Shh signaling and pancreatic cancer: implications for therapy

Hedgehog signaling has been implicated in the development of several human cancers, including small cell lung carcinomas, medulloblastomas, basal cell carcinomas, and digestive tract tumors. Elevated levels of pathway components are observed in pancreatic ductal adenocarcinoma (PDAC) precursor lesions, and these levels increase further as lesions progress to more advanced stages. Yet the mechanisms by which hedgehog signaling contributes to pancreatic tumorigenesis were poorly understood. We recently published results showing that activated hedgehog signaling enhances the proliferation and survival of pancreatic duct epithelial cells, the presumptive target cells for PDAC development. We also demonstrated that sonic hedgehog (Shh) expression, in cooperation with loss of the Trp53 and Ink4a/Arf tumor suppressor loci, was sufficient to initiate the formation of early pancreatic lesions. Furthermore, Shh signaling enhanced K-Ras-mediated pancreatic tumorigenesis and reduced the dependence of tumor cells on the sustained activation of Ras-stimulated signaling pathways. Here we discuss the significance of these findings and the implications for therapy

Observations of Hierarchical Solar-Type Multiple Star Systems

Twenty multiple stellar systems with solar-type primaries were observed at high angular resolution using the PALM-3000 adaptive optics system at the 5 m Hale telescope. The goal was to complement the knowledge of hierarchical multiplicity in the solar neighborhood by confirming recent discoveries by the visible Robo-AO system with new near-infrared observations with PALM-3000. The physical status of most, but not all, of the new pairs is confirmed by photometry in the Ks band and new positional measurements. In addition, we resolved for the first time five close sub-systems: the known astrometric binary in HIP 17129AB, companions to the primaries of HIP 33555, and HIP 118213, and the companions to the secondaries in HIP 25300 and HIP 101430. We place the components on a color-magnitude diagram and discuss each multiple system individually.Comment: Accepted to Astronomical Journa

A Reconnaissance Geophysical Survey of the Kawartha Lakes and Lake Simcoe, Ontario

