A peer-to-peer infrastructure for resilient web services

This work is funded by GR/M78403 “Supporting Internet Computation in Arbitrary Geographical Locations” and GR/R51872 “Reflective Application Framework for Distributed Architectures”, and by Nuffield Grant URB/01597/G “Peer-to-Peer Infrastructure for Autonomic Storage Architectures”This paper describes an infrastructure for the deployment and use of Web Services that are resilient to the failure of the nodes that host those services. The infrastructure presents a single interface that provides mechanisms for users to publish services and to find hosted services. The infrastructure supports the autonomic deployment of services and the brokerage of hosts on which services may be deployed. Once deployed, services are autonomically managed in a number of aspects including load balancing, availability, failure detection and recovery, and lifetime management. Services are published and deployed with associated metadata describing the service type. This same metadata may be used subsequently by interested parties to discover services. The infrastructure uses peer-to-peer (P2P) overlay technologies to abstract over the underlying network to deploy and locate instances of those services. It takes advantage of the P2P network to replicate directory services used to locate service instances (for using a service), Service Hosts (for deployment of services) and Autonomic Managers which manage the deployed services. The P2P overlay network is itself constructed using novel Web Services-based middleware and a variation of the Chord P2P protocol, which is self-managing.Postprin

Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei N -myristoyltransferase inhibitors:Identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human african trypanosomiasis

[Image: see text] Trypanosoma bruceiN-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT

Design of the distributed ProcessBase architecture

ProcessBase is an environment designed to support process modelling languages. This environment consists of a language, its interpreter and a persistent object store. Currently this environment supports concurrency through a multi-threading library, however, only a single interpreter instantiation exists as a supported architecture. ProcessBase is a simple language that provides many sophisticated features, including first-class procedures, strong typing, extension through library interfaces, hyper-programming and linguistic reflection, multi-threaded execution and compliance. This document describes the design of distributed ProcessBase architecture. The motivations behind the creation of this architecture are an exploration of compliance in a distributed setting, experimentation with distribution models and distributed garbage collection mechanisms.William Brodie-Tyrrell, Henry Detmold, Katrina Falkner, Matt Lowry, Ron Morrison, Dave Munro, Stuart Norcross, Travis Olds, Zengping Tian, Francis Vaugha

Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei <i>N</i>‑Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis

Trypanosoma brucei <i>N</i>-myristoyltransferase (<i>Tb</i>NMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (<b>1</b>), a potent inhibitor of <i>Tb</i>NMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (<b>40</b>) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT