Thioredoxin reductase-2 is essential for keeping low levels of H(2)O(2) emission from isolated heart mitochondria.

Respiring mitochondria produce H(2)O(2) continuously. When production exceeds scavenging, H(2)O(2) emission occurs, endangering cell functions. The mitochondrial peroxidase peroxiredoxin-3 reduces H(2)O(2) to water using reducing equivalents from NADPH supplied by thioredoxin-2 (Trx2) and, ultimately, thioredoxin reductase-2 (TrxR2). Here, the contribution of this mitochondrial thioredoxin system to the control of H(2)O(2) emission was studied in isolated mitochondria and cardiomyocytes from mouse or guinea pig heart. Energization of mitochondria by the addition of glutamate/malate resulted in a 10-fold decrease in the ratio of oxidized to reduced Trx2. This shift in redox state was accompanied by an increase in NAD(P)H and was dependent on TrxR2 activity. Inhibition of TrxR2 in isolated mitochondria by auranofin resulted in increased H(2)O(2) emission, an effect that was seen under both forward and reverse electron transport. This effect was independent of changes in NAD(P)H or membrane potential. The effects of auranofin were reproduced in cardiomyocytes; superoxide and H(2)O(2) levels increased, but similarly, there was no effect on NAD(P)H or membrane potential. These data show that energization of mitochondria increases the antioxidant potential of the TrxR2/Trx2 system and that inhibition of TrxR2 results in increased H(2)O(2) emission through a mechanism that is independent of changes in other redox couples.

Mobilisation of deep crustal sulfide melts as a first order control on upper lithospheric metallogeny.

Magmatic arcs are terrestrial environments where lithospheric cycling and recycling of metals and volatiles is enhanced. However, the first-order mechanism permitting the episodic fluxing of these elements from the mantle through to the outer Earth's spheres has been elusive. To address this knowledge gap, we focus on the textural and minero-chemical characteristics of metal-rich magmatic sulfides hosted in amphibole-olivine-pyroxene cumulates in the lowermost crust. We show that in cumulates that were subject to increasing temperature due to prolonged mafic magmatism, which only occurs episodically during the complex evolution of any magmatic arc, Cu-Au-rich sulfide can exist as liquid while Ni-Fe rich sulfide occurs as a solid phase. This scenario occurs within a 'Goldilocks' temperature zone at ~1100-1200 °C, typical of the base of the crust in arcs, which permits episodic fractionation and mobilisation of Cu-Au-rich sulfide liquid into permeable melt networks that may ascend through the lithosphere providing metals for porphyry and epithermal ore deposits.

Improved Models of Coalescence Ages of Y-DNA Haplogroups.

Databases of commercial DNA-testing companies now contain more customers with sequenced DNA than any completed academic study, leading to growing interest from academic and forensic entities. An important result for both these entities and the test takers themselves is how closely two individuals are related in time, as calculated through one or more molecular clocks. For Y-DNA, existing interpretations of these clocks are insufficiently accurate to usefully measure relatedness in historic times. In this article, I update the methods used to calculate coalescence ages (times to most-recent common ancestor, or TMRCAs) using a new, probabilistic statistical model that includes Y-SNP, Y-STR and ancilliary historical data, and provide examples of its use.

The contribution of the Scottish doctor Robert Erskine to the development of Russian medicine in the 18th century.

The Scottish doctor Robert Erskine (1677-1718) became Chief Doctor of Russia and personal physician to Tsar Peter the Great. Extensive archival material documents his remarkable career. From schooling in the village of Alva and apprenticeship to an Edinburgh apothecary, he went on to study medicine in Paris and Utrecht and was admitted to the Royal Society in London. Recruited into the service of the Tsar, to whom he became a trusted friend and counsellor, Erskine played a central role in the modernisation of Russian medicine, pharmacy and natural science in the early 18th century. His untimely death at age 41 was marked with a state funeral in St Petersburg. Some historians in Russia assert that in their country, the development of medicine and the natural sciences took place without the transitional stages of iatrochemistry and iatrophysics which characterised the shift in scientific thinking throughout Europe in the early modern period. This study of archival records shows that Erskine held iatrophysical and iatrochemical views in common with his European contemporaries. His influence ensured that Russia was thoroughly involved in European developments in science and medicine in the 18th century.

Platinum-group elements link the end-Triassic mass extinction and the Central Atlantic Magmatic Province.

Elevated concentrations of iridium (Ir) and other platinum-group elements (PGE) have been reported in both terrestrial and marine sediments associated with the end-Triassic mass extinction (ETE) c. 201.5 million years ago. The source of the PGEs has been attributed to condensed vapor and melt from an extraterrestrial impactor or to volcanism. Here we report new PGE data for volcanic rocks of the Central Atlantic Magmatic Province (CAMP) in Morocco and show that their Pd/Ir, Pt/Ir and Pt/Rh ratios are similar to marine and terrestrial sediments at the ETE, and very different from potential impactors. Hence, we propose the PGEs provide a new temporal correlation of CAMP volcanism to the ETE, corroborating the view that mass extinctions may be caused by volcanism.

