One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

Difluoromethyl ketones are an under-studied class of ketones which have great potential as useful building blocks for materials and drug design. Here we report a simple and convenient synthesis of this class of compounds via a one-pot difluorination/fragmentation of 1-trifluoromethyl-1,3-diketones which should now allow the chemistry of difluoromethyl ketones to be fully developed

Triggering the expression of a silent gene cluster from genetically intractable bacteria results in scleric acid discovery

In this study, we report the rapid characterisation of a novel microbial natural product resulting from the rational derepression of a silent gene cluster. A conserved set of five regulatory genes was used as a query to search genomic databases and identify atypical biosynthetic gene clusters (BGCs). A 20-kb BGC from the genetically intractable Streptomyces sclerotialus bacterial strain was captured using yeast-based homologous recombination and introduced into validated heterologous hosts. CRISPR/Cas9-mediated genome editing was then employed to rationally inactivate the key transcriptional repressor and trigger production of an unprecedented class of hybrid natural products exemplified by (2-(benzoyloxy)acetyl)-L-proline, named scleric acid. Subsequent rounds of CRISPR/Cas9-mediated gene deletions afforded a selection of biosynthetic gene mutant strains which led to a plausible biosynthetic pathway for scleric acid assembly. Synthetic standards of scleric acid and a key biosynthetic intermediate were also prepared to confirm the chemical structures we proposed. The assembly of scleric acid involves two unique condensation reactions catalysed by a single NRPS module and an ATP-grasp enzyme that link a proline and a benzoyl residue to each end of a rare hydroxyethyl-ACP intermediate respectively. Scleric acid was shown to exhibit moderate inhibition activity against Mycobacterium tuberculosis, as well as inhibition of the cancer-associated metabolic enzyme Nicotinamide N-methyltransferase (NNMT)

Isotopic Characterization of Water Masses in the Southeast Pacific Region: Paleoceanographic Implications

In this study, we used stable isotopes of oxygen (δ18O), deuterium (δD), and dissolved inorganic carbon (δ13CDIC) in combination with temperature, salinity, oxygen, and nutrient concentrations to characterize the coastal (71°–78°W) and an oceanic (82°–98°W) water masses (SAAW—Subantarctic Surface Water; STW—Subtropical Water; ESSW—Equatorial Subsurface water; AAIW—Antarctic Intermediate Water; PDW—Pacific Deep Water) of the Southeast Pacific (SEP). The results show that δ18O and δD can be used to differentiate between SAAW-STW, SAAW-ESSW, and ESSW-AAIW. δ13CDIC signatures can be used to differentiate between STW-ESSW (oceanic section), SAAW-ESSW, ESSW-AAIW, and AAIW-PDW. Compared with the oceanic section, our new coastal section highlights differences in both the chemistry and geometry of water masses above 1,000 m. Previous paleoceanographic studies using marine sediments from the SEP continental margin used the present-day hydrological oceanic transect to compare against, as the coastal section was not sufficiently characterized. We suggest that our new results of the coastal section should be used for past characterizations of the SEP water masses that are usually based on continental margin sediment samples

Six-minute walk distance after coronary artery bypass grafting compared with medical therapy in ischaemic cardiomyopathy

Background: In patients with ischaemic left ventricular dysfunction, coronary artery bypass surgery (CABG) may decrease mortality, but it is not known whether CABG improves functional capacity. Objective: To determine whether CABG compared with medical therapy alone (MED) increases 6 min walk distance in patients with ischaemic left ventricular dysfunction and coronary artery disease amenable to revascularisation. Methods: The Surgical Treatment in Ischemic Heart disease trial randomised 1212 patients with ischaemic left ventricular dysfunction to CABG or MED. A 6 min walk distance test was performed both at baseline and at least one follow-up assessment at 4, 12, 24 and/or 36 months in 409 patients randomised to CABG and 466 to MED. Change in 6 min walk distance between baseline and follow-up were compared by treatment allocation. Results: 6 min walk distance at baseline for CABG was mean 340±117 m and for MED 339±118 m. Change in walk distance from baseline was similar for CABG and MED groups at 4 months (mean +38 vs +28 m), 12 months (+47 vs +36 m), 24 months (+31 vs +34 m) and 36 months (−7 vs +7 m), P>0.10 for all. Change in walk distance between CABG and MED groups over all assessments was also similar after adjusting for covariates and imputation for missing values (+8 m, 95% CI −7 to 23 m, P=0.29). Results were consistent for subgroups defined by angina, New York Heart Association class ≥3, left ventricular ejection fraction, baseline walk distance and geographic region. Conclusion: In patients with ischaemic left ventricular dysfunction CABG compared with MED alone is known to reduce mortality but is unlikely to result in a clinically significant improvement in functional capacity

