Role of TNF-α receptor 2 (TNFR2) in the regulation of adult neural stem cells

Adult stem cells are tissue-resident undifferentiated and self-renewing cells responsible for tissue homeostasis. Under physiological conditions, stem cells co-exist in a reversible cell cycle-arrested state known as quiescence and an activated proliferative state, which results in the production of cell progeny through asymmetric division. Different types of injuries can activate stem cells to produce progeny that contributes to tissue repair, but the molecular triggers and regulators of this activation are barely known. Living organisms are constantly exposed to a variety of internal and external stimuli and some of them can be classified as danger signals. Upon detection, a complex response is set in motion that is aimed at eliminating the danger signals and eventually restoring tissue and organism homeostasis. This response is generically referred to as inflammation and is part of the ancient innate immune system present in all metazoans. Adult stem cells are sensitive to their niche as they behave by integrating actions of intrinsic regulators in response to signals emanating from their most immediate microenvironment, as well as from circulation. Inflammation has been shown to act on several stem cell niches, but the observation of changes in tissue turnover that could reflect both detrimental and beneficial effects has left the precise role of inflammation in tissue maintenance and regeneration as controversial. In the case of the central nervous system, experimental evidence has accumulated in the last decade indicating that inflammation can play a negative role in adult mammalian neurogenesis. This work has addressed the possibility that neural adult stem cells of the rodent brain could respond positively to certain inflammatory signals, a reaction that would be obscured by the more dramatic detrimental effects of inflammatory cytokines on neurogenesis. We have found that adult neural stem cells can sense and respond to remote peripheral lesions by shifting from a dormant quiescent state to an alert prone-to-activation one and that TNFR2 signalling, in response to cytokines, such as tumour necrosis factor alpha and progranulin, is mediating this process. The first finding is in line with recent data indicating that adult stem cells of different systems can react to distant injuries, suggesting a homeostatic control of their activity at the organismal level. The second one increases our understanding of the role of inflammation in the neurogenic process. Although the most accepted view is that acute or chronic inflammation plays a negative role in neurogenesis, our data uncover concomitant beneficial effects of inflammatory cytokines in at least a fraction of neural stem cells

Interaction between angiotensin type 1, type 2, and mas receptors to regulate adult neurogenesis in the brain ventricular–subventricular zone

The renin–angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.This research was funded by Spanish grants from Ministerio de Economía y Competitividad (BFU2015-70523 and SAF2017-86690-R), Instituto de Salud Carlos III (Retic TERCEL RD16/0011/0016, RD16/0011/0017, and CIBERNED), Galician Government (XUGA, ED431C2018/10; ED431G/05), FEDER (Regional European Development Fund), Generalitat Valenciana (Prometeo 2017-030), and Fundación Emilio Botín-Banco SantanderS

First data about the status of the Cabrera vole Iberomys cabrerae (Thomas, 1906) in Castelló and the expansion of its distribution to the south of the province of València

Se registra por primera vez en la provincia de Castelló el topillo de Cabrera Iberomys cabrerae (Thomas, 1906) en tiempos recientes, donde tan solo se contaba con registro fósil en varios yacimientos datados en el Neolítico. Además se amplía hacia el sur su distribución conocida en València. Se describe y comenta su descubrimiento en la sierra del Toro (l'Alt Palància) y en la Font de la Figuera (la Costera).This is the first recorded finding in recent times of the Cabrera vole Iberomys cabrerae (Thomas, 1906) in Castelló province, where previously only fossil records have been identified in several Neolithic sites. In addition, it's known distribution is expanded to the south of the province of València. These discoveries, made in the Sierra del Toro (l'Alt Palància) and la Font de la Figuera (la Costera), are described and commented upon.Este estudio ha sido financiado por el Servicio de Vida Silvestre de la Conselleria de Agricultura, Medio Ambiente, Cambio Climático y Desarrollo Rural de la Generalitat Valenciana

RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state.

