What are the participants’ perspectives of taking melatonin for the treatment of nocturia in Multiple Sclerosis? -a qualitative study embedded within a double blind RCT

Background: Multiple Sclerosis (MS) is a chronic neurological disorder caused by neurodegeneration within the central nervous system. It results in impaired physical, cognitive and psychological functioning and can also lead to lower urinary tract symptoms including nocturia. While clinical trials have suggested an association between nocturia and melatonin secretion, to our knowledge, no qualitative research has been conducted on the experience of taking melatonin to treat nocturia in progressive MS within a clinical trial. Methods: 17 semi-structured qualitative interviews were conducted as part of a double-blind, randomised, placebo controlled, crossover, clinical trial with consenting adults with MS. Interviews explored participants’ experiences of nocturia associated with MS and their experience of taking melatonin as a trial treatment for nocturia versus a placebo. Data was analysed using a thematic analysis. Results: Themes on the experience of nocturia revealed participants’ understandings of nocturia, the impact it had on their night and increased daily fatigue. Themes on the intervention showed perceived improvements to nocturia, sleep and energy and negative effects including lethargy, a lack of significant change and physical side effects including vivid dreams.Conclusion: This qualitative exploration revealed an association between nocturia and increased levels of fatigue during the day by those with MS. However, perspectives towards the effectiveness of melatonin as a potential treatment varied as both placebo and melatonin were perceived as having very similar effects

One-by-one trap activation in silicon nanowire transistors

Flicker or 1/f noise in metal-oxide-semiconductor field-effect transistors (MOSFETs) has been identified as the main source of noise at low frequency. It often originates from an ensemble of a huge number of charges trapping and detrapping. However, a deviation from the well-known model of 1/f noise is observed for nanoscale MOSFETs and a new model is required. Here, we report the observation of one-by-one trap activation controlled by the gate voltage in a nanowire MOSFET and we propose a new low-frequency-noise theory for nanoscale FETs. We demonstrate that the Coulomb repulsion between electronically charged trap sites avoids the activation of several traps simultaneously. This effect induces a noise reduction by more than one order of magnitude. It decreases when increasing the electron density in the channel due to the electrical screening of traps. These findings are technologically useful for any FETs with a short and narrow channel.Comment: One file with paper and supplementary informatio

Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells

Background: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks. Results: We report that gene expression and inhibition of triple negative breast cancer cell growth (MDA-MB-231) are markedly increased when targeting both EZH2 and EHMT2, either by siRNA knockdown or pharmacological inhibition, rather than either enzyme independently. Indeed, expression of certain genes is only induced upon dual inhibition. We sought to identify compounds which showed evidence of dual EZH2 and EHMT2 inhibition. Using a cell-based assay, based on the substrate competitive EHMT2 inhibitor BIX01294, we have identified proof-of-concept compounds that induce re-expression of a subset of genes consistent with dual HKMT inhibition. Chromatin immunoprecipitation verified a decrease in silencing marks and an increase in permissive marks at the promoter and transcription start site of re-expressed genes, while Western analysis showed reduction in global levels of H3K27me3 and H3K9me3. The compounds inhibit growth in a panel of breast cancer and lymphoma cell lines with low to sub-micromolar IC50s. Biochemically, the compounds are substrate competitive inhibitors against both EZH2 and EHMT1/2. Conclusions: We have demonstrated that dual inhibition of EZH2 and EHMT2 is more effective at eliciting biological responses of gene transcription and cancer cell growth inhibition compared to inhibition of single HKMTs, and we report the first dual EZH2-EHMT1/2 substrate competitive inhibitors that are functional in cells

Analysis of DC-RF Dispersion in AlGaN/GaN HFETs Using RF Waveform Engineering

This paper describes how dc-radio-frequency (RF) dispersion manifests itself in AlGaN/GaN heterojunction field-effect transistors when the devices are driven into different RF load impedances. The localized nature of the dispersion in the I-V plane, which is confined to the ldquokneerdquo region, is observed in both RF waveform and pulsed I-V measurements. The effect is fully reproduced using 2-D physical modeling. The difference in dispersive behaviors has been attributed to the geometry of a trap-induced virtual-gate region and the resulting carrier velocity saturation being overcome by punchthrough effects under high electric fields

Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas

Review: Allelochemicals as multi-kingdom plant defence compounds: towards an integrated approach

