View generated database

This document represents the final report for the View Generated Database (VGD) project, NAS7-1066. It documents the work done on the project up to the point at which all project work was terminated due to lack of project funds. The VGD was to provide the capability to accurately represent any real-world object or scene as a computer model. Such models include both an accurate spatial/geometric representation of surfaces of the object or scene, as well as any surface detail present on the object. Applications of such models are numerous, including acquisition and maintenance of work models for tele-autonomous systems, generation of accurate 3-D geometric/photometric models for various 3-D vision systems, and graphical models for realistic rendering of 3-D scenes via computer graphics

Modular digital holographic fringe data processing system

A software architecture suitable for reducing holographic fringe data into useful engineering data is developed and tested. The results, along with a detailed description of the proposed architecture for a Modular Digital Fringe Analysis System, are presented

Possible mechanism for achieving glass-like thermal conductivities in crystals with off-center atoms

In the filled Ga/Ge clathrate, Eu and Sr are off-center in site 2 but Ba is on-center. All three filler atoms (Ba,Eu,Sr) have low temperature Einstein modes; yet only for the Eu and Sr systems is there a large dip in the thermal conductivity, attributed to the Einstein modes. No dip is observed for Ba. Here we argue that it is the off-center displacement that is crucial for understanding this unexplained difference in behavior. It enhances the coupling between the "rattler" motion and the lattice phonons for the Eu and Sr systems, and turns on/off another scattering mechanism (for 1K < T < 20K) produced by the presence/absence of off-center sites. The random occupation of different off-center sites produces a high density of symmetry-breaking defects which scatters phonons. It may also be important for improving our understanding of other glassy systems.Comment: 4 pages, 1 figure (2 parts) -- v2: intro broadened; strengthened arguments regarding need for additional phonon scattering mechanis

The geomorphological setting of some of Scotland's east coast freshwater mills: a comment on Downward and Skinner (2005) ‘Working rivers: the geomorphological legacy...’

Many of the water mills on Scotland's east coast streams, unlike those discussed recently by Downward and Skinner (2005 Area 37 138–47), are found in predominantly bedrock reaches immediately downstream of knickpoints (i.e. bedrock steps). Bedrock knickpoints in the lower reaches of Scottish rivers are a widespread fluvial response to the glacio-isostatic rebound of northern Britain. These steps in the river profile propagate headward over time, but for intervals of a few centuries or so they are sufficiently stable to be exploited for the elevational fall necessary to power the mill wheel. Many of these mills were apparently powered by ‘run-of-the-river’, as are some today that formerly had mill dams. The typical lack of sediment storage along the erosional lower reaches of many Scottish rivers means that failure of mill structures in Scotland will probably have less dramatic geomorphological and management implications than those suggested by Downward and Skinner for southern English rivers

Efficient Genotyping of KRAS Mutant Non-Small Cell Lung Cancer Using a Multiplexed Droplet Digital PCR Approach

© 2015 Pender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Droplet digital PCR (ddPCR) can be used to detect low frequency mutations in oncogenedriven lung cancer. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach to efficient mutation detection in circulating DNA. Here we report the design and optimisation of three discriminatory ddPCR multiplex assays investigating nine different KRAS mutations using PrimePCRddPCRMutation Assays and the Bio-Rad QX100 system. Together these mutations account for 95% of the nucleotide changes found in KRAS in human cancer. Multiplex reactions were optimised on genomic DNA extracted from KRAS mutant cell lines and tested on DNA extracted from fixed tumour tissue from a cohort of lung cancer patients without prior knowledge of the specific KRAS genotype. The multiplex ddPCR assays had a limit of detection of better than 1 mutant KRAS molecule in 2,000 wild-type KRAS molecules, which compared favourably with a limit of detection of 1 in 50 for next generation sequencing and 1 in 10 for Sanger sequencing. Multiplex ddPCR assays thus provide a highly efficient methodology to identify KRAS mutations in lung adenocarcinoma

Heterodinuclear ruthenium(II)-cobalt(III) complexes as models for a new approach to selective cancer treatment

Heterodinuclear ruthenium(ii)-cobalt(iii) complexes have been prepared as part of investigations into a new approach to selective cancer treatment. A cobalt(iii) centre bearing amine ligands, which serve as models for cytotoxic nitrogen mustard ligands, is connected by a bridging ligand to a ruthenium(ii)-polypyridyl moiety. Upon excitation of the ruthenium centre by visible light, electron transfer to the cobalt(iii) centre results in reduction to cobalt(ii) and consequent release of its ligands. We have synthesised several such structures and demonstrated their ability to release ligands upon excitation of the ruthenium centre by visible light

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.Department of Defense Breast Cancer Research Program Era of Hope Award (W81XWH-07–1-0482)Mary Kay Ash Charitable Trus

JunD, not c-Jun, is the AP-1 transcription factor required for Ras-induced lung cancer.

The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer

Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor.

Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2α and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85α and p85β are dispensable, the PI3-kinase catalytic subunit p110α requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important cross-talk between Ras and PI3K pathways. Furthermore, genetic and pharmacological inhibition of Ras-MAPK pathway impeded epidermal hyperplasia in Pten animals. These results reveal a positive feedback loop connecting Pten and Ras pathways and suggest that FGF-activated Ras-MAPK pathway is an effective therapeutic target for preventing skin tumor induced by aberrant Pten signaling

IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche.

Our understanding of the signalling pathways regulating early human development is limited, despite their fundamental biological importance. Here, we mine transcriptomics datasets to investigate signalling in the human embryo and identify expression for the insulin and insulin growth factor 1 (IGF1) receptors, along with IGF1 ligand. Consequently, we generate a minimal chemically-defined culture medium in which IGF1 together with Activin maintain self-renewal in the absence of fibroblast growth factor (FGF) signalling. Under these conditions, we derive several pluripotent stem cell lines that express pluripotency-associated genes, retain high viability and a normal karyotype, and can be genetically modified or differentiated into multiple cell lineages. We also identify active phosphoinositide 3-kinase (PI3K)/AKT/mTOR signalling in early human embryos, and in both primed and naïve pluripotent culture conditions. This demonstrates that signalling insights from human blastocysts can be used to define culture conditions that more closely recapitulate the embryonic niche