A marine geophysical survey program has been conducted in lakes of southern Ontario. The survey was designed to detect neotectonic features, if they exist, and to evaluate their geological importance. High-resolution single- and multichannel seismic reflection profiling were used to delineate late- and post-glacial sedimentary strata and structures, as well as the sediment/bedrock interface, in the Kawartha Lakes and Lake Simcoe. Results show that two seismostratigraphic sequences are common within the unconsolidated overburden. The lower unit exhibits a parallel reflection configuration having strong reflection amplitudes, whereas the upper unit is acoustically transparent and overlies the lower unit conformably in some places and unconformably in others. Both units vary in thickness within lakes and from lake to lake. Typical subbottom profiles of Precambrian rock surfaces are rolling; those of Paleozoic rock surfaces are smooth. At one location in Lower Buckhorn Lake, tilted rock surfaces may be faulted but disturbance of overlying glacioge-nic sediments was not observed. In western Lake Simcoe and Kempenfelt Bay, slumping into graben-like features was observed. Also in Lake Simcoe, a diapiric feature was documented. It is speculated that these disturbances most likely result from glacier ice block melting and fluid migration. A tectonic origin, however, cannot be discounted at this stage of investigation. Additional systematic marine geophysical surveys are required in the future to map features in detail to determine whether they are of neotectonic or glaciotectonic origin.Le levé a été mené afin de déceler les éléments néotectoniques et d'évaluer leur importance géologique. Des profils de sismique réflexion de haute résolution ont servi à déterminer les couches et les structures sédimentaires tardi- et postglaciaires ainsi que l'interface sédiment-roche en place dans les lacs Kawartha et le lac Simcoe. Les résultats montrent qu'il y a deux séquences sismostratigraphiques communes dans la couverture de dépôts meubles. L'unité inférieure présente une configuration de réflexion parallèle avec de fortes amplitudes, alors que l'unité supérieure est transparente du point de vue acoustique et recouvre l'unité inférieure parfois en concordance, parfois en discordance. L'épaisseur des deux unités varie à l'intérieur d'un lac et d'un lac à l'autre. Les profils caractéristiques des surfaces précambriennes sont ondulés, tandis que ceux des surfaces paléozoïques sont plats. En un site du Lower Buckhorn Lake, Ia surface de roches basculées est peut être faillée, mais on n'a observé aucune perturbation dans les sédiments glaciaires sus-jacents. Dans la partie ouest du lac Simcoe et la Kempenfelt Bay, on a observé des glissements dans des formes ressemblant à des grabens. On a également relevé une forme diapirique dans le lac Simcoe. On croit que ces perturbations sont probablement le résultat de la fonte de blocs glaciaires et de la migration de fluides. À ce stade des recherches, on ne peut toutefois pas écarter une origine tectonique. On devra effectuer un levé géophysique systématique afin de cartographier toutes les formes et de déterminer leur origine néotectonique ou glaciotectonique.Ein marines geophysikalisches Vermessungsprogramm wurde in Seen von Sùdontario durchgefuhrt. Die Vermessung war angelegt, um eventuell vorhandene neotektonische Elemente zu entdecken und ihre geologische Bedeutung zu bestimmen. Seismische Reflexionsprofile einfacher oder mehrfacher Frequenz mit hoher Auflôsung wurden benutzt, um die spàt- und postglazia-len Sedimentschichten undstrukturen sowie das Interface Sediment/anstehendes Gestein in den Kawarthaseen und dem Simcoesee zu bestimmen. Die Ergebnisse zeigen, dafî es zwei gemeinsame seismos-tratigraphische Sequenzen innerhalb der nicht verfestigten Uberlastung gibt. Die untere Einheit zeigt eine Paralell-Reflektorstruktur mit starken Reflexion-sweiten, wohingegen die hôhere Einheit akustisch transparent ist und die untere Einheit an einigen Stellen gleichgelagert und an anderen ungleich gelagert bedeckt. Die Dicke der beiden Einheiten variiert innerhalb der Seen und von einem See zum anderen. Die typischen Unterbauprofile der pràkam-brischen Felsoberflachen sind wellig, die der palàozoischen Felsoberflachen glatt. An einer Stelle im unteren Buckhornsee sind die gekippten Felsoberflachen vielleicht verworfen, doch beobachtet man keine Stôrung der darùbergelagerten glaziogenen Sedimente. Im westlichen Simcoesee und der Kempenfelt Bay hat man Abrutschungen in gra-benartige Formen festgestellt. AuBerdem ist im Simcoesee eine diapire Form dokumen-tiert. Man vermutet, dafî dièse Stôrungen hôchstwahrscheinlich auf das Schmelzen von Gletschereisblôcken und flùssige Wanderungen zurùckzufùhren sind. Indessen kann in diesem Stadium der Forschung ein tektonischer Ursprung nicht ausgeschlossen werden

Know the Star, Know the Planet. III. Discovery of Late-Type Companions to Two Exoplanet Host Stars

We discuss two multiple star systems that host known exoplanets: HD 2638 and 30 Ari B. Adaptive optics imagery revealed an additional stellar companion to both stars. We collected multi-epoch images of the systems with Robo-AO and the PALM-3000 adaptive optics systems at Palomar Observatory and provide relative photometry and astrometry. The astrometry indicates that the companions share common proper motion with their respective primaries. Both of the new companions have projected separations less than 30 AU from the exoplanet host star. Using the projected separations to compute orbital periods of the new stellar companions, HD 2638 has a period of 130 yrs and 30 Ari B has a period of 80 years. Previous studies have shown that the true period is most likely within a factor of three of these estimated values. The additional component to the 30 Ari makes it the second confirmed quadruple system known to host an exoplanet. HD 2638 hosts a hot Jupiter and the discovery of a new companion strengthens the connection between hot Jupiters and binary stars. We place the systems on a color-magnitude diagram and derive masses for the companions which turn out to be roughly 0.5 solar mass stars.Comment: Accepted to Astronomical Journal, 16 pages, 5 Figure