Understanding the transfer of contemporary temperature signals into lake sediments via paired oxygen isotope ratios in carbonates and diatom silica: problems and potential

Although the oxygen isotope composition (δ18O) of calcite (δ18Ocalcite) and, to a lesser extent, diatom silica (δ18Odiatom) are widely used tracers of past hydroclimates (especially temperature and surface water hydrology), the degree to which these two hosts simultaneously acquire their isotope signals in modern lacustrine environments, or how these are altered during initial sedimentation, is poorly understood. Here, we present a unique dataset from a natural limnological laboratory to explore these issues. This study compares oxygen and hydrogen isotope data (δ18O, δ2H) of contemporary lake water samples at ~2-weekly intervals over a 2-year period (2010–12) with matching collections of diatoms (δ18Odiatom) and calcite (δ18Ocalcite) from sediment traps (at 10 m and 25 m) at Rostherne Mere (maximum depth 30 m), a well-monitored, eutrophic, seasonally stratified monomictic lake in the UK. The epilimnion shows a seasonal pattern of rising temperature and summer evaporative enrichment in 18O, and while there is a temperature imprint in both δ18Odiatom and δ18Ocalcite, there is significant inter-annual variability in both of these signals. The interpretation of δ18Odiatom and δ18Ocalcite values is complicated due to in-lake processes (e.g. non-equilibrium calcite precipitation, especially in spring, leading to significant 18Ocalcite depletion), and for δ18Odiatom, by post-mortem, depositional and possibly dissolution or diagenetic effects. For 2010 and 2011 respectively, there is a strong temperature dependence of δ18Ocalcite and δ18Odiatom in fresh trap material, with the fractionation slope for δ18Odiatom of ca. −0.2‰/°C, in agreement with several other studies. The δ18Odiatom data indicate the initiation of rapid post-mortem secondary alteration of fresh diatom silica (within ~6 months), with some trap material undergoing partial maturation in situ. Diatom δ18O of the trap material is also influenced by resuspension of diatom frustules from surface sediments (notably in summer 2011), with the net effect seen as an enrichment of deep-trap 18Odiatom by about +0.7‰ relative to shallow-trap values. Contact with anoxic water and anaerobic bacteria are potentially key to initiating this silica maturation process, as deep-trap samples that were removed prior to anoxia developing do not show enrichment. Dissolution (perhaps enhanced by anaerobic bacterial communities) may also be responsible for changes to δ18Odiatom that lead to increasing, but potentially predictable, error in inferred temperatures using this proxy. High resolution, multi-year monitoring can shed light on the complex dynamics affecting δ18Odiatom and δ18Ocalcite and supports the careful use of sedimentary δ18Odiatom and δ18Ocalcite as containing valuable hydroclimatic signals especially at a multi-annual resolution, although there remain substantial challenges to developing a reliable geothermometer on paired δ18Odiatom and δ18Ocalcite. In particular, δ18Odiatom needs cautious interpretation where silica post-mortem secondary alteration is incomplete and diatom preservation is not perfect, and we recommend dissolution be routinely assessed on diatom samples used for isotopic analyses

correction novel chemical probes for the investigation of nonribosomal peptide assembly

Correction for 'Novel chemical probes for the investigation of nonribosomal peptide assembly' by Y. T. Candace Ho et al., Chem. Commun., 2017, 53, 7088–7091

Astronomical constraints on the duration of the Early Jurassic Pliensbachian Stage and global climatic fluctuations

