Decentralised Commitment for Optimistic Semantic Replication

International audienceWe study large-scale distributed cooperative systems that use optimistic replication. We represent a system as a graph of actions (operations) connected by edges that reify semantic constraints between actions. Constraint types include conflict, execution order, dependence, and atomicity. The local state is some schedule that conforms to the constraints; because of conflicts, client state is only tentative. For consistency, site schedules should converge; we designed a decentralised, asynchronous commitment protocol. Each client makes a proposal, reflecting its tentative and/or preferred schedules. Our protocol distributes the proposals, which it decomposes into semantically-meaningful units called candidates, and runs an election between comparable candidates. A candidate wins when it receives a majority or a plurality. The protocol is fully asynchronous: each site executes its tentative schedule independently, and determines locally when a candidate has won an election. The committed schedule is as close as possible to the preferences expressed by clients

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Staging presymptomatic type 1 diabetes: A scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association.

Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease

Ionization states of the catalytic residues in HIV-1 protease

Chemical synthesis was used to prepare the HIV-1 protease specifically 13C-labelled in the catalytically essential Asp 25 in each monomer. The NMR chemical shift of the 13C-enriched homodimeric enzyme was measured in the presence of the inhibitor pepstatin, a mimic of the tetrahedral intermediate formed in enzyme catalysis. In this complex, the catalytic carboxyls do not titrate in the pH range where the enzyme is active; throughout the range pH 2.5-6.5, one Asp 25 side chain is protonated and the other deprotonated. By contrast, in the absence of inhibitor the two Asp side chains are chemically equivalent and both deprotonated at pH 6, the optimum for enzymatic activity. These direct observations of the chemical properties of the catalytic apparatus of the enzyme provide concrete information on which to base the design of improved HIV-1 protease inhibitors