Structural basis of TFIIH activation for nucleotide excision repair.

Nucleotide excision repair (NER) is the major DNA repair pathway that removes UV-induced and bulky DNA lesions. There is currently no structure of NER intermediates, which form around the large multisubunit transcription factor IIH (TFIIH). Here we report the cryo-EM structure of an NER intermediate containing TFIIH and the NER factor XPA. Compared to its transcription conformation, the TFIIH structure is rearranged such that its ATPase subunits XPB and XPD bind double- and single-stranded DNA, consistent with their translocase and helicase activities, respectively. XPA releases the inhibitory kinase module of TFIIH, displaces a 'plug' element from the DNA-binding pore in XPD, and together with the NER factor XPG stimulates XPD activity. Our results explain how TFIIH is switched from a transcription to a repair factor, and provide the basis for a mechanistic analysis of the NER pathway

Structural basis of human transcription–DNA repair coupling

Transcription-coupled DNA repair removes bulky DNA lesions from the genome1,2 and protects cells against ultraviolet (UV) irradiation3. Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4CSA and UV-stimulated scaffold protein A (UVSSA)3. Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published3,4 data, the structures provide a model for transcription–repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, ECTCR, uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4CSA lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA

High levels of women's satisfaction and compliance with transdermal contraception: results from a European multinational, 6-month study

Objective. To investigate compliance, satisfaction, and preference in women using a transdermal contraceptive patch. Methods. Women (18–46 years) from eight European countries used contraceptive patches (norelgestromin 6 mg, ethinylestradiol 600 mg) for six, 4-week treatment cycles. Compliance, satisfaction, and preference were assessed after 3 and 6 cycles and study completion using self-report methods. Results. Of the 778 participants, 36.8 % (n 287) used no contraception at baseline. The most common methods were oral contraceptives (67.9%, n 334) and barrier methods (21.5%, n 106). Of oral contraception users, 63.5 % (n 212) were satisfied or very satisfied with their previous method, but compliance was poor with 77.8 % (n 260) reporting missed doses. After 3 and 6 cycles,480 % of all included women were satisfied or very satisfied with the patch. At study completion, most participants (73.7%) reported a preference for the patch compared to their previous method. Of 4107 cycles, 3718 (90.5%) were completed with perfect compliance. Two pregnancies occurred during this study, representing a Pearl Index of 0.63. No new safety issues were identified and the patch was well tolerated. Conclusion. Women were highly satisfied with transdermal contraception and preferred this form of family planning over their previous method. Transdermal contraception represents a valuable addition to contraceptive options with potential t

Dynamic Nonlinear X-waves for Femtosecond Pulse Propagation in Water

Recent experiments on femtosecond pulses in water displayed long distance propagation analogous to that reported in air. We verify this phenomena numerically and show that the propagation is dynamic as opposed to self-guided. Furthermore, we demonstrate that the propagation can be interpreted as due to dynamic nonlinear X-waves whose robustness and role in long distance propagation is shown to follow from the interplay between nonlinearity and chromatic dispersion.Comment: 4 page

On the Properties of Two Pulses Propagating Simultaneously in Different Dispersion Regimes in a Nonlinear Planar Waveguide

Properties of two pulses propagating simultaneously in different dispersion regimes, anomalous and normal, in a Kerr-type planar waveguide are studied in the framework of the nonlinear Schroedinger equation. Catastrophic self-focusing and spatio-temporal splitting of the pulses is investigated. For the limiting case when the dispersive term of the pulse propagating in the normal dispersion regime can be neglected an indication of a possibility of a stable self-trapped propagation of both pulses is obtained.Comment: 18 pages (including 15 eps figures

X-wave mediated instability of plane waves in Kerr media

Plane waves in Kerr media spontaneously generate paraxial X-waves (i.e. non-dispersive and non-diffractive pulsed beams) that get amplified along propagation. This effect can be considered a form of conical emission (i.e. spatio-temporal modulational instability), and can be used as a key for the interpretation of the out of axis energy emission in the splitting process of focused pulses in normally dispersive materials. A new class of spatio-temporal localized wave patterns is identified. X-waves instability, and nonlinear X-waves, are also expected in periodical Bose condensed gases.Comment: 4 pages, 6 figure

