Homopurine guanine-rich sequences in complex with N-methyl mesoporphyrin IX form parallel G-quadruplex dimers and display a unique symmetry tetrad

DNA can fold into G-quadruplexes (GQs), non-canonical secondary structures formed by pi-pi stacking of G-tet-rads. GQs are important in many biological processes, which makes them promising therapeutic targets. We identified a 42-nucleotide long, purine-only G-rich sequence from human genome, which contains eight G- stretches connected by A and AAAA loops. We divided this sequence into five unique segments, four guanine stretches each, named GA1-5. In order to investigate the role of adenines in GQ structure formation, we per-formed biophysical and X-ray crystallographic studies of GA1-5 and their complexes with a highly selective GQ ligand, N-methyl mesoporphyrin IX (NMM). Our data indicate that all variants form parallel GQs whose stability depends on the number of flexible AAAA loops. GA1-3 bind NMM with 1:1 stoichiometry. The Ka for GA1 and GA3 is modest, similar to 0.3 mu M 1, and that for GA2 is significantly higher, similar to 1.2 mu M 1. NMM stabilizes GA1-3 by 14.6, 13.1, and 7.0 degrees C, respectively, at 2 equivalents. We determined X-ray crystal structures of GA1-NMM (1.98 A resolution) and GA3-NMM (2.01 A). The structures confirm the parallel topology of GQs with all adenines forming loops and display NMM binding at the 3 \u27 G-tetrad. Both complexes dimerize through the 5 \u27 interface. We observe two novel structural features: 1) a \u27symmetry tetrad\u27 at the dimer interface, which is formed by two guanines from each GQ monomer and 2) a NMM dimer in GA1-NMM. Our structural work confirms great flexibility of adenines as structural elements in GQ formation and contributes greatly to our understanding of the structural diversity of GQs and their modes of interaction with small molecule ligands

Ripple AT Plus - isthmus-guided vs conventional ablation in the treatment of scar-related atrial tachycardia: study protocol for a randomised controlled trial

Background Catheter ablation is routinely used to treat scar-related atrial tachycardia (s-AT). Conventional ablation often involves creating anatomical “lines” that transect myocardial tissue supporting reentry. This can be extensive, creating iatrogenic scar as a nidus for future reentry, and may account for arrhythmia recurrence. High-density mapping may identify “narrower isthmuses” requiring less ablation, with ripple mapping proven to be an effective approach in identifying. This trial explores whether ablation of narrower isthmuses in s-AT, defined using ripple mapping, results in greater freedom from arrhythmia recurrence compared to conventional ablation. Methods The Ripple-AT-Plus trial (registration ClinicalTrials.gov, NCT03915691) is a prospective, multicentre, single-blinded, randomised controlled trial with 12-month follow-up. Two hundred s-AT patients will be randomised in a 1:1 fashion to either “ripple mapping-guided isthmus ablation” vs conventional ablation on the CARTO3 ConfiDENSE system (Biosense Webster). The primary outcome will compare recurrence of any atrial arrhythmia. Multicentre data will be analysed over a secure web-based cloud-storage and analysis software (CARTONETTM). Conclusion This is the first trial that considers long-term patient outcomes post s-AT ablation, and whether targeting narrower isthmuses in the era of high density is optimal

Demulsification mechanism of asphaltene-stabilized water-in-oil emulsions by a polymeric ethylene oxide-propylene oxide demulsifier

The demulsification mechanism of asphaltene-stabilized water-in-toluene emulsions by an ethylene-oxide-propylene oxide (EO-PO) based polymeric demulsifier was studied. Demulsification efficiency was determined by bottle tests and correlated to the physicochemical properties of asphaltene interfacial films after demulsifier addition. From bottle tests and droplet coalescence experiments, the demulsifier showed an optimal performance at 2.3 ppm (mass basis) in toluene. At high concentrations, the demulsification performance deteriorated due to the intrinsic stabilizing capacity of the demulsifier, which was attributed to steric repulsion between water droplets. Addition of demulsifier was shown to soften the asphaltene film (i.e., reduce the viscoelastic moduli of asphaltene films) under both shear and compressional interfacial deformations. Study of the macrostructures and the chemical composition of asphaltene film at the toluene-water interface after demulsifier addition demonstrated gradual penetration of the demulsifier into the asphaltene film. Demulsifier penetration in the asphaltene film changed the asphaltene interfacial mobility and morphology, as probed with Brewster angle and atomic force microscopy

