Binuclear ruthenium complex linker length tunes DNA threading intercalation kinetics.

Binuclear ruthenium complexes have been investigated for potential DNA-targeted therapeutic and diagnostic applications. Studies of DNA threading intercalation, in which DNA base pairs must be broken for intercalation, have revealed means of optimizing a model binuclear ruthenium complex to obtain reversible DNA-ligand assemblies with the desired properties of high affinity and slow kinetics. Here, we used single-molecule force spectroscopy to study a binuclear ruthenium complex with a longer semi-rigid linker relative to the model complex.

Diagnostic quality electrocardiogram from a HeartMate 3 supported patient using a smartphone-based recording device.

Patients with implantable left ventricular assist devices (LVAD) are at risk of ventricular arrhythmias but these may be hemodynamically tolerated. An electrocardiogram (ECG) is essential to determine whether an LVAD-supported patient is experiencing a ventricular arrhythmia. Access to 12 lead ECG is predominantly in healthcare facilities.

Left versus right: Exploring the effects of chiral threading intercalators using optical tweezers.

Small-molecule DNA-binding drugs have shown promising results in clinical use against many types of cancer. Understanding the molecular mechanisms of DNA binding for such small molecules can be critical in advancing future drug designs. We have been exploring the interactions of ruthenium-based small molecules and their DNA-binding properties that are highly relevant in the development of novel metal-based drugs.

Elevated Notch ligands in serum are associated with HIV/TB coinfection.

Objective: There is a clear need for improved biomarkers to diagnose HIV/TB coinfection. Although numerous tests can identify the existence of both of these microbes within the host, a parallel assessment of the host response to HIV/TB coinfection may prove as useful confirmation in cases where microbiological tests are inconclusive. To this end we assessed the levels of Notch ligands found in serum samples of patients with TB, HIV or HIV/TB coinfection.

DNA threading intercalation of enantiopure [Ru(phen)bidppz] induced by hydrophobic catalysis.

The enantiomers of a novel mononuclear ruthenium(ii) complex [Ru(phen)2bidppz]2+ with an elongated dppz moiety were synthesized. Surprisingly, the complex showed no DNA intercalating capability in an aqueous environment. However, by the addition of water-miscible polyethylene glycol ether PEG-400, self-aggregation of the hydrophobic ruthenium(ii) complexes was counter-acted, thus strongly promoting the DNA intercalation binding mode.

Prevalence of ICU Delirium in Postoperative Pediatric Cardiac Surgery Patients.

Objectives: The objective of this study was to determine the prevalence of ICU delirium in children less than 18 years old that underwent cardiac surgery within the last 30 days. The secondary aim of the study was to identify risk factors associated with ICU delirium in postoperative pediatric cardiac surgical patients.

Design: A 1-day, multicenter point-prevalence study of delirium in pediatric postoperative cardiac surgery patients.

Executive Summary of the American Society of Addiction Medicine (ASAM) Clinical Practice Guideline on Alcohol Withdrawal Management.

: The American Society of Addiction Medicine (ASAM) Clinical Practice Guideline on Alcohol Withdrawal Management provides guidance on the identification and management of alcohol withdrawal in adults with varying degrees of syndrome severity. The guideline addresses both ambulatory and inpatient care and considers special patient populations. The Guideline was primarily developed following the RAND/UCLA Appropriateness Method (RAM), a process to determine the appropriateness of a set of clinical procedures.

Active restoration accelerates the carbon recovery of human-modified tropical forests.

More than half of all tropical forests are degraded by human impacts, leaving them threatened with conversion to agricultural plantations and risking substantial biodiversity and carbon losses. Restoration could accelerate recovery of aboveground carbon density (ACD), but adoption of restoration is constrained by cost and uncertainties over effectiveness. We report a long-term comparison of ACD recovery rates between naturally regenerating and actively restored logged tropical forests.

Nurse-Implemented Goal-Directed Strategy to Improve Pain and Sedation Management in a Pediatric Cardiac ICU.

Objectives: To assess the impact of a nurse-implemented goal-directed sedation strategy on patient care and nursing practice in a pediatric cardiac ICU.

