Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein's C-Terminal Helix.

The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein Rb, which inhibits cell-cycle progression until its inactivation by phosphorylation. However, the role of Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdks, and cyclin D-Cdk4,6 has other targets involved in cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the Rb C terminus, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents its phosphorylation, promotes G1 arrest, and enhances Rb's tumor suppressive function. Our work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and expands the diversity of known cyclin-based protein docking mechanisms

Annual observations of radon activity concentrations in dwellings of Silesian Voivodeship

In the paper, results of year-long measurements of radon levels in dwellings on the premises of Silesian Voivodeship are presented. Track etched detectors with polymer CR-39 foils were used in the investigations. As the studied buildings were located in different regions of Silesian Voivodeship, therefore results of measurements were analysed due to possible influence of geological structure or effect of mining operations in places, where given dwellings were situated. Elevated concentrations of radon were measured mostly in dwellings located in areas, where permeable Triassic limestone and dolomite occur, as it has been predicted. On the other hand, the impact of mining activity such as disintegration of rock-body and activation of faults plays an important role, too, because it enables radon migration and its entry into buildings. Beside the analysis of seasonal variations of radon activity concentration, the impact of temperature and pressure on these fluctuations outdoor and indoor buildings has been analysed

Palladium Membrane with High Density of Large-Angle Grain Boundaries to Promote Hydrogen Diffusivity

A higher density of large-angle grain boundaries in palladium membranes promotes hydrogen diffusion whereas small-angle grain boundaries suppress it. In this paper, the microstructure formation in 10 µm thick palladium membranes is tuned to achieve a submicronic grain size above 100 nm with a high density of large-angle grain boundaries. Moreover, changes in the grain boundaries’ structure is investigated after exposure to hydrogen at 300 and 500 °C. To attain large-angle grain boundaries in Pd, the coating was performed on yttria-stabilized zirconia/porous Crofer 22 APU substrates (intended for use later in an ultracompact membrane reactor). Two techniques of plasma sprayings were used: suspension plasma spraying using liquid nano-sized powder suspension and vacuum plasma spraying using microsized powder as feedstock. By controlling the process parameters in these two techniques, membranes with a comparable density of large-angle grain boundaries could be developed despite the differences in the fabrication methods and feedstocks. Analyses showed that a randomly oriented submicronic structure could be attained with a very similar grain sizes between 100 and 500 nm which could enhance hydrogen permeation. Exposure to hydrogen for 72 h at high temperatures revealed that the samples maintained their large-angle grain boundaries despite the increase in average grain size to around 536 and 720 nm for vacuum plasma spraying and suspension plasma spraying, respectively

Hypertension Education and the Burlington Housing Authority

Background: • 2/3 seniors are hypertensive (\u3e140/90 mm Hg) • Hypertension is the most common risk factor for premature heart disease and stroke • Non-modifiable risk factors: race, age, sex, diabetes mellitus, and hypercholesterolemia • Modifiable risk factors: smoking, obesity, and excessive alcohol • Clinical trials show that lifestylemodification and medications can reduce the incidence of adverse outcomes associated with hypertension • Patient education is a high priorityhttps://scholarworks.uvm.edu/comphp_gallery/1026/thumbnail.jp

Aquilegia, Vol. 33 No. 5, Winter 2009, Newsletter of the Colorado Native Plant Society

https://epublications.regis.edu/aquilegia/1130/thumbnail.jp

MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration.

Mitochondrial Ca(2+) uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis. Ca(2+) overload-induced mitochondrial permeability transition pore (PTP) opening is accelerated in MICU1-deficient hepatocytes. PTP inhibition prevents necrosis and rescues regeneration. Thus, our study identifies an unanticipated dependence of liver regeneration on MICU1 and highlights the importance of regulating MCU under stress conditions when the risk of Ca(2+) overload is elevated

Primate-specific Evolution of an LDLR Enhancer

Background: Sequence changes in regulatory regions have often been invoked to explain phenotypic divergence among species, but molecular examples of this have been difficult to obtain. Results: In this study we identified an anthropoid primate-specific sequence element that contributed to the regulatory evolution of the low-density lipoprotein receptor. Using a combination of close and distant species genomic sequence comparisons coupled with in vivo and in vitro studies, we found that a functional cholesterol-sensing sequence motif arose and was fixed within a pre-existing enhancer in the common ancestor of anthropoid primates. Conclusion: Our study demonstrates one molecular mechanism by which ancestral mammalian regulatory elements can evolve to perform new functions in the primate lineage leading to human

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

ObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis.MethodsGWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes.ResultsMIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS (P = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility