Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

All-sky search for long-duration gravitational wave transients with initial LIGO

We present the results of a search for long-duration gravitational wave transients in two sets of data collected by the LIGO Hanford and LIGO Livingston detectors between November 5, 2005 and September 30, 2007, and July 7, 2009 and October 20, 2010, with a total observational time of 283.0 days and 132.9 days, respectively. The search targets gravitational wave transients of duration 10–500 s in a frequency band of 40–1000 Hz, with minimal assumptions about the signal waveform, polarization, source direction, or time of occurrence. All candidate triggers were consistent with the expected background; as a result we set 90% confidence upper limits on the rate of long-duration gravitational wave transients for different types of gravitational wave signals. For signals from black hole accretion disk instabilities, we set upper limits on the source rate density between 3.4×10−5 and 9.4×10−4  Mpc−3 yr−1 at 90% confidence. These are the first results from an all-sky search for unmodeled long-duration transient gravitational waves

A state observer for the Virgo inverted pendulum

We report an application of Kalman filtering to the inverted pendulum (IP) of the Virgo gravitational wave interferometer. Using subspace method system identification techniques, we calculated a linear mechanical model of Virgo IP from experimental transfer functions. We then developed a Kalman filter, based on the obtained state space representation, that estimates from open loop time domain data, the state variables of the system. This allows the observation (and eventually control) of every resonance mode of the IP mechanical structure independently

Spatial organization of a ubiquitous eukaryotic kinetochore protein network in Drosophila chromosomes.

Chromosome segregation during meiosis and mitosis depends on the assembly of functional kinetochores within centromeric regions. Centromeric DNA and kinetochore proteins show surprisingly little sequence conservation despite their fundamental biological role. However, our identification in Drosophila melanogaster of the most diverged orthologs identified so far, which encode components of a kinetochore protein network including the Ndc80 and Mis complexes, further emphasizes the notion of a shared eukaryotic kinetochore design. To determine its spatial organization, we have analyzed by quantitative light microscopy hundreds of native chromosomes from transgenic Drosophila strains coexpressing combinations of red and green fluorescent fusion proteins, fully capable of providing the essential wild-type functions. Thereby, Cenp-A/Cid, Cenp-C, Mis12 and the Ndc80 complex were mapped along the inter sister kinetochore axis with a resolution below 10 nm. The C terminus of Cenp-C was found to be near but well separated from the innermost component Cenp-A/Cid. The N terminus of Cenp-C is further out, clustered with Mis12 and the Spc25 end of the rod-like Ndc80 complex, which is known to bind to microtubules at its other more distal Ndc80/Nuf2 end