A multi-fidelity approach for aerodynamic performance computations of formation flight

This paper introduces a multi-fidelity computational framework for the analysis of aerodynamic performance of flight formation. The Vortex Lattice and Reynolds Averaged Navier–Stokes methods form the basis of the framework, as low- and high-fidelity, respectively. Initially, the computational framework is validated for an isolated wing, and then two rectangular NACA23012 wings are considered for assessing the aerodynamic performance of this formation; the optimal relative position is through the multi-fidelity framework based on the total drag reduction. The performance estimates are in good agreement with experimental measurements of the same configuration. Total aerodynamic performance of formation flight is also assessed with respect to attitude variations of the lifting bodies involved. The framework is also employed to determine the optimal position of blended-wing-body unmanned aerial vehicles in tandem formation flight

Deletion of Endothelial Estrogen Receptor Alpha Reduces Arterial Stiffness in Angiotensin II infused-Female Mice

Vascular stiffness is a naturally occurring phenomenon associated with aging, but conditions such as obesity and type 2 diabetes accelerate its development, particularly in women. The presence of vascular stiffness increases significantly the risk of cardiovascular disease (CVD). Under physiological conditions, estrogen signaling via estrogen receptor alpha (ERα) increases bioavailable nitric oxide in the endothelium and decreases stiffness. Nevertheless, large clinical trials have failed to demonstrate beneficial cardiovascular effects of estrogen therapy. Our previous work has shown that under conditions of over-nutrition, the lack of ERα ameliorates arterial stiffening in obese and insulin resistant females. Given the central role that activation of the Renin-Angiotensin-System (RAS) has in the pathogenesis of CVD, in the present study we examine the effect of an Angiotensin II (Ang II) infusion in female mice lacking endothelial cell (EC)

Tuning graphitic oxide for initiator- and metal-free aerobic epoxidation of linear alkenes

Graphitic oxide has potential as a carbocatalyst for a wide range of reactions. Interest in this material has risen enormously due to it being a precursor to graphene via the chemical oxidation of graphite. Despite some studies suggesting that the chosen method of graphite oxidation can influence the physical properties of the graphitic oxide, the preparation method and extent of oxidation remain unresolved for catalytic applications. Here we show that tuning the graphitic oxide surface can be achieved by varying the amount and type of oxidant. The resulting materials differ in level of oxidation, surface oxygen content and functionality. Most importantly, we show that these graphitic oxide materials are active as unique carbocatalysts for low-temperature aerobic epoxidation of linear alkenes in the absence of initiator or metal. An optimum level of oxidation is necessary and materials produced via conventional permanganate-based methods are far from optimal

Modeling Kepler transit light curves as false positives: Rejection of blend scenarios for Kepler-9, and validation of Kepler-9d, a super-Earth-size planet in a multiple system

Light curves from the Kepler Mission contain valuable information on the nature of the phenomena producing the transit-like signals. To assist in exploring the possibility that they are due to an astrophysical false positive, we describe a procedure (BLENDER) to model the photometry in terms of a "blend" rather than a planet orbiting a star. A blend may consist of a background or foreground eclipsing binary (or star-planet pair) whose eclipses are attenuated by the light of the candidate and possibly other stars within the photometric aperture. We apply BLENDER to the case of Kepler-9, a target harboring two previously confirmed Saturn-size planets (Kepler-9b and Kepler-9c) showing transit timing variations, and an additional shallower signal with a 1.59-day period suggesting the presence of a super-Earth-size planet. Using BLENDER together with constraints from other follow-up observations we are able to rule out all blends for the two deeper signals, and provide independent validation of their planetary nature. For the shallower signal we rule out a large fraction of the false positives that might mimic the transits. The false alarm rate for remaining blends depends in part (and inversely) on the unknown frequency of small-size planets. Based on several realistic estimates of this frequency we conclude with very high confidence that this small signal is due to a super-Earth-size planet (Kepler-9d) in a multiple system, rather than a false positive. The radius is determined to be 1.64 (+0.19/-0.14) R(Earth), and current spectroscopic observations are as yet insufficient to establish its mass.Comment: 20 pages in emulateapj format, including 8 tables and 16 figures. To appear in ApJ, 1 January 2010. Accepted versio

