Mitokyne : a ratiometric raman probe for mitochondrial pH

Mitochondrial pH (pHmito) is intimately related to mitochondrial function and aberrant values for pHmito are linked to several disease states. We report the design, synthesis and application of mitokyne 1 – the first small molecule pHmito sensor for Stimulated Raman Scattering (SRS) microscopy. This ratiometric probe can determine subtle changes in pHmito in response to external stimuli and the inhibition of both the electron transport chain and ATP synthase with small molecule inhibitors. In addition, 1 was also used to monitor mitochondrial dynamics in a time-resolved manner with subcellular spatial resolution during mitophagy providing a powerful tool for dissecting the molecular and cell biology of this critical organelle

A global multiproxy database for temperature reconstructions of the Common Era

Reproducible climate reconstructions of the Common Era (1 CE to present) are key to placing industrial-era warming into the context of natural climatic variability. Here we present a community-sourced database of temperature- sensitive proxy records from the PAGES2k initiative. The database gathers 692 records from 648 locations, including all continental regions and major ocean basins. The records are from trees, ice, sediment, corals, speleothems, documentary evidence, and other archives. They range in length from 50 to 2000 years, with a median of 547 years, while temporal resolution ranges from biweekly to centennial. Nearly half of the proxy time series are significantly correlated with HadCRUT4.2 surface temperature over the period 1850–2014. Global temperature composites show a remarkable degree of coherence between high- and low-resolution archives, with broadly similar patterns across archive types, terrestrial versus marine locations, and screening criteria. The database is suited to investigations of global and regional temperature variability over the Common Era, and is shared in the Linked Paleo Data (LiPD) format, including serializations in Matlab, R and Python

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

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Evaluation of Novel Synthetic Methods for the Preparation of the Sodium Channel Inhibitor, GW273225X

The evaluation of efficient synthetic methods for the preparation of (<i>R</i>)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine, GW273225X (<b>1</b>), is described. The initial synthesis using ethylfluoroacetate was evaluated against three alternative routes using either nucleophilic fluorination, electrophilic fluorination, or sodium fluoroacetate

Consistent multidecadal variability in global temperature reconstructions and simulations over the Common Era.

Multidecadal surface temperature changes may be forced by natural as well as anthropogenic factors, or arise unforced from the climate system. Distinguishing these factors is essential for estimating sensitivity to multiple climatic forcings and the amplitude of the unforced variability. Here we present 2,000-year-long global mean temperature reconstructions using seven different statistical methods that draw from a global collection of temperature-sensitive palaeoclimate records. Our reconstructions display synchronous multidecadal temperature fluctuations that are coherent with one another and with fully forced millennial model simulations from the Coupled Model Intercomparison Project Phase 5 across the Common Era. A substantial portion of pre-industrial (1300–1800 CE) variability at multidecadal timescales is attributed to volcanic aerosol forcing. Reconstructions and simulations qualitatively agree on the amplitude of the unforced global mean multidecadal temperature variability, thereby increasing confidence in future projections of climate change on these timescales. The largest warming trends at timescales of 20 years and longer occur during the second half of the twentieth century, highlighting the unusual character of the warming in recent decades