Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence

Senescence accelerated mice P8 (SAMP8) is a phenotypic model of age, characterized by deficits in memory and altered behaviour. Here determined the effect of age in SAMP8, compared with the resistant strain, SAMR1, in behaviour and learning parameters linking these disturbances with oxidative stress environment. We found impairment in emotional behaviour with regard to fear and anxiety in young SAMP8 vs. age-mated SAMR1. Differences were attenuated with age. In contrast, learning capabilities are worse in SAMP8, both in young and aged animals, with regard to SAMR1. These waves in behaviour and cognition were correlated with an excess of Oxidative stress (OS) in SAMP8 at younger ages that diminished with age. In this manner, we found changes in the hippocampal expression of ALDH2, IL-6, HMOX1, COX2, CXCL10, iNOS, and MCP-1 with an altered amyloidogenic pathway by increasing the Amyloid beta precursor protein (APP) and BACE1, and reduced ADAM10 expression; in addition, astrogliosis and neuronal markers decreased. Moreover, Superoxide dismutase 1 (SOD1) and Nuclear factor-kappa beta (NF-kβ) expression and protein levels were higher in younger SAMP8 than in SAMR1. In conclusion, the accelerated senescence process present in SAMP8 can be linked with an initial deregulation in redox homeostasis, named neuroinflammaging, by inducing molecular changes that lead to neuroinflammation and the neurodegenerative process. These changes are reflected in the emotional and cognitive behaviour of SAMP8 that differs from that of SAMR1 and that highlighted the importance of earlier oxidative processes in the onset of neurodegeneration

Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer's disease

The amyloid-β protein precursor/presenilin 1 (AβPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on AβPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1β and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AβPP/PS1 mouse hippocampus, preventing memory loss

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly.Postprint (published version

Amyloid and tau pathology of familial Alzheimer's disease APP/PS1 mouse model in a senescence phenotype background (SAMP8)

The amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern at early ages, whereas senescence-accelerated mouse prone 8 (SAMP8) has a remarkable early senescence phenotype with pathological similarities to AD. The aim of this study was the investigation and characterization of cognitive and neuropathological AD markers in a novel mouse model that combines the characteristics of the APP/PS1 transgenic mouse model with a senescence-accelerated background of SAMP8 mice. Initially, significant differences were found regarding amyloid plaque formation and cognitive abnormalities. Bearing these facts in mind, we determined a general characterization of the main AD brain molecular markers, such as alterations in amyloid pathway, neuroinflammation, and hyperphosphorylation of tau in these mice along their lifetimes. Results from this analysis revealed that APP/PS1 in SAMP8 background mice showed alterations in the pathways studied in comparison with SAMP8 and APP/PS1, demonstrating that a senescence-accelerated background exacerbated the amyloid pathology and maintained the cognitive dysfunction present in APP/PS1 mice. Changes in tau pathology, including the activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 β (GSK3β), differs, but not in a parallel manner, with amyloid disturbances

Unveiling the nature of the highly obscured AGN in NGC5643 with XMM-Newton

We present results from an XMM-Newton observation of the nearby Seyfert 2 galaxy NGC5643. The nucleus exhibits a very flat X-ray continuum above 2 keV, together with a prominent K-alpha fluorescent iron line. This indicates heavy obscuration. We measure an absorbing column density N_H in the range 6-10 x 10^{23} atoms/cm/cm, either directly covering the nuclear emission, or covering its Compton-reflection. In the latter case, we might be observing a rather unusual geometry for the absorber, whereby reflection from the inner far side of a torus is in turn obscured by its near side outer atmosphere. The nuclear emission might be then either covered by a Compton-thick absorber, or undergoing a transient state of low activity. A second source (christened "X-1" in this paper) at the outskirts of NGC5643 optical surface outshines the nucleus in X-rays. If belonging to NGC5643, it is the third brightest (L_X ~ 4 x 10^{40} erg/s) known Ultra Luminous X-ray source. Comparison with past large aperture spectra of NGC 5643 unveils dramatic X-ray spectral changes above 1 keV. We interpret them as due to variability of the active nucleus and of source X-1 intrinsic X-ray powers by a factor >10 and 5, respectively.Comment: 11 LATEX pages, 12 figures, to appear in Monthly Notices of the Royal Astronomical Societ

Astrophysics with the Laser Interferometer Space Antenna

Laser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy as it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and other space-based instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA's first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed: ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or intermediate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help make progress in the different areas. New research avenues that LISA itself, or its joint exploitation with studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe

Resveratrol: New avenues for a natural compound in neuroprotection

El pdf del artículo es la versión post-print.This review summarizes the effects of resveratrol in neurodegenerative diseases and speculates on the direction the field will take in the immediate future. In particular, we emphasize studies on the effects of resveratrol on new pathways related to neurodegenerative diseases such as inflammatory processes, mitochondrial biogenesis and its control through gamma coactivator 1- (PGC1 ), and the role of the tandem sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) in neurodegeneration and in neurohormesis. While not all reported results are free from controversy, the demographic shift toward an older population makes compounds with this broad spectrum of potential clinical applications particularly interesting.This study was supported by grants SAF-2009-13093, SAF-2011-23631 and SAF-2012-39852 from the “Ministerio de Educación y Ciencia”, 2009/SGR00893 from the “Generalitat de Catalunya” and Fundación MAPFRE (Spain).Peer reviewe