KOI-54: The Kepler Discovery of Tidally Excited Pulsations and Brightenings in a Highly Eccentric Binary

Kepler observations of the star HD 187091 (KIC 8112039, hereafter KOI-54) revealed a remarkable light curve exhibiting sharp periodic brightening events every 41.8 days with a superimposed set of oscillations forming a beating pattern in phase with the brightenings. Spectroscopic observations revealed that this is a binary star with a highly eccentric orbit, e = 0.83. We are able to match the Kepler light curve and radial velocities with a nearly face-on (i = 5 degrees.5) binary star model in which the brightening events are caused by tidal distortion and irradiation of nearly identical A stars during their close periastron passage. The two dominant oscillations in the light curve, responsible for the beating pattern, have frequencies that are the 91st and 90th harmonic of the orbital frequency. The power spectrum of the light curve, after removing the binary star brightening component, reveals a large number of pulsations, 30 of which have a signal-to-noise ratio greater than or similar to 7. Nearly all of these pulsations have frequencies that are either integer multiples of the orbital frequency or are tidally split multiples of the orbital frequency. This pattern of frequencies unambiguously establishes the pulsations as resonances between the dynamic tides at periastron and the free oscillation modes of one or both of the stars. KOI-54 is only the fourth star to show such a phenomenon and is by far the richest in terms of excited modes.NASA, Science Mission DirectorateNASA NNX08AR14GEuropean Research Council under the European Community 227224W.M. Keck FoundationMcDonald Observator

Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

INTRODUCTION: Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT). METHODS: We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to investigate its pharmacokinetic properties and antitumor effects in several murine tumor models as well as patient-derived organotypic tumor spheroids (PDOTS). RESULTS: (S)-mepazine demonstrated significant antitumor effects and was synergistic with anti-PD-1 therapy in vivo and ex vivo but did not affect circulating Treg frequencies in healthy rats at effective doses. Pharmacokinetic profiling revealed favorable drug accumulation in tumors to concentrations that effectively blocked MALT1 activity, potentially explaining preferential effects on tumor-infiltrating over systemic Tregs. CONCLUSIONS: The MALT1 inhibitor (S)-mepazine showed single-agent anticancer activity and presents a promising opportunity for combination with PD-1 pathway-targeted ICT. Activity in syngeneic tumor models and human PDOTS was likely mediated by induction of tumor-associated Treg fragility. This translational study supports ongoing clinical investigations (ClinicalTrials.gov Identifier: NCT04859777) of MPT-0118, (S)-mepazine succinate, in patients with advanced or metastatic treatment-refractory solid tumors

Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

Introduction Regulatory T cells (Tregs) play a critical role in the maintenance of immune homeostasis but also protect tumors from immune-mediated growth control or rejection and pose a significant barrier to effective immunotherapy. Inhibition of MALT1 paracaspase activity can selectively reprogram immune-suppressive Tregs in the tumor microenvironment to adopt a proinflammatory fragile state, which offers an opportunity to impede tumor growth and enhance the efficacy of immune checkpoint therapy (ICT). Methods We performed preclinical studies with the orally available allosteric MALT1 inhibitor (S)-mepazine as a single-agent and in combination with anti-programmed cell death protein 1 (PD-1) ICT to investigate its pharmacokinetic properties and antitumor effects in several murine tumor models as well as patient-derived organotypic tumor spheroids (PDOTS). Results (S)-mepazine demonstrated significant antitumor effects and was synergistic with anti-PD-1 therapy in vivo and ex vivo but did not affect circulating Treg frequencies in healthy rats at effective doses. Pharmacokinetic profiling revealed favorable drug accumulation in tumors to concentrations that effectively blocked MALT1 activity, potentially explaining preferential effects on tumor-infiltrating over systemic Tregs. Conclusions The MALT1 inhibitor (S)-mepazine showed single-agent anticancer activity and presents a promising opportunity for combination with PD-1 pathway-targeted ICT. Activity in syngeneic tumor models and human PDOTS was likely mediated by induction of tumor-associated Treg fragility. This translational study supports ongoing clinical investigations (ClinicalTrials.gov Identifier: NCT04859777) of MPT-0118, (S)-mepazine succinate, in patients with advanced or metastatic treatment-refractory solid tumors

