Research Triangle Park

About: Research Triangle Park is a nonprofit organization based out in Durham, North Carolina, United States. It is known for research contribution in the topics: Population & Environmental exposure. The organization has 24961 authors who have published 35800 publications receiving 1684504 citations. The organization is also known as: RTP.

Discovery of 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a Novel and Potent Vascular Endothelial Growth Factor Receptor Inhibitor†

Abstract: Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors

The Mode of Action of the Bacillus thuringiensis Vegetative Insecticidal Protein Vip3A Differs from That of Cry1Ab δ-Endotoxin

Abstract: The Vip3A protein, secreted by Bacillus spp. during the vegetative stage of growth, represents a new family of insecticidal proteins. In our investigation of the mode of action of Vip3A, the 88-kDa Vip3A full-length toxin (Vip3A-F) was proteolytically activated to an approximately 62-kDa core toxin either by trypsin (Vip3A-T) or lepidopteran gut juice extracts (Vip3A-G). Biotinylated Vip3A-G demonstrated competitive binding to lepidopteran midgut brush border membrane vesicles (BBMV). Furthermore, in ligand blotting experiments with BBMV from the tobacco hornworm, Manduca sexta (Linnaeus), activated Cry1Ab bound to 120-kDa aminopeptidase N (APN)-like and 250-kDa cadherin-like molecules, whereas Vip3A-G bound to 80-kDa and 100-kDa molecules which are distinct from the known Cry1Ab receptors. In addition, separate blotting experiments with Vip3A-G did not show binding to isolated Cry1A receptors, such as M. sexta APN protein, or a cadherin Cry1Ab ecto-binding domain. In voltage clamping assays with dissected midgut from the susceptible insect, M. sexta, Vip3A-G clearly formed pores, whereas Vip3A-F was incapable of pore formation. In the same assay, Vip3A-G was incapable of forming pores with larvae of the nonsusceptible insect, monarch butterfly, Danaus plexippus (Linnaeus). In planar lipid bilayers, both Vip3A-G and Vip3A-T formed stable ion channels in the absence of any receptors, supporting pore formation as an inherent property of Vip3A. Both Cry1Ab and Vip3A channels were voltage independent and highly cation selective; however, they differed considerably in their principal conductance state and cation specificity. The mode of action of Vip3A supports its use as a novel insecticidal agent.

Proactive management of software aging

Abstract: Software failures are now known to be a dominant source of system outages. Several studies and much anecdotal evidence point to "software aging" as a common phenomenon, in which the state of a software system degrades with time. Exhaustion of system resources, data corruption, and numerical error accumulation are the primary symptoms of this degradation, which may eventually lead to performance degradation of the software, crash/hang failure, or other undesirable effects. "Software rejuvenation" is a proactive technique intended to reduce the probability of future unplanned outages due to aging. The basic idea is to pause or halt the running software, refresh its internal state, and resume or restart it. Software rejuvenation can be performed by relying on a variety of indicators of aging, or on the time elapsed since the last rejuvenation. In response to the strong desire of customers to be provided with advance notice of unplanned outages, our group has developed techniques that detect the occurrence of software aging due to resource exhaustion, estimate the time remaining until the exhaustion reaches a critical level, and automatically perform proactive software rejuvenation of an application, process group, or entire operating system, depending on the pervasiveness of the resource exhaustion and our ability to pinpoint the source. This technology has been incorporated into the IBM Director for xSeries servers. To quantitatively evaluate the impact of different rejuvenation policies on the availability of cluster systems, we have developed analytical models based on stochastic reward nets (SRNs). For timebased rejuvenation policies, we determined the optimal rejuvenation interval based on system availability and cost. We also analyzed a rejuvenation policy based on prediction, and showed that it can further increase system availability and reduce downtime cost. These models are very general and can capture a multitude of cluster system characteristics, failure behavior, and performability measures, which we are just beginning to explore.