The Early Jurassic was marked by multiple periods of major global climatic and palaeoceanographic change, biotic turnover and perturbed global geochemical cycles, commonly linked to large igneous province volcanism. This epoch was also characterised by the initial break-up of the super-continent Pangaea and the opening and formation of shallow-marine basins and ocean gateways, the timing of which are poorly constrained. Here, we show that the Pliensbachian Stage and the Sinemurian–Pliensbachian global carbon-cycle perturbation (marked by a negative shift in δ13Cδ13C of 2–4‰2–4‰), have respective durations of ∼8.7 and ∼2 Myr. We astronomically tune the floating Pliensbachian time scale to the 405 Kyr eccentricity solution (La2010d), and propose a revised Early Jurassic time scale with a significantly shortened Sinemurian Stage duration of 6.9±0.4 Myr6.9±0.4 Myr. When calibrated against the new time scale, the existing Pliensbachian seawater 87Sr/86Sr record shows relatively stable values during the first ∼2 Myr of the Pliensbachian, superimposed on the long-term Early Jurassic decline in 87Sr/86Sr. This plateau in 87Sr/86Sr values coincides with the Sinemurian–Pliensbachian boundary carbon-cycle perturbation. It is possibly linked to a late phase of Central Atlantic Magmatic Province (CAMP) volcanism that induced enhanced global weathering of continental crustal materials, leading to an elevated radiogenic strontium flux to the global ocean

Cycling Phosphorus and Nitrogen through Cropping Systems in an Intensive Dairy Production Region

As pressure on the dairy industry to reduce its environmental impact increases, efficient recycling of manure nutrients through local cropping systems becomes crucial. The aim of this study was to calculate annual nitrogen (N) and phosphorus (P) budgets in six counties located in the Magic Valley, Idaho and estimate what distance manure would need to be transported to be in balance with crop nutrient demand given current dairy cattle populations and cropping systems. Our analysis suggests that crop N needs will not be met solely by manure, and synthetic fertilizer will need to be applied. However, to balance P with crop production, manure would need to be transported a minimum of 12.9 km from dairies and would have to replace synthetic fertilizer P on 91% of regional cropland. Education of producers and technical specialists would be necessary to improve the management of manure use in regional cropping systems. Technical solutions such as alternative diets for cattle and nutrient capture from manure streams will also likely be necessary to bring regional P into balance to protect environmental quality and improve the sustainability of the regional dairy industry

Multi-proxy record of Holocene paleoenvironmental conditions from Yellowstone Lake, Wyoming, USA

A composite 11.82 m-long (9876e-67 cal yr BP) sediment record from Yellowstone Lake, Wyoming was analyzed using a robust set of biological and geochemical proxies to investigate the paleoenvironmental evolution of the lake and its catchment in response to long-term climate forcing. Oxygen isotopes from diatom frustules were analyzed to reconstruct Holocene climate changes, and pollen, charcoal, diatom assemblages, and biogenic silica provided information on terrestrial and limnological responses. The long-term trends recorded in the terrestrial and limnic ecosystems over the last 9800 years reflect the influence of changes in the amplification of the seasonal cycle of insolation on regional climate. The early Holocene (9880e6700 cal yr BP) summer insolation maximum and strengthening of the northeastern Pacific subtropical high-pressure system created warm dry conditions and decreasing summer insolation in the middle (6700e3000 cal yr BP) and late (3000e-67 cal yr BP) Holocene resulted in progressively cooler, wetter conditions. Submillenial climate variation is also apparent, with a wetter/cooler interval between 7000 and 6800 cal yr BP and warmer and/or drier conditions from 4500 to 3000 cal yr BP and at ca. 1100 cal yr BP. These data show that the Yellowstone Lake basin had a climate history typical of a summer-dry region, which helps to better define the spatial variability of Holocene climate in the Greater Yellowstone Ecosystem

Sea ice extent and seasonality for the Early Pliocene northern Weddell Sea

Growth increment analysis coupled with stable isotopic data (δ18O/δ13C) from Early Pliocene (ca 4.7 Ma) Austrochlamys anderssoni from shallow marine sediments of the Cockburn Island Formation, northern Antarctic Peninsula, suggest these bivalves grew through much of the year, even during the coldest parts of winter recorded in the shells. The high frequency fluctuation in growth increment width of A. anderssoni appears to reflect periodic, but year-round, agitation of the water column enhancing benthic food supply from organic detritus. This suggests that Austrochlamys favoured waters that were largely sea ice free. Our data support interpretation of the Cockburn Island Formation as an interglacial marine deposit and the previous hypothesis that Austrochlamys retreated from the Antarctic as sea ice extent expanded, this transition occurring during climate cooling in the Late Pliocene