Test and Evaluation Metrics of Crew Decision-Making And Aircraft Attitude and Energy State Awareness

NASA has established a technical challenge, under the Aviation Safety Program, Vehicle Systems Safety Technologies project, to improve crew decision-making and response in complex situations. The specific objective of this challenge is to develop data and technologies which may increase a pilot's (crew's) ability to avoid, detect, and recover from adverse events that could otherwise result in accidents/incidents. Within this technical challenge, a cooperative industry-government research program has been established to develop innovative flight deck-based counter-measures that can improve the crew's ability to avoid, detect, mitigate, and recover from unsafe loss-of-aircraft state awareness - specifically, the loss of attitude awareness (i.e., Spatial Disorientation, SD) or the loss-of-energy state awareness (LESA). A critical component of this research is to develop specific and quantifiable metrics which identify decision-making and the decision-making influences during simulation and flight testing. This paper reviews existing metrics and methods for SD testing and criteria for establishing visual dominance. The development of Crew State Monitoring technologies - eye tracking and other psychophysiological - are also discussed as well as emerging new metrics for identifying channelized attention and excessive pilot workload, both of which have been shown to contribute to SD/LESA accidents or incidents

An Assessment of Reduced Crew and Single Pilot Operations in Commercial Transport Aircraft Operations

Future reduced crew operations or even single pilot operations for commercial airline and on-demand mobility applications are an active area of research. These changes would reduce the human element and thus, threaten the precept that "a well-trained and well-qualified pilot is the critical center point of aircraft systems safety and an integral safety component of the entire commercial aviation system." NASA recently completed a pilot-in-the-loop high fidelity motion simulation study in partnership with the Federal Aviation Administration (FAA) attempting to quantify the pilot's contribution to flight safety during normal flight and in response to aircraft system failures. Crew complement was used as the experiment independent variable in a between-subjects design. These data show significant increases in workload for single pilot operations, compared to two-crew, with subjective assessments of safety and performance being significantly degraded as well. Nonetheless, in all cases, the pilots were able to overcome the failure mode effects in all crew configurations. These data reflect current-day flight deck equipage and help identify the technologies that may improve two-crew operations and/or possibly enable future reduced crew and/or single pilot operations

Limits on Quaoar's Atmosphere

Here we present high cadence photometry taken by the Acquisition Camera on Gemini South, of a close passage by the ~540 km radius Kuiper belt object, (50000) Quaoar, of a r' = 20.2 background star. Observations before and after the event show that the apparent impact parameter of the event was 0."019 ± 0."004, corresponding to a close approach of 580 ± 120 km to the center of Quaoar. No signatures of occultation by either Quaoar's limb or its potential atmosphere are detectable in the relative photometry of Quaoar and the target star, which were unresolved during closest approach. From this photometry we are able to put constraints on any potential atmosphere Quaoar might have. Using a Markov chain Monte Carlo and likelihood approach, we place pressure upper limits on sublimation supported, isothermal atmospheres of pure N_2, CO, and CH_4. For N_2 and CO, the upper limit surface pressures are 1 and 0.7 μbar, respectively. The surface temperature required for such low sublimation pressures is ~33 K, much lower than Quaoar's mean temperature of ~44 K measured by others. We conclude that Quaoar cannot have an isothermal N_2 or CO atmosphere. We cannot eliminate the possibility of a CH_4 atmosphere, but place upper surface pressure and mean temperature limits of ~138 nbar and ~44 K, respectively

Di-cationic arylimidamides Act Against Neospora caninum tachyzoites by Interference in Membrane Structure and Nucleolar Integrity and are Active Against Challenge Infection in Mice

Neospora caninum is considered to be the main cause of bovine abortion in Europe and the USA, leading to considerable financial impact. Losses are caused directly by abortions or indirectly through breeding of calves with impaired viability. Due to the lack of effective chemotherapy against bovine neosporosis, there is a need to develop new anti-protozoal compounds, which would either eliminate the parasite or avoid its transmission. In order to identify compounds of interest, the in vitro activities of 41 di-cationic pentamidine derivatives were studied employing a transgenic N. caninum clone expressing beta-galactosidase as a reporter gene. The arylimidamide DB745, previously shown to be highly active against Leishmania donovani in vitro and in vivo, appeared as the most promising compound, with an IC50 of 80 nM in 3-day growth assays and severely affecting both host cell invasion as well as intracellular proliferation. TEM of intracellular tachyzoites identified distinct alterations related to the nucleolus and the nuclear and cellular membrane. Long-term growth assays showed that DB745 acted parasiticidal upon the Nc-Liv isolate, but not against the Nc-1 isolate of N. caninum. In vivo studies in N. caninum (Nc-1 isolate) infected mice showed that daily intraperitoneal application of DB745 for a period of 14 days resulted in a decreased number of clinically affected animals, and lower cerebral parasite burdens in DB745-treated mice compared to non-treated mice. These results illustrate the potential of dicationic arylimidamides for the treatment of N. caninum infections

The adaptive potential of a survival artist: characterization of the in vitro interactions of Toxoplasma gondii tachyzoites with di-cationic compounds in human fibroblast cell cultures

