8-Oxopurines (8-oxodG and 8-oxodA) and formamidopyrimidines (FaPydG and FaPydA) are major oxidative DNA lesions involved in cancer development and aging. Their mutagenicity is believed to result from a conformational shift of the N9-C1' glycosidic bonds from anti to syn, which allows the lesions to form noncanonical Hoogsteen-type base pairs with incoming triphosphates during DNA replication. Here we present biochemical data and what are to our knowledge the first crystal structures of carbocyclic FaPydA and FaPydG containing DNA in complex with a high-fidelity polymerase. Crystallographic snapshots show that the cFaPy lesions keep the anti geometry of the glycosidic bond during error-free and error-prone replication. The observed dG·dC→dT·dA transversion mutations are the result of base shifting and tautomerization.

Photolyase‐catalyzed repair of pyrimidine (6‐4) photoadducts was modeled with synthetic, covalently linked flavin–oxetane 1. The repair reaction (oxetane splitting) requires the reduced flavin in its deprotonated form. The key step of the repair reaction involves an electron transfer from the flavin to the oxetane.

Ultraviolet irradiation of cells causes the formation of a variety of DNA lesions with known mutagenic, carcinogenic, and lethal effects. [1,2] The main UV lesions are cyclobutane ± pyrimidine dimers (CPD lesions) formed in a photochemically allowed [2p 2p] cycloaddition and (6-4) photoadducts; the latter are presumably more mutagenic. [3,4] The highly mutagenic (6-4) lesions are believed to be formed in a Paterno ¬ -B¸chi reaction between two adjacent pyrimidines in the DNA duplex to give initially an oxetane intermediate, which rearranges above À 80 8C to the (6-4) photoadduct by a proton shift and a CÀO bond scission (Scheme 1). [5] Both types of DNA lesions are repaired in many organisms by a special class of repair enzymes, namely DNA photolyases, which cleave both lesions back into the monomers in a lightdependent, single electron transfer based repair reaction. [6] In the last decade, crystallographic, [7, 8] enzymatic, [9, 10] and model compound studies [11±14] showed that the photolyases, [15] which are responsible for the repair of CPD lesions, contain a[5] K.[17] Initial synthesis of 1: A solution of 1,3,5-tris(diphenylphosphanyl)benzene (L; 63 mg, 0.1 mmol) in CH 2 Cl 2 (3 mL) was added to a solution of AgOTf (38.5 mg, 0.15 mmol) in CH 3 NO 2 (1 mL). Diffusion of diethyl ether vapor into the resulting solution over one week gave colorless hexagonal crystals of 1 in 10 % yield, together with powdery amorphous material. Higher yield synthesis: 1,3,5-tris(diphenylphosphanyl)benzene (L; 31.5 mg, 0.05 mmol) and AgOTf (17.0 mg, 0.067 mmol) were dissolved in a mixture of ethanol (7 mL) and nitromethane (3 mL), placed in a loosely stoppered polypropylene flask and partially evaporated at 88 8C overnight. Block and hexagonal colorless crystals were manually separated from the powdery amorphous byproduct. Yield: 50 ± 80 %; elemental analysis calcd (%) for [Ag 4 L 3 (OTf) 4 ] ¥ CH 3 NO 2 : C 52.79, H 3.42; found: C 52.55, H 3.32. [18] X-ray data were collected on a BrukerAXS SMART diffractometer using the SAINT-NT [26] software with omega/phi scans. A crystal was mounted on to the diffractometer under dinitrogen at approximately 120 K. The structure was solved using direct methods with the SHELXTL program package. [27] Crystal Data for the hexagonal plate crystals {C 130 H 99 F 12 Ag 4 P 9 S 4 O 12 } n (1): M 2919.54, hexagonal, space group P3 ≈ c, a 29.949(8), c 25.929(10) ä, V 20 141(11) ä À3 , Z 4, m 0.545 mm À1 . A total of 39 337 reflections were measured for the angle range 4 < 2q < 45 and 8797 independent reflections were used in the refinement. The final parameters were wR2 0.3009 and R1 0.0906 [I > 2sI]. Cell parameters for the block crystals [{C 130 H 99 F 12 Ag 4 -P 9 S 4 O 12 } n ] (1') [23] : M 2919.54, hexagonal, space group P3 ≈ c, a 30.076(1), c 25.791(1) ä, V 20 204(1) ä À3 . The residual densities (< 1 electron ä À3 ) associated with the voids indicate small amounts of very diffuse solvent molecules. Consequently, the nature of the solvent could not be determined using X-ray diffraction m...

Objectives Data from randomized controlled trials have shown the feasibility of discontinuation of bDMARD therapy in patients with RA that have reached remission. Criteria for selecting patients that are likely to remain in remission are still incompletely defined. We aimed to identify predictors of successful discontinuation of bDMARD therapy in the Swiss Clinical Quality Management (SCQM) registry, a real-world cohort of RA patients. Methods RA patients in DAS28-ESR remission who stopped bDMARD/tsDMARD treatment were included. Loss of remission was defined as a DAS28-ESR &gt; 2.6 or restart of a bDMARD/tsDMARD. Time to loss of remission was the main outcome. Kaplan-Meier methods were applied and cox regression was used for multivariable analyses adjusting for confounding factors. Missing data were imputed using multiple imputation. Results 318 patients in a bDMARD/tsDMARD-free remission were followed between 1997 and 2017. 241 patients (76%) lost remission after a median time of 0.9 years (95%CI 0.7–1.0). The time to loss of remission was shorter in women, in patients with a longer disease duration &gt;4yrs and in patients who did not meet CDAI remission criteria at baseline. Remission was longer in patients with csDMARD therapy during b/tsDMARD free remission (HR 0.8, p= 0.05, 95%CI 0.6–1.0). Conclusion In a real-world patient population the majority of patients who discontinued b/tsDMARD treatment lost remission within &lt;1 year. Our study confirms that fulfilment of more rigorous remission criteria and csDMARD treatment increases the chance of maintaining b/tsDMARD free remission.

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The reliability of the auxiliary power supply of a nuclear power plant (NPP) is of high importance for safe operation. The loss of the electrical power supply is one of the major contributions to the calculated core damage frequency in probabilistic safety assessments. Among others, the events in Forsmark in 2006 [1] and 2012 [2] as well as in Byron in 2012 [3] illustrate that disturbances in the external power grid can propagate into the NPP and have an impact on the safety important electrical equipment. Therefore, the grid reliability contributes considerably to the reliability of the auxiliary power supply. In the research work presented in this paper the international operating experience has been evaluated concerning events which include disturbance in the external grid to discover those types of grid disturbances which may have influence on the safe operation of the NPPs. The identified events have then been categorized within a developed classification scheme to determine those with the highest relevance. Based on this scheme representative scenarios of grid disturbances have been developed. The investigation of the impact of the developed scenarios on the electrical equipment of NPPs will be performed using a grid analysis, planning and optimization tool which also allows executing dynamic simulations of electrical grids [4]. Therefore, a generalized auxiliary power supply of a pressurized water reactor was modeled according to German NPPs of the type Konvoi. In this paper, an overview of the developed scenarios of grid disturbances and the actual status of the simulation of the auxiliary power supply of NPPs is presented.

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