Human papillomavirus vaccine uptake in adolescence and adherence to cervical cancer screening in Switzerland: a national cross-sectional survey.

OBJECTIVES The objectives were to measure uptake of and factors associated with human papillomavirus (HPV) vaccination initiation and to determine whether HPV vaccination reduced the uptake of cervical cancer screening. METHODS We conducted a cross-sectional survey in a random sample of Swiss women aged 18-49 years in 2014 (N = 3588). RESULTS Vaccination initiation was 69.3% and full coverage (three doses) 54.1% for 18-20-year olds, respectively, 42.4% and 33.9% for 21-24-year olds. Women with ≥ 10 lifetime sexual partners were less likely to have received any HPV vaccination than women with ≤ 2 partners (18-20 years OR 0.2, 21-24 years OR 0.5). Amongst 1000 unvaccinated women (18-24 years), reasons for not having initiated vaccination were lack of information (22.5%) and fear of vaccine side effects (18.1%). Vaccination status was not associated with adherence to cervical cancer screening recommendations (OR 1.3). 95.4% of all vaccinated participants knew about the continued need for screening. CONCLUSIONS Our data suggest that HPV vaccination is not associated with reduced uptake of cervical cancer screening. This study provides information that can be used to improve HPV vaccination uptake in Switzerland

Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: The role of water molecules examined

With an aim toward glycogenolysis control in Type 2 diabetes, we have investigated via kinetic experiments and computation the potential of indirubin (IC 50 > 50 μM), indirubin-3'-oxime (IC 50 = 144 nM), KT5720 (K i = 18.4 nM) and staurosporine (K i = 0.37 nM) as phosphorylase kinase (PhKγtrnc) ATP-binding site inhibitors, with the latter two revealed as potent inhibitors in the low nM range. Because of lack of structural information, we have exploited information from homologous kinase complexes to direct in silico calculations (docking, molecular dynamics, and MM-GBSA) to predict the binding characteristics of the four ligands. All inhibitors are predicted to bind in the same active site area as the ATP adenine ring, with binding dominated by hinge region hydrogen bonds to Asp104:O and Met106:O (all four ligands) and also Met106:NH (for the indirubins). The PhKγtrnc-staurosporine complex has the greatest number of receptor-ligand hydrogen bonds, while for the indirubin-3'-oxime and KT5720 complexes there is an important network of interchanging water molecules bridging inhibitor-enzyme contacts. The MM-GBSA results revealed the source of staurosporine's low nM potency to be favorable electrostatic interactions, while KT5720 has strong van der Waals contributions. KT5720 interacts with the greatest number of protein residues either by direct or 1-water bridged hydrogen bond interactions, and the potential for more selective PhK inhibition based on a KT5720 analogue has been established. Including receptor flexibility in Schrödinger induced-fit docking calculations in most cases correctly predicted the binding modes as compared with the molecular dynamics structures; the algorithm was less effective when there were key structural waters bridging receptor-ligand contacts. © 2010 Wiley-Liss, Inc

Effects of commonly used cryoprotectants on glycogen phosphorylase activity and structure.

The effects of a number of cryoprotectants on the kinetic and structural properties of glycogen phosphorylase b have been investigated. Kinetic studies showed that glycerol, one of the most commonly used cryoprotectants in X-ray crystallographic studies, is a competitive inhibitor with respect to substrate glucose-1-P with an apparent Ki value of 3.8% (v/v). Cryogenic experiments, with the enzyme, have shown that glycerol binds at the catalytic site and competes with glucose analogues that bind at the catalytic site, thus preventing the formation of complexes. This necessitated a change in the conditions for cryoprotection in crystallographic binding experiments with glycogen phosphorylase. It was found that 2-methyl-2,4-pentanediol (MPD), polyethylene glycols (PEGs) of various molecular weights, and dimethyl sulfoxide (DMSO) activated glycogen phosphorylase b to different extents, by stabilizing its most active conformation, while sucrose acted as a noncompetitive inhibitor and ethylene glycol as an uncompetitive inhibitor with respect to glucose-1-P. A parallel experimental investigation by X-ray crystallography showed that, at 100 K, both MPD and DMSO do not bind at the catalytic site, do not induce any significant conformational change on the enzyme molecule, and hence, are more suitable cryoprotectants than glycerol for binding studies with glycogen phosphorylase

