A subcomplex of human mitochondrial RNase P is a bifunctional methyltransferase—extensive moonlighting in mitochondrial tRNA biogenesis

Transfer RNAs (tRNAs) reach their mature functional form through several steps of processing and modification. Some nucleotide modifications affect the proper folding of tRNAs, and they are crucial in case of the non-canonically structured animal mitochondrial tRNAs, as exemplified by the apparently ubiquitous methylation of purines at position 9. Here, we show that a subcomplex of human mitochondrial RNase P, the endonuclease removing tRNA 5′ extensions, is the methyltransferase responsible for m¹G9 and m¹A9 formation. The ability of the mitochondrial tRNA:m¹R9 methyltransferase to modify both purines is uncommon among nucleic acid modification enzymes. In contrast to all the related methyltransferases, the human mitochondrial enzyme, moreover, requires a short-chain dehydrogenase as a partner protein. Human mitochondrial RNase P, thus, constitutes a multifunctional complex, whose subunits moonlight in cascade: a fatty and amino acid degradation enzyme in tRNA methylation and the methyltransferase, in turn, in tRNA 5′ end processing.     

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR)?=?1.03, 95% CI 1.00-1.06, p?=?0.023). There was evidence for heterogeneity in the ORs among studies (I(2)?=?49.3%; p?=?<0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR?=?0.89, 95%CI 0.80-1.00, p?=?0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.     

MMP-9 and CXCL8/IL-8 Are Potential Therapeutic Targets in Epidermolysis Bullosa Simplex

Epidermolysis bullosa refers to a group of genodermatoses that affects the integrity of epithelial layers, phenotypically resulting in severe skin blistering. Dowling-Meara, the major subtype of epidermolysis bullosa simplex, is inherited in an autosomal dominant manner and can be caused by mutations in either the keratin-5 (K5) or the keratin-14 (K14) gene. Currently, no therapeutic approach is known, and the main objective of this study was to identify novel therapeutic targets. We used microarray analysis, semi-quantitative real-time PCR, western blot and ELISA to identify differentially regulated genes in two K14 mutant cell lines carrying the mutations K14 R125P and K14 R125H, respectively. We found kallikrein-related peptidases and matrix metalloproteinases to be upregulated. We also found elevated expression of chemokines, and we observed deregulation of the Cdc42 pathway as well as aberrant expression of cytokeratins and junction proteins. We further demonstrated, that expression of these genes is dependent on interleukin-1 β signaling. To evaluate these data in vivo we analysed the blister fluids of epidermolysis bullosa simplex patients vs. healthy controls and identified matrix metalloproteinase-9 and the chemokine CXCL8/IL-8 as potential therapeutic targets.     

On the Application of Widom's Test Particle Method to Homogeneous and Inhomogeneous Fluids

Abstract

Chemical potentials of a homogeneous and an inhomogeneous Lennard-Jones fluid have been determined by molecular dynamics simulations on the vector computer CYBER 205 by applying essentially the fictitious test particle method of Widom. For the homogeneous fluid we find, contrary to the previous result of Guillot and Guissani, that the simulated chemical potential is independent of the particle number. The crucial point, however, is a sufficiently large cut-off radius in the evaluation of the Boltzmann factor. Comparing with our WCA-type perturbation theory, we get agreement in the chemical potentials within 0.1 kT up to the density n[sgrave]³ = 0.80 and a difference of 0.2 kT at n[sgrave]³ = 0.85. For the inhomogeneous case we consider a fluid in a cylindrical pore and integrate Widom's equation over a certain probe volume as suggested earlier by us. Chemical potentials are then calculated independently in five different probe volumes, which are cylindrical shells. The results agree well from the second to the fourth shell. Inaccuracies in the innermost cylinder can be easily explained by bad statistics. In the shell close to the wall the extremely high local density is responsible for the inaccuracies. Extending the probe volume over all cylindrical shells besides the one closest to the wall is thought to yield rather reliable results for the chemical potential. As a by-product of the simulations we also obtained diffusion coefficients, which are given in an appendix.     

Distribution of duck broods relative to habitat characteristics in the Prairie Pothole Region

Conservation programs for breeding ducks in the Prairie Pothole Region (PPR) of the United States and Canada require effective means of evaluating and characterizing breeding habitat across large landscapes. Extensive surveys of the distribution of duck broods in late-summer could help identify wetland basins with greater probabilities of occupancy. Broods are difficult to detect, however, rendering presence–absence data from single-visit surveys difficult to interpret, particularly when probability of detection is related to habitat features. Multiple-visit occupancy surveys offer a potential solution. From 20 July to 5 August 2007–2009, we conducted a 3-visit survey of wetland basins located on 167 10.4-km² study plots in the PPR. Our survey focused on broods of the 5 most common breeding duck species (Anas spp.). Our main objectives were to investigate ecological relationships between occupancy of wetland basins by broods and habitat characteristics and to examine if habitat-specific detection was of enough concern to warrant multi-survey approaches in the future. We surveyed 3,226 wetland basins during the study. Probability of occupancy of a wetland basin by a brood was positively related to the log of wet area for all 5 study species and was greater on wetlands located on plots with a greater proportion of herbaceous perennial cover for 4 of 5 species. For example, the median probability of occupancy for gadwall (Anas strepera) increased from 0.08 (90% Credible Interval [CrI]: 0.07, 0.10) to 0.28 (90% CrI: 0.23, 0.33) as wet area increased from 0.19 ha to 2.12 ha, and increased from 0.12 (90% CrI: 0.09, 0.16) to 0.20 (90% CrI: 0.16, 0.25) as proportion of perennial grass cover on the study plot increased from 0.03 to 0.99. Because occupancy and detection were both related to attributes of wetland basins, we concluded that the multiple-visit survey was a useful approach for identifying habitat relationships of duck broods. Our results indicated that most broods of the study species were found in 10.4-km² landscapes with greater densities of small- to mid-sized wetland basins and a greater proportion of herbaceous perennial vegetation. Our study provided new empirical support that could be used to help target conservation actions to the most productive landscapes for breeding ducks. © 2012 The Wildlife Society.     

Alkaloid diversification in the genus Palicourea (Rubiaceae: Palicoureeae) viewed from a (retro-)biogenetic perspective

Phytochemistry Reviews - The species-rich genus Palicourea (Rubiaceae: Palicoureeae) is source of an intriguing diversity of alkaloids derived from tryptamine and its precursor tryptophan. So far...