A Tree-­based SPH Algorithm to investigate the interaction of a young Binary Star and its gaseous disk.

The scientific target of my PhD activity in Astronomy, Astrophysics and Space Science, consists in studying several kinds of protostellar gaseous disks around young binary systems, to understand the role of the two stars on the dynamical and thermal evolution of gas. In this context, I will present some preliminary work, consisting in the implementation of a Tree-based 3D Smoothed Particle Hydrodynamics code. This algorithm is designed to treat multi phase systems made of gas and point-mass particles which can represent both stars and planets. The numerical code is suitably implemented to take efficiently into account both gravitational interactions and the internal thermodynamics in a full Lagrangian approach. The code has been parallelized on shared memory architectures. Some preliminary tests and applications on gas distributions around single and binary systems will be shown. The main motivation to start writing a new algorithm is to provide a suitable and flexible tool to study a wide ensemble of gas and stars systems, in support of the several topics (in Planetology and in self-gravitating systems) of the research groups I am involved with. In this framework, the study of the role of gas in stellar aggregates represents an important part of the research. To perform such investigations, my algorithm will be easily provided with several additional physical effects, and its level of parallelization will be increased to exploit dedicated hardware of multicore platforms, such as the composite CPU+GPU architectures

A new 3D hydrodynamical tree-based code for the investigation of the evolution of circumbinary radiative self-gravitating gaseous disks.

At present, the study of the evolution of matter around young binary systems is a key issue which can provide important answers on the possibility of forming planets in stable orbits around two stars. In the context of my PhD work in Astronomy, Astrophysics and Space Science, me and my research group aim at studying the conditions for stability of gaseous disks revolving around binary stars, during the earliest phases of planet formation, when no km-sized planetesimal has been constituted yet and the circumbinary matter is still made up of just gas and dust. The stability of such systems, maintained for a sufficiently large time-scale, will be a crucial condition for matter condensation and for the following planet constitution. For this purpose, we intend to perform several 3D high resolution simulations by implementing a Smoothed Particle Hydrodynamics tree-based code, suitably designed to take efficiently into account both the selfgravity of the system and the influence of the stellar radiation. Previously, few works focused their attention to this problem and, to overcome several issues due to computational efforts, some approximations have been used. Despite important constraints for the regions of stability have been obtained, no characterization in high details on the structure of the disk nor clear informations about its symmetry have been given. By contrast, our code will be realized to take into account several physical processes, relevant for disk stability, exploiting some suitable numerical techniques previously developed by several authors. In particular, self-gravity and stellar radiation absorption, which in many cases have been considered in a simplified theoretical scheme, are thought to play a crucial role. Our algorithm is designed to be flexible, due to its lagrangian structure, and efficient, since it will run in multi-node architectures. Such poster shows a preliminary part of our work which consists in the realization of a serial version of the code, able to simulate the hydrodynamical evolution of a gas system which interacts gravitationally with two stars (represented by point mass objects)

Effects of intrathecal administration of everolimus in a triple transgenic mouse model of Alzheimer's disease

Overwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer's disease (AD). To investigate the relation between Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline. The mTOR enzymatic activity and the levels of phosphorylated p70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis. We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice. In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression

Métro, boulot, dodo… et le reste : motifs de mobilité périurbaine et relation à l’agglomération

Souvent stéréotypé, le mode de vie des périurbains est parfois résumé par l’adage voiture, boulot, dodo. Cette analyse apparaît cependant limitée : près de 50 ans après l’émergence du phénomène (Baccaïni, Sémécurbe, 2009), la mobilité périurbaine ne peut plus se résumer aux navettes domicile-travail à destination de l’agglomération. L’émergence de pôles périurbains (Beaucire, Chalonge, 2011 ; Drevelle, 2012), le chainage de déplacements combinant plusieurs motifs (Baudelle et al., 2004) ou en..

