An Increase in Mitochondrial DNA Promotes Nuclear DNA Replication in Yeast

Coordination between cellular metabolism and DNA replication determines when cells initiate division. It has been assumed that metabolism only plays a permissive role in cell division. While blocking metabolism arrests cell division, it is not known whether an up-regulation of metabolic reactions accelerates cell cycle transitions. Here, we show that increasing the amount of mitochondrial DNA accelerates overall cell proliferation and promotes nuclear DNA replication, in a nutrient-dependent manner. The Sir2p NAD+-dependent de-acetylase antagonizes this mitochondrial role. We found that cells with increased mitochondrial DNA have reduced Sir2p levels bound at origins of DNA replication in the nucleus, accompanied with increased levels of K9, K14-acetylated histone H3 at those origins. Our results demonstrate an active role of mitochondrial processes in the control of cell division. They also suggest that cellular metabolism may impact on chromatin modifications to regulate the activity of origins of DNA replication

A Mighty Small Heart: The Cardiac Proteome of Adult Drosophila melanogaster

Drosophila melanogaster is emerging as a powerful model system for the study of cardiac disease. Establishing peptide and protein maps of the Drosophila heart is central to implementation of protein network studies that will allow us to assess the hallmarks of Drosophila heart pathogenesis and gauge the degree of conservation with human disease mechanisms on a systems level. Using a gel-LC-MS/MS approach, we identified 1228 protein clusters from 145 dissected adult fly hearts. Contractile, cytostructural and mitochondrial proteins were most abundant consistent with electron micrographs of the Drosophila cardiac tube. Functional/Ontological enrichment analysis further showed that proteins involved in glycolysis, Ca2+-binding, redox, and G-protein signaling, among other processes, are also over-represented. Comparison with a mouse heart proteome revealed conservation at the level of molecular function, biological processes and cellular components. The subsisting peptidome encompassed 5169 distinct heart-associated peptides, of which 1293 (25%) had not been identified in a recent Drosophila peptide compendium. PeptideClassifier analysis was further used to map peptides to specific gene-models. 1872 peptides provide valuable information about protein isoform groups whereas a further 3112 uniquely identify specific protein isoforms and may be used as a heart-associated peptide resource for quantitative proteomic approaches based on multiple-reaction monitoring. In summary, identification of excitation-contraction protein landmarks, orthologues of proteins associated with cardiovascular defects, and conservation of protein ontologies, provides testimony to the heart-like character of the Drosophila cardiac tube and to the utility of proteomics as a complement to the power of genetics in this growing model of human heart disease

The Association of Systemic Microvascular Changes with Lung Function and Lung Density: A Cross-Sectional Study

10.1371/journal.pone.0050224PLoS ONE712

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Serum matrix metalloproteinase-9 in children exposed to arsenic from playground dust at elementary schools in Hermosillo, Sonora, Mexico

Arsenic exposure in adults has been associated with increased serum matrix metalloproteinase-9 (MMP-9), a biomarker which is associated with chronic respiratory disease, lung inflammation, cardiovascular disease and cancer. The objective of this study was to evaluate the association between serum MMP-9 levels in children, urinary arsenic, arsenic chronic daily intake (CDI) and arsenic exposure from playground dust. This cross-sectional study examined 127 children from five elementary schools, in Hermosillo, Sonora, Mexico. Arsenic was analyzed in the dust using a portable X-ray fluorescence (XRF) analyzer. Total urinary arsenic was determined by inductively coupled plasma/optical emission spectrometry. Serum was analyzed for MMP-9 using ELISA. Arsenic levels in playground dust averaged 16.9 +/- 4.6 mg/kg. Urinary arsenic averaged 34.9 +/- 17.1 mu g/L. Arsenic concentration in playground dust was positively associated with serum MMP-9 levels in crude analyses and after adjustment (P < 0.01), MMP-9 and CDI were positively associated only after adjustment (P < 0.01), and no association was found between MMP-9 and urinary arsenic. In conclusion, our study showed an association in children between serum MMP-9 levels and playground dust arsenic concentrations. Therefore, exposure to arsenic in dust where children spend significant time may manifest toxic effects.12 month embargo; published online: 1 August 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.info:eu-repo/semantics/publishe