Identification of nine new susceptibility loci for endometrial cancer

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS) we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5,624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes and risk alleles at two of these loci that associate with decreased expression of genes which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study

Simple, Robust, and Plasticizer-Free Iodide-Selective Sensor Based on Copolymerized Triazole-Based Ionic Liquid

Novel solid-contact iodide-selective electrodes based on covalently attached 1,2,3 triazole ionic liquid (IL) were prepared and investigated in this study. Triazole-based IL moieties were synthesized using click chemistry and were further copolymerized with lauryl methacrylate via a simple one-step free radical polymerization to produce a "self-plasticized" copolymer. The mechanical properties of the copolymer are suitable for the fabrication of plasticizer-free ion-selective membrane electrodes. We demonstrate that covalently attached IL moieties provide adequate functionality to the ion-selective membrane, thus achieving a very simple, one-component sensing membrane. We also demonstrate that the presence of iodide as the counterion in the triazole moiety has direct influence on the membrane's functionality. Potentiometric experiments revealed that each electrode displays high selectivity toward iodide anions over a number of inorganic anions. Moreover, the inherent presence of the iodide in the membrane reduces the need for conditioning. The nonconditioned electrodes show strikingly similar response characteristics compared to the conditioned ones. The electrodes exhibited a near Nernstian behavior with a slope of -56.1 mV per decade across a large concentration range with lower detection limits found at approximately 6.3 × 10(-8) M or 8 ppb. These all-solid-state sensors were utilized for the selective potentiometric determination of iodide ions in artificial urine samples in the nanomolar concentration range

Evaluation and characterisation of metal sorption and retention by drinking water treatment residuals (WTRs) for environmental remediation

Drinking water treatment residuals (WTRs) are wastes generated when water is clarified using aluminium or iron salts. They are increasingly being considered as a resource with potential reuse value, particularly in relation to soil or water remediation. Adsorption–desorption capacity of Al-based (Al-WTR) and Fe-based (Fe-WTR) materials was investigated here for Pb and Zn, both separately and in combination, as a preliminary trial to assess their utility for immobilising contaminant metals in environmental settings. Maximum adsorption observed at the highest test solution concentrations imposed (400 mg/L) was similar for each WTR type and each metal; Al-WTRs sorbed Zn at 3579 mg/kg and Pb at 4025 mg/kg, while Fe-WTRs sorbed Zn and Pb at 3579 mg/kg and 3980 mg/kg, respectively. Equilibrium adsorption data were tested against Langmuir, Freundlich, and Temkin isotherm models, which indicated a substantial reserve capacity for further Pb sorption and that multiple sorption mechanisms were involved. Subsequent desorption tests with 0.001 M CaCl2 solution indicated that > 89.76% of sorbed metal remained sorbed. When in solution together, both metals were strongly sorbed by WTRs, but a slight preference for Pb was observed. The results indicate that WTRs would be very effective immobilising agents if placed in contaminated soil or if used to treat contaminated waters

Production of Androgens by Microbial Transformation of Progesterone in Vitro: A Model for Androgen Production in Rivers Receiving Paper Mill Effluent

We have previously documented the presence of progesterone and androstenedione in the water column and bottom sediments of the Fenholloway River, Taylor County, Florida. This river receives paper mill effluent and contains masculinized female mosquitofish. We hypothesized that plant sterols (e.g., β-sitosterol) derived from the pulping of pine trees are transformed by bacteria into progesterone and subsequently into 17α-hydroxyprogesterone, androstenedione, and other androgens. In this study, we demonstrate that these same androgens can be produced in vitro from the bacterium Mycobacterium smegmatis. In a second part to this study, we reextracted and reanalyzed the sediment from the Fenholloway River and verified the presence of androstadienedione, a Δ1 steroid with androgen activity

Sequential Deliberation for Social Choice

In large scale collective decision making, social choice is a normative study of how one ought to design a protocol for reaching consensus. However, in instances where the underlying decision space is too large or complex for ordinal voting, standard voting methods of social choice may be impractical. How then can we design a mechanism - preferably decentralized, simple, scalable, and not requiring any special knowledge of the decision space - to reach consensus? We propose sequential deliberation as a natural solution to this problem. In this iterative method, successive pairs of agents bargain over the decision space using the previous decision as a disagreement alternative. We describe the general method and analyze the quality of its outcome when the space of preferences define a median graph. We show that sequential deliberation finds a 1.208- approximation to the optimal social cost on such graphs, coming very close to this value with only a small constant number of agents sampled from the population. We also show lower bounds on simpler classes of mechanisms to justify our design choices. We further show that sequential deliberation is ex-post Pareto efficient and has truthful reporting as an equilibrium of the induced extensive form game. We finally show that for general metric spaces, the second moment of of the distribution of social cost of the outcomes produced by sequential deliberation is also bounded

An exceptionally bright flare from SGR1806-20 and the origins of short-duration gamma-ray bursts

Soft-gamma-ray repeaters (SGRs) are galactic X-ray stars that emit numerous short-duration (about 0.1 s) bursts of hard X-rays during sporadic active periods. They are thought to be magnetars: strongly magnetized neutron stars with emissions powered by the dissipation of magnetic energy. Here we report the detection of a long (380 s) giant flare from SGR 1806-20, which was much more luminous than any previous transient event observed in our Galaxy. (In the first 0.2 s, the flare released as much energy as the Sun radiates in a quarter of a million years.) Its power can be explained by a catastrophic instability involving global crust failure and magnetic reconnection on a magnetar, with possible large-scale untwisting of magnetic field lines outside the star. From a great distance this event would appear to be a short-duration, hard-spectrum cosmic gamma-ray burst. At least a significant fraction of the mysterious short-duration gamma-ray bursts therefore may come from extragalactic magnetars.Comment: 21 pages, 5 figures. Published in Natur

A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families