Purposive discovery of operations

The Generate, Prune & Prove (GPP) methodology for discovering definitions of mathematical operators is introduced. GPP is a task within the IL exploration discovery system. We developed GPP for use in the discovery of mathematical operators with a wider class of representations than was possible with the previous methods by Lenat and by Shen. GPP utilizes the purpose for which an operator is created to prune the possible definitions. The relevant search spaces are immense and there exists insufficient information for a complete evaluation of the purpose constraint, so it is necessary to perform a partial evaluation of the purpose (i.e., pruning) constraint. The constraint is first transformed so that it is operational with respect to the partial information, and then it is applied to examples in order to test the generated candidates for an operator's definition. In the GPP process, once a candidate definition survives this empirical prune, it is passed on to a theorem prover for formal verification. We describe the application of this methodology to the (re)discovery of the definition of multiplication for Conway numbers, a discovery which is difficult for human mathematicians. We successfully model this discovery process utilizing information which was reasonably available at the time of Conway's original discovery. As part of this discovery process, we reduce the size of the search space from a computationally intractable size to 3468 elements

Kentucky Law Survey: Administrative Law

This article provides a survey of administrative law in the Commonwealth of Kentucky, including discussions of de novo review and the delegation doctrine

Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns

ABSTRACT: BACKGROUND: Aberrant CpG island promoter DNA hypermethylation is frequently observed in cancer and is believed to contribute to tumor progression by silencing the expression of tumor suppressor genes. Previously, we observed that promoter hypermethylation in breast cancer reflects cell lineage rather than tumor progression and occurs at genes that are already repressed in a lineage-specific manner. To investigate the generality of our observation we analyzed the methylation profiles of 1,154 cancers from 7 different tissue types. RESULTS: We find that 1,009 genes are prone to hypermethylation in these 7 types of cancer. Nearly half of these genes varied in their susceptibility to hypermethylation between different cancer types. We show that the expression status of hypermethylation prone genes in the originator tissue determines their propensity to become hypermethylated in cancer; specifically, genes that are normally repressed in a tissue are prone to hypermethylation in cancers derived from that tissue. We also show that the promoter regions of hypermethylation-prone genes are depleted of repetitive elements and that DNA sequence around the same promoters is evolutionarily conserved. We propose that these two characteristics reflect tissue-specific gene promoter architecture regulating the expression of these hypermethylation prone genes in normal tissues. CONCLUSIONS: As aberrantly hypermethylated genes are already repressed in pre-cancerous tissue, we suggest that their hypermethylation does not directly contribute to cancer development via silencing. Instead aberrant hypermethylation reflects developmental history and the perturbation of epigenetic mechanisms maintaining these repressed promoters in a hypomethylated state in normal cells.Publisher PDFPeer reviewe

Lateral Membrane Waves Constitute a Universal Dynamic Pattern of Motile Cells

We have monitored active movements of the cell circumference on specifically coated substrates for a variety of cells including mouse embryonic fibroblasts and T cells, as well as wing disk cells from fruit flies. Despite having different functions and being from multiple phyla, these cell types share a common spatiotemporal pattern in their normal membrane velocity; we show that protrusion and retraction events are organized in lateral waves along the cell membrane. These wave patterns indicate both spatial and temporal long-range periodic correlations of the actomyosin gel

WIP deficiency reveals a differential role for WIP and the actin cytoskeleton in T and B cell activation

Producción CientíficaWIP stabilizes actin filaments and is important for filopodium formation. To define the role of WIP in immunity, we generated WIP-deficient mice. WIP(minus sign/minus sign) mice have normal lymphocyte development, but their T cells fail to proliferate, secrete IL-2, increase their F-actin content, polarize and extend protrusions following T cell receptor ligation, and are deficient in conjugate formation with superantigen-presenting B cells and anti-CD3 bilayers. In contrast, WIP-deficient B lymphocytes have enhanced proliferation and CD69 expression following B cell receptor ligation and mount normal antibody responses to T-independent antigens. Both WIP-deficient T and B cells show a profound defect in their subcortical actin filament networks. These results suggest that WIP is important for immunologic synapse formation and T cell activation

