and

The purpose of this paper is to study codes over finite principal ideal rings. To do this, we begin with codes over finite chain rings as a natural generalization of codes over Galois rings GR(pe, l) (including Zpe). We give sufficient conditions on the existence of MDS codes over finite chain rings and on the existence of self-dual codes over finite chain rings. We also construct MDS self-dual codes over Galois rings GF (2e, l) of length n = 2l for any a ≥ 1 and l ≥ 2. Torsion codes over residue fields of finite chain rings are introduced, and some of their properties are derived. Finally, we describe MDS codes and self-dual codes over finite principal ideal rings by examining codes over their component chain rings, via a generalized Chinese remainder theorem

Structural and Functional Characterisation of Glutathione-S-Transferases to Combat Multiple Herbicide Resistance in Black Grass (Alopecurus myosuroides)

Black grass (Alopecurus myosuroides) is one of the most common weeds in Western Europe. With the increasing use of herbicides, in response to pressure to produce higher crop yields, incidences of multiple herbicide resistance have been widely reported. Previous work in this area has identified a phi class glutathione-s-transferase, AmGSTF1, as playing a causative role in this multiple herbicide resistance. Two classes of inhibitor have previously been identified: the first CNBF, a multi drug resistance drug; and the second a group of flavone compounds identified from ligand fishing experiments. These have been shown to have activity in vitro inhibiting the action of AmGSTF1 and in vivo against multiple herbicide resistant black grass. However, little was known about their mode of action. This work has focussed on investigating the interactions between these inhibitors and AmGSTF1 using crystallographic, biochemical and complementary biophysical techniques. Apo AmGSTF1 has successfully been crystallised, with the structure solved to 1.5 Å. In addition a structure has been solved to 2.0 Å with CNBF covalently modifying the Cys120 residue. For both these structures the crystal packing results in loops in the active site region being disordered as well as preventing small molecule binding within the active site. In order to determine the complete structure, a series of mutants were designed to alter crystal packing. The structure of these were determined, and they adopt a different packing arrangement which results in the previously disordered loops being ordered, as well as exposing the binding site. The structure of the F122T mutant was used for in silico modelling to determine the likely binding site for flavonoid ligands. The mutants were subsequently used for seeding and soaking experiments which allowed for a complete structure of wild type AmGSTF1 to be determined in complex with a glutathione conjugate of CNBF in the active site. This structure gives a significantly better understanding of the mode of action of these inhibitors, in addition to allowing for the possibility of future development of the inhibitors using structure based design

Geosynchronous platform definition study. Volume 5: Geosynchronous platform synthesis

The development is described of the platform configurations, support subsystems, mission equipment, and servicing concepts. A common support module is developed; subsystem concepts are traded off; data relay, TDRS, earth observational, astro-physics, and advanced navigation and traffic control mission equipment concepts are postulated; and ancillary equipment required for delivery and on-orbit servicing interfaces with geosynchronous platforms is grossly defined. The general approach was to develop a platform concept capable of evolving through three on-orbit servicing modes: remote, EVA, and shirtsleeve. The definition of the equipment is to the assembly level. Weight, power, and volumetric data are compiled for all the platforms

Discovery by Virtual Screening of Ethionamide Boosters for Tuberculosis Treatment

Tuberculosis remains the world’s deadliest communicable bacterial disease with an unacceptably high death rate. In 2013 an estimated 1.5 million people died as a direct result of TB, and nine million new cases were reported. Multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis cases are on the rise and without novel approaches to combat their spread, tuberculosis will continue to claim the lives of millions worldwide. One such novel approach is to rejuvenate the use of the second-line antibiotic ethionamide. Ethionamide is a structural analogue of the first-line pro-drug isoniazid, which is used widely and to which there is growing resistance. Ethionamide was introduced in the 1960s and primarily used in cases of drug-resistant TB due to its severe adverse effects. This makes ethionamide an exploitable target for small-molecule booster drugs. Expression of the enzyme responsible for ethionamide activation, EthA, is regulated by a transcriptional repressor EthR which can be inhibited to improve ethionamide activation and so reduce ethionamide treatment doses and bring an old drug new life in the clinic. EthR inhibitors are currently in development; here, chemoinformatic pipelining and virtual screening in GOLD were used to identify hits with novel scaffolds for hit-to-lead efforts from an initial library of over six million drug-like molecules. Thermal shift assays were used to identify EthR-binding molecules and SPR was utilised to confirm and potentially quantify binding affinities. Herein are reported the co-crystal structures of several hit molecules, used to confirm and characterise the EthR-ligand complexes. Through the application of computational, biophysical and crystallographic methods, this thesis presents several novel scaffolds for development against EthR. These novel hits will be developed to expand our arsenal against the growing, global problem of drug-resistant TB

Structural investigation on p-glycoprotein 1, bile salt export pump, and sodium/calcium exchanger