Design: Quality improvement project with a pre-post interval measurement plan.

Setting: Thirty-one bed pediatric cardiac ICU in a freestanding tertiary care children's hospital.

Canonical DNA minor groove insertion of bisbenzamidine-Ru(ii) complexes with chiral selectivity.

We report the first Ru(ii) coordination compounds that interact with DNA through a canonical minor groove insertion mode and with selectivity for A/T rich sites. This was made possible by integrating a bis-benzamidine minor groove DNA-binding agent with a ruthenium(ii) complex. Importantly, one of the enantiomers (Δ-[Ru(bpy) ], ) shows a considerably higher DNA affinity than the parent organic ligand and the other enantiomer, particularly for the AATT sequence, while the other enantiomer preferentially targets long AAATTT sites with overall lower affinity.

Another step toward understanding the binding mode of other derivatives of [Ru(phen)L] complexes.

Linear dichroism (LD), UV-Vis and fluorescence spectroscopy were used to investigate the interaction of the Δ- and Λ-enantiomers of the two complexes of [Ru(phen) 2-phenylimidazophenanthroline] (referred to as B-complex) and [Ru(phen) 2-(1-pyrenyl)limidazophenanthroline] (named as P-complex), with ct-DNA. Absorption titration experiments of the enantiomers showed significant hypochromism with red shift indicating a strong perturbation of the DNA on the intra-ligand (IL) and the metal-to-ligand charge transfer (MLCT) transitions of the complexes, and fluorescence titration curves indicate strong binding. LD spectra for the B-enantiomers bound to DNA were qualitatively similar to spectra for the well-studied intercalator [Ru(phen)dppz], indicating intercalation of the phenyl-imidazophenanthroline part of the complex.

Hydrophobic catalysis and a potential biological role of DNA unstacking induced by environment effects.

Hydrophobic base stacking is a major contributor to DNA double-helix stability. We report the discovery of specific unstacking effects in certain semihydrophobic environments. Water-miscible ethylene glycol ethers are found to modify structure, dynamics, and reactivity of DNA by mechanisms possibly related to a biologically relevant hydrophobic catalysis.

Diastereomeric Crowding Effects in the Competitive DNA Intercalation of Ru(phenanthroline)dipyridophenazine Enantiomers.

The biexponential excited-state emission decay characteristic of DNA intercalated tris-bidentate dppz-based ruthenium complexes of the general form Ru(L)dppz has previously been explained by a binding model with two distinct geometry orientations of the bound ligands, with a distinct lifetime associated with each orientation. However, it has been found that upon DNA binding of Ru(phen)dppz the fractions of short and long lifetimes are strongly dependent on environmental factors such as salt concentration and, in particular, temperature. Analyzing isothermal titration calorimetry for competitive binding of Ru(phen)dppz enantiomers to poly(dAdT), we find that a consistent binding model must assume that the short and long lifetimes states of intercalated complexes are in equilibrium and that this equilibrium is altered when neighboring bound ligands affect each other.

Improving anticoagulation of patients with an implantable left ventricular assist device.

Patients supported with implantable left ventricular assist devices (LVAD) have a significant risk of bleeding and thromboembolic complications. All patients require anticoagulation with warfarin, aiming for a target international normalised ratio (INR) of 2.5 and most patients also receive antiplatelet therapy.

Local action on outdoor air pollution to improve public health.

Objectives: The National Institute for Health and Care Excellence, jointly with Public Health England, have developed a guideline on outdoor air pollution and its links to health. The guideline makes recommendations on local interventions that can help improve air quality and prevent a range of adverse health outcomes associated with road-traffic-related air pollution.

Methods: The guideline was based on a rigorous assessment of the scientific evidence by an independent advisory committee, with input from public health professionals and other professional groups.

Effects of methyl substitution on DNA binding enthalpies of enantiopure Ru(phenanthroline)dipyridophenazine complexes.

