The Amundsen Sea Polynya International Research Expedition (ASPIRE)

In search of an explanation for some of the greenest waters ever seen in coastal Antarctica and their possible link to some of the fastest melting glaciers and declining summer sea ice, the Amundsen Sea Polynya International Research Expedition (ASPIRE) challenged the capabilities of the US Antarctic Program and RVIB Nathaniel B. Palmer during Austral summer 2010–2011. We were well rewarded by both an extraordinary research platform and a truly remarkable oceanic setting. Here we provide further insights into the key questions that motivated our sampling approach during ASPIRE and present some preliminary findings, while highlighting the value of the Palmer for accomplishing complex, multifaceted oceanographic research in such a challenging environment

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

Controls on the composition and lability of dissolved organic matter in Siberia's Kolyma River basin

High-latitude northern rivers export globally significant quantities of dissolved organic carbon (DOC) to the Arctic Ocean. Climate change, and its associated impacts on hydrology and potential mobilization of ancient organic matter from permafrost, is likely to modify the flux, composition, and thus biogeochemical cycling and fate of exported DOC in the Arctic. This study examined DOC concentration and the composition of dissolved organic matter (DOM) across the hydrograph in Siberia's Kolyma River, with a particular focus on the spring freshet period when the majority of the annual DOC load is exported. The composition of DOM within the Kolyma basin was characterized using absorbance-derived measurements (absorbance coefficienta330, specific UV absorbance (SUVA254), and spectral slope ratio SR) and fluorescence spectroscopy (fluorescence index and excitation-emission matrices (EEMs)), including parallel factor analyses of EEMs. Increased surface runoff during the spring freshet led to DOM optical properties indicative of terrestrial soil inputs with high humic-like fluorescence, SUVA254, and low SRand fluorescence index (FI). Under-ice waters, in contrast, displayed opposing trends in optical properties representing less aromatic, lower molecular weight DOM. We demonstrate that substantial losses of DOC can occur via biological (∼30% over 28 days) and photochemical pathways (>29% over 14 days), particularly in samples collected during the spring freshet. The emerging view is therefore that of a more dynamic and labile carbon pool than previously thought, where DOM composition plays a fundamental role in controlling the fate and removal of DOC at a pan-Arctic scale

Comprehensive analysis of chemical and biological problems associated with browning agents used in aquatic studies

Inland waters receive and process large amounts of colored organic matter from the terrestrial surroundings. These inputs dramatically affect the chemical, physical, and biological properties of water bodies, as well as their roles as global carbon sinks and sources. However, manipulative studies, especially at ecosystem scale, require large amounts of dissolved organic matter with optical and chemical properties resembling indigenous organic matter. Here, we compared the impacts of two leonardite products (HuminFeed and SuperHume) and a freshly derived reverse osmosis concentrate of organic matter in a set of comprehensive mesocosm- and laboratory-scale experiments and analyses. The chemical properties of the reverse osmosis concentrate and the leonardite products were very different, with leonardite products being low and the reverse osmosis concentrate being high in carboxylic functional groups. Light had a strong impact on the properties of leonardite products, including loss of color and increased particle formation. HuminFeed presented a substantial impact on microbial communities under light conditions, where bacterial production was stimulated and community composition modified, while in dark potential inhibition of bacterial processes was detected. While none of the browning agents inhibited the growth of the tested phytoplankton Gonyostomum semen, HuminFeed had detrimental effects on zooplankton abundance and Daphnia reproduction. We conclude that the effects of browning agents extracted from leonardite, particularly HuminFeed, are in sharp contrast to those originating from terrestrially derived dissolved organic matter. Hence, they should be used with great caution in experimental studies on the consequences of terrestrial carbon for aquatic systems

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Tuning fresh: radiation through rewiring of central metabolism in streamlined bacteria

Most free-living planktonic cells are streamlined and in spite of their limitations in functional flexibility, their vast populations have radiated into a wide range of aquatic habitats. Here we compared the metabolic potential of subgroups in the Alphaproteobacteria lineage SAR11 adapted to marine and freshwater habitats. Our results suggest that the successful leap from marine to freshwaters in SAR11 was accompanied by a loss of several carbon degradation pathways and a rewiring of the central metabolism. Examples for these are C1 and methylated compounds degradation pathways, the Entner–Doudouroff pathway, the glyoxylate shunt and anapleuretic carbon fixation being absent from the freshwater genomes. Evolutionary reconstructions further suggest that the metabolic modules making up these important freshwater metabolic traits were already present in the gene pool of ancestral marine SAR11 populations. The loss of the glyoxylate shunt had already occurred in the common ancestor of the freshwater subgroup and its closest marine relatives, suggesting that the adaptation to freshwater was a gradual process. Furthermore, our results indicate rapid evolution of TRAP transporters in the freshwater clade involved in the uptake of low molecular weight carboxylic acids. We propose that such gradual tuning of metabolic pathways and transporters toward locally available organic substrates is linked to the formation of subgroups within the SAR11 clade and that this process was critical for the freshwater clade to find and fix an adaptive phenotype.This work was supported by the Swedish Research Council (Grant Numbers 2012-4592 to AE and 2012-3892 to SB) and the Communiy Sequencing Programme of the US Department of Energy Joint Genome Institute. The work conducted by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, is supported under Contract No. DE-AC02-05CH11231

Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR

Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5α-androstan-3β-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches