Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

The Redox Behaviour of Randomly Dispersed Single Walled Carbon Nanotubes both in the Absence and in the Presence of Adsorbed Glucose Oxidase

The electrochemical behaviour of SWCNTs randomly dispersed on gold and glassy carbon electrode surfaces was characterised via cyclic voltammetry and complex impedance spectroscopy, using the ferri/ferrocyanide couple as a redox active test probe . In subsequent investigations glucose oxidase (GOx) was adsorbed onto the SWCNT ensemble without apparent denaturation of the enzyme. Cyclic voltammetry and potential step chronoamperometry were used to quantify and understand the process of electron transfer between the immobilised protein redox site and the working electrode. The effect of pH on the system was also investigated. In particular, we have shown that, for the calculation of electron transfer rate constants for surface-immobilised redox systems, chronoamperometry is preferable to voltammetry, which has been the technique of choice until now

Pt Sub-Monolayer on Au: System Stability and Insights into Platinum Electrochemical Dissolution

Platinum is the best single element oxygen reduction reaction electrocatalyst. In recent years, several advanced catalysts have been suggested. One of them is the so-called “platinum monolayer electrocatalyst”. In this work we demonstrate the potential- and time-resolved dissolution characteristics of such sub-monolayer platinum supported on gold in potentiodynamic and potentiostatic regimes. It is shown that the as-prepared Pt@Au is not stable, but rather shows significant dissolution of both Pt and Au similar to the pure elements. Potential-resolved dissolution profiles reveal that anodic dissolution scales with Pt coverage, while cathodic dissolution and quasi-steady-state dissolution are Pt coverage independent. This implies a significantly higher Pt coverage normalized dissolution of Pt@Au, viz. a factor of four higher dissolution amounts for Pt coverage of 0.25. The onsets of Pt and Au dissolution are also comparable to the pure elements. Only after intermixing during potential cycling does the system become somewhat stabilized. The onset of Pt transient anodic dissolution shifts to more positive values. The data obtained in the current work provide new insights into the mechanism of platinum dissolution. It also aids the understanding of the previously observed effect of stabilization of Pt catalysts by addition of Au, and will therefore guide future developments for improving catalyst performance

Transparent ultrathin conducting carbon films

Ultrathin conductive carbon layers (UCCLs) were created by spin coating resists and subsequently converting them to conductive films by pyrolysis. Homogeneous layers as thin as 3 nm with nearly atomically smooth surfaces could be obtained. Layer characterization was carried out with the help of atomic force microscopy, profilometry, four-point probe measurements, Raman spectroscopy and ultraviolet–visible spectroscopy. The Raman spectra and high-resolution transmission electron microscopy image indicated that a glassy carbon like material was obtained after pyrolysis. The electrical properties of the UCCL could be controlled over a wide range by varying the pyrolysis temperature. Variation in transmittance with conductivity was investigated for applications as transparent conducting films. It was observed that the layers are continuous down to a thickness below 10 nm, with conductivities of 1.6×104 S/m, matching the best values observed for pyrolyzed carbon films. Further, the chemical stability of the films and their utilization as transparent electrochemical electrodes has been investigated using cyclic voltammetry and electrochemical impedance spectroscopy

Fabrication of High Performing and Durable Nickel-Based Catalyst Coated Diaphragms for Alkaline Water Electrolyzers

In this work, a catalyst coated-diaphragm (CCD) for classical alkaline electrolysis was prepared by the blade-coating method, using Raney nickel as HER catalyst and a Zirfon® (AGFA Perl UTP 500) diaphragm. Our best CCD reduced the overvoltage in an alkaline single cell by 270 mV at 300 mA cm−2 compared to the benchmark, mainly due to the higher catalytic activity and surface area of the Raney nickel electrode. The new electrode system also showed a low degradation rate of 22 μA cm−2 h−1 after 1000 h at a cell voltage of 2 V. The gas purity tests showed that the CCD has hydrogen in oxygen contamination well below the lower explosion limit, even at low current densities. Therefore, we propose the use of our novel CCD architecture for atmospheric alkaline electrolyzers, which have a partly separated electrolyte cycl