Spiral2 Project: Integration of the Accelerator Processes, Construction of the Buildings and Process Connections

TUA2C01International audienceThe GANIL SPIRAL 2 Project is based on the construction of a superconducting ion CW LINAC (up to 5 mA - 40 MeV deuteron and 33 MeV proton beams, up to 1 mA - 14.5 MeV/u heavy ion beams) with two experimental areas named S3 ('Super Separator Spectrometer' for very heavy and super heavy element production) and NFS ('Neutron For Science'), The building studies as well as the accelerator and experimental equipment integration started in 2009. The ground breaking started at the end of 2010. The integration task of the different equipments into the buildings is managed by a trade-oriented integration unit gathering the accelerator integration team, the building prime contractor and a dedicated contracting assistant. All work packages are synthesized at the same time using 3D models. 3D tools are used to carry out integration, synthesis, process connections and the preparation of the future assembly. Since 2014, the buildings and process connections are received and the accelerator installation is well advanced. This contribution will describe these 3D tools, the building construction, the process connection status and our experience feedback

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Differences in conformational dynamics between Plasmodium falciparum and human Hsp90 orthologues enable the structure-based discovery of pathogen-selective inhibitors

The high sequence conservation of druggable pockets of closely related proteins can make it challenging to develop selective inhibitors. We designed a new drug discovery approach that exploits both the static and dynamic differences of two orthologues. We applied it, as a proof of concept, to identify compounds that discriminate between the molecular chaperone Hsp90 of the protozoan pathogen Plasmodium falciparum (Pf) and that of its human host. We found that the ATP-binding pocket has a Pf-specific extension, whose sequence lining is identical in human Hsp90 but which differs by tertiary structure and dynamics. Using these insights for a structure-based drug screen, we discovered novel 7-azaindole compounds that exclusively bind the recombinant N-terminal domain of PfHsp90 but not of human Hsp90 nor of a PfHsp90 mutant with "human-like" dynamics. Moreover, these compounds preferentially inhibit the growth of yeast complemented by PfHsp90 and block the growth of Pf in culture

Les technologies educatives assistees par ordinateur et l'enseignement de la gestion

SIGLEAvailable at INIST (FR), Document Supply Service, under shelf-number : DO 2145 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Ostéointégration et maladies générales. Recommandations cliniques

L’ostéointégration dans un os sain est un processus largement documenté et maîtrisé. De nombreuses données montrent que ce processus peut être perturbé chez des patients souffrant de maladies générales ou polymédicamentés. Le but de cet article est de fournir au praticien des recommandations cliniques quant à leur influence sur l’ostéointégration des implants