Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons

41 breast cancer or breast-ovarian cancer families, including 12 families with at least one affected first-degree male relative, were screened for mutations in the BRCA2 gene. Mutations had not been found in the BRCA1 gene of these families. Chemical cleavage of Mismatch was used to identify nucleotide changes within large PCR products (average size 1.2 kb) that carried strand-specific fluorescent end-labels. 15 amplicons were sufficient to scan 18 exons, including the large exon 11. The remaining 9 small exons were examined by Denaturing Gradient Gel Electrophoresis. The high sensitivity of this approach was documented by the detection, in these 41 patients, of all 9 exonic single nucleotide polymorphisms reported with heterozygosity >0.1. Truncating BRCA2 mutations were found in 7 of the 41 families. 3 of them were in the group of 12 families comprising cases of male breast cancer. Since the methods used here have no bias for particular types of mutations, these data confirm the high proportion of frameshifts among mutations in BRCA2. However, relevant single nucleotide substitutions were also found: one resulting in a stop codon and another one, present in a male patient, was the previously reported change Asp2723His, that affects a highly conserved region of the BRCA2 protein. This study indicates a BRCA2 contribution of 10% (95% CI 2.5–17.5) to our original cohort of 59 breast-ovarian cancer families, whereas the contribution of BRCA1 had been estimated at 46% (95% CI 33–59). © 2001 Cancer Research Campaign http://www.bjcancer.co

A framework for dissecting affinities of multidrug efflux transporter AcrB to fluoroquinolones

Sufficient concentration of antibiotics close to their target is key for antimicrobial action. Among the tools exploited by bacteria to reduce the internal concentration of antibiotics, multidrug efflux pumps stand out for their ability to capture and expel many unrelated compounds out of the cell. Determining the specificities and efflux efficiency of these pumps towards their substrates would provide quantitative insights into the development of antibacterial strategies. In this light, we developed a competition efflux assay on whole cells, that allows measuring the efficacy of extrusion of clinically used quinolones in populations and individual bacteria. Experiments reveal the efficient competitive action of some quinolones that restore an active concentration of other fluoroquinolones. Computational methods show how quinolones interact with the multidrug efflux transporter AcrB. Combining experiments and computations unveils a key molecular mechanism acting in vivo to detoxify bacterial cells. The developed assay can be generalized to the study of other efflux pumps

Lessons learned from the ATLAS performance studies of the Iberian Cloud for the first LHC running period

In this contribution we describe the performance of the Iberian (Spain and Portugal) ATLAS cloud during the first LHC running period (March 2010-January 2013) in the context of the GRID Computing and Data Distribution Model. The evolution of the resources for CPU, disk and tape in the Iberian Tier-1 and Tier-2s is summarized. The data distribution over all ATLAS destinations is shown, focusing on the number of files transferred and the size of the data. The status and distribution of simulation and analysis jobs within the cloud are discussed. The Distributed Analysis tools used to perform physics analysis are explained as well. Cloud performance in terms of the availability and reliability of its sites is discussed. The effect of the changes in the ATLAS Computing Model on the cloud is analyzed. Finally, the readiness of the Iberian Cloud towards the first Long Shutdown (LS1) is evaluated and an outline of the foreseen actions to take in the coming years is given. The shutdown will be a good opportunity to improve and evolve the ATLAS Distributed Computing system to prepare for the future challenges of the LHC operation.Peer Reviewe

Chapter Globally Optimised Energy-Efficient Data Centres

A great deal of energy in Information and Communication Technology (ICT) systems can be wasted by software, regardless of how energy-efficient the underlying hardware is. To avoid such waste, programmers need to understand the energy consumption of programs during the development process rather than waiting to measure energy after deployment. Such understanding is hindered by the large conceptual gap from hardware, where energy is consumed, to high-level languages and programming abstractions. The approaches described in this chapter involve two main topics: energy modelling and energy analysis. The purpose of modelling is to attribute energy values to programming constructs, whether at the level of machine instructions, intermediate code or source code. Energy analysis involves inferring the energy consumption of a program from the program semantics along with an energy model. Finally, the chapter discusses how energy analysis and modelling techniques can be incorporated in software engineering tools, including existing compilers, to assist the energy-aware programmer to optimise the energy consumption of code

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Interglacials of the last 800,000 years

Interglacials, including the present (Holocene) period, are warm, low land ice extent (high sea level), end-members of glacial cycles. Based on a sea level definition, we identify eleven interglacials in the last 800,000 years, a result that is robust to alternative definitions. Data compilations suggest that despite spatial heterogeneity, Marine Isotope Stages (MIS) 5e (last interglacial) and 11c (~400 ka ago) were globally strong (warm), while MIS 13a (~500 ka ago) was cool at many locations. A step change in strength of interglacials at 450 ka is apparent only in atmospheric CO$_{2}$ and in Antarctic and deep ocean temperature. The onset of an interglacial (glacial termination) seems to require a reducing precession parameter (increasing Northern Hemisphere summer insolation), but this condition alone is insufficient. Terminations involve rapid, nonlinear, reactions of ice volume, CO$_{2}$, and temperature to external astronomical forcing. The precise timing of events may be modulated by millennial-scale climate change that can lead to a contrasting timing of maximum interglacial intensity in each hemisphere. A variety of temporal trends is observed, such that maxima in the main records are observed either early or late in different interglacials. The end of an interglacial (glacial inception) is a slower process involving a global sequence of changes. Interglacials have been typically 10–30 ka long. The combination of minimal reduction in northern summer insolation over the next few orbital cycles, owing to low eccentricity, and high atmospheric greenhouse gas concentrations implies that the next glacial inception is many tens of millennia in the future.This paper arose as a result of a succession of workshops of the Past Interglacials Group (PIGS), sponsored by the Past Global Changes Project (PAGES). The authors acknowledge the contributions of all participants at those workshops, of whom the listed authors are only a subset. Numerous funding agencies have contributed to the work of this paper including NSF (USA), NERC and The Royal Society (UK), F.R.S –FNRS (Belgium), and SNF (Switzerland). Most data described in this paper are available through relevant data repositories, http://www.ncdc.noaa.gov/data-access/paleoclimatology-data and www.pangaea.de in particular. In addition, the datasets from which Tables 2 and 3 were derived have been compiled into a spreadsheet as a supplement to this paper. Insolation data for Figure 5 can be calculated using programs available at ftp://ftp.elic.ucl.ac.be/berger/berger78/ and ftp://ftp.elic.ucl.ac.be/berger/ellipticintegrals/.  This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/2015RG00048