Progress on testing Lorentz symmetry with MICROSCOPE

The Weak Equivalence Principle (WEP) and the local Lorentz invariance (LLI) are two major assumptions of General Relativity (GR). The MICROSCOPE mission, currently operating, will perform a test of the WEP with a precision of $10^{-15}$. The data will also be analysed at SYRTE for the purposes of a LLI test realised in collaboration with J. Tasson (Carleton College, Minnesota) and Q. Bailey (Embry-Riddle Aeronautical University, Arizona). This study will be performed in a general framework, called the Standard Model Extension (SME), describing Lorentz violations that could appear at Planck scale ($10^{19}$ GeV). The SME allows us to derive a Lorentz violating observable designed for the MICROSCOPE experiment and to search for possible deviations from LLI in the differential acceleration of the test masses

Nouvelles trappes à sédiment destinées aux milieux peu profonds vidangeables

Les mesures de taux de sédimentation en milieux aquatiques peu profonds sont rares et sont souvent réalisées à l'aide de méthodes inadaptées. Les trappes à sédiment utilisées ont au minimum 25 cm de haut. Par conséquent, pour beaucoup de milieux peu profonds, plus de 25 % de la colonne d'eau ne sont pas échantillonnés. Nous avons pallié ce problème en développant un réceptacle mis en place dans les sédiments et destiné à recevoir des trappes à sédiment cylindriques. Le sommet des trappes peut alors être situé à moins de 5 cm de la surface des sédiments. Ce système est utilisable pour des milieux de profondeur inférieure à cinq mètres. Nos résultats montrent que les trappes à sédiments généralement utilisées sous-estiment de 35 à 79 % du taux de sédimentation. Les particules négligées proviennent des flux sédimentaires primaire et secondaire.Sediment traps are a unique tool that can be used to investigate particle settling flux throughout the water column, whereas other methods such as sediment dating can only measure accumulation rates of bottom sediments. Several works on trapping efficiency have shown that cylindrical traps with height/diameter ratio greater than to 5 (10 in turbulent systems) are the more appropriate instruments to correctly measure the downward settling flux of particulate matter. Furthermore, traps with a diameter narrower than 5 cm should be avoided. It is well documented that bottle-type vessels overestimate the settling sediment whereas funnels and flat containers underestimate it. All this support the idea that an ideal trap must be at least 25 cm high, and in this sense, numerous studies investigating shallow aquatic systems have neglected a large proportion of the water column. Consequently, mechanical and biological processes occurring in this layer of the water column have not been taken into accountWe have overcome this problem with a structure composed of two parts (figure 2).The first part is a receptacle (bucket) buried in the sediment and intended to receive cylindrical traps. The top of the receptacle is placed 2 cm above the sediment. A guide made of a rope covered with a PVC tube is placed in the centre of the receptacle. This receptacle is intended to receive cylindrical traps whose tops stand less than 5 cm higher than the surface of the sediments.The second part is composed of seven cylinders (height/diameter ratio=10) which are fixed in a PVC disc 600 mm in diameter and 15 mm deep. The cylinders are placed around the central axis of the PVC disc. The bottom of the cylinders is closed with a removable polyethylene cap. Another cylinder, through which the guide can slide, is placed on the central axis. The bottom part of this last cylinder is ballasted with concrete. The stability of this second part, during both deposition and removal steps, is ensured by the low density of the PVC disc, the ballast at the bottom of the central cylinder, and the symmetry of the structure. This removable part may be lifted from the receptacle with three 2 mm diameter ropes attached to the PVC disc and fixed to a float. This apparatus may be used as deep as five meters.The sediment traps were tested in two extensively-managed fish ponds in North-Eastern France. Our investigations showed that tubes with a diameter between 26 and 140 mm could be efficiently used to estimate the sedimentation rate, whereas cylinders with a narrower diameter missed a large amount of particles. The use of tubes with a diameter above 50 mm, which is preferable for the study of turbulent systems, seems to allow the collection of sufficient sediment during a short period of time. We selected tubes with a diameter of 57 mm, which made it possible to handle them easily during the removal. Our investigations showed that in turbulent systems and for high sedimentation rates (> 5 kg·m-2 ·month-1), the top of the cylinders must be placed 1 cm above the top of the PVC disc. When considering low sedimentation rates (< 5 kg·m-2 ·month-1), we did not observe any significant differences between the cylinders placed 0 and 1 cm above the PVC disc.Complementary investigations were conducted in order to compare sedimentation rates estimated 1) by the apparatus we designed, in which the top of the cylinders was placed 5 cm above the sediment surface, 2) by traditional traps (57 mm in diameter and a height/diameter ratio of 5) in which the top of the cylinders was 28.5 cm above the sediment surface.These results showed that in shallow systems (1.2 m deep), traditional traps underestimate the downward settling flux of particulate matter by 35 to 79%. Furthermore, we compared the organic matter content of the sediment collected by the two types of traps with the organic matter content of bottom sediment, suspended particles, and submerged macrophytes. Results showed that the underestimation of particles was not only due to the resuspension of bottom sediment, but also to the sedimentation of phytoplankton and submerged macrophyte fragments which are not collected by the traditional traps

