A rotational and vibrational investigation of phenylpropiolonitrile (C6_6H5_5C3_3N)

The evidence for benzonitrile (C$_6$H$_5$CN}) in the starless cloud core TMC-1 makes high-resolution studies of other aromatic nitriles and their ring-chain derivatives especially timely. One such species is phenylpropiolonitrile (3-phenyl-2-propynenitrile, C$_6$H$_5$C$_3$N), whose spectroscopic characterization is reported here for the first time. The low resolution (0.5 cm$^{-1}$) vibrational spectrum of C$_6$H$_5$C$_3$N} has been recorded at far- and mid-infrared wavelengths (50 - 3500 cm$^{-1}$) using a Fourier Transform interferometer, allowing for the assignment of band centers of 14 fundamental vibrational bands. The pure rotational spectrum of the species has been investigated using a chirped-pulse Fourier transform microwave (FTMW) spectrometer (6 - 18 GHz), a cavity enhanced FTMW instrument (6 - 20 GHz), and a millimeter-wave one (75 - 100 GHz, 140 - 214 GHz). Through the assignment of more than 6200 lines, accurate ground state spectroscopic constants (rotational, centrifugal distortion up to octics, and nuclear quadrupole hyperfine constants) have been derived from our measurements, with a plausible prediction of the weaker bands through calculations. Interstellar searches for this highly polar species can now be undertaken with confidence since the astronomically most interesting radio lines have either been measured or can be calculated to very high accuracy below 300 GHz.Comment: 7 figures, 4 tables. Accepted for publication in J. Mol. Spe

The shadow knows: using shadows to investigate the structure of the pretransitional disk of HD 100453

We present GPI polarized intensity imagery of HD 100453 in Y-, J-, and K1 bands which reveals an inner gap ($9 - 18$ au), an outer disk ($18-39$ au) with two prominent spiral arms, and two azimuthally-localized dark features also present in SPHERE total intensity images (Wagner 2015). SED fitting further suggests the radial gap extends to $1$ au. The narrow, wedge-like shape of the dark features appears similar to predictions of shadows cast by a inner disk which is misaligned with respect to the outer disk. Using the Monte Carlo radiative transfer code HOCHUNCK3D (Whitney 2013), we construct a model of the disk which allows us to determine its physical properties in more detail. From the angular separation of the features we measure the difference in inclination between the disks 45$^{\circ}$, and their major axes, PA = 140$^{\circ}$ east of north for the outer disk and 100$^{\circ}$for the inner disk. We find an outer disk inclination of $25 \pm 10^{\circ}$ from face-on in broad agreement with the Wagner 2015 measurement of 34$^{\circ}$. SPHERE data in J- and H-bands indicate a reddish disk which points to HD 100453 evolving into a young debris disk

Differences in the gas and dust distribution in the transitional disk of a sun-like young star, PDS 70

We present ALMA 0.87 mm continuum, HCO+ J=4--3 emission line, and CO J=3--2 emission line data of the disk of material around the young, Sun-like star PDS 70. These data reveal the existence of a possible two component transitional disk system with a radial dust gap of 0."2 +/- 0."05, an azimuthal gap in the HCO+ J=4--3 moment zero map, as well as two bridge-like features in the gas data. Interestingly these features in the gas disk have no analogue in the dust disk making them of particular interest. We modeled the dust disk using the Monte Carlo radiative transfer code HOCHUNK3D (Whitney et al. 2013) using a two disk components. We find that there is a radial gap that extends from 15-60 au in all grain sizes which differs from previous work

Wavelength-Dependent Extinction and Grain Sizes in Dippers

We have examined inter-night variability of K2-discovered Dippers that are not close to being viewed edge-on, as determined from previously-reported ALMA images, using the SpeX spectrograph and the NASA Infrared Telescope facility (IRTF). The three objects observed were EPIC 203850058, EPIC 205151387, and EPIC 204638512 (2MASS J16042165-2130284). Using the ratio of the fluxes between two successive nights, we find that for EPIC 204638512 and EPIC 205151387, we find that the properties of the dust differ from that seen in the diffuse interstellar medium and denser molecular clouds. However, the grain properties needed to explain the extinction does resemble those used to model the disks of many young stellar objects. The wavelength-dependent extinction models of both EPIC 204638512 and EPIC 205151387 includes grains at least 500 microns in size, but lacks grains smaller than 0.25 microns. The change in extinction during the dips, and the timescale for these variations to occur, imply obscuration by the surface layers of the inner disks. The recent discovery of a highly mis-inclined inner disk in EPIC 204638512 is suggests that the variations in this disk system may point to due to rapid changes in obscuration by the surface layers of its inner disk, and that other face-on Dippers might have similar geometries. The He I line at 1.083 microns in EPIC 205151387 and EPIC 20463851 were seen to change from night to night, suggesting that we are seeing He I gas mixed in with the surface dust.Comment: 13 pages, 6 figures, 2 table

Variability of Disk Emission in Pre-Main Sequence and Related Stars IV. Investigating the Structural Changes in the Inner Disk Region of MWC 480

We present five epochs of near IR observations of the protoplanetary disk around MWC 480 (HD31648) obtained with the SpeX spectrograph on NASA's Infrared Telescope Facility (IRTF) between 2007 and 2013, inclusive. Using the measured line fluxes in the Pa beta and Br gamma lines, we found the mass accretion rates to be (1.43 - 2.61)x10^-8 Msun y^-1 and (1.81 - 2.41)x10^-8 Msun y^-1 respectively, but which varied by more than 50% from epoch to epoch. The spectral energy distribution (SED)reveals a variability of about 30% between 1.5 and 10 microns during this same period of time. We investigated the variability using of the continuum emission of the disk in using the Monte-Carlo Radiative Transfer Code (MCRT) HOCHUNK3D. We find that varying the height of the inner rim successfully produces a change in the NIR flux, but lowers the far IR emission to levels below all measured fluxes. Because the star exhibits bipolar flows, we utilized a structure that simulates an inner disk wind to model the variability in the near IR, without producing flux levels in the far IR that are inconsistent with existing data. For this object, variable near IR emission due to such an outflow is more consistent with the data than changing the scale height of the inner rim of the disk.Comment: 19 pages, 14 figure

Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

D-brane potentials in the warped resolved conifold and natural inflation

In this paper we obtain a model of Natural Inflation from string theory with a Planckian decay constant. We investigate D-brane dynamics in the background of the warped resolved conifold (WRC) throat approximation of Type IIB string compactifications on Calabi-Yau manifolds. When we glue the throat to a compact bulk Calabi-Yau, we generate a D-brane potential which is a solution to the Laplace equation on the resolved conifold. We can exactly solve this equation, including dependence on the angular coordinates. The solutions are valid down to the tip of the resolved conifold, which is not the case for the more commonly used deformed conifold. This allows us to exploit the effect of the warping, which is strongest at the tip. We inflate near the tip using an angular coordinate of a D5-brane in the WRC which has a discrete shift symmetry, and feels a cosine potential, giving us a model of Natural Inflation, from which it is possible to get a Planckian decay constant whilst maintaining control over the backreaction. This is because the decay constant for a wrapped brane contains powers of the warp factor, and so can be made large, while the wrapping parameter can be kept small enough so that backreaction is under control.Comment: 41 pages, 3 appendices, 1 figure, PDFLaTex; various clarifications added along with a new appendix on b-axions and wrapped D5 branes;version matches the one published in JHE

Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions