Prescribing Zonally Asymmetric Ozone Climatologies in Climate Models: Performance Compared to a Chemistry-Climate Model.

Three different methods of specifying ozone in an atmosphere-only version of the HadGEM3-A global circulation model are compared to the coupled chemistry configuration of this model. These methods include a specified zonal-mean ozone climatology, a specified 3-D ozone climatology, and a calculated-asymmetry scheme in which a specified zonal-mean ozone field is adapted online to be consistent with dynamically produced zonal asymmetries. These simulations all use identical boundary conditions and, by construction, have the same climatological zonal-mean ozone, that of the coupled chemistry configuration of the model. Prescribing ozone, regardless of scheme, results in a simulation which is 3-4 times faster than the coupled chemistry-climate model (CCM). Prescribing climatological zonal asymmetries leads to a vortex which is the correct intensity but which is systematically displaced over regions with lower prescribed ozone. When zonal asymmetries in ozone are free to evolve interactively with model dynamics, the modeled wintertime stratospheric vortex shape and mean sea level pressure patterns closely resemble that produced by the full CCM in both hemispheres, in terms of statistically significant differences. Further, we separate out the two distinct pathways by which zonal ozone asymmetries influence modeled dynamics. We present this interactive-ozone zonal-asymmetry scheme as an inexpensive tool for accurately modeling the impacts of dynamically consistent ozone fields as seen in a CCM which ultimately influence mean sea level pressure and tropospheric circulation (particularly during wintertime in the Northern Hemisphere, when ozone asymmetries are generally largest), without the computational burden of simulating interactive chemistry

Effectiveness of community-links practitioners in areas of high socioeconomic deprivation

PURPOSE: To assess the effect of a primary care–based community-links practitioner (CLP) intervention on patients’ quality of life and well-being. METHODS: Quasi-experimental cluster-randomized controlled trial in socioeconomically deprived areas of Glasgow, Scotland. Adult patients (aged 18 years or older) referred to CLPs in 7 intervention practices were compared with a random sample of adult patients from 8 comparison practices at baseline and 9 months. Primary outcome: health-related quality of life (EQ-5D-5L, a standardized measure of self-reported health-related quality of life that assesses 5 dimensions at 5 levels of severity). Secondary outcomes: well-being (Investigating Choice Experiments for the Preferences of Older People Capability Measure for Adults [ICECAP-A]), depression (Hospital Anxiety and Depression Scale, Depression [HADS-D]), anxiety (Hospital Anxiety and Depression Scale, Anxiety [HADS-A]), and self-reported exercise. Multilevel, multiregression analyses adjusted for baseline differences. Patients were not blinded to the intervention, but outcome analysis was masked. RESULTS: Data were collected on 288 and 214 (74.3%) patients in the intervention practices at baseline and follow-up, respectively, and on 612 and 561 (92%) patients in the comparison practices. Intention-to-treat analysis found no differences between the 2 groups for any outcome. In subgroup analyses, patients who saw the CLP on 3 or more occasions (45% of those referred) had significant improvements in EQ-5D-5L, HADS-D, HADS-A, and exercise levels. There was a high positive correlation between CLP consultation rates and patient uptake of suggested community resources. CONCLUSIONS: We were unable to prove the effectiveness of referral to CLPs based in primary care in deprived areas for improving patient outcomes. Future efforts to boost uptake and engagement could improve overall outcomes, although the apparent improvements in those who regularly saw the CLPs may be due to reverse causality. Further research is needed before wide-scale deployment of this approach

Whole Genome Amplification of DNA for Genotyping Pharmacogenetics Candidate Genes

Whole genome amplification (WGA) technologies can be used to amplify genomic DNA when only small amounts of DNA are available. The Multiple Displacement Amplification Phi polymerase based amplification has been shown to accurately amplify DNA for a variety of genotyping assays; however, it has not been tested for genotyping many of the clinically relevant genes important for pharmacogenetic studies, such as the cytochrome P450 genes, that are typically difficult to genotype due to multiple pseudogenes, copy number variations, and high similarity to other related genes. We evaluated whole genome amplified samples for Taqman™ genotyping of SNPs in a variety of pharmacogenetic genes. In 24 DNA samples from the Coriell human diversity panel, the call rates, and concordance between amplified (∼200-fold amplification) and unamplified samples was 100% for two SNPs in CYP2D6 and one in ESR1. In samples from a breast cancer clinical trial (Trial 1), we compared the genotyping results in samples before and after WGA for three SNPs in CYP2D6, one SNP in CYP2C19, one SNP in CYP19A1, two SNPs in ESR1, and two SNPs in ESR2. The concordance rates were all >97%. Finally, we compared the allele frequencies of 143 SNPs determined in Trial 1 (whole genome amplified DNA) to the allele frequencies determined in unamplified DNA samples from a separate trial (Trial 2) that enrolled a similar population. The call rates and allele frequencies between the two trials were 98 and 99.7%, respectively. We conclude that the whole genome amplified DNA is suitable for Taqman™ genotyping for a wide variety of pharmacogenetically relevant SNPs

