Conceptual mechanization studies for a horizon definition spacecraft attitude control subsystem, phase A, part II, 10 October 1966 - 29 May 1967

Attitude control subsystem for spin stabilized spacecraft for mapping earths infrared horizon radiance profiles in 15 micron carbon dioxide absorption ban

3 W of single-frequency output at 532 nm by intracavity frequency doubling of a diode-bar-pumped Nd:YAG ring laser 3 W of single-frequency output at 532 nm by intracavity frequency doubling of a diode-bar-pumped Nd:YAG ring laser

A beam-shaped 20W diode-bar has longitudinally pumped a Nd:YAG laser in a ring configuration. Unidirectional single-frequency operation is enforced by a Faraday rotator. Intracavity frequency doubling, using a KTP crystal has produced 3W of stable, single-frequency TEMoo output at 532nm

Pharmacology of DB844, an orally active aza analogue of pafuramidine, in a monkey model of second stage human African trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma C(max) values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible

Human African trypanosomiasis: pharmacological re-engagement with a neglected disease

This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease

Integrated engineering environments for large complex products

An introduction is given to the Engineering Design Centre at the University of Newcastle upon Tyne, along with a brief explanation of the main focus towards large made-to-order products. Three key areas of research at the Centre, which have evolved as a result of collaboration with industrial partners from various sectors of industry, are identified as (1) decision support and optimisation, (2) design for lifecycle, and (3) design integration and co-ordination. A summary of the unique features of large made-to-order products is then presented, which includes the need for integration and co-ordination technologies. Thus, an overview of the existing integration and co-ordination technologies is presented followed by a brief explanation of research in these areas at the Engineering Design Centre. A more detailed description is then presented regarding the co-ordination aspect of research being conducted at the Engineering Design Centre, in collaboration with the CAD Centre at the University of Strathclyde. Concurrent Engineering is acknowledged as a strategy for improving the design process, however design coordination is viewed as a principal requirement for its successful implementation. That is, design co-ordination is proposed as being the key to a mechanism that is able to maximise and realise any potential opportunity of concurrency. Thus, an agentoriented approach to co-ordination is presented, which incorporates various types of agents responsible for managing their respective activities. The co-ordinated approach, which is implemented within the Design Co-ordination System, includes features such as resource management and monitoring, dynamic scheduling, activity direction, task enactment, and information management. An application of the Design Co-ordination System, in conjunction with a robust concept exploration tool, shows that the computational design analysis involved in evaluating many design concepts can be performed more efficiently through a co-ordinated approach

Suppression of respiratory syncytial virus infection in cotton rats by bis(5-amidino-2-benzimidazolyl)methane.

Intraperitoneal administration of bis(5-amidino-2-benzimidazolyl)methane at well-tolerated daily doses of 25 mg/kg subsequent to challenge and for 3 days thereafter effected over a 1-log reduction in the amount of virus recovered from lungs of cotton rats inoculated intratracheally with respiratory syncytial virus. When animals were immunosuppressed to prolong virus shedding, the reduction in recovered virus achieved with a 7-day dosing schedule of bis(5-amidino-2-benzimidazolyl)methane exceeded 2 logs

CYP1A1 and CYP1B1-mediated biotransformation of the antitrypanosomal methamidoxime prodrug DB844 forms novel metabolites through intramolecular rearrangement

DB844 (CPD-594-12), N-methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}- nicotinamidine, is an oral prodrug that has shown promising efficacy in both mouse and monkey models of second stage human African trypanosomiasis. However, gastrointestinal (GI) toxicity was observed with high doses in a vervet monkey safety study. In the current study, we compared the metabolism of DB844 by hepatic and extrahepatic cytochrome P450s to determine if differences in metabolite formation underlie the observed GI toxicity. DB844 undergoes sequential O-demethylation and N-dehydroxylation in the liver to form the active compound DB820 (CPD-593-12). However, extrahepatic CYP1A1 and CYP1B1 produced two new metabolites, MX and MY. Accurate mass and collision-induced dissociation mass spectrometry analyses of the metabolites supported proposed structures of MX and MY. In addition, MY was confirmed with a synthetic standard and detection of nitric oxide release when DB844 was incubated with CYP1A1. Taken altogether, we propose that MX is formed by insertion of an oxygen into the amidine C=N to form an oxaziridine, which is followed by intramolecular rearrangement of the adjacent O-methyl group and subsequent release of nitric oxide. The resulting imine ester, MX, is further hydrolyzed to form MY. These findings may contribute to furthering the understanding of toxicities associated with benzamidoxime- and benzmethamidoxime-containing molecules

A High-Throughput, High-Resolution Strategy for the Study of Site-Selective DNA Binding Agents: Analysis of a “Highly Twisted” Benzimidazole-Diamidine

A general strategy for the rapid structural analysis of DNA binding ligands is described as it was applied to the study of RT29, a new benzimidazole-diamidine compound containing a highly twisted diphenyl ether linkage. By combining the existing high-throughput fluorescent intercalator displacement (HT-FID) assay developed by Boger et al. and a high-resolution (HR) host-guest crystallographic technique, a system was produced that was capable of determining detailed structural information pertaining to RT29-DNA interactions within ~ 3 days. Our application of the HT-HR strategy immediately revealed that RT29 has a preference for four-base pair, A/T-rich sites (AATT) and a similar tolerance and affinity for three A·T-base pair sites (such as ATTC) containing a G·C base pair. Based on these selectivities, oligonucleotides were designed and the host-guest crystallographic method was used to generate diffraction quality crystals. Analysis of the resulting crystal structures revealed that the diphenyl ether moiety of RT29 undergoes conformational changes that allow it to adopt a crescent shape that now complements the minor groove structure. The presence of a G·C base pair in the RT29 binding site of ATTC did not overly perturb its interaction with DNA - the compound adjusted to the nucleobases that were available through water-mediated interactions. Our analyses suggest that the HT-HR strategy may be used to expedite the screening of novel minor groove binding compounds leading to a direct, HR structural determination

Generation of a wave packet tailored to efficient free space excitation of a single atom

We demonstrate the generation of an optical dipole wave suitable for the process of efficiently coupling single quanta of light and matter in free space. We employ a parabolic mirror for the conversion of a transverse beam mode to a focused dipole wave and show the required spatial and temporal shaping of the mode incident onto the mirror. The results include a proof of principle correction of the parabolic mirror's aberrations. For the application of exciting an atom with a single photon pulse we demonstrate the creation of a suitable temporal pulse envelope. We infer coupling strengths of 89% and success probabilities of up to 87% for the application of exciting a single atom for the current experimental parameters.Comment: to be published in Europ. Phys. J.

Effect of Bio-Oss® Collagen and Collagen Matrix on Bone Formation

Objective: to compare the amount of new bone produced by Bio-Oss ® Collagen to that produced by collagen matrix in vivo. Method: eighteen bone defects, 5mm by 10mm were created in the parietal bone of 9 New Zealand White rabbits. 6 defects were grafted with Bio-Oss ® Collagen. 6 defects were grafted with collagen matrix alone (positive control) and 6 were left empty (negative control). Animals were killed on day 14 and the defects were dissected and prepared for histological assessment. Quantitative analysis of new bone formation was made on 100 sections (50 sections for each group) using image analysis. Results: A total of 339% more new bone was present in defects grafted with Bio-Oss ® Collagen than those grafted with collagen matrix (positive control). No bone was formed in the negative control group. Conclusion: Bio-Oss ® Collagen has the effect of stimulating new bone formation locally compared with collagen matrix in vivo. Bio-Oss ® Collagen may be utilized as a bone graft material. © Wong and Rabie; Licensee Bentham Open.published_or_final_versio