Combinatorial synthesis of 3-(amidoalkyl) and 3-(aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors.

Preparation and screening of mixture libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors.     

Biodegradation of monoaromatic hydrocarbons by aquifer microorganisms using oxygen, nitrate, or nitrous oxide as the terminal electron acceptor.

Microcosms were prepared from aquifer material, spiked with monoaromatic hydrocarbons, and amended with oxygen, nitrate, and nitrous oxide. Benzene and alkylbenzenes were degraded to concentrations below 5 micrograms/liter within 7 days under aerobic conditions, whereas only the alkylbenzenes were degraded when either nitrate or nitrous oxide was used. With limited oxygen, monoaromatic hydrocarbons were degraded but removal ceased once oxygen was consumed. However, when nitrate was also present, biodegradation of the alkylbenzenes continued with no apparent lag. Although benzene was still recalcitrant, levels were reduced compared with levels after treatment with nitrate or limited oxygen alone.     

Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys

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The conservation status of Texas groundwater invertebrates

Biodiversity conservation requires an objective and consistent method for evaluating the conservation status of species. Conservation status assessments can identify conservation priorities and can highlight data gaps, effective conservation strategies, and groups of taxa that are underrepresented in conservation efforts relative to charismatic flagship and umbrella species. Groundwater invertebrates have a suite of traits that make them inherently vulnerable. But they go largely unnoticed by the general public and conservation practitioners, and comprehensive conservation status assessments are lacking for most species. In this article, the conservation status of all sixty-nine described groundwater-obligate invertebrates recorded from Texas, U.S.A. was assessed using NatureServe methodology. Some of the smallest taxa (e.g. copepods, ostracods, and mites) are too poorly known to evaluate their conservation status. Species restricted to springs were generally more at risk than species in other groundwater habitats, and beetles and snails were the most imperiled taxonomic groups. Most species faced low or medium severity threats, and only seven percent faced high or very high magnitude threats. Threat level varied among aquifers and among sites within aquifers and was primarily dependent on human population density and the adequacy of regulatory mechanisms protecting groundwater quality and quantity. Regardless of threat severity, fifty-five percent of evaluated species were ranked as imperiled or critically imperiled, largely due to extreme small-range endemism. Relative to other regions, Texas’ groundwater fauna is not unique in terms of rarity and threat, suggesting that as an ecological group, groundwater-obligate species are probably among the world’s most imperiled taxa.     

Discovery and optimization of novel constrained pyrrolopyridone BET family inhibitors

Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.     

Staining Scab Actinomyces in Potato Tuber Tissues

Actinomyces hyphae imbedded in the middle lamellae of potato tuber cells may be stained in sections by the use of a modified Gram's stain. The modifications are: a very strong (5%) solution of crystal violet in anilin oil; a 24-hour exposure to both the dye and the iodine solution; and a slow decolorization in absolute alcohol until no more color flows.     

Influenza H5N1 virus infection of polarized human alveolar epithelial cells and lung microvascular endothelial cells

Background

Highly pathogenic avian influenza (HPAI) H5N1 virus is entrenched in poultry in Asia and Africa and continues to infect humans zoonotically causing acute respiratory disease syndrome and death. There is evidence that the virus may sometimes spread beyond respiratory tract to cause disseminated infection. The primary target cell for HPAI H5N1 virus in human lung is the alveolar epithelial cell. Alveolar epithelium and its adjacent lung microvascular endothelium form host barriers to the initiation of infection and dissemination of influenza H5N1 infection in humans. These are polarized cells and the polarity of influenza virus entry and egress as well as the secretion of cytokines and chemokines from the virus infected cells are likely to be central to the pathogenesis of human H5N1 disease.

Aim

To study influenza A (H5N1) virus replication and host innate immune responses in polarized primary human alveolar epithelial cells and lung microvascular endothelial cells and its relevance to the pathogenesis of human H5N1 disease.

Methods

We use an in vitro model of polarized primary human alveolar epithelial cells and lung microvascular endothelial cells grown in transwell culture inserts to compare infection with influenza A subtype H1N1 and H5N1 viruses via the apical or basolateral surfaces.

Results

We demonstrate that both influenza H1N1 and H5N1 viruses efficiently infect alveolar epithelial cells from both apical and basolateral surface of the epithelium but release of newly formed virus is mainly from the apical side of the epithelium. In contrast, influenza H5N1 virus, but not H1N1 virus, efficiently infected polarized microvascular endothelial cells from both apical and basolateral aspects. This provides a mechanistic explanation for how H5N1 virus may infect the lung from systemic circulation. Epidemiological evidence has implicated ingestion of virus-contaminated foods as the source of infection in some instances and our data suggests that viremia, secondary to, for example, gastro-intestinal infection, can potentially lead to infection of the lung. HPAI H5N1 virus was a more potent inducer of cytokines (e.g. IP-10, RANTES, IL-6) in comparison to H1N1 virus in alveolar epithelial cells, and these virus-induced chemokines were secreted onto both the apical and basolateral aspects of the polarized alveolar epithelium.

Conclusion

The predilection of viruses for different routes of entry and egress from the infected cell is important in understanding the pathogenesis of influenza H5N1 infection and may help unravel the pathogenesis of human H5N1 disease.