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

A note on multiobjective second-order symmetric duality

In this paper, we establish a strong duality theorem for a pair of multiobjective second-order symmetric dual programs. This removes an omission in an earlier result by Yang et al. [X.M. Yang, X.Q. Yang, K.L. Teo, S.H. Hou, Multiobjective second-order symmetric duality with F-convexity, Euro. J. Oper. Res. 165 (2005) 585-591].Nonlinear programming Second-order symmetric duality F-convexity Duality theorems Efficient solution

Additive Manufacturing of Magnetostrictive Cobalt Ferrite Thin Films for Structural Energy Harvesting

Magnetostrictive energy harvesters that convert ambient structural vibrations to useful electricity have the potential to supplement or replace batteries, especially in portable and wearable electronics. The magneto-mechanical coupling of magnetostricive materials converts mechanical energy to magnetic energy, and electro-magnetic coupling of electrical circuits converts magnetic energy to electrical energy. Additive manufacturing of magnetostrictive thin films is essential for building small-scale and flexible energy harvesters, which are difficult or even impossible to manufacture using traditional processes. To develop this technique, cobalt ferrite nanopowder was used to synthesize aqueous and non-aqueous inks for inkjet printing. Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM) were used to analyze particle and agglomeration sizes. The viscosity of the inks was measured using a rotational rheometer. The ink properties, including specific particle size and viscosity, were fine-tuned to ensure successful printing. Different heat treatments and sintering processes for the printed thin films will be explored to determine their effects on the magnetostrictive properties

Duality in nondifferentiable minimax fractional programming with <it>B</it>-(<it>p</it>, <it>r</it>)<b>-</b>invexity

Abstract In this article, we are concerned with a nondifferentiable minimax fractional programming problem. We derive the sufficient condition for an optimal solution to the problem and then establish weak, strong, and strict converse duality theorems for the problem and its dual problem under B-(p, r)-invexity assumptions. Examples are given to show that B-(p, r)-invex functions are generalization of (p, r)-invex and convex functions AMS Subject Classification: 90C32; 90C46; 49J35.</p

Generalized Second-Order Mixed Symmetric Duality in Nondifferentiable Mathematical Programming

This paper is concerned with a pair of second-order mixed symmetric dual programs involving nondifferentiable functions. Weak, strong, and converse duality theorems are proved for aforementioned pair using the notion of second-order F-convexity/pseudoconvexity assumptions

Nonlinear Effect of Depression Symptoms on the Time Course of Emotional Reactivity

The literature on emotion reactivity among people with major depressive disorder (MDD) indicates that people with MDD show diminished reactivity to negative events as compared to non-depressed controls. This diminished reactivity may only be at the highest levels of depression symptoms, suggesting a nonlinear association between depression symptoms and emotion reactivity. Unfortunately, depression has not been examined as a continuum in this line of research; moreover, the time course of reactivity during an emotional event has not been adequately examined. Participants (N = 100) completed a measure of depression symptoms and then viewed a sadness-inducing 11-min film clip while their facial expressions were video recorded and coded separately for each minute of the film clip. Growth-curve analyses indicated a quadratic effect of depression symptoms on curves for facial expressions of sadness and happiness, such that the change in growth/decay first increased and then decreased from low to high levels of depression symptoms. This result supports the idea that the negative mood inherent in depression potentiates reactivity at lower ends of the depression continuum but that reactivity is dampened at higher levels of depression. This suggests that researchers specify the specific range of depression symptoms under investigation (e.g., mild, moderate, dysphoric, severely depressed) when studying the role of depression on emotional reactivity