Crestone (United States)

BackgroundListeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes.MethodsRodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies. CRS0540 pharmacokinetics/pharmacodynamics studies in an intracellular hollow-fibre system model of disseminated listeriosis (HFS-Lister) examined the effect of eight treatment doses, administered daily over 7 days, in duplicate units. Total bacterial burden versus AUC/MIC exposures on each day were modelled using the inhibitory sigmoid Emax model, while CRS0540-resistant bacterial burden was modelled using a quadratic function. Ten thousand-subject Monte Carlo simulations were used to predict an optimal clinical dose for treatment.ResultsThe mean CRS0540 intracellular/extracellular AUC0–24 ratio was 34.07 (standard error: 15.70) as measured in the HFS-Lister. CRS0540 demonstrated exposure-dependent bactericidal activity in the HFS-Lister, with the highest exposure killing approximately 5.0 log10 cfu/mL. The free drug AUC0–24/MIC associated with 80% of maximal kill (EC80) was 36.4. Resistance emergence versus AUC/MIC was described by a quadratic function, with resistance amplification at an AUC/MIC of 54.8 and resistance suppression at an AUC/MIC of 119. Monte Carlo simulations demonstrated that for the EC80 target, IV CRS0540 doses of 100 mg/kg achieved PTAs of >90% at MICs up to 1.0 mg/L.ConclusionsCRS0540 is a promising orphan drug candidate for listeriosis. Future PK/PD studies comparing it with penicillin, the standard of care, could lead to this drug as a new treatment in immunocompromised patients.

The 20th Annual 3D Seismic Symposium was held 13 February 2014, in Denver, Colorado. The theme was “20/20 3D Vision.” The 3D Symposium is jointly sponsored by the Rocky Mountain Association of Geologists and the Denver Geophysical Society.

This chapter contains sections titled: Introduction Regional Tectonics Deformation Fronts Discussion Conclusions

Mountain ridges in the western Yakutat microplate are riddled with swarms of antislope scarps and troughs. These landforms were previously interpreted as gravity failures (sackungen), but if partly or wholly tectonic (flexural slip or bending moment faults), they represent part of the strain budget from ongoing plate collision. To determine scarp origin, we mapped landforms, bedrock structure, and trenched scarps at Kushtaka Mountain and south of Martin Lake. The Kushtaka scarps paralleled west-dipping coal and sandstone beds in the Tertiary Kultieth Formation, and were spaced 35–60 m apart with heights of 1–4 m. Structural and paleosol relationships in a 6-m-long, 1.3-m-deep trench indicate the scarp was produced by Holocene creep on a normal fault underlying the scarp. The Kushtaka scarps thus represent toppling-style slip on bedding-plane faults in the eastern limb of a syncline, as the fold “unfolds” due to gravitational spreading. The Martin Lake scarps are more complex and include downslope-facing landslide scarps, upslope-facing flexural toppling scarps, and an oblique-slip tectonic scarp. A 2-m-deep trench across the WNW-trending tectonic scarp exposed the underlying bedrock fault plane with slickensides raking only 17°–20°, indicating mainly left-lateral slip on a sinistral-normal fault. In contrast, swarms of ENE-trending antislope scarps showed normal-oblique (dextral) slip. The two scarp sets may form a conjugate pair that simultaneously accommodates left-lateral tectonic slip and NNE-directed gravitational spreading. Our results, plus those recently published by [Li et al. (2010)][1], show that most antislope scarps in the western Yakutat microplate are formed by normal slip on bedding-plane faults that dip into the mountain, and represent gravitational spreading expressed as toppling-style failure or “unfolding” of strata on fold limbs. Conversely, the sinistral-oblique slip fault at Martin Lake is one in a family of east-trending faults accommodating accretion of the Yakutat microplate into the cuspate syntaxis of the Alaskan plate margin. [1]: #ref-14

SynopsisBarley stripe mosaic virus has caused severe losses in spring wheat yields and moderate losses in test‐weights in experimental trials in Montana since 1956. Field readings for incidence of virus show the disease has increased in Pilot and Centana, has about maintained itself in Rescue, and has decreased in Lee, C.I. 13041, C.I. 13042, Supreme, and Thatcher. Greenhouse plantings showed that storage had little or no effect on the percentage of seed which carried the virus.