Improvements in micelle promoted DNA-encoded library synthesis by surfactant optimisation

DNA-encoded libraries are increasingly important in hit identification at the early stage of the drug discovery process. The approach relies on efficient methods for synthesis of drug-like compounds attached to coding DNA sequences. Many reactions employed for library synthesis are inefficient and result in significant DNA-damage, incomplete conversion and the formation of side products, which compromise the fidelity of the resulting library. We have developed a wide array of reactions that are promoted by the micelle-forming surfactant TPGS-750-M that address these issues and lead to improved efficiency. Here we demonstrate further improvements to key reactions Suzuki-Miyaura coupling, reductive amination and amide coupling by surfactant screening using principal component-based surfactant maps which lead to improved conversion for problematic substrates. This work demonstrates the utility of surfactant maps in reaction optimisation for DNA-encoded library synthesis and leads to further improvements in these important transformations

An assessment of upper ocean salinity content from the ocean reanalyses inter-comparison project (ORA-IP)

Many institutions worldwide have developed ocean reanalyses systems (ORAs) utilizing a variety of ocean models and assimilation techniques. However, the quality of salinity reanalyses arising from the various ORAs has not yet been comprehensively assessed. In this study, we assess the upper ocean salinity content (depth-averaged over 0–700 m) from 14 ORAs and 3 objective ocean analysis systems (OOAs) as part of the Ocean Reanalyses Intercomparison Project. Our results show that the best agreement between estimates of salinity from different ORAs is obtained in the tropical Pacific, likely due to relatively abundant atmospheric and oceanic observations in this region. The largest disagreement in salinity reanalyses is in the Southern Ocean along the Antarctic circumpolar current as a consequence of the sparseness of both atmospheric and oceanic observations in this region. The West Pacific warm pool is the largest region where the signal to noise ratio of reanalysed salinity anomalies is >1. Therefore, the current salinity reanalyses in the tropical Pacific Ocean may be more reliable than those in the Southern Ocean and regions along the western boundary currents. Moreover, we found that the assimilation of salinity in ocean regions with relatively strong ocean fronts is still a common problem as seen in most ORAs. The impact of the Argo data on the salinity reanalyses is visible, especially within the upper 500m, where the interannual variability is large. The increasing trend in global-averaged salinity anomalies can only be found within the top 0–300m layer, but with quite large diversity among different ORAs. Beneath the 300m depth, the global-averaged salinity anomalies from most ORAs switch their trends from a slightly growing trend before 2002 to a decreasing trend after 2002. The rapid switch in the trend is most likely an artefact of the dramatic change in the observing system due to the implementation of Argo

Mixed layer depth (MLD) variability in the southern Bay of Biscay. Deepening of winter MLDs concurrent with generalized upper water warming trends

Mixed layer depth (MLD) variability from seasonal to decadal time scales in the Bay of Biscay is studied in this work. A hydrographic time series running since 1991 in the study area, a climatology of the upper layer vertical structure based on the topology of this temperature profile time series and a one-dimensional water column model have been used for this purpose. The prevailing factors driving MLD variability have been determined with detail, and agreement with observations is achieved. Tests carried out to investigate climatological profile skill to reproduce the upper layer temporal evolution have demonstrated its ability to simulate variability at seasonal time scales and reproduce the most conspicuous events observed. This has enabled us to carry out a reconstruction of the MLD variability for the last 60 years in the study area. Favourable sequence of intense mixing events explains interannual differences and cases of extraordinary deepening of winter mixed layer. The negative phase of the Eastern Atlantic pattern seems to determine important interannual variability through intense episodes of cooling and mixing as in winter 2005 in the Bay of Biscay. Low-frequency variability is also observed. A very striking and unexpected shallower winter MLD during the 1970s and 1980s than those observed from 1995 has been found. Simulation results support this counter-intuitive outcome of shallower winter mixed layers concurrent with generalized upper water warming trends reported on several occasions for the area. The long-term trends in MLD seem related with decadal variability in the North Atlantic Oscillation, being in phase and opposition with other deepening-shallowing cycles found from subtropical-to-subpolar areas in the North Atlantic.Publicado