High-Resolution Near Infrared Spectroscopy of HD 100546: II. Analysis of variable rovibrational CO emission lines

We present observations of rovibrational CO in HD 100546 from four epochs spanning January 2003 through December 2010. We show that the equivalent widths of the CO lines vary during this time period with the v=1-0 CO lines brightening more than the UV fluoresced lines from the higher vibrational states. While the spectroastrometric signal of the hot band lines remains constant during this period, the spectroastrometric signal of the v=1--0 lines varies substantially. At all epochs, the spectroastrometric signals of the UV fluoresced lines are consistent with the signal one would expect from gas in an axisymmetric disk. In 2003, the spectroastrometric signal of the v=1-0 P26 line was symmetric and consistent with emission from an axisymmetric disk. However, in 2006, there was no spatial offset of the signal detected on the red side of the profile, and in 2010, the spectroastrometric offset was yet more strongly reduced toward zero velocity. A model is presented that can explain the evolution of the equivalent width of the v=1-0 P26 line and its spectroastrometric signal by adding to the system a compact source of CO emission that orbits the star near the inner edge of the disk. We hypothesize that such emission may arise from a circumplanetary disk orbiting a gas giant planet near the inner edge of the circumstellar disk. We discuss how this idea can be tested observationally and be distinguished from an alternative interpretation of random fluctuations in the disk emission.Comment: 18 pages, 10 figure

High-Resolution Near Infrared Spectroscopy of HD 100546: I. Analysis of Asymmetric Ro-Vibrational OH Emission Lines

We present observations of ro-vibrational OH and CO emission from the Herbig Be star HD 100546. The emission from both molecules arises from the inner region of the disk extending from approximately 13 AU from the central star. The velocity profiles of the OH lines are narrower than the velocity profile of the [O I] 6300 Angstrom line indicating that the OH in the disk is not cospatial with the O I. This suggests that the inner optically thin region of the disk is largely devoid of molecular gas. Unlike the ro-vibrational CO emission lines, the OH lines are highly asymmetric. We show that the average CO and average OH line profiles can be fit with a model of a disk comprised of an eccentric inner wall and a circular outer disk. In this model, the vast majority of the OH flux (75%) originates from the inner wall, while the vast majority of the CO flux (65%) originates on the surface of the disk at radii greater than 13 AU. Eccentric inner disks are predicted by hydrodynamic simulations of circumstellar disks containing an embedded giant planet. We discuss the implications of such a disk geometry in light of models of planet disk tidal interactions and propose alternate explanations for the origin of the asymmetry

Surface Buildup Scenarios and Outpost Architectures for Lunar Exploration

The Constellation Program Architecture Team and the Lunar Surface Systems Project Office have developed an initial set of lunar surface buildup scenarios and associated polar outpost architectures, along with preliminary supporting element and system designs in support of NASA's Exploration Strategy. The surface scenarios are structured in such a way that outpost assembly can be suspended at any time to accommodate delivery contingencies or changes in mission emphasis. The modular nature of the architectures mitigates the impact of the loss of any one element and enhances the ability of international and commercial partners to contribute elements and systems. Additionally, the core lunar surface system technologies and outpost operations concepts are applicable to future Mars exploration. These buildup scenarios provide a point of departure for future trades and assessments of alternative architectures and surface elements

Ro-vibrational CO Detected in the β Pictoris Circumstellar Disk

We present high-resolution near-infrared spectra of β Pictoris—a nearby young star with a debris disk. Fundamental low-J CO absorption lines are detected and strict upper limits are placed on the flux of v = 2–1 low-J CO emission lines. The limit on the UV fluorescent emission flux in the v = 2–1 lines is used to place a tight constraint on the inner extent of the CO gas. Assuming Hi is the primary collision partner, the sub-thermal population of the low-J v = 0 rotational levels constrains the density of the gas in the disk to nH = (2.5+7.1 −1.2)×105 cm−3. If the distribution of hydrogen follows that of the other metals in the disk, we find that the mass of the gas in the disk is 0.17+0.47 −0.08M⊕. We compare this mass to the gas mass necessary to brake the metals in the disk through ion–neutral reactions

Phospholipase C-γ Modulates Epithelial Tight Junction Permeability through Hyperphosphorylation of Tight Junction Proteins

Phospholipase C-gamma (PLC-gamma) is stimulated by epidermal growth factor via activation of the epidermal growth factor receptors. The PLC inhibitor, 3-nitrocoumarin (3-NC), selectively inhibited PLC-gamma in Madin-Darby canine kidney cells without affecting the activity of PLC-beta. In contrast, inhibitors of PLC-beta, hexadecylphosphocholine and, had no effect on the activity of PLC-gamma. Inhibition of PLC-gamma by 3-NC was associated with an increase in tight junction permeability across Madin-Darby canine kidney cell monolayers, as evidenced by 3-NC-induced decrease in transepithelial electrical resistance and increase in mannitol flux over a concentration range that was inhibitory to PLC-gamma. An analog of 3-NC, 7-hydroxy-3-NC (7-OH-3-NC), which was inactive as an inhibitor of PLC-gamma, also had no effect on tight junction permeability. Treatment with 3-NC caused punctate disruption in the cortical actin filaments. The PLC-gamma inhibitor, 3-NC, but not the inactive analog, 7-OH-3-NC, caused hyperphosphorylation of the tight junction proteins, occludin, ZO-1, and ZO-2. The serine/threonine kinase inhibitor, staurosporine (50-200 nm), significantly attenuated 3-NC-induced hyperphosphorylation of ZO-2. This corresponded with attenuation by staurosporine of 3-NC-induced increase in tight junction permeability, suggesting a relationship between ZO-2 phosphorylation and tight junction permeability

Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

High-resolution Near-infrared Spectroscopy of HD 100546. I. Analysis of Asymmetric Ro-vibrational OH Emission Lines

We present observations of ro-vibrational OH and CO emission from the Herbig Be star HD 100546. The emission from both molecules arises from the inner region of the disk extending from approximately 13 AU from the central star. The velocity profiles of the OH lines are narrower than the velocity profile of the [O i] λ6300 line, indicating that the OH in the disk is not cospatial with the Oi. This suggests that the inner optically thin region of the disk is largely devoid of molecular gas. Unlike the ro-vibrational CO emission lines, the OH lines are highly asymmetric. We show that the average CO and average OH line profiles can be fit with a model of a disk comprised of an eccentric inner wall and a circular outer disk. In this model, the vast majority of the OH flux (75%) originates from the inner wall, while the vast majority of the CO flux (65%) originates on the surface of the disk at radii greater than 13 AU. Eccentric inner disks are predicted by hydrodynamic simulations of circumstellar disks containing an embedded giant planet. We discuss the implications of such a disk geometry in light of models of planet–disk tidal interactions and propose alternative explanations for the origin of the asymmetry