High resolution mass spectrometry based profiling of diet-related deoxyribonucleic acid adducts

Exposure of DNA to endo- and exogenous DNA binding chemicals can result in the formation of DNA adducts and is believed to be the first step in chemically induced carcinogenesis. DNA adductomics is a relatively new field of research which studies the formation of known and unknown DNA adducts in DNA due to exposure to genotoxic chemicals. In this study, a new UHPLC-HRMS(/MS)-based DNA adduct detection method was developed and validated. Four targeted DNA adducts, which all have been linked to dietary genotoxicity, were included in the described method; O⁶-methylguanine (O⁶-MeG), O⁶-carboxymethylguanine (O⁶-CMG), pyrimidopurinone (M1G) and methylhydroxypropanoguanine (CroG). As a supplementary tool for DNA adductomics, a DNA adduct database, which currently contains 123 different diet-related DNA adducts, was constructed. By means of the newly developed method and database, all 4 targeted DNA adducts and 32 untargeted DNA adducts could be detected in different DNA samples. The obtained results clearly demonstrate the merit of the described method for both targeted and untargeted DNA adduct detection in vitro and in vivo, whilst the diet-related DNA adduct database can distinctly facilitate data interpretation.     

Variable Selection in Varying-Coefficient Models Using P-Splines

In this article, we consider nonparametric smoothing and variable selection in varying-coefficient models. Varying-coefficient models are commonly used for analyzing the time-dependent effects of covariates on responses measured repeatedly (such as longitudinal data). We present the P-spline estimator in this context and show its estimation consistency for a diverging number of knots (or B-spline basis functions). The combination of P-splines with nonnegative garrote (which is a variable selection method) leads to good estimation and variable selection. Moreover, we consider APSO (additive P-spline selection operator), which combines a P-spline penalty with a regularization penalty, and show its estimation and variable selection consistency. The methods are illustrated with a simulation study and real-data examples. The proofs of the theoretical results as well as one of the real-data examples are provided in the online supplementary materials.     

Split buildings of type $$\mathsf {F_4}$$ in buildings of type $$\mathsf {E_6}$$E6

A symplectic polarity of a building \(\varDelta \) of type \(\mathsf {E_6}\) is a polarity whose fixed point structure is a building of type \(\mathsf {F_4}\) containing residues isomorphic to symplectic polar spaces (i.e., so-called split buildings of type \(\mathsf {F_4}\)). In this paper, we show in a geometric way that every building of type \(\mathsf {E_6}\) contains, up to conjugacy, a unique class of symplectic polarities. We also show that the natural point-line geometry of each split building of type \(\mathsf {F_4}\) fully embedded in the natural point-line geometry of \(\varDelta \) arises from a symplectic polarity.     

Sensitive routine liquid chromatography–tandem mass spectrometry method for serum estradiol and estrone without derivatization

The need for a routinely applicable assay to measure low estradiol levels in adult men, postmenopausal women, and young adolescents was recently discussed in an Endocrine Society position statement. Our aim was to develop a sensitive liquid chromatography–tandem mass spectrometry method for estradiol and estrone in human serum without the need for derivatization or extended extraction protocols. After protein precipitation of serum with a mixture of methanol/acetonitrile (85/15) (v/v) containing isotopic internal standards (17β-estradiol-16,16,17-d ₃ and estrone-2,3,4-¹³C), we quantified estradiol and estrone by two-dimensional liquid chromatography–tandem mass spectrometry with electrospray ionization in the negative mode monitoring 5?×?271.20→145.00 (17β-estradiol) and 269.20→145.00 (estrone). Sensitivity was increased by using fluoride and summation of 5 identical transitions for estradiol. Our method was analytically validated, compared against direct immunoassays using serum of 25 adult men, and clinically tested by measuring samples of 3 men at baseline and after chemical castration, 30 postmenopausal women and 15 patients receiving aromatase inhibitors. Total imprecision was below 20 % for the low quality controls. Limit of quantification was 1.3 ng/L (4.8 pmol/L) for estradiol and 1.2 ng/L (4.4 pmol/L) for estrone. Estradiol in Certified Reference Material BCR-576 was within specified uncertainty limits. No significant ion suppression or interference was observed. Our method showed modest correlation with direct immunoassay for estradiol (r ²?=?0.64) but no correlation for estrone (r ²?=?0.12). Patient sample results were within expected ranges. In conclusion, we developed a routinely applicable liquid chromatography–tandem mass spectrometry method for estradiol and estrone measurement which is sensitive enough for use in men, postmenopausal women, and young adolescents.