Productivity and dissolved oxygen controls on the Southern Ocean deep‐sea benthos during the Antarctic Cold Reversal

Funding was provided by an Antarctic Bursary awarded to J.A.S., ERC and NERC grants awarded to L.F.R. (278705, NE/S001743/1, NE/R005117/1) and L.F.R. and J.W.B.R. (NE/N003861/1).The Antarctic Cold Reversal (ACR; 14.7 to 13 thousand years ago; ka) phase of the last deglaciation saw a pause in the rise of atmospheric CO2 and Antarctic temperature, that contrasted with warming in the North. A re-expansion of sea ice and a northward shift in the position of the westerly winds in the Southern Ocean are well-documented, but the response of deep-sea biota and the primary drivers of habitat viability remain unclear. Here we present a new perspective on ecological changes in the deglacial Southern Ocean, including multi-faunal benthic assemblage (foraminifera and cold-water corals) and coral geochemical data (Ba/Ca and δ11B) from the Drake Passage. Our records show that, during the ACR, peak abundances of thick-walled benthic foraminifera Uvigerina bifurcata and corals are observed at shallow depths in the sub-Antarctic (∼300 m), while coral populations at greater depths and further south diminished. Our ecological and geochemical data indicate that habitat shifts were dictated by (i) a northward migration of food supply (primary production) into the Subantarctic Zone and (ii) poorly oxygenated seawater at depth during this Antarctic cooling interval.Publisher PDFPeer reviewe

Cavin-1/PTRF alters prostate cancer cell-derived extracellular vesicle content and internalization to attenuate extracellular vesicle-mediated osteoclastogenesis and osteoblast proliferation

Background: Tumour-derived extracellular vesicles (EVs) play a role in tumour progression; however, the spectrum of molecular mechanisms regulating EV secretion and cargo selection remain to be fully elucidated. We have reported that cavin-1 expression in prostate cancer PC3 cells reduced the abundance of a subset of EV proteins, concomitant with reduced xenograft tumour growth and metastasis. Methods: We examined the functional outcomes and mechanisms of cavin-1 expression on PC3-derived EVs (PC3-EVs). Results: PC3-EVs were internalized by osteoclast precursor RAW264.7 cells and primary human osteoblasts (hOBs) in vitro, stimulating osteoclastogenesis 37-fold and hOB proliferation 1.5-fold, respectively. Strikingly, EVs derived from cavin-1-expressing PC3 cells (cavin-1-PC3-EVs) failed to induce multinucleate osteoblasts or hOB proliferation. Cavin-1 was not detected in EVs, indicating an indirect mechanism of action. EV morphology, size and quantity were also not affected by cavin-1 expression, suggesting that cavin-1 modulated EV cargo recruitment rather than release. While cavin-1-EVs had no osteoclastogenic function, they were internalized by RAW264.7 cells but at a reduced efficiency compared to control EVs. EV surface proteins are required for internalization of PC3-EVs by RAW264.7 cells, as proteinase K treatment abolished uptake of both control and cavin-1-PC3-EVs. Removal of sialic acid modifications by neuraminidase treatment increased the amount of control PC3-EVs internalized by RAW264.7 cells, without affecting cavin-1-PC3-EVs. This suggests that cavin-1 expression altered the glycosylation modifications on PC3-EV surface. Finally, cavin-1 expression did not affect EV in vivo tissue targeting as both control and cavin-1-PC3-EVs were predominantly retained in the lung and bone 24 hours after injection into mice. Discussion: Taken together, our results reveal a novel pathway for EV cargo sorting, and highlight the potential of utilizing cavin-1-mediated pathways to attenuate metastatic prostate cancer

High sensitivity of summer temperatures to stratospheric sulfur loading from volcanoes in the Northern Hemisphere