Operando tracking of oxidation-state changes by coupling electrochemistry with time-resolved X-ray absorption spectroscopy demonstrated for water oxidation by a cobalt-based catalyst film

Transition metal oxides are promising electrocatalysts for water oxidation, i.e., the oxygen evolution reaction (OER), which is critical in electrochemical production of non-fossil fuels. The involvement of oxidation state changes of the metal in OER electrocatalysis is increasingly recognized in the literature. Tracing these oxidation states under operation conditions could provide relevant information for performance optimization and development of durable catalysts, but further methodical developments are needed. Here, we propose a strategy to use single-energy X-ray absorption spectroscopy for monitoring metal oxidation-state changes during OER operation with millisecond time resolution. The procedure to obtain time-resolved oxidation state values, using two calibration curves, is explained in detail. We demonstrate the significance of this approach as well as possible sources of data misinterpretation. We conclude that the combination of X-ray absorption spectroscopy with electrochemical techniques allows us to investigate the kinetics of redox transitions and to distinguish the catalytic current from the redox current. Tracking of the oxidation state changes of Co ions in electrodeposited oxide films during cyclic voltammetry in neutral pH electrolyte serves as a proof of principle

Donor-acceptor recombination emission in hydrogen-terminated nanodiamond: Novel single-photon source for room-temperature quantum photonics

In fluorescence spectra of nanodiamonds (NDs) synthesized at high pressure from adamantane and other organic compounds, very narrow (~1 nm) lines of unknown origin are observed in a wide spectroscopic range from ~500 to 800 nm. Here, we propose and experimentally substantiate the hypothesis that these mysterious lines arise from radiative recombination of donor-acceptor pairs (DAPs). To confirm our hypothesis, we study the fluorescence spectra of undoped and nitrogen-doped NDs of different sizes, before and after thermal oxidation of their surface. The results obtained with a high degree of confidence allowed us to conclude that the DAPs are formed through the interaction of donor-like substitutional nitrogen present in the diamond lattice, and a 2D layer of acceptors resulting from the transfer doping effect on the surface of hydrogen-terminated NDs. A specific behavior of the DAP-induced lines was discovered in the temperature range of 100-10 K: their energy increases and most lines are split into 2 or more components with decreasing temperature. It is shown that the majority of the studied DAP emitters are sources of single photons, with an emission rate of up to >1 million counts/s at room temperature, which significantly surpasses that of nitrogen-vacancy and silicon-vacancy centers under the same detection conditions. Despite an observed temporal instability in the emission, the DAP emitters of H-terminated NDs represent a powerful room-temperature single-photon source for quantum optical technologies

Ultrashort filaments of light in weakly-ionized, optically-transparent media

Modern laser sources nowadays deliver ultrashort light pulses reaching few cycles in duration, high energies beyond the Joule level and peak powers exceeding several terawatt (TW). When such pulses propagate through optically-transparent media, they first self-focus in space and grow in intensity, until they generate a tenuous plasma by photo-ionization. For free electron densities and beam intensities below their breakdown limits, these pulses evolve as self-guided objects, resulting from successive equilibria between the Kerr focusing process, the chromatic dispersion of the medium, and the defocusing action of the electron plasma. Discovered one decade ago, this self-channeling mechanism reveals a new physics, widely extending the frontiers of nonlinear optics. Implications include long-distance propagation of TW beams in the atmosphere, supercontinuum emission, pulse shortening as well as high-order harmonic generation. This review presents the landmarks of the 10-odd-year progress in this field. Particular emphasis is laid to the theoretical modeling of the propagation equations, whose physical ingredients are discussed from numerical simulations. Differences between femtosecond pulses propagating in gaseous or condensed materials are underlined. Attention is also paid to the multifilamentation instability of broad, powerful beams, breaking up the energy distribution into small-scale cells along the optical path. The robustness of the resulting filaments in adverse weathers, their large conical emission exploited for multipollutant remote sensing, nonlinear spectroscopy, and the possibility to guide electric discharges in air are finally addressed on the basis of experimental results.Comment: 50 pages, 38 figure