Comparison of dimethyl sulfoxide treated highly conductive poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) electrodes for use in indium tin oxide-free organic electronic photovoltaic devices

Indium tin oxide (ITO)-free organic photovoltaic (OPV) devices were fabricated using highly conductive poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as the transparent conductive electrode (TCE). The intrinsic conductivity of the PEDOT:PSS films was improved by two different dimethyl sulfoxide (DMSO) treatments – (i) DMSO was added directly to the PEDOT:PSS solution (PEDOT:PSSADD) and (ii) a pre-formed PEDOT:PSS film was immersed in DMSO (PEDOT:PSSIMM). X-ray photoelectron spectroscopy (XPS) and conductive atomic force microscopy (CAFM) studies showed a large amount of PSS was removed from the PEDOT:PSSIMM electrode surface. OPV devices based on a poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PCBM) bulk hetrojunction showed that the PEDOT:PSSIMM electrode out-performed the PEDOT:PSSADD electrode, primarily due to an increase in short circuit current density from 6.62 mA cm−2 to 7.15 mA cm−2. The results highlight the importance of optimising the treatment of PEDOT:PSS electrodes and demonstrate their potential as an alternative TCE for rapid processing and low-cost OPV and other organic electronic devices

Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors

A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp9

Simulations of the OzDES AGN Reverberation Mapping Project

As part of the OzDES spectroscopic survey we are carrying out a large scale reverberation mapping study of $\sim$500 quasars over five years in the 30 deg$^2$ area of the Dark Energy Survey (DES) supernova fields. These quasars have redshifts ranging up to 4 and have apparent AB magnitudes between $16.8<r<22.5$ mag. The aim of the survey is to measure time lags between fluctuations in the quasar continuum and broad emission line fluxes of individual objects in order to measure black hole masses for a broad range of AGN and constrain the radius-luminosity ($R-L$) relationship. Here we investigate the expected efficiency of the OzDES reverberation mapping campaign and its possible extensions. We expect to recover lags for $\sim$35-45\% of the quasars. AGN with shorter lags and greater variability are more likely to yield a lag, and objects with lags $\lesssim$6 months or $\sim$1 year are expected be recovered the most accurately. The baseline OzDES reverberation mapping campaign is predicted to produce an unbiased measurement of the $R-L$ relationship parameters for H$\beta$, Mg II $\lambda$2798, and C IV $\lambda$1549. However, extending the baseline survey by either increasing the spectroscopic cadence, extending the survey season, or improving the emission line flux measurement accuracy will significantly improve the $R-L$ parameter constraints for all broad emission lines.Comment: Published online in MNRAS. 28 page

High-Q Si3N4 Ring Resonators for Locking 780nm GaAs-Based Distributed Feedback Laser

High-Q microring resonators have applications in gyroscopes, frequency comb generation, and feedback systems to control narrow linewidth integrated lasers [1–3]. This paper demonstrates the highest Q values measured for microring resonators at 780 nm wavelength. These sub mm integrated cavities can be used to provide an error signal for locking a distributed feedback laser (DFB), Fig. 1(a), using the Pound-Drever-Hall (PDH) method. High stability DFBs can also be achieved using a micro-electro-mechanical system (MEMS) cell containing 87 Rb vapour and taking advantage of the absorption line at 780.24 nm. This provides an absolute reference for locking the laser but only to the 87 Rb transition wavelengths. The microring resonator can be tailor made for any wavelength but is susceptible to thermal effects; this could in part be overcome using a top cladding with a thermo-optic coefficient that counteracts that of the waveguide core

Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS

The HAT TRICK programme for improving physical activity, healthy eating and connectedness among overweight, inactive men: Study protocol of a pragmatic feasibility trial

