX-19-IET-007 through the Marseille Maladies Rares (MarMaRa) Institute (phD fellowship to CL)

Methods to study adult hippocampal neurogenesis in humans and across the phylogeny

The hippocampus hosts the continuous addition of new neurons throughout life—a phenomenon named adult hippocampal neurogenesis (AHN). Here we revisit the occurrence of AHN in more than 110 mammalian species, including humans, and discuss the further validation of these data by single-cell RNAseq and other alternative techniques. In this regard, our recent studies have addressed the long-standing controversy in the field, namely whether cells positive for AHN markers are present in the adult human dentate gyrus (DG). Here we review how we developed a tightly controlled methodology, based on the use of high-quality brain samples (characterized by short postmortem delays and ≤24 h of fixation in freshly prepared 4% paraformaldehyde), to address human AHN. We review that the detection of AHN markers in samples fixed for 24 h required mild antigen retrieval and chemical elimination of autofluorescence. However, these steps were not necessary for samples subjected to shorter fixation periods. Moreover, the detection of labile epitopes (such as Nestin) in the human hippocampus required the use of mild detergents. The application of this strictly controlled methodology allowed reconstruction of the entire AHN process, thus revealing the presence of neural stem cells, proliferative progenitors, neuroblasts, and immature neurons at distinct stages of differentiation in the human DG. The data reviewed here demonstrate that methodology is of utmost importance when studying AHN by means of distinct techniques across the phylogenetic scale. In this regard, we summarize the major findings made by our group that emphasize that overlooking fundamental technical principles might have consequences for any given research fieldAssociation for Frontotemporal Degeneration; Banco de Santander; Center for Networked Biomedical Research on Neurodegenerative Diseases; Consejo Nacional de Ciencia y Tecnología (CONACYT), Grant/Award Number: 385084; European Research Council, Grant/Award Number: ERC-CoG2020-101001916; Fundacion Ram on Areces; Secretaria de Educacion, Ciencia Tecnología e Innovacion (SECTEI) of the Regional Government of Ciudad de México (CDMX), Grant/Award Number: SECTEI/159/2021; Spanish Ministry of Economy and Competitiveness, Grant/Award Numbers: PID2020-113007RB-I00, RYC-2015-171899, SAF-2017-82185-R; The Alzheimer's Association, Grant/Award Numbers: 2015-NIRG-340709, AARG-17-528125, AARG-17-528125-RAPI

Sphingolipid distribution, content and gene expression during olive-fruit development and ripening

Los esfingolípidos vegetales participan en la construcción de la matriz de las membranas celulares y en las vías de señalización de los procesos fisiológicos y las respuestas ambientales. Sin embargo, se desconoce la información relativa a su papel en el desarrollo y la maduración de los frutos, un proceso específico de las plantas. El presente estudio trata de determinar si los esfingolípidos participan en el desarrollo y la maduración del fruto carnoso en una especie de cultivo oleaginoso como el olivo (Olea europaea L. cv. Picual) y, en caso afirmativo, de qué manera. Aquí, en las membranas plasmáticas de los protoplastos vivos, usamos la fluorescencia para examinar varias manchas lipofílicas específicas en las regiones enriquecidas con esfingolípidos e investigamos la composición de las bases de cadena larga de los esfingolípidos (LCB), así como los patrones de expresión de los genes relacionados con los esfingolípidos, OeSPT, OeSPHK, OeACER, y OeGlcCerase, durante el desarrollo y la maduración del fruto del olivo. Los resultados demuestran el aumento del contenido de esfingolípidos y el tráfico de vesículas en los protoplastos de la fruta del olivo al comienzo de la maduración. Además, la concentración de LCB [t18:1(8Z), t18:1 (8E), t18:0, d18:2 (4E/8Z), d18:2 (4E/8E), d18:1(4E), y 1,4-anhidrot18: 1(8E)] aumenta durante el desarrollo del fruto hasta alcanzar un máximo al inicio de la maduración, aunque estas especies moleculares disminuyeron durante la maduración del fruto. Por otra parte, la OeSPT, la OeSPHK y la OeGlcCerase se expresaron de manera diferente durante el desarrollo y la maduración del fruto, mientras que la expresión del gen OeACER se detectó sólo en la etapa de madurez completa. Los resultados proporcionan datos novedosos sobre la distribución de los esfingolípidos, el contenido y la biosíntesis/transcripción de los genes de rotación durante la maduración del fruto carnoso, lo que indica que todos ellos están muy regulados en cuanto al desarrollo.Plant sphingolipids are involved in the building of the matrix of cell membranes and in signaling pathways of physiological processes and environmental responses. However, information regarding their role in fruit development and ripening, a plant-specific process, is unknown. The present study seeks to determine whether and, if so, how sphingolipids are involved in fleshy-fruit development and ripening in an oil-crop species such as olive (Olea europaea L. cv. Picual). Here, in the plasma-membranes of live protoplasts, we used fluorescence to examine various specific lipophilic stains in sphingolipid-enriched regions and investigated the composition of the sphingolipid longchain bases (LCBs) as well as the expression patterns of sphingolipid-related genes, OeSPT, OeSPHK, OeACER, and OeGlcCerase, during olive-fruit development and ripening. The results demonstrate increased sphingolipid content and vesicle trafficking in olive-fruit protoplasts at the onset of ripening. Moreover, the concentration of LCB [t18:1(8Z), t18:1 (8E), t18:0, d18:2 (4E/8Z), d18:2 (4E/8E), d18:1(4E), and 1,4-anhydrot18: 1(8E)] increases during fruit development to reach a maximum at the onset of ripening, although these molecular species decreased during fruit ripening. On the other hand, OeSPT, OeSPHK, and OeGlcCerase were expressed differentially during fruit development and ripening, whereas OeACER gene expression was detected only at the fully ripe stage. The results provide novel data about sphingolipid distribution, content, and biosynthesis/turnover gene transcripts during fleshy-fruit ripening, indicating that all are highly regulated in a developmental manner.• Ministerio de Economía, y Competitividad y Fondos FEDER. Proyectos BFU2010-18116, AGL2014-52194R (I+D+i) • Consejo Nacional de Ciencia y Tecnología (México). Ayuda 238368peerReviewe

