On the Behaviour of General-Purpose Applications on Cloud Storages

Managing data over cloud infrastructures raises novel challenges with respect to existing and well studied approaches such as ACID and long running transactions. One of the main requirements is to provide availability and partition tolerance in a scenario with replicas and distributed control. This comes at the price of a weaker consistency, usually called eventual consistency. These weak memory models have proved to be suitable in a number of scenarios, such as the analysis of large data with Map-Reduce. However, due to the widespread availability of cloud infrastructures, weak storages are used not only by specialised applications but also by general purpose applications. We provide a formal approach, based on process calculi, to reason about the behaviour of programs that rely on cloud stores. For instance, one can check that the composition of a process with a cloud store ensures `strong' properties through a wise usage of asynchronous message-passing

An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency

The DNA mismatch repair system (MMR) maintains genome stability through recognition and repair of single-base mismatches and small insertion-deletion loops. Inactivation of the MMR pathway causes microsatellite instability and the accumulation of genomic mutations that can cause or contribute to cancer. In fact, 10-20% of certain solid and hematologic cancers are MMR-deficient. MMR-deficient cancers do not respond to some standard of care chemotherapeutics because of presumed increased tolerance of DNA damage, highlighting the need for novel therapeutic drugs. Toward this goal, we generated isogenic cancer cell lines for direct comparison of MMR-proficient and MMR-deficient cells. We engineered NCI-H23 lung adenocarcinoma cells to contain a doxycycline-inducible shRNA designed to suppress the expression of the mismatch repair gene MLH1, and compared single cell subclones that were uninduced (MLH1-proficient) versus induced for the MLH1 shRNA (MLH1-deficient). Here we present the characterization of these MMR-inducible cell lines and validate a novel class of rhodium metalloinsertor compounds that differentially inhibit the proliferation of MMR-deficient cancer cells

Automated Validation of State-Based Client-Centric Isolation with TLA ⁺

Clear consistency guarantees on data are paramount for the design and implementation of distributed systems. When implementing distributed applications, developers require approaches to verify the data consistency guarantees of an implementation choice. Crooks et al. define a state-based and client-centric model of database isolation. This paper formalizes this state-based model in, reproduces their examples and shows how to model check runtime traces and algorithms with this formalization. The formalized model in enables semi-automatic model checking for different implementation alternatives for transactional operations and allows checking of conformance to isolation levels. We reproduce examples of the original paper and confirm the isolation guarantees of the combination of the well-known 2-phase locking and 2-phase commit algorithms. Using model checking this formalization can also help finding bugs in incorrect specifications. This improves feasibility of automated checking of isolation guarantees in synthesized synchronization implementations and it provides an environment for experimenting with new designs.</p

Essential and checkpoint functions of budding yeast ATM and ATR during meiotic prophase are facilitated by differential phosphorylation of a meiotic adaptor protein, Hop1

A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis

RAD51C Germline Mutations in Breast and Ovarian Cancer Cases from High-Risk Families

BRCA1 and BRCA2 are the most well-known breast cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. One such gene, RAD51C, is essential for homologous recombination repair. Several likely pathogenic RAD51C mutations have been identified in BRCA1- and BRCA2-negative breast and ovarian cancer families. We performed complete sequencing of RAD51C in germline DNA of 286 female breast and/or ovarian cancer cases with a family history of breast and ovarian cancers, who had previously tested negative for mutations in BRCA1 and BRCA2. We screened 133 breast cancer cases, 119 ovarian cancer cases, and 34 with both breast and ovarian cancers. Fifteen DNA sequence variants were identified; including four intronic, one 5′ UTR, one promoter, three synonymous, and six non-synonymous variants. None were truncating. The in-silico SIFT and Polyphen programs were used to predict possible pathogenicity of the six non-synonomous variants based on sequence conservation. G153D and T287A were predicted to be likely pathogenic. Two additional variants, A126T and R214C alter amino acids in important domains of the protein such that they could be pathogenic. Two-hybrid screening and immunoblot analyses were performed to assess the functionality of these four non-synonomous variants in yeast. The RAD51C-G153D protein displayed no detectable interaction with either XRCC3 or RAD51B, and RAD51C-R214C displayed significantly decreased interaction with both XRCC3 and RAD51B (p<0.001). Immunoblots of RAD51C-Gal4 activation domain fusion peptides showed protein levels of RAD51C-G153D and RAD51C-R214C that were 50% and 60% of the wild-type, respectively. Based on these data, the RAD51C-G153D variant is likely to be pathogenic, while the RAD51C- R214C variant is hypomorphic of uncertain pathogenicity. These results provide further support that RAD51C is a rare breast and ovarian cancer susceptibility gene