Evaluation of a LC-MS method for everolimus preclinical determination in brain by using [(13)C2D4]RAD001 internal standard

Isotopic internal standards are increasingly frequent in LC-MS analysis to control biological matrix effects in the quantitation of immunosuppressant drugs, such as everolimus (RAD001). Here we present the evaluation of a LC-MS method, exploiting [(13)C2D4]RAD001 as internal standard, for preclinical determination of RAD001 in mice brain tissue. Samples were purified by solid phase extraction. Brain and blood were collected from vehicle-treated and RAD001-treated mice. The QTOF MS detector was set to select RAD001 ammonium adducts (m/z 975.6152) and [(13)C2D4]RAD001 (m/z 981.6481). Two different UHPLC columns were preliminarily tested. The method showed linear behavior between 4 and 100ng/mL (r(2)=0.99943) and linearity was preserved in the presence of blood (r(2)=0.99107) and brain (r(2)=0.99098) matrix components. Intra-day and inter-day precision (3-19%) and accuracy (82-109%) were comparable between standards and spiked blood and brain samples. As resulting from recovery comparison (82-98%), [(13)C2D4]RAD001 compensated ion suppression phenomena maintaining method performance over a wide range of consecutive analytical runs. The comparison with a HPLC-UV method showed reliability of the method with good correlation between blood (r(2)=0.94319) and brain (r(2)=0.97773) samples and acceptable biases (<15%). This validation suggests that the investigated method could be useful for the preclinical monitoring of RAD001 brain therapeutic concentrations in animal models

TFEB activation restores migration ability to Tsc1-deficient adult neural stem/progenitor cells

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs). Therefore, reactivation of cell migration of NSPCs might be the crucial step for the treatment of patients. In order to identify potential in vitro targets activating migration, we generated Tsc1-deficent NSPCs. These cells summarize most of the biochemical and morphological characteristics of TSC neural cells, such as the mTORC1 activation, the formation of abnormally enlarged astrocytes-like cells, the reduction of autophagy flux and the impairment of cell migration. Moreover, nuclear translocation, namely activation of the transcription factor EB (TFEB) was markedly impaired. Herein we show that compounds such as everolimus, ionomycin and curcumin, which directly or indirectly stimulate TFEB nuclear translocation, restore Tsc1-deficent NSPC migration. Our data suggest that reduction of TFEB activation, caused by mTORC1 hyperactivation, contributes to the migration deficit characterizing Tsc1-deficent NSPCs. The present work highlights TFEB as a druggable protein target for SEGAs therapy, which can be additionally or alternatively exploited for the mTORC1-directed inhibitory approach

In vitro treatment of congenital disorder of glycosylation type Ia using PLGA nanoparticles loaded with GDP‑Man

Congenital disorder of glycosylation (CDG) type Ia is a multisystem disorder that occurs due to mutations in the phosphomannomutase 2 (PMM2) gene, which encodes for an enzyme involved in the N‑glycosylation pathway. Mutated PMM2 leads to the reduced conversion of mannose‑6‑P to mannose‑1‑P, which results in low concentration levels of guanosine 5'‑diphospho‑D‑mannose (GDP‑Man), a nucleotide‑activated sugar essential for the construction of protein oligosaccharide chains. In the present study, an in vitro therapeutic approach was used, based on GDP‑Man‑loaded poly (D,L‑lactide‑co‑glycolide) (PLGA) nanoparticles (NPs), which were used to treat CDG‑Ia fibroblast cultures, thus bypassing the glycosylation pathway reaction catalysed by PMM2. To assess the degree of hypoglycosylation in vitro, the present study examined the activities of α‑mannosidase, β‑glucoronidase and β‑galactosidase in defective and normal fibroblasts. GDP‑Man (30 µg/ml GDP‑Man PLGA NPs) was incubated for 48 h with the cells and the specific activities of α‑mannosidase and β‑galactosidase were estimated at 69 and 92% compared with healthy controls. The residual activity of β‑glucoronidase increased from 6.5 to 32.5% and was significantly higher compared with that noted in the untreated CDG‑Ia fibroblasts. The glycosylation process of fibroblasts was also analysed by two‑dimensional electrophoresis. The results demonstrated that treatment caused the reappearance of several glycosylated proteins. The data in vitro showed that GDP‑Man PLGA NPs have desirable efficacy and warrant further evaluation in a preclinical validation animal model