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer

The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2

Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manne

Declive acusado del bigotudo, Panurus biarmicus, en el litoral mediterráneo español

The apparent stability of the bearded reedling in Spanish inland wetlands contrasts with its threatened status in Spanish coastal wetlands. The species has already disappeared from some coastal areas in Catalonia and its situation is critical in the region of Valencia. In 2013 we studied the breeding populations in three wetlands in Valencia using two methods: census by exhaustive search of individuals (territory mapping) and distance sampling using line transects. We estimated the trend of these populations from data obtained in previous censuses (2005 and 2006), and assessed their viability in the medium and short term using count–based population viability analysis (PVA). Results were alarming in the three studied wetlands, especially in the Albufera de Valencia, where only one breeding pair was found. The percentage of decrease of estimated pairs was similar in all wetlands: ca. 90% between 2005 and 2013. Results from the PVAs predicted a 90% probability of reaching the quasi–extinction threshold before 2024 or 2028 for the largest population of bearded reedling in the Valencia region, El Hondo, while for the Santa Pola population this threshold would be reached before 2016 or 2017. The parallel trend and generalized decline in the Spanish coastal wetlands suggests that these Mediterranean wetlands probably share some specific factors that have adversely affected their populations. Given that all these natural spaces are surrounded by intensively irrigated crops that are subjected to the intense use of pesticides, we hypothesize that these products could have had a detrimental effect on the bearded reedling. This hypothesis is supported by the fact that the healthiest populations are situated in Iberian inland wetlands that are surrounded by dry crops where the use of pesticides is less intense. We propose cataloguing the species as Endangered at regional level.La delicada situación del bigotudo en los humedales litorales españoles contrasta con la aparente estabilidad de la especie en los humedales interiores. La especie ha desaparecido de algunos enclaves costeros de Cataluña y su situación es crítica en la Comunidad Valenciana. En 2013 estimamos las poblaciones reproductoras en tres humedales de esta última comunidad usando dos métodos: censo mediante búsqueda exhaustiva de individuos reproductores (mapeo de territorios) y muestreo de distancia mediante transectos. Además, con los datos obtenidos en censos anteriores (2005 y 2006) estimamos la tendencia de estas poblaciones y calculamos su viabilidad a corto y medio plazo mediante un análisis de viabilidad poblacional (AVP) basado en conteos. Los resultados fueron muy preocupantes en los tres humedales estudiados, especialmente en La Albufera de Valencia, donde tan solo se encontró una pareja reproductora. El porcentaje de disminución de las parejas estimadas entre 2005 y 2013 en todos los humedales fue muy parecido, alrededor del 90%. Los resultados de los AVP para la mayor población de la Comunidad Valenciana, El Hondo, predicen un 90% de probabilidad de alcanzar el umbral de cuasi–extinción antes de 2024 o 2028, según el método de censo empleado. En el caso de Santa Pola, este umbral se alcanzaría antes de 2016 o 2017. El descenso generalizado y paralelo en los humedales costeros españoles sugiere que probablemente estos hábitats comparten algunos factores específicos que han afectado negativamente a sus poblaciones de bigotudo. Puesto que todos estos espacios naturales están rodeados de cultivos intensivos de regadío sometidos a un elevado uso de plaguicidas, hipotetizamos que estos productos podrían haber tenido un efecto perjudicial en el bigotudo. Esta hipótesis se ve apoyada por el hecho de que las poblaciones más saludables están situadas en el interior peninsular, en humedales rodeados de cultivos de secano, en los que el uso de plaguicidas es menos intenso. Se propone recatalogar la especie a escala regional como en peligro de extinción.This work was partly funded by the Consellería d’Infraestructures, Territori i Medi Ambient de la Generalitat Valenciana though the project 'Recerca aus passeriformes amenaçades 2012'

Cell population analysis of the adult murine subependymal neurogenic lineage by flow cytometry

