Thiazole Antibiotic Thiostrepton Synergize with Bortezomib to Induce Apoptosis in Cancer Cells

Thiazole antibiotic, thiostrepton was recently identified as proteasome inhibitor. We investigated the therapeutic potential of the combination of thiostrepton and proteasome inhibitor bortezomib (Velcade) on various human tumor cell lines. Combination of sub-lethal concentrations of thiostrepton and bortezomib induced potent apoptosis and inhibition of long-term colony formation in a wide variety of human cancer cell lines. The synergistic relationship between thiostrepton and bortezomib combination was also quantitatively demonstrated by calculating their combination index values that were much lower than 1 in all studied cell lines. The synergy between these drugs was based on their proteasome inhibitory activities, because thiostrepton modification, thiostrepton methyl ester, which did not have intact quinaldic acid ring and did not inhibit proteasome activity failed to demonstrate any synergy in combination with bortezomib

Submillimeter Studies of Prestellar Cores and Protostars: Probing the Initial Conditions for Protostellar Collapse

Improving our understanding of the initial conditions and earliest stages of protostellar collapse is crucial to gain insight into the origin of stellar masses, multiple systems, and protoplanetary disks. Observationally, there are two complementary approaches to this problem: (1) studying the structure and kinematics of prestellar cores observed prior to protostar formation, and (2) studying the structure of young (e.g. Class 0) accreting protostars observed soon after point mass formation. We discuss recent advances made in this area thanks to (sub)millimeter mapping observations with large single-dish telescopes and interferometers. In particular, we argue that the beginning of protostellar collapse is much more violent in cluster-forming clouds than in regions of distributed star formation. Major breakthroughs are expected in this field from future large submillimeter instruments such as Herschel and ALMA.Comment: 12 pages, 9 figures, to appear in the proceedings of the conference "Chemistry as a Diagnostic of Star Formation" (C.L. Curry & M. Fich eds.

Field Application of a Subunit Vaccine against an Enteric Protozoan Disease

Background: Coccidiosis is a major global veterinary health problem in intensively reared chickens. It is caused by apicomplexan parasites of the genus Eimeria. Principal Findings: A subunit vaccine composed of purified antigens from the gametocytes of Eimeria maxima was used to stimulate the production and transfer of maternal antibodies between breeding hens and their hatchlings. The vaccine was injected into hens twice before they began laying eggs. Immunization had no adverse affects on egg laying or health of the hens and resulted in high antibody levels throughout the life of the hens. Progeny of immunized hens excreted significantly less oocysts of various species of Eimeria in their faeces than chicks from unvaccinated hens. Furthermore, the offspring of vaccinated hens developed stronger natural immunity to Eimeria, so that they were resistant to challenge infection even at 8 weeks of age, well after all maternal antibodies had left their circulation. Field trials were conducted in South Africa, Brazil and Thailand, involving at least 1 million progeny of vaccinated hens and at least 1 million positive control birds (raised on feed containing anticoccidial drugs or immunized with a live vaccine) in each country. Additionally, trials were carried out in Israel involving 60 million progeny of vaccinated hens and 112 million positive control birds. There were no significant differences in growth rate, feed conversion ratios or mortality in the offspring of vaccinated hens compared with the positive control chickens in any of these countries regardless of different management practices, different breeds of chickens or climate. Conclusions: These results demonstrate that a vaccine composed of antigens purified from the gametocytes of Eimeria can be used safely and effectively to prevent the deleterious effects of coccidiosis. It is the first subunit vaccine against any protozoan parasite to be successfully applied on a commercial scale. © 2008 Wallach et al

A Minimum Column Density of 1 g cm^-2 for Massive Star Formation

Massive stars are very rare, but their extreme luminosities make them both the only type of young star we can observe in distant galaxies and the dominant energy sources in the universe today. They form rarely because efficient radiative cooling keeps most star-forming gas clouds close to isothermal as they collapse, and this favors fragmentation into stars <~1 Msun. Heating of a cloud by accreting low-mass stars within it can prevent fragmentation and allow formation of massive stars, but what properties a cloud must have to form massive stars, and thus where massive stars form in a galaxy, has not yet been determined. Here we show that only clouds with column densities >~ 1 g cm^-2 can avoid fragmentation and form massive stars. This threshold, and the environmental variation of the stellar initial mass function (IMF) that it implies, naturally explain the characteristic column densities of massive star clusters and the difference between the radial profiles of Halpha and UV emission in galactic disks. The existence of a threshold also implies that there should be detectable variations in the IMF with environment within the Galaxy and in the characteristic column densities of massive star clusters between galaxies, and that star formation rates in some galactic environments may have been systematically underestimated.Comment: Accepted for publication in Nature; Nature manuscript style; main text: 14 pages, 3 figures; supplementary text: 8 pages, 1 figur

Molecular Cloning and Characterization of Two Genes Encoding Dihydroflavonol-4-Reductase from Populus trichocarpa

Dihydroflavonol 4-reductase (DFR, EC 1.1.1.219) is a rate-limited enzyme in the biosynthesis of anthocyanins and condensed tannins (proanthocyanidins) that catalyzes the reduction of dihydroflavonols to leucoanthocyanins. In this study, two full-length transcripts encoding for PtrDFR1 and PtrDFR2 were isolated from Populus trichocarpa. Sequence alignment of the two PtrDFRs with other known DFRs reveals the homology of these genes. The expression profile of PtrDFRs was investigated in various tissues of P. trichocarpa. To determine their functions, two PtrDFRs were overexpressed in tobacco (Nicotiana tabacum) via Agrobacterium-mediated transformation. The associated color change in the flowers was observed in all 35S:PtrDFR1 lines, but not in 35S:PtrDFR2 lines. Compared to the wild-type control, a significantly higher accumulation of anthocyanins was detected in transgenic plants harboring the PtrDFR1. Furthermore, overexpressing PtrDFR1 in Chinese white poplar (P. tomentosa Carr.) resulted in a higher accumulation of both anthocyanins and condensed tannins, whereas constitutively expressing PtrDFR2 only improved condensed tannin accumulation, indicating the potential regulation of condensed tannins by PtrDFR2 in the biosynthetic pathway in poplars

Correlates of Obsessive–Compulsive Disorder in a Sample of HIV-Positive, Methamphetamine-using Men Who have Sex with Men

Substance use has been identified as a risk factor for elevated levels of obsessive–compulsive disorder (OCD). This study examined methamphetamine use and sexual risk behaviors as correlates of OCD in a sample of 245 HIV-positive men having sex with men (MSM) in San Diego, CA. In a logistic regression analysis, OCD was associated with greater frequency of methamphetamine use, more depressive symptoms, seeking out risky venues and risky sexual partners when “high” on methamphetamine, and reporting fewer sex acts in the past 2 months. These data suggest the need for increased awareness and understanding of the role that OCD may play in the drug use behaviors and risky sexual practices of methamphetamine users

Epigenetic Regulation of Cell Type–Specific Expression Patterns in the Human Mammary Epithelium

Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type–specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type–specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation