Utilising solution processed zirconium acetylacetonate as an electron extracting layer in both regular and inverted small molecule organic photovoltaic cells

AbstractInterfacial layers are commonly employed in organic photovoltaic (OPV) cells in order to improve device performance. These layers must be transparent, stable, be compatible with the photo-active materials and provide efficient charge extraction with a good energetic match to the relevant organic material. In this report we demonstrate the compatibility of zirconium acetylacetonate (ZrAcac) electron extracting layers in both regular and inverted small molecule OPV cells. When the ZrAcac was processed in both air and under N2, low work function (3.9 and 3.7eV respectively), highly transparent layers were formed, with good energetic alignment to both C60 and hexachlorinated boron subphthalocyanine chloride (Cl6-SubPc) acceptors. Initial measurements indicate similar stabilities when using the ZrAcac in either device architecture. These results indicate that the ZrAcac layer can be used as a direct replacement for the commonly used bathocuproine (BCP) in small molecule OPV cells

Multiple ion channel block by the cation channel inhibitor SKF-96365 in myocytes from the rabbit atrioventricular node

The atrioventricular node (AVN) of the cardiac conduction system coordinates atrial–ventricular excitation and can act as a subsidiary pacemaker. Recent evidence suggests that an inward background sodium current, I (B,Na), carried by nonselective cation channels (NSCCs), contributes to AVN cell pacemaking. The study of the physiological contribution of I (B,Na) has been hampered, however, by a lack of selective pharmacological antagonists. This study investigated effects of the NSCC inhibitor SKF‐96365 on spontaneous activity, I (B,Na), and other ionic currents in AVN cells isolated from the rabbit. Whole‐cell patch‐clamp recordings of action potentials (APs) and ionic currents were made at 35–37°C. A concentration of 10 μmol/L SKF‐96365 slowed spontaneous action potential rate by 13.9 ± 5.3% (n = 8) and slope of the diastolic depolarization from 158.1 ± 30.5 to 86.8 ± 30.5 mV sec(−1) (P < 0.01; n = 8). Action potential upstroke velocity and maximum diastolic potential were also reduced. Under I (B,Na)‐selective conditions, 10 μmol/L SKF‐96365 inhibited I (B,Na) at −50 mV by 36.1 ± 6.8% (n = 8); however, effects on additional channel currents were also observed. Thus, the peak l‐type calcium current (I (Ca,L)) at +10 mV was inhibited by 38.6 ± 8.1% (n = 8), while the rapid delayed rectifier current, I (Kr), tails at −40 mV following depolarization to +20 mV were inhibited by 55.6 ± 4.6% (n = 8). The hyperpolarization‐activated current, I (f), was unaffected by SKF‐96365. Collectively, these results indicate that SKF‐96365 exerts a moderate inhibitory effect on I (B,Na) and slows AVN cell pacemaking. However, additional effects of the compound on I (Ca,L) and I (Kr) confound the use of SKF‐96365 to dissect out selectively the physiological role of I (B,Na) in the AVN

Ranolazine inhibition of hERG potassium channels: Drug–pore interactions and reduced potency against inactivation mutants

AbstractThe antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited IhERG with an IC50 of 8.03μM; peak IhERG during ventricular action potential clamp was inhibited ~62% at 10μM. The IC50 values for ranolazine inhibition of the S620T inactivation deficient and N588K attenuated inactivation mutants were respectively ~73-fold and ~15-fold that for WT IhERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC50s between ~8 and 19-fold that for WT IhERG, whilst the Y652A and F656A S6 mutations had IC50s ~22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore helix and S6 mutations, but was sensitive to direction of K+ flux and particularly to loss of inactivation, with an IC50 for S620T-hERG ~49-fold that for WT IhERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against IKr/hERG in SQT1 patients

Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide

AbstractThe class Ic antiarrhythmic drug flecainide inhibits KCNH2-encoded “hERG” potassium channels at clinically relevant concentrations. The aim of this study was to elucidate the underlying molecular basis of this action. Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. Wild-type (WT) IhERG was inhibited with an IC50 of 1.49μM and this was not significantly altered by reversing the direction of K+ flux or raising external [K+]. The use of charged and uncharged flecainide analogues showed that the charged form of the drug accesses the channel from the cell interior to produce block. Promotion of WT IhERG inactivation slowed recovery from inhibition, whilst the N588K and S631A attenuated-inactivation mutants exhibited IC50 values 4–5 fold that of WT IhERG. The use of pore-helix/selectivity filter (T623A, S624A V625A) and S6 helix (G648A, Y652A, F656A) mutations showed <10-fold shifts in IC50 for all but V625A and F656A, which respectively exhibited IC50s 27-fold and 142-fold their WT controls. Docking simulations using a MthK-based homology model suggested an allosteric effect of V625A, since in low energy conformations flecainide lay too low in the pore to interact directly with that residue. On the other hand, the molecule could readily form π–π stacking interactions with aromatic residues and particularly with F656. We conclude that flecainide accesses the hERG channel from the cell interior on channel gating, binding low in the inner cavity, with the S6 F656 residue acting as a principal binding determinant

Systematic scoping review of frameworks used to develop rehabilitation interventions for older adults

Objectives: Rehabilitation interventions for older adults are complex as they involve a number of interacting components, have multiple outcomes of interest and are influenced by a number of contextual factors. The importance of rigorous intervention development prior to formal evaluation has been acknowledged and a number of frameworks have been developed. This review explored which frameworks have been used to guide the development of rehabilitation interventions for older adults.Design: Systematic scoping review.Setting: Studies were not limited for inclusion based on setting.Participants: Studies were included that featured older adults (>65 years of age).Interventions: Studies were included that reported the development of a rehabilitation intervention.Primary and secondary outcome measures: Data was extracted on study population, setting, type of intervention developed and frameworks used. The primary outcome of interest was the type of intervention development framework.Results: Thirty-five studies were included. There was a range of underlying medical conditions including mild cognitive impairment and dementia (n=5), cardiac (n=4), stroke (n=3), falls (n=3), hip fracture (n=2), diabetes (n=2), breast cancer (n=1), Parkinson’s disease (n=1), depression (n=1), chronic health problems (n=1), osteoarthritis (n=1), leg ulcer (n=1), neck pain (n=1) and foot problems (n=1). The intervention types being developed included multicomponent, support-based, cognitive, physical activities, nursing-led, falls prevention and occupational therapy-led. Twelve studies (34%) did not report using a framework. Five frameworks were reported with the Medical Research Council (MRC) Framework for Developing and Evaluating Complex Interventions being the most frequently cited(77%, n=17).Conclusion: At present the MRC Framework is the most popular for developing rehabilitation interventions for older adults. Many studies do not report using a framework. Further, specific guidance to assist this complex field of rehabilitation research is required

Inhibition of the hERG Potassium Channel by a Methanesulphonate-Free E-4031 Analogue

hERG (human Ether-à-go-go Related Gene)-encoded potassium channels underlie the cardiac rapid delayed rectifier (IKr) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, “E-4031-17”, to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG. Whole-cell patch-clamp measurements of the hERG current (IhERG) were made at physiological temperature from HEK 293 cells expressing wild-type (WT) and mutant hERG constructs. For E-4031, WT IhERG was inhibited by a half-maximal inhibitory concentration (IC50) of 15.8 nM, whilst the comparable value for E-4031-17 was 40.3 nM. Both compounds exhibited voltage- and time-dependent inhibition, but they differed in their response to successive applications of a long (10 s) depolarisation protocol, consistent with greater dissociation of E-4031-17 than the parent compound between applied commands. Voltage-dependent inactivation was left-ward voltage shifted for E-4031 but not for E-4031-17; however, inhibition by both compounds was strongly reduced by attenuated-inactivation mutations. Mutations of S6 and S5 aromatic residues (F656V, Y652A, F557L) greatly attenuated actions of both drugs. The S624A mutation also reduced IhERG inhibition by both molecules. Overall, these results demonstrate that the lack of a methanesulphonate in E-4031-17 is not an impediment to high potency inhibition of IhERG