ALBERT

Description: Three distinct types of granitoids, and intrusive contacts between them, are exposed in the central White Mfolozi Inlier, northern KwaZulu-Natal, where they form the basement on which the Mesoarchaean Pongola Supergroup had been deposited. In order to assess the position of these granites within the geochronological framework of Archaean felsic magmatism in the southeastern Kaapvaal Craton, to clarify the precise age relationships between these granitoids, and to examine their early petrogenesis, zircons extracted from these three granitoids have been analysed by LA-MC-ICPMS for their U-Pb and Hf isotopic compositions. The three U-Pb ages obtained from upper concordia-discordia intercepts are 3254 ± 7 Ma, 3245 ± 5 Ma and 3234 ± 5 Ma, which are taken to reflect magmatic crystallisation. Hence, all three granitoids belong to the late Palaeoarchaean group of Kaapvaal intrusives that appear to be prominent in the southeastern Kaapvaal Craton. In terms of Hf isotopes, the samples studied overlap with ~3.25 to 3.20 Ga granitoids from the southeastern part of the Kaapvaal Craton, the Barberton North and South terranes and coeval granitoids from Swaziland. The average Hf isotopic signature ( Hf ~ 0) points to early magma extraction processes from an original mantle source prior to ~3.3 Ga.

Description: The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (beta = 3.8 mmol l(-1), P = 2.5 x 10(-35)) and serum insulin (beta = 165 pmol l(-1), P = 1.5 x 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (beta = -0.18 mmol l(-1), P = 1.1 x 10(-6)) and fasting serum insulin (beta = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 x 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (beta = 0.43 mmol l(-1), P = 5.3 x 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moltke, Ida -- Grarup, Niels -- Jorgensen, Marit E -- Bjerregaard, Peter -- Treebak, Jonas T -- Fumagalli, Matteo -- Korneliussen, Thorfinn S -- Andersen, Marianne A -- Nielsen, Thomas S -- Krarup, Nikolaj T -- Gjesing, Anette P -- Zierath, Juleen R -- Linneberg, Allan -- Wu, Xueli -- Sun, Guangqing -- Jin, Xin -- Al-Aama, Jumana -- Wang, Jun -- Borch-Johnsen, Knut -- Pedersen, Oluf -- Nielsen, Rasmus -- Albrechtsen, Anders -- Hansen, Torben -- England -- Nature. 2014 Aug 14;512(7513):190-3. doi: 10.1038/nature13425. Epub 2014 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA [3]. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2]. ; Steno Diabetes Center, 2820 Gentofte, Denmark. ; National Institute of Public Health, University of Southern Denmark, 1353 Copenhagen, Denmark. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. ; Department of Integrative Biology, University of California, Berkeley, California 94720, USA. ; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark. ; The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark [2] Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Stockholm, Sweden. ; Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] BGI-Shenzhen, Shenzhen 518083, China [2] The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2] BGI-Shenzhen, Shenzhen 518083, China [3] The Department of Genetic Medicine, Faculty of Medicine and Princess Al Jawhara Albrahim Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [4] Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark [5] Macau University of Science and Technology, Macau 999078, China. ; Holbaek Hospital, 4300 Holbaek, Denmark. ; 1] Department of Integrative Biology, University of California, Berkeley, California 94720, USA [2] Department of Statistics, University of California, Berkeley, California 94720, USA. ; The Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark. ; 1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark [2] Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043022" target="_blank"〉PubMed〈/a〉

Description: The Quaternary Period, by virtue of the near-surface preservation and widespread accessibility of its environmental archives, provides fundamental data to test models of climate change, sea level variation, geomagnetic field variation, human and faunal migration, cultural evolution and more. Spatially disparate records of past environmental change with subannual to multimillennial temporal resolution are compared to examine the relative timing of events and consider causal mechanisms, and this analysis puts great demands on the chronological tools available. Highly precise and accurate age estimates are required, in concert with correlative tools or chronostratigraphic markers. We focus on radioisotope chronometers (e.g. U-series, 40 Ar/ 39 Ar and 14 C) and illustrate their application in three vignettes for which different strategies are required: (1) the dramatic decades of the last deglaciation (~14.7 ka), (2) before and after one of the last geomagnetic excursions (~41 ka) and (3) the glacial–interglacial cycles of the Middle Pleistocene (125–780 ka).

Description: Assessing the shape of dose–response curves for DNA-damage in cellular systems and for the consequences of DNA damage in intact animals remains a controversial topic. This overview looks at aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of cellular DNA-damage/repair and their role in defining the shape of dose–response curves using an in vivo example with formaldehyde and in vitro examples for micronuclei (MN) formation with several test compounds. Formaldehyde is both strongly mutagenic and an endogenous metabolite in cells. With increasing inhaled concentrations, there were transitions in gene changes, from activation of selective stress pathway genes at low concentrations, to activation of pathways for cell-cycle control, p53-DNA damage, and stem cell niche pathways at higher exposures. These gene expression changes were more consistent with dose-dependent transitions in the PD responses to formaldehyde in epithelial cells in the intact rat rather than the low-dose linear extrapolation methods currently used for carcinogens. However, more complete PD explanations of non-linear dose response for creation of fixed damage in cells require detailed examination of cellular responses in vitro using measures of DNA damage and repair that are not easily accessible in the intact animal. In the second section of the article, we illustrate an approach from our laboratory that develops fit-for-purpose, in vitro assays and evaluates the PD of DNA damage and repair through studies using prototypical DNA-damaging agents. Examination of a broad range of responses in these cells showed that transcriptional upregulation of cell cycle control and DNA repair pathways only occurred at doses higher than those causing overt damage fixed damage—measured as MN formation. Lower levels of damage appear to be handled by post-translational repair process using pre-existing proteins. In depth evaluation of the PD properties of one such post-translational process (formation of DNA repair centers; DRCs) has indicated that the formation of DRCs and their ability to complete repair before replication are consistent with threshold behaviours for mutagenesis and, by extension, with chemical carcinogenesis.