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

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

Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures.

The capabilities of pentamidine and nine pentamidine analogs to inhibit the development of Toxoplasma gondii were examined in vitro. Treatment of infected cultures with pentamidine and five of its analogs caused a significant (P less than 0.05) reduction in the numbers of tachyzoites produced. Analogs of pentamidine may be useful agents in the treatment of toxoplasmosis

Inspædia: [Almost] Everything About Simplicity, Playfulness and Inspiration

The aim of this paper is to disclose the new research developments and the results from the systematization of experience and user interaction with the Inspædia (a new web knowledge “Agora”), to inspire a dynamic, collaborative, and interactive intelligence among the inspædiers. We will explain in detail and describe the design process and discuss the ultimate design interaction concept & development regarding (almost everything about) simplicity and playfulness of the inspædiers’ experience to transform relevant information (related > meanfull > useful) in productive knowledge (inspiration > insight > foresight) in a very easy and quick way (usability: learnability; understandability; operability; attractiveness...), with a smile in the face (satisfaction) and a wow in the mind (or in the soul).Inspædia is the natural consequence and development of the prototype resulting from the research in Design PhD thesis Innovation, design et cetera (FA/UTL, 2012). Therefore, it is being developed with the Science Without Borders Program (2013-2016) with a Special Visiting Researcher fellowship grant of CAPES (Brazil), and under the post-doctoral in Design at the Faculty of Architecture, University of Lisbon (FA/UL); CIAUD – Reseach Centre of Architecture, Urbanism and Design (FA/UL); Faculty of Sciences and Technology, Nova University of Lisbon (FCT/UNL); NOVA-LINCS (FCT/UNL) and CITAD - Research Centre for Territory, Architecture and Design (FAA/ULL). The Inspædia research project was ranked in first place in Design scientific area and obtained a post-doctoral fellowship by FCT – Foundation for Science and Technology (Portugal). The project has been internationally disseminated at international Design conferences with indexed publications. It was presented and published both at AHFE 2014 (Krakow) and AHFE 2015 (Las Vegas). It was part of the biennial Experimentadesign tangential events in 2013 (EXD'13), 2015 (EXD'15) and was presented, by invitation, at the International Congress DESIGN I-CON (2015). During the last year we prototyped and tested (usability testing) with some inspædiers different approaches to achieve users’ needs > desires > expectations) in a challenging way, in order to provide the most powerful and memorable user experience

Efficacy, safety, and dose of Pafuramidine, a new oral drug for treatment of first stage sleeping sickness, in a phase 2a clinical study and phase 2b randomized clinical studies

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.; The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.; Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3

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.

Easing into the Academy: Using Technology to Foster Cross-Institutional Critical Friendships

This article addresses the ways in which early career teacher educators can support each other as they enter the academic community. By utilizing technology as an instrument to engage in a cross-country critical friendship, the authors were able to engage in a dialogue that grew out of mutual interests and concerns. Through critical reflection, they were able to address the question: How can we, two early-career teacher educators, push ourselves and one another to more critically examine our teaching practices? In doing so, each “new educator” grew more confident in claiming one\u27s voice as a sustainable critical friendship emerged

Carbenic nitrile imines: Properties and reactivity

Structures and properties of nitrile imines were investigated computationally at B3LYP and CCSD(T) levels. Whereas NBO analysis at the B3LYP DFT level invariably predicts a propargylic electronic structure, CCSD(T) calculations permit a clear distinction between propargylic, allenic, and carbenic structures. Nitrile imines with strong IR absorptions above ca. 2150 cm-1 have propargylic structures with a CN triple bond (RCNNSiMe 3 and R2BCNNBR2), and those with IR absorptions below ca. 2150 cm-1 are allenic (HCNNH, PhCNNH, and HCNNPh). Nitrile imines lacking significant cumulenic IR absorptions at 1900-2200 cm -1 are carbenic (R-(C:)-N=N-R′). Electronegative but lone pair-donating groups NR2, OR, and F stabilize the carbenic form of nitrile imines in the same way they stabilize "normal" singlet carbenes, including N-heterocyclic carbenes. NBO analyses at the CCSD(T) level confirm the classification into propargylic, allenic, and carbenic reactivity types. Carbenic nitrile imines are predicted to form azoketenes 21 with CO, to form [2+2] and [2+4] cycloadducts and borane adducts, and to cyclize to 1H-diazirenes of the type 24 in mildly exothermic reactions with activation energies in the range 29-38 kcal/mol. Such reactions will be readily accessible photochemically and thermally, e.g., under the conditions of matrix photolysis and flash vacuum thermolysis

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family