Characterisation of breast fine-needle aspiration biopsies by centrosome aberrations and genomic instability

Recent studies have suggested that aneuploidy in malignant tumours could be a consequence of centrosome aberrations. Using immunofluorescence analysis with an antibody against γ-tubulin and DNA image cytometry, we measured centrosome aberrations and DNA ploidy patterns in fine-needle aspiration biopsies (FNABs) of 58 breast lesions. Benign lesions did not show any centrosome aberrations. DNA diploid carcinomas showed a mean percentage of cells with centrosomal defects of 2.1%. The aneuploid invasive carcinomas could be divided into two subgroups by their significantly (P=0.0003) different percentage of cells with centrosome aberrations (2.0 and 10.3%, respectively) and their significantly (P=0.0003) different percentage of cells with nonmodal DNA content values determined by the Stemline Scatter Index (SSI), a measure of genomic instability. The percentage of cells with centrosome aberrations demonstrated a positive, linear correlation with the corresponding SSI (r=0.82, P<0.0001) and loss of tissue differentiation (r=0.78, P<0.0001). Our results indicate the percentage of cells with centrosome aberrations as being sufficient to divide the investigated tumours into three significantly different groups: benign lesions with no centrosomal aberrations, and two malignant tumour types with mean values of 2.1 and 9.6% of centrosomal defects, respectively. Together, these results demonstrate that centrosome aberrations correlate with genomic instability and loss of tissue differentiation. Furthermore, this study shows the feasibility of centrosomal analysis in FNAB of the breast and suggests centrosomal aberrations as possessing diagnostic and prognostic value

Aurora kinase-C-T191D is constitutively active mutant

<p>Abstract</p> <p>Background</p> <p>Aurora kinases (Aurora-A, B and C) belong to a family of conserved serine/threonine kinases which are key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved in cell cycle regulation while aurora-C is meiotic chromosome passenger protein. As Aurora kinase C is rarely expressed in normal somatic cells and has been found over expressed in many cancer lines. It is suggested that Aurora-C-T191D is not hyperactive mutant.</p> <p>Result</p> <p>Aurora-C-T191D variant form was investigated and compared with wild type. The overexpression of Aurora-C-T191D was observed that it behaves like Aurora-C wild type (aurC-WT). Both Aurora-C-T191D and aurC-WT induce abnormal cell division resulting in centrosome amplification and multinucleation in transiently transfected cells as well as in stable cell lines. Similarly, Aurora-C-T191D and aurC-WT formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3 T3 stable cell lines overexpressing Aurora-C-T191D and its wild type partner induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumour aggressiveness was positively correlated with the rate of kinase activity, making Aurora-C a potential anti-cancer therapeutic target.</p> <p>Conclusion</p> <p>These findings proved that Aurora C-T191D is not hyperactive but is constitutively active mutant.</p

The retroviral oncoprotein Tax targets the coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication

Emerging evidence suggests that supernumerary centrosomes drive genome instability and oncogenesis. Human T-cell leukaemia virus type I (HTLV-I) is etiologically associated with adult T-cell leukaemia (ATL). ATL cells are aneuploid, but the causes of aneuploidy are incompletely understood. Here, we show that centrosome amplification is frequent in HTLV-I-transformed cells and that this phenotype is caused by the viral Tax oncoprotein. We also show that the fraction of Tax protein that localizes to centrosomes interacts with TAX1BP2, a novel centrosomal protein composed almost entirely of coiled-coil domains. Overexpression of TAX1BP2 inhibited centrosome duplication, whereas depletion of TAX1BP2 by RNAi resulted in centrosome hyperamplification. Our findings suggest that the HTLV-I Tax oncoprotein targets TAX1BP2 causing genomic instability and aneuploidy. © 2006 Nature Publishing Group.postprin

Aurora-A/STK15/BTAK overexpression induces centrosome amplification, chromosomal instability, and transformation in human urothelial cells

