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Rodent populations often undergo large, regular fluctuations. We studied immunological condition and physiological stress in the common vole and how it varied with environmental factors linked with population fluctuations, namely flea and Francisella tularensis (the bacterium causing tularemia) prevalence. We used two leukocyte indices, neutrophil-to-lymphocyte ratio (N:L) and proportion of eosinophils, as physiological long-term stress indicators, and measured levels of immunoglobulins (Ig) as a generic index of immunological condition. Leukocyte indices showed a hump-shaped relationship with Ig levels, consistent with an interdependence between physiological stress and immunological condition. N:L was negatively associated with vole density only in males. Eosinophil proportion was explained by the interaction between flea burden and tularemia prevalence, with highest levels in flea-infested voles also infected with tularemia. Ig levels did not vary with sex or flea prevalence but increased in tularemia-infected voles. When Ig levels were included as covariates in our models, the associations between leukocyte indices and environmental factors remained significant. Results suggest sex-specific associations between physiological stress and population density, and an influence of tularemia infection depending on ectoparasite load. We recommend using immunological parameters complementarily to leukocyte indices when studying physiological stress and infection dynamics in wild populations.

Las investigaciones centradas en el estudio de la familia, en el clero y en las estrategias de reproducción social cuentan con un sólido y largo recorrido historiográfico. A partir de un amplio abanico de fuentes hemos intentado reconstruir la carrera eclesiástica de los varones de la familia Rodríguez Lorenzana que no estaban destinados a recibir el mayorazgo. Su principal campo de actuación estuvo en el cabildo leonés, donde las sucesivas generaciones se organizaron para privatizar el arcedianato de Mayorga; tampoco faltó su presencia en el cabildo de San Marcos ni en el de San Isidoro y, con el tiempo, sus miras estuvieron depositadas en instituciones con mayor poder.

The Concordat of 1851 marked the beginning of substantial restructuring of the diocesan territory of León, which was not completed until a few decades later. As a result, new archpriestships emerged while others were annulled, and some parishes changed their boundaries. Apart from these territorial changes, another question that was of particular interest to the prelates was the spiritual and moral health of the diocesan province under their authority. One of the means to gather information on this was through pastoral visits. Based on such visits conducted in the mid-18th century, “secret instructions” were drawn up for the vicars, who were charged with correcting the clergy’s behaviour, which had revealed itself to be reprehensible., El Concordato de 1851 supuso el inicio de una notable reorganización del territorio diocesano leonés, que no finalizaría hasta pasadas unas décadas. Fruto de la misma surgieron nuevos arciprestazgos, se anularos otros y algunas parroquias cambiaron de demarcación. Al margen de esos vaivenes territoriales, hubo una cuestión que interesó especialmente a los prelados, la salud espiritual y moral de la provincia diocesana que estaba bajo su autoridad. Uno de los medios para recabar esa información eran las visitas pastorales. A partir de las efectuadas a mediados del siglo XVIII se confeccionaron unas “instrucciones secretas” destinadas a los vicarios, a los que encomendaban corregir las conductas, que habían encontrado reprobables, de los eclesiásticos.

Huntington’s disease and X-linked dystonia parkinsonism are two monogenic basal ganglia model diseases. Huntington’s disease is caused by a polyglutamine-encoding CAG repeat expansion in the Huntingtin (HTT) gene leading to several toxic interactions of both the expanded CAG-containing mRNA and the polyglutamine-containing protein, while X-linked dystonia parkinsonism is caused by a retrotransposon insertion in the TAF1 gene, which decreases expression of this core scaffold of the basal transcription factor complex TFIID. SRSF6 is an RNA-binding protein of the serine and arginine-rich (SR) protein family that interacts with expanded CAG mRNA and is sequestered into the characteristic polyglutamine-containing inclusion bodies of Huntington’s disease brains. Here we report decreased levels of the SRSF6 interactor and regulator SREK1—another SR protein involved in RNA processing—which includes TAF1 as one of its targets. This led us to hypothesize that Huntington’s disease and X-linked dystonia parkinsonism pathogeneses converge in TAF1 alteration. We show that diminishing SRSF6 through RNA interference in human neuroblastoma cells leads to a decrease in SREK1 levels, which, in turn, suffices to cause diminished TAF1 levels. We also observed decreased SREK1 and TAF1 levels in striatum of Huntington’s disease patients and transgenic model mice. We then generated mice with neuronal transgenic expression of SREK1 (TgSREK1 mice) that, interestingly, showed transcriptomic alterations complementary to those in Huntington’s disease mice. Most importantly, by combining Huntington’s disease and TgSREK1 mice we verify that SREK1 overexpression corrects TAF1 deficiency and attenuates striatal atrophy and motor phenotype of Huntington’s disease mice. Our results therefore demonstrate that altered RNA processing upon SREK1 dysregulation plays a key role in Huntington’s disease pathogenesis and pinpoint TAF1 as a likely general determinant of selective vulnerability of the striatum