A First Comparison of Kepler Planet Candidates in Single and Multiple Systems

In this letter we present an overview of the rich population of systems with multiple candidate transiting planets found in the first four months of Kepler data. The census of multiples includes 115 targets that show 2 candidate planets, 45 with 3, 8 with 4, and 1 each with 5 and 6, for a total of 170 systems with 408 candidates. When compared to the 827 systems with only one candidate, the multiples account for 17 percent of the total number of systems, and a third of all the planet candidates. We compare the characteristics of candidates found in multiples with those found in singles. False positives due to eclipsing binaries are much less common for the multiples, as expected. Singles and multiples are both dominated by planets smaller than Neptune; 69 +2/-3 percent for singles and 86 +2/-5 percent for multiples. This result, that systems with multiple transiting planets are less likely to include a transiting giant planet, suggests that close-in giant planets tend to disrupt the orbital inclinations of small planets in flat systems, or maybe even to prevent the formation of such systems in the first place.Comment: 13 pages, 13 figures, submitted to ApJ Letter

Kepler-21b: A 1.6REarth Planet Transiting the Bright Oscillating F Subgiant Star HD 179070

We present Kepler observations of the bright (V=8.3), oscillating star HD 179070. The observations show transit-like events which reveal that the star is orbited every 2.8 days by a small, 1.6 R_Earth object. Seismic studies of HD 179070 using short cadence Kepler observations show that HD 179070 has a frequencypower spectrum consistent with solar-like oscillations that are acoustic p-modes. Asteroseismic analysis provides robust values for the mass and radius of HD 179070, 1.34{\pm}0.06 M{\circ} and 1.86{\pm}0.04 R{\circ} respectively, as well as yielding an age of 2.84{\pm}0.34 Gyr for this F5 subgiant. Together with ground-based follow-up observations, analysis of the Kepler light curves and image data, and blend scenario models, we conservatively show at the >99.7% confidence level (3{\sigma}) that the transit event is caused by a 1.64{\pm}0.04 R_Earth exoplanet in a 2.785755{\pm}0.000032 day orbit. The exoplanet is only 0.04 AU away from the star and our spectroscopic observations provide an upper limit to its mass of ~10 M_Earth (2-{\sigma}). HD 179070 is the brightest exoplanet host star yet discovered by Kepler.Comment: Accepted to Ap

Planet Occurrence within 0.25 AU of Solar-type Stars from Kepler

We report the distribution of planets as a function of planet radius (R_p), orbital period (P), and stellar effective temperature (Teff) for P < 50 day orbits around GK stars. These results are based on the 1,235 planets (formally "planet candidates") from the Kepler mission that include a nearly complete set of detected planets as small as 2 Earth radii (Re). For each of the 156,000 target stars we assess the detectability of planets as a function of R_p and P. We also correct for the geometric probability of transit, R*/a. We consider first stars within the "solar subset" having Teff = 4100-6100 K, logg = 4.0-4.9, and Kepler magnitude Kp < 15 mag. We include only those stars having noise low enough to permit detection of planets down to 2 Re. We count planets in small domains of R_p and P and divide by the included target stars to calculate planet occurrence in each domain. Occurrence of planets varies by more than three orders of magnitude and increases substantially down to the smallest radius (2 Re) and out to the longest orbital period (50 days, ~0.25 AU) in our study. For P < 50 days, the radius distribution is given by a power law, df/dlogR= k R^\alpha. This rapid increase in planet occurrence with decreasing planet size agrees with core-accretion, but disagrees with population synthesis models. We fit occurrence as a function of P to a power law model with an exponential cutoff below a critical period P_0. For smaller planets, P_0 has larger values, suggesting that the "parking distance" for migrating planets moves outward with decreasing planet size. We also measured planet occurrence over Teff = 3600-7100 K, spanning M0 to F2 dwarfs. The occurrence of 2-4 Re planets in the Kepler field increases with decreasing Teff, making these small planets seven times more abundant around cool stars than the hottest stars in our sample. [abridged]Comment: Submitted to ApJ, 22 pages, 10 figure