Key indicators to track current progress and future ambition of the Paris Agreement

Current emission pledges to the Paris Agreement appear insufficient to hold the global average temperature increase to well below 2 °C above pre-industrial levels. Yet, details are missing on how to track progress towards the â € Paris goal', inform the five-yearly â € global stocktake', and increase the ambition of Nationally Determined Contributions (NDCs). We develop a nested structure of key indicators to track progress through time. Global emissions track aggregated progress, country-level decompositions track emerging trends that link directly to NDCs, and technology diffusion indicates future reductions. We find the recent slowdown in global emissions growth is due to reduced growth in coal use since 2011, primarily in China and secondarily in the United States. The slowdown is projected to continue in 2016, with global CO 2 emissions from fossil fuels and industry similar to the 2015 level of 36 GtCO 2. Explosive and policy-driven growth in wind and solar has contributed to the global emissions slowdown, but has been less important than economic factors and energy efficiency. We show that many key indicators are currently broadly consistent with emission scenarios that keep temperatures below 2 °C, but the continued lack of large-scale carbon capture and storage threatens 2030 targets and the longer-term Paris ambition of net-zero emissions

The charcoal trap: Miombo forests and the energy needs of people

<p>Abstract</p> <p>Background</p> <p>This study evaluates the carbon dioxide and other greenhouse gas fluxes to the atmosphere resulting from charcoal production in Zambia. It combines new biomass and flux data from a study, that was conducted in a <it>miombo </it>woodland within the Kataba Forest Reserve in the Western Province of Zambia, with data from other studies.</p> <p>Results</p> <p>The measurements at Kataba compared protected area (3 plots) with a highly disturbed plot outside the forest reserve and showed considerably reduced biomass after logging for charcoal production. The average aboveground biomass content of the reserve (Plots 2-4) was around 150 t ha^-1, while the disturbed plot only contained 24 t ha^-1. Soil carbon was not reduced significantly in the disturbed plot. Two years of eddy covariance measurements resulted in net ecosystem exchange values of -17 ± 31 g C m^-2y^-1, in the first and 90 ± 16 g C m^-2in the second year. Thus, on the basis of these two years of measurement, there is no evidence that the <it>miombo </it>woodland at Kataba represents a present-day carbon sink. At the country level, it is likely that deforestation for charcoal production currently leads to a per capita emission rate of 2 - 3 t CO₂y^-1. This is due to poor forest regeneration, although the resilience of <it>miombo </it>woodlands is high. Better post-harvest management could change this situation.</p> <p>Conclusions</p> <p>We argue that protection of <it>miombo </it>woodlands has to account for the energy demands of the population. The production at national scale that we estimated converts into 10,000 - 15,000 GWh y^-1of energy in the charcoal. The term "Charcoal Trap" we introduce, describes the fact that this energy supply has to be substituted when woodlands are protected. One possible solution, a shift in energy supply from charcoal to electricity, would reduce the pressure of forests but requires high investments into grid and power generation. Since Zambia currently cannot generate this money by itself, the country will remain locked in the charcoal trap such as many other of its African neighbours. The question arises whether and how money and technology transfer to increase regenerative electrical power generation should become part of a post-Kyoto process. Furthermore, better inventory data are urgently required to improve knowledge about the current state of the woodland usage and recovery. Net greenhouse gas emissions could be reduced substantially by improving the post-harvest management, charcoal production technology and/or providing alternative energy supply.</p