Ischemic stroke is a major cause of death and the first leading cause of long-term disability worldwide. The only therapeutic strategy available to date is reperfusion and not all the patients are suitable for this treatment. Blood flow blockage or reduction leads to considerable brain damage, affecting both gray and white matter. The detrimental effects of ischemia have been studied extensively in the former but not in the latter. Previous reports indicate that preservation of white matter integrity reduces deleterious effect of ischemia on the brain. Oligodendrocytes are sensitive to ischemic damage, however, some reports demonstrate that oligodendrogenesis occurs after ischemia. These glial cells have a complex cytoskeletal network, including tau, that plays a key role to proper myelination. 4R-Tau/3R-Tau, which differ in the presence/absence of Exon 10, are found in oligodendrocytes; but the precise role of each isoform is not understood. Using permanent middle cerebral artery occlusion model and immunofluorescence, we demonstrate that cerebral ischemia induces an increase in 3R-Tau versus 4R-Tau in oligodendrocytes in the damaged area. In addition, cellular distribution of Tau undergoes a change after ischemia, with some oligodendrocytic processes showing positive staining for 3R-Tau. This occurs simultaneously with the amelioration of neurological damage in ischemic rats. We propose that ischemia triggers an endogenous mechanism involving 3R-Tau, that induces colonization of the ischemic damaged area by oligodendrocytes in an attempt to myelinate-injured axons. Understanding the molecular mechanism of this phenomenon could pave the way for the design of therapeutic strategies that exploit glial cells for the treatment of ischemia.

Intense efforts are being undertaken to understand the pathophysiological mechanisms triggered after brain ischemia and to develop effective pharmacological treatments. However, the underlying molecular mechanisms are complex and not completely understood. One of the main problems is the fact that the ischemic damage is time-dependent and ranges from negligible to massive, involving different cell types such as neurons, astrocytes, microglia, endothelial cells, and some blood-derived cells (neutrophils, lymphocytes, etc.). Thus, approaching such a complicated cellular response generates a more complex combination of molecular mechanisms, in which cell death, cellular damage, stress and repair are intermixed. For this reason, animal and cellular model systems are needed in order to dissect and clarify which molecular mechanisms have to be promoted and/or blocked. Brain ischemia may be analyzed from two different perspectives: that of oxygen deprivation (hypoxic damage per se) and that of deprivation of glucose/serum factors. For investigations of ischemic stroke, middle cerebral artery occlusion (MCAO) is the preferred in vivo model, and uses two different approaches: transient (tMCAO), where reperfusion is permitted; or permanent (pMCAO). As a complement to this model, many laboratories expose different primary cortical neuron or neuronal cell lines to oxygen-glucose deprivation (OGD). This ex vivo model permits the analysis of the impact of hypoxic damage and the specific response of different cell types implicated in vivo, such as neurons, glia or endothelial cells. Using in vivo and neuronal OGD models, it was recently established that mTORC1 (mammalian Target of Rapamycin Complex-1), a protein complex downstream of PI3K-Akt pathway, is one of the players deregulated after ischemia and OGD. In addition, neuroprotective intervention either by estradiol or by specific AT2R agonists shows an important regulatory role for the mTORC1 activity, for instance regulating