Introduction&nbsp; Physical activity, healthy eating and maintaining a healthy weight are associated with reduced risk of cardiovascular disease, type 2 diabetes and cancer and with improved mental health. Despite these benefits, many men do not meet recommended physical activity guidelines and have poor eating behaviours. Many health promotion programmes hold little appeal to men and consequently fail to influence men's health practices. HAT TRICK was designed as a 12-week face-to-face, gender-sensitised intervention for overweight and inactive men focusing on physical activity, healthy eating and social connectedness and was delivered in collaboration with a major junior Canadian ice hockey team (age range 16-20 years). The programme was implemented and evaluated to assess its feasibility. This article describes the intervention design and study protocol of HAT TRICK.&nbsp; Methods and analysis&nbsp; HAT TRICK participants (n=60) were men age 35 years, residing in the Okanagan Region of British Columbia, who accumulate 150 min of moderate to vigorous physical activity a week, with a body mass index of &gt;25 kg/m 2 and a pant waist size of &gt;38'. Each 90 min weekly session included targeted health education and theory-guided behavioural change techniques, as well as a progressive (ie, an increase in duration and intensity) group physical activity component. Outcome measures were collected at baseline, 12 weeks and 9 months and included the following: objectively measured anthropometrics, blood pressure, heart rate, physical activity and sedentary behaviour, as well as self-reported physical activity, sedentary behaviour, diet, smoking, alcohol consumption, sleep habits, risk of depression, health-related quality of life and social connectedness. Programme feasibility data (eg, recruitment, satisfaction, adherence, content delivery) were assessed at 12 weeks via interviews and self-report.&nbsp; Ethics and dissemination&nbsp; Ethical approval was obtained from the University of British Columbia Okanagan Behavioural Research Ethics Board (reference no H1600736). Study findings will be disseminated through academic meetings, peer-reviewed publication, web-based podcasts, social media, plain language summaries and co-delivered community presentations.&nbsp; Trial registration number&nbsp; ISRCTN43361357,Pre results

LRP-1-mediated intracellular antibody delivery to the Central Nervous System

The blood-brain barrier (BBB) is by far the most important target in developing new approaches to improve delivery of drugs and diagnostic tools into the Central Nervous System (CNS). Here we report the engineering of pH-sensitive polymersomes (synthetic vesicles formed by amphiphilic copolymers) that exploit endogenous transport mechanisms to traverse the BBB, enabling delivery of large macromolecules into both the CNS parenchyma and CNS cells. We achieve this by targeting the Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1) receptor. We show that LRP-1 is associated with endothelial transcytosis that does not involve acidification of cargo in membrane-trafficking organelles. By contrast, this receptor is also associated with traditional endocytosis in CNS cells, thus aiding the delivery of relevant cargo within their cytosol. We prove this using IgG as a model cargo, thus demonstrating that the combination of appropriate targeting combined with pH-sensitive polymersomes enables the efficient delivery of macromolecules into CNS cells.</p

Alginate inhibits iron absorption from ferrous gluconate in a randomized controlled trial and reduces iron uptake into Caco-2 cells

Previous in vitro results indicated that alginate beads might be a useful vehicle for food iron fortification. A human study was undertaken to test the hypothesis that alginate enhances iron absorption. A randomised, single blinded, cross-over trial was carried out in which iron absorption was measured from serum iron appearance after a test meal. Overnight-fasted volunteers (n=15) were given a test meal of 200g cola-flavoured jelly plus 21 mg iron as ferrous gluconate, either in alginate beads mixed into the jelly or in a capsule. Iron absorption was lower from the alginate beads than from ferrous gluconate (8.5% and 12.6% respectively, p=0.003). Sub-group B (n=9) consumed the test meals together with 600 mg calcium to determine whether alginate modified the inhibitory effect of calcium. Calcium reduced iron absorption from ferrous gluconate by 51%, from 11.5% to 5.6% (p=0.014), and from alginate beads by 37%, from 8.3% to 5.2% (p=0.009). In vitro studies using Caco-2 cells were designed to explore the reasons for the difference between the previous in vitro findings and the human study; confirmed the inhibitory effect of alginate. Beads similar to those used in the human study were subjected to simulated gastrointestinal digestion, with and without cola jelly, and the digestate applied to Caco-2 cells. Both alginate and cola jelly significantly reduced iron uptake into the cells, by 34% (p=0.009) and 35% (p=0.003) respectively. The combination of cola jelly and calcium produced a very low ferritin response, 16.5% (p<0.001) of that observed with ferrous gluconate alone. The results of these studies demonstrate that alginate beads are not a useful delivery system for soluble salts of iron for the purpose of food fortification