Design for validation: An approach to systems validation

Every complex system built is validated in some manner. Computer validation begins with review of the system design. As systems became too complicated for one person to review, validation began to rely on the application of adhoc methods by many individuals. As the cost of the changes mounted and the expense of failure increased, more organized procedures became essential. Attempts at devising and carrying out those procedures showed that validation is indeed a difficult technical problem. The successful transformation of the validation process into a systematic series of formally sound, integrated steps is necessary if the liability inherent in the future digita-system-based avionic and space systems is to be minimized. A suggested framework and timetable for the transformtion are presented. Basic working definitions of two pivotal ideas (validation and system life-cyle) are provided and show how the two concepts interact. Many examples are given of past and present validation activities by NASA and others. A conceptual framework is presented for the validation process. Finally, important areas are listed for ongoing development of the validation process at NASA Langley Research Center

Array-based carbon black-polymer composite vapor detectors for detection of DNT in environments containing complex analyte mixtures

Thin films of carbon black-organic polymer composites have been deposited across two metallic leads, with sorption of vapors producing swelling-induced resistance changes of the detector films. To identify and classify vapors, arrays of such vapor sensing elements have been constructed in which each element of the array contains a different polymer as the insulating phase and a common conductor, carbon black, as the conducting phase. The differing gas-solid partition coefficients for the various polymers of the detector array produce a pattern of differential resistance changes that is used to classify vapors and vapor mixtures. The performance of this detector array system towards 2,4-dinitrotoluene, the predominant signature in the vapor phase above land mines, in the presence high concentrations of water or of acetone has been evaluated

Vapor Detection, Classification, and Quantification Performance Using Arrays of Conducting Polymer Composite Chemically Sensitive Resistors

We describe a method for generating a variety of chemically diverse, broadly responsive, low power vapor sensors. A key to our ability to fabricate chemically diverse sensing elements is the preparation of processable, air stable films of electrically conducting organic polymers. An array of such sensing elements produces a chemically reversible, diagnostic pattern of electrical resistance changes upon exposure to different odorants. Such conducting polymer elements are simply prepared and are readily modified chemically to respond to a broad range of analytes. In addition, these sensors yield a fairly rapid, low power, de electrical signal in response to the vapor of interest, and their signals are readily integrated with software or hardware-based neural networks for purposes of analyte identification. Principle component analysis has demonstrated that such sensors can identify and quantify different airborne organic solvents, and can yield information on the components of gas mixtures

Optimal Design of Passive Flow Control for a Boundary-Layer-Ingesting Offset Inlet Using Design-of-Experiments

This research will investigate the use of Design-of-Experiments (DOE) in the development of an optimal passive flow control vane design for a boundary-layer-ingesting (BLI) offset inlet in transonic flow. This inlet flow control is designed to minimize the engine fan face distortion levels and first five Fourier harmonic half amplitudes while maximizing the inlet pressure recovery. Numerical simulations of the BLI inlet are computed using the Reynolds-averaged Navier-Stokes (RANS) flow solver, OVERFLOW, developed at NASA. These simulations are used to generate the numerical experiments for the DOE response surface model. In this investigation, two DOE optimizations were performed using a D-Optimal Response Surface model. The first DOE optimization was performed using four design factors which were vane height and angles-of-attack for two groups of vanes. One group of vanes was placed at the bottom of the inlet and a second group symmetrically on the sides. The DOE design was performed for a BLI inlet with a free-stream Mach number of 0.85 and a Reynolds number of 2 million, based on the length of the fan face diameter, matching an experimental wind tunnel BLI inlet test. The first DOE optimization required a fifth order model having 173 numerical simulation experiments and was able to reduce the DC60 baseline distortion from 64% down to 4.4%, while holding the pressure recovery constant. A second DOE optimization was performed holding the vanes heights at a constant value from the first DOE optimization with the two vane angles-of-attack as design factors. This DOE only required a second order model fit with 15 numerical simulation experiments and reduced DC60 to 3.5% with small decreases in the fourth and fifth harmonic amplitudes. The second optimal vane design was tested at the NASA Langley 0.3-Meter Transonic Cryogenic Tunnel in a BLI inlet experiment. The experimental results showed a 80% reduction of DPCPavg, the circumferential distortion level at the engine fan face