This work was funded by an ERC (European Research Council) Marie Curie Career Integration Grant (CIG14-631752) and a Philip Leverhulme prize in Earth Sciences (PLP-2021-167) from the Leverhulme Trust awarded to A.B. WH is funded by a UKRI Future Leaders Fellowship (MR/S033505/1). M.S. acknowledges the support of the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 820047). H.M.I. and L.C. were both funded by IAPETUS and IAPETUS2 NERC Doctoral Training Partnership. The Tunu2013 and NEEM_2011_S1 ice cores were collected and analyzed for sulfur and other chemical species used to establish the ice core chronologies with funding from NSF grants 1204176 and 0909541 to J.R.M., respectively, and ice cores were sampled with funding from NSF grant 1340174.The 540s, 1450s, and 1600s represent three of the five coldest decades in the Common Era (CE). In each of these cases, the cause of these cold pulses has been attributed to large volcanic eruptions. However, the provenance of the eruption and magnitude of the volcanic forcing remains uncertain. Here, we use high-resolution sulfur isotopes in Greenland and Antarctic ice cores measured across these events to provide a means of improving sulfur loading estimates for these eruptions. In each case, the largest reconstructed tree-ring cooling is associated with an extratropical eruption, and the high-altitude stratospheric sulfate loading of these events is substantially smaller than previous estimates (by up to a factor of two). These results suggest an increased sensitivity of the reconstructed Northern Hemisphere summer temperature response to extratropical eruptions. This highlights the importance of climate feedbacks and processes that amplify and prolong the cooling signal from high latitudes, such as changes in sea ice extent and ocean heat content.Publisher PDFPeer reviewe

Overturning circulation, nutrient limitation, and warming in the Glacial North Pacific

This work was funded by NERC grant NE/N011716/1 to J.W.B.R., a NERC studentship to B.T., and NSF grant OPP 1643445 to I.E. A.R. acknowledges support from NSF grant 1736771.Although the Pacific Ocean is a major reservoir of heat and CO2, and thus an important component of the global climate system, its circulation under different climatic conditions is poorly understood. Here, we present evidence that during the Last Glacial Maximum (LGM), the North Pacific was better ventilated at intermediate depths and had surface waters with lower nutrients, higher salinity, and warmer temperatures compared to today. Modeling shows that this pattern is well explained by enhanced Pacific meridional overturning circulation (PMOC), which brings warm, salty, and nutrient-poor subtropical waters to high latitudes. Enhanced PMOC at the LGM would have lowered atmospheric CO2—in part through synergy with the Southern Ocean—and supported an equable regional climate, which may have aided human habitability in Beringia, and migration from Asia to North America.Publisher PDFPeer reviewe

On the origin and processes controlling the elemental and isotopic composition of carbonates in hypersaline Andean lakes

H.J. and J.W.B. Rae acknowledge funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 805246).The Altiplano-Puna Plateau of the Central Andes hosts numerous lakes, playa-lakes, and salars with a great diversity and abundance of carbonates forming under extreme climatic, hydrologic, and environmental conditions. To unravel the underlying processes controlling the formation of carbonates and their geochemical signatures in hypersaline systems, we investigated coupled brine-carbonate samples in a high-altitude Andean lake using a wide suite of petrographic (SEM, XRD) and geochemical tools (δ2H, δ18O, δ13C, δ11B, major and minor ion composition, aqueous modelling). Our findings show that the inflow of hydrothermal springs in combination with strong CO2 degassing and evaporation plays an important role in creating a spatial diversity of hydro-chemical sub-environments allowing different types of microbialites (microbial mounds and mats), travertines, and fine-grained calcite minerals to form. Carbonate precipitation occurs in hot springs triggered by a shift in carbonate equilibrium by hydrothermal CO2 degassing and microbially-driven elevation of local pH at crystallisation. In lakes, carbonate precipitation is induced by evaporative supersaturation, with contributions from CO2 degassing and microbiological processes. Lake carbonates largely record the evaporitic enrichment (hence salinity) of the parent water which can be traced by Na, Li, B, and δ18O, although other factors (such as e.g., high precipitation rates, mixing with thermal waters, groundwater, or precipitation) also affect their signatures. This study is of significance to those dealing with the fractionation of oxygen, carbon, and boron isotopes and partitioning of elements in natural brine-carbonate environments. Furthermore, these findings contribute to the advancement in proxy development for these depositional environments.Peer reviewe

Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer

PURPOSE: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients. METHODS: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. RESULTS: The ranges of baseline estrogen concentrations were <LLOQ-361 pg/mL for E2, <LLOQ-190 pg/mL for E1, and 8.3-4060 pg/mL for E1S. For E2, the frequency of suppression below the LLOQ was not statistically significantly different between AIs (exemestane: 89.0%, letrozole: 86.9%, p = 0.51). However, patients on letrozole were more likely to achieve suppression below the LLOQ of both E1 (exemestane: 80.1%, letrozole: 90.1%, p = 0.005) and E1S (exemestane: 17.4%, letrozole: 54.9%, p = 4.34e-15). After 3 months of AI therapy, the ranges of estrogen concentrations were <LLOQ-63.8 pg/mL, <LLOQ-36.7 pg/mL, and <LLOQ-1090 pg/mL for E2, E1, and E1S, respectively. During treatment, 16 patients had an increased concentration compared to the baseline concentration of at least one estrogen. CONCLUSIONS: Letrozole had greater suppression of plasma E1 and E1S than exemestane, though the response was highly variable among patients. Additional research is required to examine the clinical relevance of differential estrogen suppression