Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.     

Canyon grassland vegetation changes following fire in northern Idaho

Native and nonnative vegetation mosaics are common in western rangelands. If land managers could better predict changes in the abundance of native and nonnative species following disturbances, maintenance of native plant cover and diversity may be improved. In August 2000, during suppression of a wildfire near Lewiston, Idaho, a backing fire burned canyon grassland plots. A previous study had recorded species composition and cover prior to the fire, so we were able to evaluate changes in species composition and abundance on established plots before and after the fire. Overall, summer burning had little effect on the grassland communities. Pseudoroegneria spicata recovered to prefire coverage by the third postfire year. In the third postfire year, cover of native and nonnative annual species was significantly greater on burned than unburned sites ( P Bromus tectorum cover increased, as expected, on burned plots. Prefire and postfire cover values for Centaurea solstitialis were nearly equal, and there were no significant cover differences between burned and unburned plots in any year. As part of this study, we also evaluated changes in the cover of dominant native and nonnative species with respect to their prefire seral stage on burned and unburned plots. Because our sample sizes were small, we only report community-level trends but suggest that this type of community analysis could make for an interesting future study. Los mosaicos de vegetaci&oacute;n nativa y no nativa son comunes en los pastizales del occidente de Norteam&eacute;rica. Si los administradores de tierras pudieran predecir mejor los cambios en la abundancia de especies nativas y no nativas despu&eacute;s de las perturbaciones, se podr&iacute;a mejorar el mantenimiento de la cobertura y diversidad de las plantas nativas. En agosto de 2000, los remanentes de un incendio quemaron terrenos de pradera de ca&ntilde;&oacute;n durante la supresi&oacute;n de un incendio cerca de Lewiston, Idaho. Un estudio previo registr&oacute; la composici&oacute;n y cobertura de especies antes del incendio, por lo que pudimos evaluar los cambios en la composici&oacute;n y abundancia de especies en determinados terrenos antes y despu&eacute;s del incendio. En general, las quemas de verano no afectaron mucho a las comunidades de pradera. Para el tercer a&ntilde;o despu&eacute;s del incendio, Pseudoroegneria spicata se hab&iacute;a repuesto al nivel de cobertura que tuvo antes del incendio y la cobertura de especies anuales nativas y no nativas fue significativamente mayor ( P Bromus tectorum aument&oacute; en los terrenos quemados. Los niveles de cobertura de Centaurea solstitialis antes y despu&eacute;s del incendio fueron casi iguales, y no hubo ninguna diferencia significativa en la cobertura de los terrenos quemados y la de los no quemados en ninguno de estos a&ntilde;os. Como parte de este estudio, tambi&eacute;n evaluamos los cambios en la cobertura de especies dominantes nativas y no nativas con respecto a su estado sucesional previo al incendio en terrenos quemados y no quemados. Debido a que tuvimos un reducido tama&ntilde;o de muestra, s&oacute;lo reportamos tendencias a nivel de comunidad, pero sugerimos que esta clase de an&aacute;lisis de comunidades podr&iacute;an servir como modelo para estudios interesantes en el futuro.     

Protein arginine deiminase 4: a target for an epigenetic cancer therapy

The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines (NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4 inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic agents for this disease.     

Stereospecificity of the prostaglandin 15-dehydrogenase from swine lung

Zusammenfassung Die stereochemischen Voraussetzungen der Prostaglandin-15-Dehydrogenase aus Schweinelunge werden im Hinblick auf die pharmakologische Aktivität anhand einer Reihe synthetischer Prostaglandin E₁-Präparate abgeklärt.

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This work was supported by grants from the U.S. National Institutes of Health to Harvard University and by O.N.R. and N.I.H. grants to the Worcester Foundation for Experimental Biology.     

Event-horizon-scale structure in the supermassive black hole candidate at the Galactic Centre

The cores of most galaxies are thought to harbour supermassive black holes, which power galactic nuclei by converting the gravitational energy of accreting matter into radiation. Sagittarius A* (Sgr A*), the compact source of radio, infrared and X-ray emission at the centre of the Milky Way, is the closest example of this phenomenon, with an estimated black hole mass that is 4,000,000 times that of the Sun. A long-standing astronomical goal is to resolve structures in the innermost accretion flow surrounding Sgr A*, where strong gravitational fields will distort the appearance of radiation emitted near the black hole. Radio observations at wavelengths of 3.5 mm and 7 mm have detected intrinsic structure in Sgr A*, but the spatial resolution of observations at these wavelengths is limited by interstellar scattering. Here we report observations at a wavelength of 1.3 mm that set a size of 37(+16)(-10) microarcseconds on the intrinsic diameter of Sgr A*. This is less than the expected apparent size of the event horizon of the presumed black hole, suggesting that the bulk of Sgr A* emission may not be centred on the black hole, but arises in the surrounding accretion flow.     

Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions

Systematic genetic interaction studies have illuminated many cellular processes. Here we quantitatively examine genetic interactions among 26 Saccharomyces cerevisiae genes conferring resistance to the DNA-damaging agent methyl methanesulfonate (MMS), as determined by chemogenomic fitness profiling of pooled deletion strains. We constructed 650 double-deletion strains, corresponding to all pairings of these 26 deletions. The fitness of single- and double-deletion strains were measured in the presence and absence of MMS. Genetic interactions were defined by combining principles from both statistical and classical genetics. The resulting network predicts that the Mph1 helicase has a role in resolving homologous recombination-derived DNA intermediates that is similar to (but distinct from) that of the Sgs1 helicase. Our results emphasize the utility of small molecules and multifactorial deletion mutants in uncovering functional relationships and pathway order.