Neurocognitive profile of the post-COVID condition in adults in Catalonia. A mixed method prospective cohort and nested case-control study: Study Protocol

The diagnosis of the post-COVID condition is usually achieved by excluding other diseases; however, cognitive changes are often found in the post-COVID disorder. Therefore, monitoring and treating the recovery from the post-COVID condition is necessary to establish biomarkers to guide the diagnosis of symptoms, including cognitive impairment. Our study employs a prospected cohort and nested case-control design with mixed methods, including statistical analyses, interviews, and focus groups. Our main aim is to identify biomarkers (functional and structural neural changes, inflammatory and immune status, vascular and vestibular signs and symptoms) easily applied in primary care to detect cognitive changes in post-COVID cases. The results will open up a new line of research to inform diagnostic and therapeutic decisions with special considerations for cognitive impairment in the post-COVID condition

Kinetics of humoral immune response over 17 months of COVID-19 pandemic in a large cohort of healthcare workers in Spain : the ProHEpiC-19 study

Understanding the immune response to the SARS-CoV-2 virus is critical for efficient monitoring and control strategies. The ProHEpic-19 cohort provides a fine-grained description of the kinetics of antibodies after SARS-CoV-2 infection with an exceptional resolution over 17 months. We established a cohort of 769 healthcare workers including healthy and infected with SARS-CoV-2 in northern Barcelona to determine the kinetics of the IgM against the nucleocapsid (N) and the IgG against the N and spike (S) of SARS-CoV-2 in infected healthcare workers. The study period was from 5 May 2020 to 11 November 2021.We used non-linear mixed models to investigate the kinetics of IgG and IgM measured at nine time points over 17 months from the date of diagnosis. The model included factors of time, gender, and disease severity (asymptomatic, mild-moderate, severe-critical) to assess their effects and their interactions. 474 of the 769 participants (61.6%) became infected with SARS-CoV-2. Significant effects of gender and disease severity were found for the levels of all three antibodies. Median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease at day 270 after the diagnosis, while IgG(N and S) levels remained positive at least until days 450 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay with a rate depending on disease severity. IgG(S) levels remained relatively constant from day 15 over time. IgM(N) and IgG(N, S) SARS-CoV-2 antibodies showed a heterogeneous kinetics over the 17 months. Only the IgG(S) showed a stable increase, and the levels and the kinetics of antibodies varied according to disease severity. The kinetics of IgM and IgG observed over a year also varied by clinical spectrum can be very useful for public health policies around vaccination criteria in adult population. Regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478). The online version contains supplementary material available at 10.1186/s12879-022-07696-6

Aula itinerante de Patrimonio Cultural II

Memoria final del PIMCD UCM 2020/2021 número 31

Técnicas de recogida de información y elaboración de documentos técnicos utilizados en la formación del estudiantado

El proyecto se concibe como una herramienta didáctica para facilitar al profesorado de la Facultad de Trabajo Social su actividad pedagógica en el aula. Para ello, hemos elaborado un CD que contiene material audiovisual y documentos técnicos profesionales utilizados por los/las trabajadores/as sociales. Este material servirá para realizar la valoración social del caso y el proyecto de intervención social

Homérica: estudiar y vivir el mundo griego II

Depto. de Filología ClásicaFac. de FilologíaFALSEsubmitte

Planeación, gobernanza y sustentabilidad Retos y desafíos desde el enfoque territorial

Frente a la compleja realidad actual, resulta ineludible el desarrollo de la investigación científica de los fenómenos y procesos urbanos, territoriales y ambientales, que contribuya a su comprensión y la construcción de alternativas de solución a los retos y desafíos vigentes. En este contexto, el abordaje de las ciudades y regiones metropolitanas, el ordenamiento del territorio y la ocupación del espacio, así como la relación sociedad-naturaleza y la complejidad ambiental, precisa la generación de metodologías y procesos de investigación multi e inter disciplinarios que contribuyan a la comprensión de los procesos socioterritoriales, el mejoramiento de las condiciones de vida y la conservación ambiental.Programa de Fortalecimiento de la Calidad Educativa PFCE-2016 proyecto K0313101