Activating transcription factor-5 (ATF5) is a stress-response transcription factor induced upon different cell stressors like fasting, amino-acid limitation, cadmium or arsenite. ATF5 is also induced, and promotes transcription of anti-apoptotic target genes like MCL1, during the unfolded protein response (UPR) triggered by endoplasmic reticulum stress. In the brain, high ATF5 levels are found in gliomas and also in neural progenitor cells, which need to decrease their ATF5 levels for differentiation into mature neurons or glia. This initially led to believe that ATF5 is not expressed in adult neurons. More recently, we reported basal neuronal ATF5 expression in adult mouse brain and its neuroprotective induction during UPR in a mouse model of status epilepticus. Here we aimed to explore whether ATF5 is also expressed by neurons in human brain both in basal conditions and in Huntington’s disease (HD), where UPR has been described to be partially impaired due to defective ATF6 processing. Apart from confirming that ATF5 is present in human adult neurons, here we report accumulation of ATF5 within the characteristic polyglutamine-containing neuronal nuclear inclusions in brains of HD patients and mice. This correlates with decreased levels of soluble ATF5 and of its antiapoptotic target MCL1. We then confirmed the deleterious effect of ATF5 deficiency in a Caenorhabditis elegans model of polyglutamine-induced toxicity. Finally, ATF5 overexpression attenuated polyglutamine-induced apoptosis in a cell model of HD. These results reflect that decreased ATF5 in HD—probably secondary to sequestration into inclusions—renders neurons more vulnerable to mutant huntingtin-induced apoptosis and that ATF5-increasing interventions might have therapeutic potential for HD.

Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-¿B/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-¿B/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders.

La familia es el centro en torno al cual gravitan toda una serie de comportamientos sociales tendentes al amparo y protección de sus miembros. Este trabajo analiza el tipo de familia; el sistema de herencia, como factor para la expulsión de miembros útiles o como socorro a los más desamparados

Reseña

In the mid eighteenth century three hospitals were in operation in the town of Benavente in the Province of Zamora in Spain. These were the hospitals of San Juan Bautista, Nuestra Señora de La Piedad and San José, which had been founded in the Middle Ages, in the sixteenth century, and in the seventeenth century, respectively. Of the three, Nuestra Señora de La Piedad was to become the principal centre for medical assistance in the zone covering the North of the Province of Zamora and the South of the Province of Leon. However, it also had another, particularly numerous, group of users: seasonal workers from Galicia, who each year travelled up to the central plateau to earn a living as agricultural labourers during the summer months. This paper will address the question of the centre’s catchment area, from which its clientele came, and also will look into their characteristics, the period for which they convalesced, or their mortality rates, laying special emphasis on the various different types of patient treated there., A mediados del siglo XVIII estaban funcionando en la villa zamorana de Benavente tres hospitales: el de san Juan Bautista, Nuestra Señora de La Piedad y San José, fundados en la época medieval, en el siglo XVI y en el XVII, respectivamente. De todos ellos, el de Piedad se convertiría en el centro con asistencia médica más importante del norte de Zamora y sur de la provincia de León. Pero, también tuvo otra clientela especialmente numerosa, la de los temporeros gallegos. En este trabajo, además de analizar el radio de influencia del centro, o de capitación de enfermos, estudiaremos las características de los mismos, el periodo de convalecencia o la mortalidad, haciendo especial hincapié en los diferentes colectivos que allí fueron atendidos.

En esta monografía se ha procurado una representación de los diversos grupos de población que formaban parte del colectivo marginal de la sociedad, si bien ese era mucho más amplio de lo que hoy conocemos como tal; de los diferentes medios de asistencia que las sociedades se fueron procurando para dar respuesta al fenómeno; así como de las directrices de actuación que dictaba el ordenamiento político y moral de la época, que, de una forma u otra, aparece recogido en todos los trabajos

© 2014 The Author. All rights reserved. Axon properties, including action potential initiation and modulation, depend on both AIS integrity and the regulation of ion channel expression in the AIS. Alteration of the axon initial segment (AIS) has been implicated in neurodegenerative, psychiatric, and brain trauma diseases, thus identification of the physiological mechanisms that regulate the AIS is required to understand and circumvent AIS alterations in pathological conditions. Here, we show that the purinergic P2X7 receptor and its agonist, adenosine triphosphate (ATP), modulate both structural proteins and ion channel density at the AIS in cultured neurons and brain slices. In cultured hippocampal neurons, an increment of extracellular ATP concentration or P2X7-green fluorescent protein (GFP) expression reduced the density of ankyrin G and voltage-gated sodium channels at the AIS. This effect is mediated by P2X7-regulated calcium influx and calpain activation, and impaired by P2X7 inhibition with Brilliant Blue G (BBG), or P2X7 suppression. Electrophysiological studies in brain slices showed that P2X7-GFP transfection decreased both sodium current amplitude and intrinsic neuronal excitability, while P2X7 inhibition had the opposite effect. Finally, inhibition of P2X7 with BBG prevented AIS disruption after ischemia/reperfusion in rats. In conclusion, our study demonstrates an involvement of P2X7 receptors in the regulation of AIS mediated neuronal excitability in physiological and pathological conditions.