Summary: This protocol provides a flow-cytometry-based procedure to classify and isolate all cells of the adult rodent subependymal zone (SEZ) neurogenic lineage, without the need for reporter mice, into different cell populations, including three neural stem cell (NSC) fractions with molecular signatures that are coherent with single-cell transcriptomics. Additionally, their cycling behavior can be assessed by means of 5-ethynyl-2′-deoxyuridine (EdU) incorporation. Our method allows the isolation of different NSC fractions and the functional assay of their cycling heterogeneity and quiescence-activation transitions.For complete details on the use, execution, and outcomes of this protocol, please refer to Belenguer et al. (2021)

Respiratory Complications Are the Main Predictors of 1-Year Mortality in Patients with Hip Fractures: The Results from the Alzira Retrospective Cohort Study

Resumen: Introducción: Las fracturas de cadera representan un desafío importante para las personas mayores dada su Alta incidencia y tasa de mortalidad a un año. El objetivo de este estudio fue identificar las principales predictores de mortalidad a un año en adultos mayores hospitalizados por fracturas de cadera. Métodos: Realizamos un estudio de cohorte retrospectivo en el que participaron adultos de 70 años o más que ingresaron en el hospital para fracturas de cadera por fragilidad entre el 1 de enero de 2014 y el 31 de diciembre de 2021. Un total de 3229 pacientes fueron reclutados, y 846 (26,2%) experimentaron mortalidad al año. Resultados: complicaciones respiratorias (HR 2,42, IC 95% 1,42–4,14; p = 0,001) fueron los predictores más significativos de mortalidad a un año, seguido del reingreso hospitalario (HR 1,96, IC 95% 1,66-2,32; p < 0,001), el sexo masculino (HR 1,88, IC 95% 1,46–2,32; p < 0,001), complicaciones cardíacas (HR 1,88, IC 95% 1,46-2,32; p < 0,001) y un diagnóstico de demencia al ingreso (HR 1,37, IC95% 1,13-1,66; p = 0,001). El índice Charlson y el índice americano El sistema de clasificación del estado físico de la Sociedad de Anestesiólogos también aumentó significativamente el riesgo de mortalidad. Por el contrario, niveles más altos de hemoglobina al ingreso y albúmina elevada al alta. redujo significativamente el riesgo de mortalidad. Conclusiones: La tasa de mortalidad a un año es sustancial. en adultos mayores con fracturas de cadera que ingresan en una unidad de ortogeriatría. La Apropiada Manejo de la anemia, los trastornos nutricionales y la comorbilidad al ingreso y durante el seguimiento. podría potencialmente mitigar la mortalidad a largo plazo después de fracturas de cadera. Palabras clave: fractura de cadera; adultos mayores; Mortalidad a 1 año; factores de riesgo; atención ortogeriátrica; fragilidad fracturasQ2Q2Abstract: Introduction: Hip fractures pose a significant challenge for older individuals given their high incidence and one-year mortality rate. The objective of this study was to identify the primary predictors of one-year mortality in older adults hospitalized for hip fractures. Methods: We conducted a retrospective cohort study involving adults aged 70 years or older who were admitted to the hospital for fragility hip fractures between 1 January 2014 and 31 December 2021. A total of 3229 patients were recruited, with 846 (26.2%) experiencing one-year mortality. Results: Respiratory complications (HR 2.42, 95%CI 1.42–4.14; p = 0.001) were the most significant predictors of one-year mortality, followed by hospital readmission (HR 1.96, 95%CI 1.66–2.32; p < 0.001), the male sex (HR 1.88, 95%CI 1.46–2.32; p < 0.001), cardiac complications (HR 1.88, 95%CI 1.46–2.32; p < 0.001), and a diagnosis of dementia at admission (HR 1.37, 95%CI 1.13–1.66; p = 0.001). The Charlson Index and the American Society of Anesthesiologists physical status classification system also significantly increased the mortality risk. Conversely, higher hemoglobin levels at admission and elevated albumin at discharge significantly reduced the mortality risk. Conclusions: The one-year mortality rate is substantial in older adults with hip fractures who are admitted to an orthogeriatric unit. The appropriate management of anemia, nutritional disorders, and comorbidity at admission and during the followup could potentially mitigate long-term mortality after hip fractures. Keywords: hip fracture; older adults; 1-year mortality; risk factors; orthogeriatric care; fragility fractureshttps://orcid.org/0000-0001-5832-0603https://scholar.google.com/citations?user=MrICwaMAAAAJ&hl=enhttps://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001429659Revista Internacional - IndexadaS