Transmembrane proteins span biological membranes and provide essential functions to the cell. Here we provide structural insight into three transmembrane proteins involved in substrate transport and signal transduction. Our goal is to understand the mechanism underlying the function of those proteins and to contribute thereby to improvements for future medical treatments. P-glycoprotein 1 (Pgp) is an ABC transporter involved in multidrug transport. It provides protection from potentially toxic substances by exporting them from the cell. However in cancer cells upregulation of Pgp expression can interfere with therapy. Here we provide a near-atomic resolution structure of cross-linked nucleotide free Pgp interacting with UIC2, an inhibitory antibody, and the third generation Pgp inhibitor zosuquidar. Our structure shows binding of two zosuquidar molecules in the transmembrane domain of an occluded conformation. In addition we describe the binding interface of UIC2 binding, providing insight to the mechanism of conformational trapping. Characterized binding interfaces may be exploited for therapeutic purposes. BSEP is the only bile salt transporter at the canalicular membrane of hepatocytes. Despite a very high sequence identity compared to Pgp, BSEP is way more selective. While diseases effected by mutations in BSEP are considerably rare, inhibition of BSEP can be the result of not intended interactions between BSEP and a variety of pharmaceutical compounds. I determined four structures of BSEP including a drug inhibited state using the antidiabetic drug glibenclamide and two structures in presence of the substrate taurocholate. These structures give rise to multiple potential models for the transport mechanism. In addition I could show that glibenclamide binds to the cytosolic facing cavity of BSEP, either repressing the connecting loop between the N- and C-terminal BSEP or locking BSEP in a inside open conformation. In addition mutations of BSEP associated with disease could be explained on structural basis. NCX are a sodium/calcium exchangers widely spread among species, involved in calcium signalling. We have solved two crystal structures of the bacterial NCX from Thermotoga maritima in the outward facing conformation. Both conformations are substrate free, but show differences in the ion binding site. Comparison of our structures the NCX homolog from Methanococcus jannaschii suggest a simple reorientation of N-termianl helix 7 to switch NCX to the occluded state, indicating transition to the inward facing site

Tracking and Data Relay Satellite System configuration and tradeoff study. Volume 2: Delta 2914 launched TDRSS, Configuration 2. Part 2: Final Report, 22 August 1972 - 1 April 1973

Configuration data and design information for a Delta 2914 launched configuration with greatly enhanced telecommunication service over the Part I Delta 2914 configuration is contained. The overall system definition, operations and control, and telecommunication service system, including link budgets are discussed. A brief description of the user transceiver and ground station is presented. A final section includes a summary description of the TDR spacecraft and all the subsystems. The data presented are largely in tabular form

Exploitation of underused Streptomyces through a combined metabolomics-genomics workflow to enhance natural product diversity.

The genus Streptomyces is the source of approximately two-thirds of all clinically-used antibiotics. Despite being the source of so many specialised metabolites, genomic analysis indicates that most Streptomyces strains have the potential to produce around twenty-five bioactive metabolites, some of which may be the basis of novel therapies. This makes culture collections of Streptomyces spp. an easily accessible (but under-used) resource to mine for genomic and metabolomic variety. Therefore, the main aim of this project was to initiate exploitation of the culture collection at NCIMB Ltd., by expanding the available chemical space from under-utilised Streptomyces for the production of novel antibiotics. This primarily used a mixture of metabolomic and genomic methods. A high-throughput culture parameter screen was designed around multiple carbon sources, nitrogen sources and extraction sample times. This was tested on the model species S. coelicolor A3(2) to compare differences in the production of known specialised metabolites, using UPLC-MS to analyse crude extracts from growth on agar. Data was analysed using MZmine and putative metabolites were identified using freely-available MS/MS databases - primarily GNPS. This showed clear variation in production of nine identified metabolites - including deferoxamines, germicidins, undecylprodigiosin and coelichelin - as a result of different culture parameters. Therefore, the screen successfully expanded the available chemical space, so was applied to non-model Streptomyces strains. The screen was used to compare the total metabolomic variety produced by three Streptomyces, isolated from different environments, in order to select a strain for further investigation. Comparing metabolomic features using principal component analysis showed the Costa Rican soil isolate S. costaricanus to produce the most variety versus the other two Streptomyces strains. The metabolite family most responsible for principal component separation was identified as the actinomycins. Scale-up of both agar and broth culture was used for metabolite dereplication and bioassays against multidrug resistant Acinetobacter baumannii, which is one of the bacteria on the World Health Organisation's list of pathogens that most urgently require new therapies. Fractions were derived from broth culture supernatant and agar crude extract by flash chromatography, resulting in semi-purified fractions. The predominant metabolite families in fractions were actinomycins and deferoxamines, which were further split by polarity into separate fractions. This resulted in rapid purification of metabolites, with one fraction comprising 80% deferoxamine B by weight. Fractions were tested against A. baumannii using the 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assay, which showed partial inhibition of growth at 50 µg/ml. Examining the bioactive fractions showed potentially novel minor peaks that could be responsible for bioactivity. A high-quality full genome of S. costaricanus was obtained using a combination of MiSeq and MinION sequences. This was analysed with RAST and antiSMASH to determine the specialised metabolite potential of S. costaricanus. AntiSMASH detected thirty-three biosynthetic gene clusters (BGCs), above the mean for Streptomyces. Thus, the confirmed genomic potential also suggested a wider metabolite variety, as indicated by the metabolomic screen. Some of the thirty-three BGC products had been previously detected by UPLC-MS, like actinomycin D and deferoxamine B. Other BGCs had 0% homology to known BGCs, including a terpene BGC which only showed core gene homology to two other Streptomyces. One of these strains shared all of the BGCs with S. costaricanus, including their sequential order and closely approximated genomic locations. Comparison of marker genes with autoMLST gave preliminary evidence for the taxonomic reclassification of S. costaricanus as a strain of S. griseofuscus. Starting from a large collection of unexploited Streptomyces, this project catalogued the metabolomic and genomic diversity of a single strain and its bioactive potential. Together, the project stages formed a workflow for further exploitation of NCIMB Streptomyces and other microbes