The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Cell entry of Lassa virus induces tyrosine phosphorylation of dystroglycan.

The extracellular matrix (ECM) receptor dystroglycan (DG) serves as a cellular receptor for the highly pathogenic arenavirus Lassa virus (LASV) that causes a haemorrhagic fever with high mortality in human. In the host cell, DG provides a molecular link between the ECM and the actin cytoskeleton via the adapter proteins utrophin or dystrophin. Here we investigated post-translational modifications of DG in the context of LASV cell entry. Using the tyrosine kinase inhibitor genistein, we found that tyrosine kinases are required for efficient internalization of virus particles, but not virus-receptor binding. Engagement of cellular DG by LASV envelope glycoprotein (LASV GP) in human epithelial cells induced tyrosine phosphorylation of the cytoplasmic domain of DG. LASV GP binding to DG further resulted in dissociation of the adapter protein utrophin from virus-bound DG. This virus-induced dissociation of utrophin was affected by genistein treatment, suggesting a role of receptor tyrosine phosphorylation in the process.

Elemental analysis of New Zealand Nephrite Jade (pounamu) for forensic purposes

Pounamu (NZ jade), or nephrite, is a protected mineral in its natural form following thetransfer of ownership back to Ngai Tahu under the Ngai Tahu (Pounamu Vesting) Act 1997.Any theft of nephrite is prosecutable under the Crimes Act 1961. Scientific evidence isessential in cases where origin is disputed. A robust method for discrimination of thismaterial through the use of elemental analysis and compositional data analysis is required.Initial studies have characterised the variability within a given nephrite source. This hasincluded investigation of both in situ outcrops and alluvial material. Methods for thediscrimination of two geographically close nephrite sources are being developed.Key Words: forensic, jade, nephrite, laser ablation, inductively coupled plasma massspectrometry, multivariate analysis, elemental analysis, compositional data analysis

Discovery and refinement of loci associated with lipid levels.

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Anxiety and Psychological Stress Before Prenatal Screening in First-Time Mothers Who Conceived Through IVF/ICSI or Spontaneously.

Mothers' general anxiety, anxiety about the well-being of the child and psychological stress before prenatal testing was studied by comparing women who conceived through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) with women who conceived naturally. Before the first trimester screening test for Down's syndrome, a group of 51 women who conceived through IVF/ICSI and a group of 54 women who conceived spontaneously completed the State Scale of the State-Trait Anxiety Inventory (S-Anxiety; Spielberger, 1983), the Fear of Bearing a Physically or Mentally Handicapped Child Subscale of the Pregnancy-related Anxiety Questionnaire (PRAQ-R; Huizink et al., 2004), the Psychological Stress Measure (PSM; Lemyre & Tessier, 1988), and the Prenatal Psychosocial Profile (PPP; Curry, Campbell, & Christian, 1994). Women who conceived through IVF/ICSI had more elevated levels of general anxiety and psychological stress than the women who conceived naturally; however, no difference was observed between the two groups for anxiety specifically related to the health of the child. These results underline the need to monitor women's emotional state after conception via IVF/ICSI-when counseling usually ends-and around the time of the first trimester screening. Counseling might thus be extended.

21/2/20 [i.e. 22/2/20], anniversaire de Washington [M. Hugh Wallace, place d'Iena] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 58155

Dernier Conseil suprême, 9-1-20, [Hugh Wallace], Lloyd George, Bonar Law [Paris, ministère des Affaires étrangères] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57551

[Portrait de] M. [Hugh] Wallace, ambassadeur des U.S. [Etats-Unis] à Paris : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 58172

O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.

Alpha-dystroglycan (alpha-DG) is a cell-surface glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains and certain arenaviruses. Receptor binding is thought to be mediated by a posttranslational modification, and defective binding with laminin underlies a subclass of congenital muscular dystrophy. Using mass spectrometry- and nuclear magnetic resonance (NMR)-based structural analyses, we identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. We demonstrated that patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the like-acetylglucosaminyltransferase (LARGE) protein. These findings expand our understanding of the mechanisms that underlie congenital muscular dystrophy.

Common variants associated with plasma triglycerides and risk for coronary artery disease.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

CUBN is a gene locus for albuminuria.

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

High-resolution seismic images of potentially seismogenic structures beneath the northwest Canterbury Plains, New Zealand

The transpressional boundary between the Australian and Pacific plates in the central South Island of New Zealand comprises the Alpine Fault and a broad region of distributed strain concentrated in the Southern Alps but encompassing regions further to the east, including the northwest Canterbury Plains. Low to moderate levels of seismicity (e. g., 2 > M 5 events since 1974 and 2 > M 4.0 in 2009) and Holocene sediments offset or disrupted along rare exposed active fault segments are evidence for ongoing tectonism in the northwest plains, the surface topography of which is remarkably flat and even. Because the geology underlying the late Quaternary alluvial fan deposits that carpet most of the plains is not established, the detailed tectonic evolution of this region and the potential for larger earthquakes is only poorly understood. To address these issues, we have processed and interpreted high-resolution (2.5 m subsurface sampling interval) seismic data acquired along lines strategically located relative to extensive rock exposures to the north, west, and southwest and rare exposures to the east. Geological information provided by these rock exposures offer important constraints on the interpretation of the seismic data. The processed seismic reflection sections image a variably thick layer of generally undisturbed younger (i.e., < 24 ka) Quaternary alluvial sediments unconformably overlying an older (> 59 ka) Quaternary sedimentary sequence that shows evidence of moderate faulting and folding during and subsequent to deposition. These Quaternary units are in unconformable contact with Late Cretaceous-Tertiary interbedded sedimentary and volcanic rocks that are highly faulted, folded, and tilted. The lowest imaged unit is largely reflection-free Permian Triassic basement rocks. Quaternary-age deformation has affected all the rocks underlying the younger alluvial sediments, and there is evidence for ongoing deformation. Eight primary and numerous secondary faults as well as a major anticlinal fold are revealed on the seismic sections. Folded sedimentary and volcanic units are observed in the hanging walls and footwalls of most faults. Five of the primary faults represent plausible extensions of mapped faults, three of which are active. The major anticlinal fold is the probable continuation of known active structure. A magnitude 7.1 earthquake occurred on 4 September 2010 near the southeastern edge of our study area. This predominantly right-lateral strike-slip event and numerous aftershocks (ten with magnitudes >= 5 within one week of the main event) highlight the primary message of our paper: that the generally flat and topographically featureless Canterbury Plains is underlain by a network of active faults that have the potential to generate significant earthquakes.