Declive acusado del bigotudo, Panurus biarmicus, en el litoral mediterráneo español

The apparent stability of the bearded reedling in Spanish inland wetlands contrasts with its threatened status in Spanish coastal wetlands. The species has already disappeared from some coastal areas in Catalonia and its situation is critical in the region of Valencia. In 2013 we studied the breeding populations in three wetlands in Valencia using two methods: census by exhaustive search of individuals (territory mapping) and distance sampling using line transects. We estimated the trend of these populations from data obtained in previous censuses (2005 and 2006), and assessed their viability in the medium and short term using count–based population viability analysis (PVA). Results were alarming in the three studied wetlands, especially in the Albufera de Valencia, where only one breeding pair was found. The percentage of decrease of estimated pairs was similar in all wetlands: ca. 90% between 2005 and 2013. Results from the PVAs predicted a 90% probability of reaching the quasi–extinction threshold before 2024 or 2028 for the largest population of bearded reedling in the Valencia region, El Hondo, while for the Santa Pola population this threshold would be reached before 2016 or 2017. The parallel trend and generalized decline in the Spanish coastal wetlands suggests that these Mediterranean wetlands probably share some specific factors that have adversely affected their populations. Given that all these natural spaces are surrounded by intensively irrigated crops that are subjected to the intense use of pesticides, we hypothesize that these products could have had a detrimental effect on the bearded reedling. This hypothesis is supported by the fact that the healthiest populations are situated in Iberian inland wetlands that are surrounded by dry crops where the use of pesticides is less intense. We propose cataloguing the species as Endangered at regional level.La delicada situación del bigotudo en los humedales litorales españoles contrasta con la aparente estabilidad de la especie en los humedales interiores. La especie ha desaparecido de algunos enclaves costeros de Cataluña y su situación es crítica en la Comunidad Valenciana. En 2013 estimamos las poblaciones reproductoras en tres humedales de esta última comunidad usando dos métodos: censo mediante búsqueda exhaustiva de individuos reproductores (mapeo de territorios) y muestreo de distancia mediante transectos. Además, con los datos obtenidos en censos anteriores (2005 y 2006) estimamos la tendencia de estas poblaciones y calculamos su viabilidad a corto y medio plazo mediante un análisis de viabilidad poblacional (AVP) basado en conteos. Los resultados fueron muy preocupantes en los tres humedales estudiados, especialmente en La Albufera de Valencia, donde tan solo se encontró una pareja reproductora. El porcentaje de disminución de las parejas estimadas entre 2005 y 2013 en todos los humedales fue muy parecido, alrededor del 90%. Los resultados de los AVP para la mayor población de la Comunidad Valenciana, El Hondo, predicen un 90% de probabilidad de alcanzar el umbral de cuasi–extinción antes de 2024 o 2028, según el método de censo empleado. En el caso de Santa Pola, este umbral se alcanzaría antes de 2016 o 2017. El descenso generalizado y paralelo en los humedales costeros españoles sugiere que probablemente estos hábitats comparten algunos factores específicos que han afectado negativamente a sus poblaciones de bigotudo. Puesto que todos estos espacios naturales están rodeados de cultivos intensivos de regadío sometidos a un elevado uso de plaguicidas, hipotetizamos que estos productos podrían haber tenido un efecto perjudicial en el bigotudo. Esta hipótesis se ve apoyada por el hecho de que las poblaciones más saludables están situadas en el interior peninsular, en humedales rodeados de cultivos de secano, en los que el uso de plaguicidas es menos intenso. Se propone recatalogar la especie a escala regional como en peligro de extinción.This work was partly funded by the Consellería d’Infraestructures, Territori i Medi Ambient de la Generalitat Valenciana though the project 'Recerca aus passeriformes amenaçades 2012'