Inhibition of a viral enzyme by a small-molecule dimer disruptor.

We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma-associated herpesvirus (KSHV) by screening an alpha-helical mimetic library. Next, we synthesized a second generation of low-micromolar inhibitors with improved potency and solubility. Complementary methods including size exclusion chromatography and 1H-13C HSQC titration using selectively labeled 13C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. 1H-15N HSQC titration studies mapped the inhibitor binding site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small-molecule inhibitors

Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

AbstractHepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment

Chaenothecopsis schefflerae (Ascomycota: Mycocaliciales): a widespread fungus on semi-hardened exudates of endemic New Zealand Araliaceae

Ascomycetes specialised to live on hardened plant exudates occur worldwide, but the number of species so far described is relatively small (c.30). Particularly within the genus Chaenothecopsis (Ascomycota:Mycocaliciales), many species produce their ascomata on hardened but still relatively fresh outpourings of conifer resin or angiosperm exudate. Temperate rainforests of New Zealand provide habitat for several endemic Chaenothecopsis species, including Chaenothecopsis schefflerae, which was previously known from a single sample collected from the exudate of Schefflera digitata (Araliaceae) in the early 1980s. Here we show that C.schefflerae is neither lost nor very rare, but occurs sporadically throughout New Zealand. The fungus does not primarily grow on Schefflera but on exudate of several species of Pseudopanax (Araliaceae),also endemic to the region. We compare the morphology of the new specimens to the type specimen of C. schefflerae and provide a detailed description of the new material. Phylogenetic analyses based on nuclear ITS and LSU rDNA place C.schefflerae together with other morphologically similar Chaenothecopsis species growing on angiosperm exudates.Peer reviewe

Chaenothecopsis (Mycocaliciales, Ascomycota) from exudates of endemic New Zealand Podocarpaceae

The order Mycocaliciales (Ascomycota) comprises fungal species with diverse, often highly specialized substrate ecologies. Particularly within the genus Chaenothecopsis, many species exclusively occur on fresh and solidified resins or other exudates of vascular plants. In New Zealand, the only previously known species growing on plant exudate is Chaenothecopsis schefflerae, found on several endemic angiosperms in the family Araliaceae. Here we describe three new species; Chaenothecopsis matai Rikkinen, Beimforde, Tuovila & A.R. Schmidt, C. nodosa Beimforde, Tuovila, Rikkinen & A.R. Schmidt, and C. novae-zelandiae Rikkinen, Beimforde, Tuovila & A.R. Schmidt, all growing on exudates of endemic New Zealand conifers of the Podocarpaceae family, particularly on Prumnopitys taxifolia. Phylogenetic analyses based on ribosomal DNA regions (ITS and LSU) grouped them into a distinct, monophyletic clade. This, as well as the restricted host range, suggests that all three taxa are endemic to New Zealand. Copious insect frass between the ascomata contain ascospores or show an early stage of ascomata development, indicating that the fungi are spread by insects. The three new species represent the first evidence of Chaenothecopsis from any Podocarpaceae species and the first from any gymnosperm exudates in New Zealand.Peer reviewe

Near-equality of the Penrose Inequality for rotationally symmetric Riemannian manifolds

This article is the sequel to our previous paper [LS] dealing with the near-equality case of the Positive Mass Theorem. We study the near-equality case of the Penrose Inequality for the class of complete asymptotically flat rotationally symmetric Riemannian manifolds with nonnegative scalar curvature whose boundaries are outermost minimal hypersurfaces. Specifically, we prove that if the Penrose Inequality is sufficiently close to being an equality on one of these manifolds, then it must be close to a Schwarzschild space with an appended cylinder, in the sense of Lipschitz Distance. Since the Lipschitz Distance bounds the Intrinsic Flat Distance on compact sets, we also obtain a result for Intrinsic Flat Distance, which is a more appropriate distance for more general near-equality results, as discussed in [LS]Comment: 19 pages, 2 figure

Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis

SummaryHerein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments

Evaluation of the New York City Out-of-School Time Initiative: Report on the First Year: Executive Summary

Describes an out-of-school program initiative serving more than 51,000 youth citywide. Presents data on the first year of program implementation and findings on participant engagement and associated academic and social development outcomes

The SLUGGS Survey: Globular cluster system kinematics and substructure in NGC 4365

We present a kinematic analysis of the globular cluster (GC) system of the giant elliptical galaxy NGC 4365 and find several distinct kinematic substructures. This analysis is carried out using radial velocities for 269 GCs, obtained with the DEIMOS instrument on the Keck II telescope as part of the SAGES Legacy Unifying Globulars and Galaxies Survey (SLUGGS). We find that each of the three (formerly identified) GC colour subpopulations reveal distinct rotation properties. The rotation of the green GC subpopulation is consistent with the bulk of NGC 4365's stellar light, which `rolls' about the photometric major axis. The blue and red GC subpopulations show `normal' rotation about the minor axis. We also find that the red GC subpopulation is rotationally dominated beyond 2.5 arcmin (~17 kpc) and that the root mean squared velocity of the green subpopulation declines sharply with radius suggesting a possible bias towards radial orbits relative to the other GC subpopulations. Additionally, we find a population of low velocity GCs that form a linear structure running from the SW to the NE across NGC 4365 which aligns with the recently reported stellar stream towards NGC 4342. These low velocity GCs have g'-i' colours consistent with the overall NGC 4365 GC system but have velocities consistent with the systemic velocity of NGC 4342. We discuss the possible formation scenarios for the three GC subpopulations as well as the possible origin of the low velocity GC population.Comment: 15 pages, 12 figures, accepted for publication in MNRAS. For more information on "The SLUGGS Survey" see: http://sluggs.swin.edu.au