Aurora-A/STK15/BTAK kinase encoding gene, located on chromosome 20q13, is frequently amplified and overexpressed in human cancers. Sen et al. previously demonstrated that Aurora-A amplification and overexpression are associated with aneuploidy and clinically aggressive bladder cancer (J Natl Cancer Inst (2002) 94, 1320-1329). To examine if this association is the direct result of Aurora-A gene amplification and overexpression, an immortalized human urothelial cell line (SV-HUC) was infected with an adenoviral Aurora-A-green fluorescent protein (Ad-Aurora-A-GFP) fusion construct inducing ectopic expression of the resulting fusion protein. Controls included mock-infected and adenoviral-GFP infected cells. Ectopic expression of transduced Aurora-A did not alter the doubling time of the SV-HUC cells but significantly increased the number of cells with multiple centrosomes displaying aneuploidy and increased colony formation in soft agar. This is the first report demonstrating that overexpression of Aurora-A induces centrosome anomalies together with chromosomal instability and malignant transformation-associated phenotypic changes in immortalized human urothelial cells, thus supporting the hypothesis that this gene plays an important role in the development of aggressive bladder cancer

Evolution of Resistance to Aurora Kinase B Inhibitors in Leukaemia Cells

Aurora kinase inhibitors are new mitosis-targeting drugs currently in clinical trials for the treatment of haematological and solid malignancies. However, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Herein, we developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor ZM447439. Human T-cell acute lymphoblastic leukaemia cells, CCRF-CEM, were selected for resistance in 4 µM ZM447439. CEM/AKB4 cells showed no cross-resistance to tubulin-targeted and DNA-damaging agents, but were hypersensitive to an Aurora kinase A inhibitor. Sequencing revealed a mutation in the Aurora B kinase domain corresponding to a G160E amino acid substitution. Molecular modelling of drug binding in Aurora B containing this mutation suggested that resistance is mediated by the glutamate substitution preventing formation of an active drug-binding motif. Progression of resistance in the more highly selected CEM/AKB8 and CEM/AKB16 cells, derived sequentially from CEM/AKB4 in 8 and 16 µM ZM447439 respectively, was mediated by additional defects. These defects were independent of Aurora B and multi-drug resistance pathways and are associated with reduced apoptosis mostly likely due to reduced inhibition of the catalytic activity of aurora kinase B in the presence of drug. Our findings are important in the context of the use of these new targeted agents in treatment regimes against leukaemia and suggest resistance to therapy may arise through multiple independent mechanisms

Downregulation of the anaphase-promoting complex (APC)7 in invasive ductal carcinomas of the breast and its clinicopathologic relationships

INTRODUCTION: The anaphase-promoting complex (APC) is a multiprotein complex with E3 ubiquitin ligase activity, which is required for the ubiquitination of securin and cyclin-B. Moreover, the mitotic spindle checkpoint is activated if APC activation is prevented. In addition, several APC-targeting molecules such as securin, polo-like kinase, aurora kinase, and SnoN have been reported to be oncogenes. Therefore, dysregulation of APC may be associated with tumorigenesis. However, the clinical significance and the involvement of APC in tumorigenesis have not been investigated. METHODS: The expression of APC7 was immunohistochemically investigated in 108 invasive ductal carcinomas of the breast and its relationship with clinicopathologic parameters was examined. The expression of APC7 was defined as positive when the summed scores of staining intensities (0 to 3+) and stained proportions (0 to 3+) exceeded 3+. RESULTS: Positive APC7 expression was less frequent than its negative expression when histologic (P = 0.009) or nuclear grade (P = 0.009), or mitotic number (P = 0.0016) was elevated. The frequency of APC7 negative expression was higher in high Ki-67 or aneuploid groups than in low Ki-67 or diploid groups. CONCLUSION: These data show that loss of APC7 expression is more common in breast carcinoma cases with poor prognostic parameters or malignant characteristics. They therefore suggest that dysregulation of APC activity, possibly through downregulation of APC7, may be associated with tumorigenesis in breast cancer

A Role for Polyploidy in the Tumorigenicity of Pim-1-Expressing Human Prostate and Mammary Epithelial Cells

Polyploidy is a prominent feature of many human cancers, and it has long been hypothesized that polyploidy may contribute to tumorigenesis by promoting genomic instability. In this study, we investigated whether polyploidy per se induced by a relevant oncogene can promote genomic instability and tumorigenicity in human epithelial cells.When the oncogenic serine-threonine kinase Pim-1 is overexpressed in immortalized, non-tumorigenic human prostate and mammary epithelial cells, these cells gradually converted to polyploidy and became tumorigenic. To assess the contribution of polyploidy to tumorigenicity, we obtained sorted, matched populations of diploid and polyploid cells expressing equivalent levels of the Pim-1 protein. Spectral karyotyping revealed evidence of emerging numerical and structural chromosomal abnormalities in polyploid cells, supporting the proposition that polyploidy promotes chromosomal instability. Polyploid cells displayed an intact p53/p21 pathway, indicating that the viability of polyploid cells in this system is not dependent on the inactivation of the p53 signaling pathway. Remarkably, only the sorted polyploid cells were tumorigenic in vitro and in vivo.Our results support the notion that polyploidy can promote chromosomal instability and the initiation of tumorigenesis in human epithelial cells