Isothermal titration calorimetry (ITC) has been utilized to investigate the effect of methyl substituents on the intercalating dppz ligand of the enantiomers of the parent complex Ru(phen)2dppz2+ (phen = 1,10-phenanthroline; dppz = dipyrido[3,2-a:2',3'-c]phenazine) on DNA binding thermodynamics. The methylated complexes (10-methyl-dppz and 11,12-dimethyl-dppz) have large, concentration-dependent, positive heats of dilution, and a strong endothermic background is also apparent in the ITC-profiles from titration of methylated complexes into poly(dAdT)2, which make direct comparison between complexes difficult. By augmenting a simple cooperative binding model with one equilibrium for complex self-aggregation in solution and one equilibrium for complex aggregation on saturated DNA, it was possible to find an excellent global fit to the experimental data with DNA affinity parameters restricted to be equal for all Δ-enantiomers as well as for all Λ-enantiomers.

The resilience of postglacial hunter-gatherers to abrupt climate change.

Understanding the resilience of early societies to climate change is an essential part of exploring the environmental sensitivity of human populations. There is significant interest in the role of abrupt climate events as a driver of early Holocene human activity, but there are very few well-dated records directly compared with local climate archives. Here, we present evidence from the internationally important Mesolithic site of Star Carr showing occupation during the early Holocene, which is directly compared with a high-resolution palaeoclimate record from neighbouring lake beds.

Competitive DNA binding of Ru(bpy)dppz enantiomers studied with isothermal titration calorimetry (ITC) using a direct and general binding isotherm algorithm.

While isothermal titration calorimetry (ITC) is widely used and sometimes referred to as the "gold standard" for quantitative measurements of biomolecular interactions, its usage has so far been limited to the analysis of the binding to isolated, non-cooperative binding sites. Studies on more complicated systems, where the binding sites interact, causing either cooperativity or anti-cooperativity between neighboring bound ligands, are rare, probably due to the complexity of the methods currently available. Here we have developed a simple algorithm not limited by the complexity of a binding system, meaning that it can be implemented by anyone, from analyzing systems of simple, isolated binding sites to complicated interactive multiple-site systems.

Reshaping the Energy Landscape Transforms the Mechanism and Binding Kinetics of DNA Threading Intercalation.

Molecules that bind DNA via threading intercalation show high binding affinity as well as slow dissociation kinetics, properties ideal for the development of anticancer drugs. To this end, it is critical to identify the specific molecular characteristics of threading intercalators that result in optimal DNA interactions. Using single-molecule techniques, we quantify the binding of a small metal-organic ruthenium threading intercalator (Δ,Δ-B) and compare its binding characteristics to a similar molecule with significantly larger threading moieties (Δ,Δ-P).

Algorithms to guide ambulance clinicians in the management of emergencies in patients with implanted rotary left ventricular assist devices.

Advances in left ventricular assist device (LVAD) therapy have resulted in increasing numbers of adult LVAD recipients in the community. However, device failure, stroke, bleeding, LVAD thrombosis and systemic infection can be life-threatening emergencies. Currently, four LVAD systems are implanted in six UK transplant centres, each of which provides device-specific information to local emergency services.

Exploring medical students' conceptions of substance use: A follow-up evaluation.

Background: Despite the devastating impact of alcohol and other drug involvement and misuse within society, medical students still receive very limited exposure to these issues. The Scaife Advanced Medical Student Fellowship in Alcohol and Other Drug Dependency, offered by the Institute for Research, Education and Training in Addictions for over 10 years, offers a unique, 3-week intensive educational experience, including didactic, observation, and experiential learning in these topics to first-year medical students. The goal of this project was to evaluate the impact of the Scaife Fellowship on medical students' attitudes toward patients with alcohol and other drug involvement 1 to 5 years after completion of the experience.

Appropriate Use of Drug Testing in Clinical Addiction Medicine.

: Biological drug testing is a tool that provides information about an individual's recent substance use. Like any tool, its value depends on using it correctly; that is, on selecting the right test for the right person at the right time. This document is intended to clarify appropriate clinical use of drug testing in addiction medicine and aid providers in their decisions about drug testing for the identification, diagnosis, treatment, and recovery of patients with, or at risk for, addiction.