Absorption of ipratropium and L-carnitine into the pulmonary circulation of the ex-vivo rat lung is driven by passive processes rather than active uptake by OCT/OCTN transporters

The organic cation transporters OCT and OCTN have been reported to play a significant role in the cellular uptake of substrates within in vitro lung cells. However, no studies to date have investigated the effect of these transporters upon transepithelial absorption of substrates into the pulmonary circulation. We investigated the contribution of OCT and OCTN transporters to total pulmonary absorption of L-carnitine and the anti-muscarinic drug, ipratropium, across an intact isolated perfused rat lung (IPRL). The results obtained from the IPRL were contrasted with active transport in vitro using three human pulmonary cell lines and primary rat alveolar epithelial cells. Ex-vivo studies showed that OCT/OCTN transporters do not play a role in the overall pulmonary absorption of L-carnitine or ipratropium, as evidenced by the effect of chemical inhibition of these transporters upon pulmonary absorption. In contrast, in-vitro studies showed that OCT/OCTN transporters play a significant role in cellular accumulation of substrates with preferential uptake of ipratropium by OCTs, and of L-carnitine uptake by OCTNs. The results show that in-vitro uptake studies cannot be predictive of airway to blood absorption in-vivo. Nevertheless, localised submucosal pulmonary concentrations of inhaled drugs and their pulmonary pharmacodynamic profiles may be influenced by OCT/OCTN transport activity

Transcriptional Activation of the Adenoviral Genome Is Mediated by Capsid Protein VI

Gene expression of DNA viruses requires nuclear import of the viral genome. Human Adenoviruses (Ads), like most DNA viruses, encode factors within early transcription units promoting their own gene expression and counteracting cellular antiviral defense mechanisms. The cellular transcriptional repressor Daxx prevents viral gene expression through the assembly of repressive chromatin remodeling complexes targeting incoming viral genomes. However, it has remained unclear how initial transcriptional activation of the adenoviral genome is achieved. Here we show that Daxx mediated repression of the immediate early Ad E1A promoter is efficiently counteracted by the capsid protein VI. This requires a conserved PPxY motif in protein VI. Capsid proteins from other DNA viruses were also shown to activate the Ad E1A promoter independent of Ad gene expression and support virus replication. Our results show how Ad entry is connected to transcriptional activation of their genome in the nucleus. Our data further suggest a common principle for genome activation of DNA viruses by counteracting Daxx related repressive mechanisms through virion proteins

Epigenetic mechanisms in virus-induced tumorigenesis

About 15–20% of human cancers worldwide have viral etiology. Emerging data clearly indicate that several human DNA and RNA viruses, such as human papillomavirus, Epstein–Barr virus, Kaposi’s sarcoma-associated herpesvirus, hepatitis B virus, hepatitis C virus, and human T-cell lymphotropic virus, contribute to cancer development. Human tumor-associated viruses have evolved multiple molecular mechanisms to disrupt specific cellular pathways to facilitate aberrant replication. Although oncogenic viruses belong to different families, their strategies in human cancer development show many similarities and involve viral-encoded oncoproteins targeting the key cellular proteins that regulate cell growth. Recent studies show that virus and host interactions also occur at the epigenetic level. In this review, we summarize the published information related to the interactions between viral proteins and epigenetic machinery which lead to alterations in the epigenetic landscape of the cell contributing to carcinogenesis

Measuring Spatio-temporal Trends in Residential Landscape Irrigation Extent and Rate in Los Angeles, California Using SPOT-5 Satellite Imagery

Irrigation is a large component of urban water budgets in semi-arid regions and is critical for the management of landscape vegetation and water resources. This is particularly true for Mediterranean climate cities such as Los Angeles, where water availability is limited during dry summers. These interactions were examined by using 10-m resolution satellite imagery and a database of monthly water use records for all residential water customers in Los Angeles in order to map vegetation greenness, the extent and distribution of irrigated areas, and irrigation rates. A water conservation ratio between rates of irrigation and vegetation water demand was calculated to assess over-irrigation. The analyses were conducted for the water years (WY) 2005–2007, which included wet, average, and dry extremes of annual rainfall. Although outdoor water usage was highest in the dry year, vegetation greenness could not be maintained as well as in wetter years, suggesting that lower greenness was due to water stress. However, annual rainfall from WY 2005 to 2007 did not significantly influence the variability in the magnitude and spatial pattern of irrigation, with mean irrigated rates ranging only from 81 to 86 mm. The water conservation ratio showed that 7 % of the postal carrier routes across the city were over-irrigated in the dry year, but 43 % were over-irrigated in the wet year. This was largely because the climatic demand for water by vegetation decreased in wet years, but irrigation rates changed little from year-to-year. This overwatering can be addressed by water conservation, planning and public education, especially in the current California drought. The approach demonstrated here should be transferable to other cities in semi-arid climates