© 2020 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. The capability of synthetic pesticides to manage weeds, insect pests and pathogens in crops has diminished due to evolved resistance. Sustainable management is thus becoming more challenging. Novel solutions are needed and, given the ubiquity of biologically active secondary metabolites in nature, such compounds require further exploration as leads for novel crop protection chemistry. Despite improving understanding of allelochemicals, particularly in terms of their potential for use in weed control, their interactions with multiple biotic kingdoms have to date largely been examined in individual compounds and not as a recurrent phenomenon. Here, multi-kingdom effects in allelochemicals are introduced by defining effects on various organisms, before exploring current understanding of the inducibility and possible ecological roles of these compounds with regard to the evolutionary arms race and dose–response relationships. Allelochemicals with functional benefits in multiple aspects of plant defence are described. Gathering these isolated areas of science under the unified umbrella of multi-kingdom allelopathy encourages the development of naturally-derived chemistries conferring defence to multiple discrete biotic stresses simultaneously, maximizing benefits in weed, insect and pathogen control, while potentially circumventing resistance. © 2020 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry

The YARHG Domain: An Extracellular Domain in Search of a Function

We have identified a new bacterial protein domain that we hypothesise binds to peptidoglycan. This domain is called the YARHG domain after the most highly conserved sequence-segment. The domain is found in the extracellular space and is likely to be composed of four alpha-helices. The domain is found associated with protein kinase domains, suggesting it is associated with signalling in some bacteria. The domain is also found associated with three different families of peptidases. The large number of different domains that are found associated with YARHG suggests that it is a useful functional module that nature has recombined multiple times

Synthetic sling or artificial urinary sphincter for men with urodynamic stress incontinence after prostate surgery: the MASTER non-inferiority RCT

Background Stress urinary incontinence is common in men after prostate surgery and can be difficult to improve. Implantation of an artificial urinary sphincter is the most common surgical procedure for persistent stress urinary incontinence, but it requires specialist surgical skills, and revisions may be necessary. In addition, the sphincter is relatively expensive and its operation requires adequate patient dexterity. New surgical approaches include the male synthetic sling, which is emerging as a possible alternative. However, robust comparable data, derived from randomised controlled trials, on the relative safety and efficacy of the male synthetic sling and the artificial urinary sphincter are lacking. Objective We aimed to compare the clinical effectiveness and cost-effectiveness of the male synthetic sling with those of the artificial urinary sphincter surgery in men with persistent stress urinary incontinence after prostate surgery. Design This was a multicentre, non-inferiority randomised controlled trial, with a parallel non-randomised cohort and embedded qualitative component. Randomised controlled trial allocation was carried out by remote web-based randomisation (1 : 1), minimised on previous prostate surgery (radical prostatectomy or transurethral resection of the prostate), radiotherapy (or not, in relation to prostate surgery) and centre. Surgeons and participants were not blind to the treatment received. Non-randomised cohort allocation was participant and/or surgeon preference. Setting The trial was set in 28 UK urological centres in the NHS. Participants Participants were men with urodynamic stress incontinence after prostate surgery for whom surgery was deemed appropriate. Exclusion criteria included previous sling or artificial urinary sphincter surgery, unresolved bladder neck contracture or urethral stricture after prostate surgery, and an inability to give informed consent or complete trial documentation. Interventions We compared male synthetic sling with artificial urinary sphincter

Transthoracic coronary flow reserve and dobutamine derived myocardial function: a 6-month evaluation after successful coronary angioplasty

After percutaneous transluminal coronary angioplasty (PTCA), stress-echocardiography and gated single photon emission computerized tomography (g-SPECT) are usually performed but both tools have technical limitations. The present study evaluated results of PTCA of left anterior descending artery (LAD) six months after PTCA, by combining transthoracic Doppler coronary flow reserve (CFR) and color Tissue Doppler (C-TD) dobutamine stress. Six months after PTCA of LAD, 24 men, free of angiographic evidence of restenosis, underwent standard Doppler-echocardiography, transthoracic CFR of distal LAD (hyperemic to basal diastolic coronary flow ratio) and C-TD at rest and during dobutamine stress to quantify myocardial systolic (S(m)) and diastolic (E(m )and A(m), E(m)/A(m )ratio) peak velocities in middle posterior septum. Patients with myocardial infarction, coronary stenosis of non-LAD territory and heart failure were excluded. According to dipyridamole g-SPECT, 13 patients had normal perfusion and 11 with perfusion defects. The 2 groups were comparable for age, wall motion score index (WMSI) and C-TD at rest. However, patients with perfusion defects had lower CFR (2.11 ± 0.4 versus 2.87 ± 0.6, p < 0.002) and septal S(m )at high-dose dobutamine (p < 0.01), with higher WMSI (p < 0.05) and stress-echo positivity of LAD territory in 5/11 patients. In the overall population, CFR was related negatively to high-dobutamine WMSI (r = -0.50, p < 0.01) and positively to high-dobutamine S(m )of middle septum (r = 0.55, p < 0.005). In conclusion, even in absence of epicardial coronary restenosis, stress perfusion imaging reflects a physiologic impairment in coronary microcirculation function whose magnitude is associated with the degree of regional functional impairment detectable by C-TD