Experience Gained and Lessons Learned during the BA3 Fire Repair and Cleanup May-July 1997

The paper presents an overview of the recovery from the fire which took place in BA3 on 13th May 1997. Brief outlines are given of the material damage sustained, the pollution encountered, and the cleaning processes employed. Repairs and cleaning of the building and equipment took over 2 months to complete at a cost in excess of 10 MCHF. The SPS physics program was interrupted for a period of 10 weeks and the LEP start-up was delayed for 6 weeks. The experience gained by the co-ordination team is discussed and advice which may be useful for future reference is included

Reducing the SPS Machine Impedance

The SPS as LHC Injector project has been working for some time to prepare the SPS for its role as final injector for the LHC. This included major work related to injection, acceleration, extraction and beam instrumentation for the LHC beams [1]. Measurements carried out with the high brightness LHC beam showed that a major improvement of the machine impedance would also be necessary [2]. In addition to removing all lepton related components (once LEP operation ended in 2000), the decision was made to shield the vacuum system pumping port cavities. These accidental cavities had been identified as having characteristic frequencies in the 1-1.5GHz range. Since the SPS vacuum system contains roughly 1000 of these cavities, they constitute a major fraction of the machine impedance. As removal of the ports and associated bellows is not possible, transition shields (PPS) had to be designed to insert within the pumping port cavities

Final Report on the Consequences of LHC Civil Engineering for the SPS and LEP

The excavation of the shafts and caverns for the ATLAS and CMS experiments and the transfer lines between the SPS and LHC will start whilst LEP and the SPS are running. This will be during a period when LEP should be at its peak performance and the SPS will be providing beams for LEP, fixed target physics and LHC test beams. Simulations show that movements of the machine tunnels can be expected during the excavation and it is essential that this does not affect the performance of the SPS and LEP. The predicted movements are of sufficient amplitude to prevent machine operation if no precautions are taken. This report contains the conclusions of the working group which has been studying these problems

Screening a protein kinase inhibitor library against <i>Plasmodium falciparum</i>

Abstract Background Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interest to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets. Results As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described. Discussion This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation. Conclusions Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library

Report on the Working Group set up to Study the Requirements for Operating the SPS within the INB Framework (INBOPS)

The convention signed with the French authorities for the LHC defines a new Installation Nucléaire de Base (INB). The LHC machine tunnel, the experiments, some buildings which cover access shafts to the machine and the SPS with its extraction lines up to the targets are all inside the new perimeter. The new convention came into effect in September 2000 and therefore the SPS fell within the new context from that time. As a consequence, SL has to operate the SPS within this new regulatory framework and a small working group was set up to look at the requirements and to estimate the resources required. The conclusions of the working group are reported in this paper

Emerging nuclear collectivity in 124-130Te

The emergence of nuclear collectivity near doubly-magic 132Sn was explored along the stable, eveneven 124−130Te isotopes. Preliminary measurements of the B(E2; 41+ → 21+) transition strengths are reported from Coulomb excitation experiments primarily aimed at measuring the g factors of the 41+ states. Isotopically enriched Te targets were excited by 198-205 MeV 58Ni beams. A comparison of transition strengths obtained is made to large-scale shell-model calculations with successes and limitations discussed

<i>Trypanosoma brucei</i> DHRF-TS revisited:characterisation of a bifunctional and highly unstable recombinant dihydrofolate reductase-thymidylate synthase

<div><p>Bifunctional dihydrofolate reductase–thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA^- <i>Escherichia coli</i>, retains DHFR activity, but lacks any TS activity. TS activity was found to be extremely unstable (half-life of 28 s) following desalting of clarified bacterial lysates to remove small molecules. Stability could be improved 700-fold by inclusion of dUMP, but not by other pyrimidine or purine (deoxy)-nucleosides or nucleotides. Inclusion of dUMP during purification proved insufficient to prevent inactivation during the purification procedure. Methotrexate and trimetrexate were the most potent inhibitors of DHFR (<i>K</i>_i 0.1 and 0.6 nM, respectively) and FdUMP and nolatrexed of TS (<i>K</i>_i 14 and 39 nM, respectively). All inhibitors showed a marked drop-off in potency of 100- to 1,000-fold against trypanosomes grown in low folate medium lacking thymidine. The most potent inhibitors possessed a terminal glutamate moiety suggesting that transport or subsequent retention by polyglutamylation was important for biological activity. Supplementation of culture medium with folate markedly antagonised the potency of these folate-like inhibitors, as did thymidine in the case of the TS inhibitors raltitrexed and pemetrexed.</p></div

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (<b>1</b>) for VL