WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks

DNA double-strand breaks (DSBs) at RNA polymerase II (RNAPII) transcribed genes lead to inhibition of transcription. The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in transcription inhibition at DSBs by stimulating proteasome-dependent eviction of RNAPII at these lesions. How DNA-PK triggers RNAPII eviction to inhibit transcription at DSBs remains unclear. Here we show that the HECT E3 ubiquitin ligase WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII transcribed genes. In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. The lack of WWP2 or expression of nonubiquitylatable RPB1 abrogates the binding of nonhomologous end joining (NHEJ) factors, including DNA-PK and XRCC4/DNA ligase IV, and impairs DSB repair. These findings suggest that WWP2 operates in a DNA-PK-dependent shutoff circuitry for RNAPII clearance that promotes DSB repair by protecting the NHEJ machinery from collision with the transcription machinery

Plague Circulation and Population Genetics of the Reservoir Rattus rattus: The Influence of Topographic Relief on the Distribution of the Disease within the Madagascan Focus.

International audienceBACKGROUND: Landscape may affect the distribution of infectious diseases by influencing the population density and dispersal of hosts and vectors. Plague (Yersinia pestis infection) is a highly virulent, re-emerging disease, the ecology of which has been scarcely studied in Africa. Human seroprevalence data for the major plague focus of Madagascar suggest that plague spreads heterogeneously across the landscape as a function of the relief. Plague is primarily a disease of rodents. We therefore investigated the relationship between disease distribution and the population genetic structure of the black rat, Rattus rattus, the main reservoir of plague in Madagascar. METHODOLOGYPRINCIPAL FINDINGS: We conducted a comparative study of plague seroprevalence and genetic structure (15 microsatellite markers) in rat populations from four geographic areas differing in topology, each covering about 150-200 km(2) within the Madagascan plague focus. The seroprevalence levels in the rat populations mimicked those previously reported for humans. As expected, rat populations clearly displayed a more marked genetic structure with increasing relief. However, the relationship between seroprevalence data and genetic structure differs between areas, suggesting that plague distribution is not related everywhere to the effective dispersal of rats. CONCLUSIONSSIGNIFICANCE: Genetic diversity estimates suggested that plague epizootics had only a weak impact on rat population sizes. In the highlands of Madagascar, plague dissemination cannot be accounted for solely by the effective dispersal of the reservoir. Human social activities may also be involved in spreading the disease in rat and human populations

Insights into the Complex Associations Between MHC Class II DRB Polymorphism and Multiple Gastrointestinal Parasite Infestations in the Striped Mouse

Differences in host susceptibility to different parasite types are largely based on the degree of matching between immune genes and parasite antigens. Specifically the variable genes of the major histocompatibility complex (MHC) play a major role in the defence of parasites. However, underlying genetic mechanisms in wild populations are still not well understood because there is a lack of studies which deal with multiple parasite infections and their competition within. To gain insights into these complex associations, we implemented the full record of gastrointestinal nematodes from 439 genotyped individuals of the striped mouse, Rhabdomys pumilio. We used two different multivariate approaches to test for associations between MHC class II DRB genotype and multiple nematodes with regard to the main pathogen-driven selection hypotheses maintaining MHC diversity and parasite species-specific co-evolutionary effects. The former includes investigations of a ‘heterozygote advantage’, or its specific form a ‘divergent-allele advantage’ caused by highly dissimilar alleles as well as possible effects of specific MHC-alleles selected by a ‘rare allele advantage’ ( = negative ‘frequency-dependent selection’). A combination of generalized linear mixed models (GLMMs) and co-inertia (COIA) analyses made it possible to consider multiple parasite species despite the risk of type I errors on the population and on the individual level. We could not find any evidence for a ‘heterozygote’ advantage but support for ‘divergent-allele’ advantage and infection intensity. In addition, both approaches demonstrated high concordance of positive as well as negative associations between specific MHC alleles and certain parasite species. Furthermore, certain MHC alleles were associated with more than one parasite species, suggesting a many-to-many gene-parasite co-evolution. The most frequent allele Rhpu-DRB*38 revealed a pleiotropic effect, involving three nematode species. Our study demonstrates the co-existence of specialist and generalist MHC alleles in terms of parasite detection which may be an important feature in the maintenance of MHC polymorphism

Synthesis and cycloadditions of 1-[(tert-butyldimethylsilyl)oxy]alkenyl isocyanates

1-[(tert-Butyldimethylsilyl)oxy] alkenyl isocyanates 1a and 1b have been conveniently prepared from acetyl or propionyl chloride, silver cyanate and tert-butyldimethylsilyl triflate in the presence of triethylamine. They react with electron-deficient acetylenic dienophiles or with tosyl cyanide to give highly functionalised pyridines or derivatives of uracil or thymine in moderate yields. They also cycloadd with 1-(diethylamino)prop-1-yne, an electron-rich dienophile, to yield glutaconimides and pyridine derivatives

[3+2] cycloadditions with 1,2-difluorovinylphenylsulfone

[3+2] Cycloaddition reactions of (E) and (Z)-1,2-difluorovinylphenylsulfones with diphenylnitrone, ethyl- and mesitylnitrile oxides and diphenylnitrile imine have been studied. The behaviour of these new dipolarophiles has been compared to that of the related phenylvinylsulfone and 1-fluorovinylphenylsulfone

Dopant solubility and lattice contraction in gadolinia and gadolinia-chromia doped UO2 fuels

Gadolinia doped UO 2 fuel is widely used as burnable neutron absorber in Light Water Reactors to reduce power peaking and excess reactivity during the first reactor cycle of fresh fuel assemblies. The thermal conductivity of gadolinia doped fuel is substantially lower than that of standard UO 2. To maintain safety margins later in life, some design or operating restrictions can be defined, for example to compensate higher fission gas release levels. Development of large grain U/Gd fuel by suitable doping, e.g. Cr 2O 3, could offer a solution to such restrictions, but solid state information about the double doped (U 1-x-yGd xCr y)O 2 system is very scarce. In the present paper, we present X-ray diffraction and microstructure results of standard U/Gd fuel and chromia doped U/Gd fuel manufactured by powder metallurgy. The dissolution of chromium in (U 1-xGd x)O 2 as a function of Gd content, the role of free UO 2 and the lattice contraction at different Gd and Cr doping levels of (U 1-x-yGd xCr y)O 2 is studied both for the single doped and double doped system. On the basis of lattice contraction and precise measurements of the composition of the solid solution phases, the evolution of theoretical density with dopant concentration is derived. © 2012 Elsevier B.V. All rights reserved.status: publishe

Design and manufacturing interface modelling for manufacturing processes selection and knowledge synthesis in design

This research is part of the regional French project IFP2R : “ Manufacturing constraints integration in rapid prototyped part design ” with IFTS (Higher Technical Formation Institute of Charleville Mézières- France).The research results presented in this paper are related to the specification of a method and models that tackle the problem of manufacturing processes selection and the integration, as soon as possible, of their constraints in the product modelling (i.e. information synthesis). This method is based on a skin and skeleton design/manufacturing interface model that ensures connection between design and manufacturing information. The use of these features is justified by their capacity to make a product representation which allows integration of both design and manufacture data and therefore assists the product breakdown definition (including the 3D forms) by least commitment. This method first analyses the product data issued from functional analysis and component selection (form, roughness, tolerance interval, etc.). Then, it deals with manufacturing information (manufacturing processes constraints). The approach is formalised with IDEF and UML models and has been consolidated with software developments based on C++ and open CASCADE technologies