Chemistry and DNA alkylation reactions of aziridinyl quinones: development of an efficient alkylating agent of the phosphate backbone

Described herein are detailed hydrolytic studies of a series of aziridinyl quinones, which trap nucleophiles when protonated. This study provided a compilation of the rate constants for nucleophile trapping and of the pKa values for the protonated aziridinyl quinones. A linear free energy relationship, including the antitumor agent DZQ, as well as other synthetic quinone derivatives, was obtained as a result of this study. Protonated DZQ has the relatively high pKa value of 3.8, which explains the enhanced cross-linking of DNA by DZQ and other related aziridinyl quinones at pH 4. The literature often shows aziridinyl quinone protonation occurring at the aziridinyl nitrogen, but the dependence of pKa values on quinone substituents indicates the presence of delocalization, which must arise from O-protonation. Also investigated were the DNA alkylation reactions of protonated aziridinyl quinones. At the outset of this study, we postulated that these "hard" electrophiles would alkylate the phosphate backbone of DNA. Bulk DNA is up to 35% alkylated by protonated aziridinyl quinones as judged by the incorporation of the quinone chromophore into the DNA. The presence of phosphate alkylation was verified by a 1H-31P NMR correlation experiment with DZQ-alkylated hexamer. Our modeling studies present a new picture of DZQ alkylation of DNA, where there is competition between N(7) and phosphate alkylation. The conclusions of this part of our study are that the phosphate backbone should be considered as a possible target of any DNA-alkylating agent and that an assessment of phosphate alkylation is best made with a 1H-31P NMR correlation experiment. Finally, the benzimidazole-based aziridinyl quinone 2 was observed to undergo aziridine ring opening followed by hydrolytic removal of the aminoethyl group from the quinone ring. This reaction was used to tag the phosphate backbone of DNA with aminoethyl groups. Such tags render anionic phosphates cationic and could also be employed as points of attachment for chromophores, spin labels, or other moieties to DNA.     

The urethral sling and stress urinary incontinence

We report the case of a 40-year-old Filippino woman, with a 5-year history of a slowly spreading, painful skin lesion on her left foot. Histological examination showed a dermal, granulomatous infiltrate consisting of neutrophils, histiocytes and lymphocytes, with "sclerotic bodies" in the cytoplasm of phagocytic cells. Mycological culture revealed the presence of Phialophora verrucosa and confirmed the histopathological diagnosis of chromo-blastomycosis. Association of surgical curettage of the exuberant, infected tissue with systemic fluconazole administration gave good therapeutic results with no relevant side effects.     

Combining Bayesian optimization and Lipschitz optimization

Machine Learning - Bayesian optimization and Lipschitz optimization have developed alternative techniques for optimizing black-box functions. They each exploit a different form of prior about the...     

Control Mechanisms and Agile Methodology Use: Data from the Industry

This research investigates the relationship between the degree of agile methodology use and four types of control mechanisms that are widely used in the management of a software project and its personnel: outcome control, behavioral control, clan control, and self-control. We conducted two studies: a survey of software professionals and a follow-up interview in six organizations. We found the following: 1) software professionals reported high outcome and clan controls regardless of their levels of agile methodology use; 2) the high agile group reported some use of behavioral and self-controls while the low agile group did not; 3) even though behavioral control was minimum in the low agile group, all professionals we interviewed strongly agreed that using established materials and following existing procedures should be standardized practices in software development. Implications of this research are discussed.     

Enhanced injection method for synthetically generated turbulence within the flow domain of eddy-resolving simulations

The quality of eddy-resolving turbulence simulations strongly depends on appropriate inflow conditions. In most cases they have to be time-dependent and satisfy certain conditions for the first (mean velocities) and second-order moments (Reynolds stresses) as well as concerning suitable length scales. To mimic a physically realistic incoming flow, synthetically generated turbulent velocity fluctuations superimposed on the mean velocity field are a valuable solution. However, the resolution of the grid near the inlet has to be sufficiently fine to avoid excessive damping of the turbulence intensity. In order to circumvent this problem, the injection of synthetically generated inflow data not at the inlet itself but inside the flow domain near the area of interest, where the grid is typically much finer, is an elegant loophole. In the present study two different injection techniques based on a source-term formulation are analyzed and evaluated. In addition to these techniques the injected data are weighted by a Gaussian distribution defining the influence area. In the recent work the definition of the influence area is enhanced compared to the initial version of Schmidt and Breuer (2017) extending the application range. The case of a rather small influence area in comparison with the grid cell size is now tackled which is often relevant for industrial applications.The flow past a wall-mounted hemisphere is chosen as test case. The bluff body is exposed to a thick turbulent boundary layer at Re $=$ 50,000. The generation of the turbulent velocity fluctuations in the present investigation relies on the digital filter concept, but the injection techniques evaluated are not restricted to this inflow generator. The synthetic turbulent velocity fluctuations are injected about one diameter upstream of the hemisphere. Wall-resolved large-eddy simulations are carried out for two grid resolutions and the corresponding results are analyzed and compared with the reference measurements by Wood et al. (2016). Finally, one injection technique is found to be clearly superior to the other, since it guarantees the correct level of the velocity fluctuations and the reproduction of the autocorrelations.     

NDNetGaming - development of a no-reference deep CNN for gaming video quality prediction

Multimedia Tools and Applications - Gaming video streaming services are growing rapidly due to new services such as passive video streaming of gaming content, e.g. Twitch.tv, as well as cloud...     

Photorheology of Fast UV‐Curing Multifunctional Acrylates

Summary: The fast photopolymerization of different multifunctional acrylates was analyzed by means of photorheology. The materials studied included a penta/hexaacrylate monomer and two different acrylated hyperbranched polymers. The sensitivity of the commercial rheometer was improved several‐fold, by a combination of an adaptive filter algorithm and improved data treatment, using powerful oversampling acquisition hardware. The novel set‐up was capable of monitoring up to a five orders of magnitude increase in shear modulus within short experiment timescales (about 10 s). The improvement in sensitivity and acquisition rate enabled the induction time, gelation, and vitrification of the multifunctional acrylates to be determined. In addition, the influence of UV intensity on stiffness build‐up within these materials was studied. In the case of the penta/hexaacrylate system, gelation and vitrification were detected as distinct events, in contrast to the second‐generation hyperbranched polyester, for which vitrification could not be identified. These findings are related to the difference in the glass transition temperature of the cured networks.

Absolute value of the complex shear modulus as a function of time for different acrylate monomers during UV curing.     

Development of a new experimental method to determine critical pigment–volume–concentrations using impedance spectroscopy

The critical pigment–volume–concentration (CPVC) of a solvent-based epoxy coating with various pigment–volume–concentrations (PVC) was analyzed. It was shown that electrochemical impedance spectroscopy (EIS) is a suitable method to detect the CPVC of coatings. The CPVC can be derived from EIS Bode plots or by fitting the EIS-curves using simple equivalent circuit diagrams. The parameters pore resistance R_P, capacitance C of the constant phase element (CPE), the relative dielectric constant _R derived from C, and the exponent n of the CPE allow the determination of the CPVC.