Characterization of traverse slippage experienced by Spirit rover on Husband Hill at Gusev crater

Spirit rover experienced significant slips traversing Husband Hill. This paper analyzes the slippage Spirit experienced from Sol 154 to Sol 737. Slippage with respect to terrain type and slope is computed using data downlinked from the rover, rover position, and orientation estimations from visual odometry (VO) and photogrammetry based bundle adjustment (BA) method. Accumulated slippage reached a maximum of 83.86 m on Sol 648. However, as Spirit descended into the Inner Basin, the direction of slippage reversed, and accumulated slippage approached zero by the end of the entire traverse. Eight local regions with significant slips and nineteen traverse segments have been analyzed. Slippage was found to be highly correlated to slope direction and magnitude; the reverse of slope directions in the ascending and descending portions of the traverse proves to be the main contributor to the observed cancellation of slippage. While the horizontal component of the slippage almost canceled out, the difference in elevation continually accumulated, mainly during the ascent. In general, long traverse segments created more slips than short ones. This is reflected in both the accumulated and individual slippages. In considering the four major Mars terrain types, Spirit performed best on bedrock, managing to drive on slopes close to 30°. Fine-grain surfaces were the most challenging; though progress was made on slopes up to 15°, slippages of over 100% (more slippage than distance traveled) occurred for short segments. The results of this work can be incorporate into a traverse planning framework in which rover slippage is minimized. Results can be employed in landed planetary missions for precision navigation to avoid potentially dangerous regions by considering expected slippage

Bactobolin Resistance Is Conferred by Mutations in the L2 Ribosomal Protein

Burkholderia thailandensis produces a family of polyketide-peptide molecules called bactobolins, some of which are potent antibiotics. We found that growth of B. thailandensis at 30°C versus that at 37°C resulted in increased production of bactobolins. We purified the three most abundant bactobolins and determined their activities against a battery of bacteria and mouse fibroblasts. Two of the three compounds showed strong activities against both bacteria and fibroblasts. The third analog was much less potent in both assays. These results suggested that the target of bactobolins might be conserved across bacteria and mammalian cells. To learn about the mechanism of bactobolin activity, we isolated four spontaneous bactobolin-resistant Bacillus subtilis mutants. We used genomic sequencing technology to show that each of the four resistant variants had mutations in rplB, which codes for the 50S ribosome-associated L2 protein. Ectopic expression of a mutant rplB gene in wild-type B. subtilis conferred bactobolin resistance. Finally, the L2 mutations did not confer resistance to other antibiotics known to interfere with ribosome function. Our data indicate that bactobolins target the L2 protein or a nearby site and that this is not the target of other antibiotics. We presume that the mammalian target of bactobolins involves the eukaryotic homolog of L2 (L8e)

Bactobolin Resistance Is Conferred by Mutations in the L2 Ribosomal Protein

Burkholderia thailandensis produces a family of polyketide-peptide molecules called bactobolins, some of which are potent antibiotics. We found that growth of B. thailandensis at 30°C versus that at 37°C resulted in increased production of bactobolins. We purified the three most abundant bactobolins and determined their activities against a battery of bacteria and mouse fibroblasts. Two of the three compounds showed strong activities against both bacteria and fibroblasts. The third analog was much less potent in both assays. These results suggested that the target of bactobolins might be conserved across bacteria and mammalian cells. To learn about the mechanism of bactobolin activity, we isolated four spontaneous bactobolin-resistant Bacillus subtilis mutants. We used genomic sequencing technology to show that each of the four resistant variants had mutations in rplB, which codes for the 50S ribosome-associated L2 protein. Ectopic expression of a mutant rplB gene in wild-type B. subtilis conferred bactobolin resistance. Finally, the L2 mutations did not confer resistance to other antibiotics known to interfere with ribosome function. Our data indicate that bactobolins target the L2 protein or a nearby site and that this is not the target of other antibiotics. We presume that the mammalian target of bactobolins involves the eukaryotic homolog of L2 (L8e)