POTENT INHIBITION OF GLYCOGEN-PHOSPHORYLASE BY A SPIROHYDANTOIN OF GLUCOPYRANOSE - FIRST PYRANOSE ANALOGS OF HYDANTOCIDIN

The synthesis of two epimeric spirohydantoins of glucopyranose provides the first examples of pyranose analogues of hydantocidin: molecular modelling correctly predicted that one of the epimers would be a potent inhibitor of glycogen phosphorylase. This is the first example of specific enzyme inhibition by a spirohydantoin at the anomeric position of a sugar. © 1995

Transfer of physically-based models from process to device simulations: Application to advanced SOI MOSFETs

International audienceDopant implantation, followed by spike annealing is one of the main focus areas in the simulation of silicon processing due to its ability to form highly-activated ultra-shallow junctions. Coupled with the growing interest in the use of silicon-on-insulator (SOI) wafers, modelling and simulation of the influence of SOI structure on damage evolution and ultra-shallow junction formation on one hand, and on electrical MOSFET device characteristics on the other hand, are required. In this work, physically-based models of dopant implantation and diffusion, including amorphization, defect interactions and evolution, as well as dopant-defect interactions in both bulk silicon and SOI are integrated within a unique simulation tool to model the different physical mechanisms involved in the process of ultra-shallow junction formation. The application to 65 nm SOI MOSFET devices demonstrated the strong impact of the process simulation models on the simulated electrical device characteristics, in particular for both defect evolution and defect dopant interaction with the additional silicon/buried oxide (Si/BOX) interface. Simulation results of the threshold voltage (V th) and the variation of the on-and off-state currents of the explored structures are in good agreement with experimental data and can provide important insight for optimizing the process in both bulk silicon and SOI technologies

Kinetics, in silico docking, molecular dynamics and MM-GBSA binding studies on prototype indirubins, KT5720 and staurosporine as phosphorylase kinase ATP-binding site inhibitors: The role of water molecules examined

With an aim toward glycogenolysis control in Type 2 diabetes, we have investigated via kinetic experiments and computation the potential of indirubin (IC₅₀ > 50 μM), indirubin-3'-oxime (IC₅₀ = 144 nM), KT5720 (K(i) = 18.4 nM) and staurosporine (K(i) = 0.37 nM) as phosphorylase kinase (PhKγtrnc) ATP-binding site inhibitors, with the latter two revealed as potent inhibitors in the low nM range. Because of lack of structural information, we have exploited information from homologous kinase complexes to direct in silico calculations (docking, molecular dynamics, and MMGBSA) to predict the binding characteristics of the four ligands. All inhibitors are predicted to bind in the same active site area as the ATP adenine ring, with binding dominated by hinge region hydrogen bonds to Asp104:O and Met106:O (all four ligands) and also Met106:NH (for the indirubins). The PhKγtrnc-staurosporine complex has the greatest number of receptor-ligand hydrogen bonds, while for the indirubin-3'-oxime and KT5720 complexes there is an important network of interchanging water molecules bridging inhibitor-enzyme contacts. The MM-GBSA results revealed the source of staurosporine's low nM potency to be favorable electrostatic interactions, while KT5720 has strong van der Waals contributions. KT5720 interacts with the greatest number of protein residues either by direct or 1-water bridged hydrogen bond interactions, and the potential for more selective PhK inhibition based on a KT5720 analogue has been established. Including receptor flexibility in Schrödinger induced-fit docking calculations in most cases correctly predicted the binding modes as compared with the molecular dynamics structures; the algorithm was less effective when there were key structural waters bridging receptor-ligand contacts