The impact of di-cationic pentamidine-analogues against Toxoplama gondii (Rh- and Me49-background) was investigated. The 72 h-growth assays showed that the arylimidamide DB750 inhibited the proliferation of tachyzoites of T. gondii Rh and T. gondii Me49 with an IC50 of 0·11 and 0·13 μm, respectively. Pre-incubation of fibroblast monolayers with 1 μm DB750 for 12 h and subsequent culture in the absence of the drug also resulted in a pronounced inhibiton of parasite proliferation. However, upon 5-6 days of drug exposure, T. gondii tachyzoites adapted to the compound and resumed proliferation up to a concentration of 1·2 μm. Out of a set of 32 di-cationic compounds screened for in vitro activity against T. gondii, the arylimidamide DB745, exhibiting an IC50 of 0·03 μm and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC50=0·07 μm). In contrast to DB750, DB745 also had a profound negative impact on extracellular non-adapted T. gondii tachyzoites, but not on DB750-adapted T. gondii. Adaptation of T. gondii to DB745 (up to a concentration of 0·46 μm) was much more difficult to achieve and feasible only over a period of 110 days. In cultures infected with DB750-adapted T. gondii seemingly intact parasites could occasionally be detected by TEM. This illustrates the astonishing capacity of T. gondii tachyzoites to adapt to environmental changes, at least under in vitro conditions, and suggests that DB745 could be an interesting drug candidate for further assessments in appropriate in vivo model

The adaptive potential of a survival artist: characterization of the in vitro interactions of Toxoplasma gondii tachyzoites with di-cationic compounds in human fibroblast cell cultures

The impact of di-cationic pentamidine-analogues against Toxoplama gondii (Rh- and Me49-background) was investigated. The 72 h-growth assays showed that the arylimidamide DB750 inhibited the proliferation of tachyzoites of T. gondii Rh and T. gondii Me49 with an IC50 of 0·11 and 0·13 μm, respectively. Pre-incubation of fibroblast monolayers with 1 μm DB750 for 12 h and subsequent culture in the absence of the drug also resulted in a pronounced inhibiton of parasite proliferation. However, upon 5-6 days of drug exposure, T. gondii tachyzoites adapted to the compound and resumed proliferation up to a concentration of 1·2 μm. Out of a set of 32 di-cationic compounds screened for in vitro activity against T. gondii, the arylimidamide DB745, exhibiting an IC50 of 0·03 μm and favourable selective toxicity was chosen for further studies. DB745 also inhibited the proliferation of DB750-adapted T. gondii (IC50=0·07 μm). In contrast to DB750, DB745 also had a profound negative impact on extracellular non-adapted T. gondii tachyzoites, but not on DB750-adapted T. gondii. Adaptation of T. gondii to DB745 (up to a concentration of 0·46 μm) was much more difficult to achieve and feasible only over a period of 110 days. In cultures infected with DB750-adapted T. gondii seemingly intact parasites could occasionally be detected by TEM. This illustrates the astonishing capacity of T. gondii tachyzoites to adapt to environmental changes, at least under in vitro conditions, and suggests that DB745 could be an interesting drug candidate for further assessments in appropriate in vivo model

Structure-dependent Inhibition of the ETS-Family Transcription Factor PU.1 by Novel Heterocyclic Diamidines

ETS transcription factors mediate a wide array of cellular functions and are attractive targets for pharmacological control of gene regulation. We report the inhibition of the ETS-family member PU.1 with a panel of novel heterocyclic diamidines. These diamidines are derivatives of furamidine (DB75) in which the central furan has been replaced with selenophene and/or one or both of the bridging phenyl has been replaced with benzimidazole. Like all ETS proteins, PU.1 binds sequence specifically to 10-bp sites by inserting a recognition helix into the major groove of a 50-GGAA-30 consensus, accompanied by contacts with the flanking minor groove. We showed that diamidines target the minor groove of AT-rich sequences on one or both sides of the consensus and disrupt PU.1 binding. Although all of the diamidines bind to one or both of the expected sequences within the binding site, considerable heterogeneity exists in terms of stoichiometry, site–site interactions and induced DNA conformation. We also showed that these compounds accumulate in live cell nuclei and inhibit PU.1-dependent gene transactivation. This study demonstrates that heterocyclic diamidines are capable of inhibiting PU.1 by targeting the flanking sequences and supports future efforts to develop agents for inhibiting specific members of the ETS family

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

Kuiper Belt Occultation Predictions

Here we present observations of seven large Kuiper Belt objects. From these observations, we extract a point source catalog with ∼0.01″ precision, and astrometry of our target Kuiper Belt objects with 0.04–0.08″ precision within that catalog. We have developed a new technique to predict the future occurrence of stellar occultations by Kuiper Belt objects. The technique makes use of a maximum likelihood approach which determines the best-fit adjustment to cataloged orbital elements of an object. Using simulations of a theoretical object, we discuss the merits and weaknesses of this technique compared to the commonly adopted ephemeris offset approach. We demonstrate that both methods suffer from separate weaknesses, and thus together provide a fair assessment of the true uncertainty in a particular prediction. We present occultation predictions made by both methods for the seven tracked objects, with dates as late as 2015. Finally, we discuss observations of three separate close passages of Quaoar to field stars, which reveal the accuracy of the element adjustment approach, and which also demonstrate the necessity of considering the uncertainty in stellar position when assessing potential occultations

Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease: In Vivo Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

Arylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day × 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day × 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.This work was supported by a grant from the Bill and Melinda Gates Foundation, contract N01-AI-60011 with SRI International from the National Institute of Allergy and Infectious Diseases, FIOCRUZ, and by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) PPSUS, APQ1, and Pensa-Rio (16/2009-E-26/110-313/2010), Conselho Nacional Desenvolvimento científico e Tecnológico (CNPq), PDTIS/FIOCRUZ, and PROEP. We thank the other members of the Consortium for Parasitic Drug Development for helpful discussions