Efecto del resveratrol en modelos murinos de envejecimiento y enfermedad de Alzheimer

[spa] El resveratrol es un polifenol que se encuentra principalmente en la uva y el vino tinto. Además se ha demostrado que es un mimético de la restricción calórica a través de la activación de Sirtuina 1. Diversos estudios indican que la restricción calórica, y por consiguiente el resveratrol, puede incrementar la longevidad. El resveratrol aumenta la tasa metabólica, la sensibilidad a insulina, la biogénesis mitocondrial, la resistencia física y reduce la acumulación de grasas en ratones. Asimismo, el resveratrol puede ser un fármaco efectivo para prevenir la neurodegeneración asociada a la edad y mejorar los déficits cognitivos y los marcadores neuropatológicos de la enfermedad de Alzheimer (EA). En este estudio hemos analizado el efecto de una dosis baja de resveratrol administrada a través de la dieta durante 8 semanas en ratones SAMP8, un modelo de envejecimiento acelerado que presenta marcadores relacionados con la EA; y una dosis alta durante 7-10 meses en ratones SAMP8 y APP/PS1, un modelo de EA familiar. Los resultados indicaron que la dosis alta de resveratrol aumenta la esperanza de vida en SAMP8. Además, observamos un aumento en la activación de las vías de AMPK y SIRT1, junto con una reducción del déficit cognitivo y de la carga de amiloide tanto en SAMP8 como en APP/PS1. Por último, se caracterizó el estado cognitivo y los marcadores neuropatológicos de la EA en un nuevo modelo que combina las características de los ratones transgénicos APP/PS1 con un fondo génico de senescencia acelerada proveniente de los ratones SAMP8. Los resultados muestran que este nuevo modelo presenta alteraciones en las vías estudiadas, demostrando que el fenotipo de senescencia acelerada exacerba la patología amiloide y tau a edades tardías manteniendo los déficits cognitivos presentes en APP/PS1 y SAMP8.[eng] Resveratrol is a polyphenol found primarily in grapes and red wine. It has also proven to be a caloric restriction mimetic through activation Sirtuin 1. Several studies indicate that caloric restriction and therefore resveratrol, can increase longevity. Resveratrol increases the metabolic rate, insulin sensitivity, mitochondrial biogenesis, physical endurance and reduces fat accumulation in mice. Furthermore, resveratrol may be an effective drug for preventing age-related neurodegeneration, improve cognition and decrease the neuropathological markers of Alzheimer's disease (AD). In this study we analyzed the effect of a low dose of resveratrol administered via the diet for 8 weeks in SAMP8 mice, a model of accelerated aging; and a high dose for 7-10 months in SAMP8 and APP/PS1 mice, a model of familial AD. The results indicated that high doses of resveratrol increases lifespan in SAMP8. In addition, we observed an increase in the activation of AMPK and SIRT1 pathways, along with a reduction of cognitive deficits and amyloid burden in both SAMP8 and APP/PS1. Finally, cognitive status and neuropathologic markers of AD were characterized in a new model that combines characteristics of APP/PS1 transgenic mice in a senescence-accelerated background from SAMP8 mice. The results showed that this new model presents alterations in the studied pathways, demonstrating that the phenotype of accelerated senescence exacerbates amyloid and tau pathology in later life, maintaining the cognitive deficits present in APP/PS1 and SAMP8

Vitamine D, parathormone et insuffisance rénale (physiopathologie et approche thérapeutique )

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Un algorithme de compression efficace de LUTs 3D couleur basé sur un schéma de diffusion anisotrope multi-échelle

National audienceLes CLUTs 3D (Color Look Up Tables) sont des modèles numériques très utilisés en traitement d'images et de vidéos, pour l'étalonnage couleur, la simulation de films argentiques, et plus généralement pour l'application de transformées colorimétriques quelconques. La dimension élevée de ces modèles pose des problèmes de stockage, lorsque l'on cherche à les distribuer à grande échelle. Nous proposons ici une technique de compression (avec perte) très efficace de CLUTs 3D, fondée sur un schéma de reconstruction par diffusion anisotrope multi-échelle. Notre méthode affiche un taux de compression moyen supérieur à 99%, pour une dégradation résultante visuellement indiscernable. Abstract-3D CLUTs (Color Look Up Tables) are popular digital models used in image and video processing for color grading, simulation of analog films, and more generally for the application of various color transformations. The large size of these models leads to data storage issues when trying to distribute them on a large scale. Here, a highly effective lossy compression technique for 3D CLUTs is proposed. It is based on a multi-scale anisotropic diffusion scheme. Our method exhibits an average compression rate of more than 99%, while ensuring visually indistinguishable differences with the application of the original CLUTs