A metasomatized lithospheric mantle control on the metallogenic signature of post-subduction magmatism.

Ore deposits are loci on Earth where energy and mass flux are greatly enhanced and focussed, acting as magnifying lenses into metal transport, fractionation and concentration mechanisms through the lithosphere. Here we show that the metallogenic architecture of the lithosphere is illuminated by the geochemical signatures of metasomatised mantle rocks and post-subduction magmatic-hydrothermal mineral systems. Our data reveal that anomalously gold and tellurium rich magmatic sulfides in mantle-derived magmas emplaced in the lower crust share a common metallogenic signature with upper crustal porphyry-epithermal ore systems. We propose that a trans-lithospheric continuum exists whereby post-subduction magmas transporting metal-rich sulfide cargoes play a fundamental role in fluxing metals into the crust from metasomatised lithospheric mantle. Therefore, ore deposits are not merely associated with isolated zones where serendipitous happenstance has produced mineralisation. Rather, they are depositional points along the mantle-to-upper crust pathway of magmas and hydrothermal fluids, synthesising the concentrated metallogenic budget available.

Achiral, selective CCK2 receptor antagonists based on a 1,3,5-benzotriazepine-2,4-dione template.

Novel, achiral 1H-1,3,5-benzotriazepine-2,4(3H,5H)-diones have been prepared and structurally characterized. These compounds are potent CCK(2) receptor antagonists that display a high degree of selectivity over CCK(1) receptors.

A large impact crater beneath Hiawatha Glacier in northwest Greenland.

We report the discovery of a large impact crater beneath Hiawatha Glacier in northwest Greenland. From airborne radar surveys, we identify a 31-kilometer-wide, circular bedrock depression beneath up to a kilometer of ice. This depression has an elevated rim that cross-cuts tributary subglacial channels and a subdued central uplift that appears to be actively eroding. From ground investigations of the deglaciated foreland, we identify overprinted structures within Precambrian bedrock along the ice margin that strike tangent to the subglacial rim. Glaciofluvial sediment from the largest river draining the crater contains shocked quartz and other impact-related grains. Geochemical analysis of this sediment indicates that the impactor was a fractionated iron asteroid, which must have been more than a kilometer wide to produce the identified crater. Radiostratigraphy of the ice in the crater shows that the Holocene ice is continuous and conformable, but all deeper and older ice appears to be debris rich or heavily disturbed. The age of this impact crater is presently unknown, but from our geological and geophysical evidence, we conclude that it is unlikely to predate the Pleistocene inception of the Greenland Ice Sheet.

Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.

Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.

Discovery and characterization of novel, potent, non-peptide parathyroid hormone-1 receptor antagonists.

A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.

Novel, achiral 1,3,4-benzotriazepine analogues of 1,4-benzodiazepine-based CCK(2) antagonists that display high selectivity over CCK(1) receptors.

A series of 1,3,4-benzotriazepine-based CCK(2) antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine-based CCK(2) antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK(2) receptors to the earlier molecules and are highly selective over CCK(1) receptors.

Optimization of the in vitro and in vivo properties of a novel series of 2,4,5-trisubstituted imidazoles as potent cholecystokinin-2 (CCK2) antagonists.

The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.

Maximal extent of translocation of single-walled carbon nanotubes from lung airways of the rat.

This study aimed to examine the extent of pulmonary translocation of single-walled carbon nanotubes (SWCNTs) from lung airways of rat. It utilised an ex vivo isolated perfused rat lung (IPRL) model that retains the intact lung architecture while eliminating the confounding issue of systemic pharmacokinetics. Doses (100 µg) of SWCNTs were instilled into the airways of the IPRL and the pulmonary translocation of SWCNTs quantified by inductively coupled plasma mass spectroscopy using CNT-associated nickel as the probe. SWCNT translocation from the airways across an intact pulmonary barrier into what would be the systemic circulation was no greater than 0.05% of the instilled dose over 90 min. Pharmacokinetic simulation incorporating a term for mucociliary clearance would predict over a 14 day an approximate cumulative pulmonary translocation from rat lung of no greater than 0.15% from a 100 µg deposited dose.

Strategies for the design of non-peptide CCK2 receptor agonist and antagonist ligand.

There has been an effort towards the design and preparation of non-peptide antagonists of the CCK(2) receptor going back for over fifteen years. However, as no obvious unmet medical need for this type of molecule has emerged, the interest has somewhat declined. A number of comprehensive reviews have been written where much of the early work is described and so this article focuses on the information generated in the last five years. It is to be hoped that the area will regain some impetus following the recent disclosure of clinical trial data demonstrating the possible utility of a CCK(2) antagonist in pancreatic cancer. When considering non-peptide agonists for the CCK(2) receptor, traditionally, much less work has been reported in the area. However, recent suggestions of possible clinical utility in the treatment of diabetes, functionally different subtypes of the receptor and molecular models of receptor-ligand interactions should act as a spur for work towards potent small molecule ligands.