New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Quantification of Acylfulvene– and Illudin S–DNA Adducts in Cells with Variable Bioactivation Capacities

Illudin S and its semisynthetic analogue acylfulvene (AF) are structurally similar but elicit different biological responses. AF is a bioreductive alkylating anticancer agent with a favorable therapeutic index, while illudin S is in general highly toxic. AF toxicity is dependent on the reductase enzyme prostaglandin reductase 1 (PTGR1) for activation to a cytotoxic reactive intermediate. While illudin S can be metabolized by PTGR1, available data suggest that its toxicity does not correspond with PTGR1 function. The goal of this study was to understand how drug cytotoxicity relates to cellular bioactivation capacity and the identity and quantity of AF– or illudin S–DNA adducts. The strategy involved identification of novel illudin S–DNA adducts and their quantitation in a newly engineered SW-480 colon cancer cell line that stably overexpresses PTGR1 (PTGR1-480). These data were compared with cytotoxicity data for both compounds in PTGR1-480 versus normal SW-480 cells, demonstrating that AF forms more DNA adducts and is more cytotoxic in cells with higher levels of PTGR1, whereas illudin S cytotoxicity and adduct formation are not influenced by PTGR1 levels. Results are discussed in the context of an overall model for how changes in relative propensities of these compounds to undergo cellular processes, such as bioactivation, contributes to DNA damage, and cytotoxicity

Depositional history and archaeology of the central Lake Mungo lunette, Willandra Lakes, southeast Australia

Lake Mungo, presently a dry lake in the semi-arid zone of southeastern Australia, preserves a unique record of human settlement and past environmental change within the transverse lunette that built up on its downwind margin. The lunette is \u3e30 km long and the variable morphology along its length suggests spatial variability in deposition over time. Consequently this presents differential potential for the preservation of past activity traces of different ages along the lunette. Earlier work at Lake Mungo focused primarily on the southern section of the lunette, where two ritual burials of considerable antiquity were found. Here we describe the depositional history of the central section of the Lake Mungo lunette, together with the first single grain optically stimulated luminescence (OSL) chronology of the full stratigraphic sequence and of three hearths. We thereby lay the foundation for systematic investigation of the distribution of archaeological traces through the sedimentary record. The older depositional units (Lower and Upper Mungo) were deposited ca. 50–40 ka and ∼34 ka respectively, and are substantially thinner in the central section of the lunette compared with the south. By contrast, the overlying unit of interbedded sands and clayey sands (Arumpo–Zanci units), deposited ca. 25–14 ka, is markedly thicker and dominates the stratigraphic sequence in the central portion of the lunette. Although the sequence broadly reflects previous models of the lunette\u27s depositional history and changing hydrological conditions, our results indicate spatially variable deposition of sediments, possibly as a result of changes in prevailing wind regimes. Archaeological traces are exposed in all stratigraphic units deposited after ca. 50 ka, including sediments deposited after the final lake drying ca. 15 ka, indicating human occupation of the area under a range of palaeoenvironmental conditions. Dating and stratigraphical examination of individual hearth features demonstrates that even within individual stratigraphic units, human occupation persisted under variable conditions. Mid-Holocene occupation of the area following the final lake retreat took place during a period of relatively humid climate