The TRENDS High-Contrast Imaging Survey. VII. Discovery of a Nearby Sirius-like White Dwarf System (HD 169889)

Monitoring the long-term radial velocity (RV) and acceleration of nearby stars has proven an effective method for directly detecting binary and substellar companions. Some fraction of nearby RV trend systems are expected to be comprised of compact objects that likewise induce a systemic Doppler signal. In this paper, we report the discovery of a white dwarf companion found to orbit the nearby ($\pi = 28.297 \pm 0.066$ mas) G9 V star HD 169889. High-contrast imaging observations using NIRC2 at Keck and LMIRCam at the LBT uncover the ($\Delta H = 9.76 \pm 0.16$, $\Delta L' = 9.60 \pm 0.03$) companion at an angular separation of 0.8'' (28 au). Thirteen years of precise Doppler observations reveal a steep linear acceleration in RV time series and place a dynamical constraint on the companion mass of $M \geq 0.369 \pm 0.010 M_{\odot}$. This "Sirius-like" system adds to the census of white dwarf companions suspected to be missing in the solar neighborhood.Comment: Accepted to Ap

Processing CCD Images to Detect Transits of Earth-Sized Planets: Maximizing Sensitivity While Achieving Reasonable Downlink Requirements

We have performed end-to-end laboratory and numerical simulations to demonstrate the capability of differential photometry under realistic operating conditions to detect transits of Earth-sized planets orbiting solar-like stars. Data acquisition and processing were conducted using the same methods planned for the proposed Kepler Mission. These included performing aperture photometry on large-format CCD images of an artificial star fields obtained without a shutter at a readout rate of 1 megapixel/sec, detecting and removing cosmic rays from individual exposures and making the necessary corrections for nonlinearity and shutterless operation in the absence of darks. We will discuss the image processing tasks performed `on-board' the simulated spacecraft, which yielded raw photometry and ancillary data used to monitor and correct for systematic effects, and the data processing and analysis tasks conducted to obtain lightcurves from the raw data and characterize the detectability of transits. The laboratory results are discussed along with the results of a numerical simulation carried out in parallel with the laboratory simulation. These two simulations demonstrate that a system-level differential photometric precision of 10-5 on five- hour intervals can be achieved under realistic conditions

Using a Differential Emission Measure and Density Measurements in an Active Region Core to Test a Steady Heating Model

The frequency of heating events in the corona is an important constraint on the coronal heating mechanisms. Observations indicate that the intensities and velocities measured in active region cores are effectively steady, suggesting that heating events occur rapidly enough to keep high temperature active region loops close to equilibrium. In this paper, we couple observations of Active Region 10955 made with XRT and EIS on \textit{Hinode} to test a simple steady heating model. First we calculate the differential emission measure of the apex region of the loops in the active region core. We find the DEM to be broad and peaked around 3\,MK. We then determine the densities in the corresponding footpoint regions. Using potential field extrapolations to approximate the loop lengths and the density-sensitive line ratios to infer the magnitude of the heating, we build a steady heating model for the active region core and find that we can match the general properties of the observed DEM for the temperature range of 6.3 $<$ Log T $<$ 6.7. This model, for the first time, accounts for the base pressure, loop length, and distribution of apex temperatures of the core loops. We find that the density-sensitive spectral line intensities and the bulk of the hot emission in the active region core are consistent with steady heating. We also find, however, that the steady heating model cannot address the emission observed at lower temperatures. This emission may be due to foreground or background structures, or may indicate that the heating in the core is more complicated. Different heating scenarios must be tested to determine if they have the same level of agreement.Comment: 16 pages, 9 figures, accepted to Ap

The LEECH Exoplanet Imaging Survey: Limits on Planet Occurrence Rates Under Conservative Assumptions

We present the results of the largest $L^{\prime}$ ($3.8~\mu$m) direct imaging survey for exoplanets to date, the Large Binocular Telescope Interferometer (LBTI) Exozodi Exoplanet Common Hunt (LEECH). We observed 98 stars with spectral types from B to M. Cool planets emit a larger share of their flux in $L^{\prime}$ compared to shorter wavelengths, affording LEECH an advantage in detecting low-mass, old, and cold-start giant planets. We emphasize proximity over youth in our target selection, probing physical separations smaller than other direct imaging surveys. For FGK stars, LEECH outperforms many previous studies, placing tighter constraints on the hot-start planet occurrence frequency interior to $\sim20$ au. For less luminous, cold-start planets, LEECH provides the best constraints on giant-planet frequency interior to $\sim20$ au around FGK stars. Direct imaging survey results depend sensitively on both the choice of evolutionary model (e.g., hot- or cold-start) and assumptions (explicit or implicit) about the shape of the underlying planet distribution, in particular its radial extent. Artificially low limits on the planet occurrence frequency can be derived when the shape of the planet distribution is assumed to extend to very large separations, well beyond typical protoplanetary dust-disk radii ($\lesssim50$ au), and when hot-start models are used exclusively. We place a conservative upper limit on the planet occurrence frequency using cold-start models and planetary population distributions that do not extend beyond typical protoplanetary dust-disk radii. We find that $\lesssim90\%$ of FGK systems can host a 7 to 10 $M_{\mathrm{Jup}}$ planet from 5 to 50 au. This limit leaves open the possibility that planets in this range are common.Comment: 31 pages, 13 figures, accepted to A

The TRENDS High-contrast Imaging Survey. VII. Discovery of a Nearby Sirius-like White Dwarf System (HD 169889)

Monitoring the long-term radial velocity (RV) and acceleration of nearby stars has been proven as an effective method for directly detecting binary and substellar companions. Some fraction of nearby RV trend systems are expected to be comprised of compact objects that likewise induce a systemic Doppler signal. In this paper, we report the discovery of a white dwarf (WD) companion found to orbit the nearby (π = 28.297 ± 0.066 mas) G9 V star HD 169889. High-contrast imaging observations using NIRC2 at the W. M. Keck Observatory and LMIRCam at the Large Binocular Telescope (LBT) Observatory uncover the (ΔH = 9.76 ± 0.16, ΔL' = 9.60 ± 0.03) companion at an angular separation of 0.”8 (28 au). Thirteen years of precise Doppler observations reveal a steep linear acceleration in the RV time series and place a dynamical constraint on the companion mass of M ≥ 0.369 ± 0.010 M_⊙. This "Sirius-like" system adds to the census of WD companions suspected to be missing from surveys of in the solar neighborhood

Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia.

Background & Aims Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. Methods We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. Results Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. Conclusions In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer

The metabolic enzyme hexokinase 2 localizes to the nucleus in AML and normal haematopoietic stem and progenitor cells to maintain stemness

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity. Mitochondrial metabolites regulate leukaemic and normal stem cells by affecting epigenetic marks. How mitochondrial enzymes localize to the nucleus to control stem cell function is less understood. We discovered that the mitochondrial metabolic enzyme hexokinase 2 (HK2) localizes to the nucleus in leukaemic and normal haematopoietic stem cells. Overexpression of nuclear HK2 increases leukaemic stem cell properties and decreases differentiation, whereas selective nuclear HK2 knockdown promotes differentiation and decreases stem cell function. Nuclear HK2 localization is phosphorylation-dependent, requires active import and export, and regulates differentiation independently of its enzymatic activity. HK2 interacts with nuclear proteins regulating chromatin openness, increasing chromatin accessibilities at leukaemic stem cell-positive signature and DNA-repair sites. Nuclear HK2 overexpression decreases double-strand breaks and confers chemoresistance, which may contribute to the mechanism by which leukaemic stem cells resist DNA-damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes influence stem cell function independently of their metabolic function