Trace-element abundances in the shallow lithospheric mantle of the North Atlantic Craton margin: implications for melting and metasomatism beneath Northern Scotland

Bulk rock geochemistry and major- and trace-element compositions of clinopyroxene have been determined for three suites of peridotitic mantle xenoliths from the North Atlantic Craton (NAC) in northern Scotland, to establish the magmatic and metasomatic history of subcontinental lithospheric mantle (SCLM) below this region. Spinel lherzolites from the southernmost locality (Streap Com'laidh) have non-NAC mantle compositions, while the two northern xenolith suites (Loch Roag and Rinibar) are derived from the thinned NAC marginal keel. Clinopyroxene compositions have characteristic trace-element signatures which show both 'primary' and 'metasomatic' origins. We use Zr and Hf abundances to identify ancient cryptic refertilization in 'primary' clinopyroxenes. We suggest that Loch Roag and Rinibar peridotite xenoliths represent an ancient Archaean-Palaeoproterozoic SCLM with original depleted cratonic signatures which were overprinted by metasomatism around the time of intrusion of the Scourie Dyke Swarm (∼2.4 Ga). This SCLM keel was preserved during Caledonian orogenesis, although some addition of material and/or metasomatism probably also occurred, as recorded by Rinibar xenoliths. Rinibar and Streap xenoliths were entrained in Permo-Carboniferous magmas and thus were isolated from the SCLM ∼200 Ma before Loch Roag xenoliths (in an Eocene dyke). Crucially, despite their geographical location, lithospheric mantle peridotite samples from Loch Roag show no evidence of recent melting or refertilization during the Palaeogene opening of the Atlantic

Targeting translational read-through of premature termination mutations in BMPR2 with PTC124 for pulmonary arterial hypertension

Pulmonary arterial hypertension is a fatal disorder of the lung circulation in which accumulation of vascular cells progressively obliterates the pulmonary arterioles. This results in sustained elevation in pulmonary artery pressure leading eventually to right heart failure. Approximately, 80% of familial and 20% of sporadic idiopathic pulmonary arterial hypertension cases are caused by mutations in the bone morphogenetic protein receptor type 2 (BMPR2). Nonsense mutations in BMPR2 are amongst the most common mutations found, where the insertion of a premature termination codon causes mRNA degradation via activation of the nonsense-mediated decay pathway leading to a state of haploinsufficiency. Ataluren (PTC124), a compound that permits ribosomal read-through of premature stop codons, has been previously reported to increase BMPR2 protein expression in cells derived from pulmonary arterial hypertension patients harbouring nonsense mutations. In this study, we characterised the effects of PTC124 on a range of nonsense BMPR2 mutations, focusing on the R584X mutation both in vitro and in vivo. Treatment with PTC124 partially restored BMPR2 protein expression in blood outgrowth endothelial cells isolated from a patient harbouring the R584X mutation. Furthermore, a downstream bone morphogenetic protein signalling target, Id1, was rescued by PTC124 treatment. Mutant cells also exhibited increased lipopolysaccharide-induced permeability, which was reversed by PTC124 treatment. Increased proliferation and apoptosis in R584X blood outgrowth endothelial cells were also significantly reduced by PTC124. Moreover, oral PTC124 increased lung BMPR2 protein expression in mice harbouring the R584X mutation (Bmpr2+/R584X). Our findings provide support for future experimental medicine studies of PTC124 in pulmonary arterial hypertension patients with specific nonsense BMPR2 mutations

Paradoxical co-existing base metal sulphides in the mantle: The multi-event record preserved in Loch Roag peridotite xenoliths, North Atlantic Craton

The role of the subcontinental lithospheric mantle as a source of precious metals for mafic magmas is contentious and, given the chalcophile (and siderophile) character of metals such as the platinum-group elements (PGE), Se, Te, Re, Cu and Au, the mobility of these metals is intimately linked with that of sulphur. Hence the nature of the host phase(s), and their age and stability in the subcontinental lithospheric mantle may be of critical importance. We investigate the sulphide mineralogy and sulphide in situ trace element compositions in base metal sulphides (BMS) in a suite of spinel lherzolite mantle xenoliths from northwest Scotland (Loch Roag, Isle of Lewis). This area is situated on the margin of the North Atlantic Craton which has been overprinted by a Palaeoproterozoic orogenic belt, and occurs in a region which has undergone magmatic events from the Palaeoproterozoic to the Eocene. We identify two populations of co-existing BMS within a single spinel lherzolite xenolith (LR80) and which can also be recognised in the peridotite xenolith suite as a whole. Both populations consist of a mixture of Fe-Ni-Cu sulphide minerals, and we distinguished between these according to BMS texture, petrographic setting (i.e., location within the xenolith in terms of ‘interstitial’ or within feldspar-spinel symplectites, as demonstrated by X-ray Computed Microtomography) and in situ trace element composition. Group A BMS are coarse, metasomatic, have low concentrations of total PGE (< 40 ppm) and high (Re/Os)N (ranging 1 to 400). Group B BMS strictly occur within symplectites of spinel and feldspar, are finer-grained rounded droplets, with micron-scale PtS (cooperite), high overall total PGE concentrations (15–800 ppm) and low (Re/Os)N ranging 0.04 to 2. Group B BMS sometimes coexist with apatite, and both the Group B BMS and apatite can preserve rounded micron-scale Ca-carbonate inclusions indicative of sulphide-carbonate-phosphate immiscibility. This carbonate-phosphate metasomatic association appears to be important in forming PGE-rich sulphide liquids, although the precise mechanism for this remains obscure. As a consequence of their position within the symplectites, Group B BMS are particularly vulnerable to being incorporated in ascending mantle-derived magmas (either by melting or physical entrainment). Based on the cross-cutting relationships of the symplectites, it is possible to infer the relative ages of each metasomatic BMS population. We tally these with major tectono-magmatic events for the North Atlantic region by making comparisons to carbonatite events recorded in crustal and mantle rocks, and we suggest that the Pt-enrichment was associated with a pre-Carboniferous carbonatite episode. This method of mantle xenolith base metal sulphide documentation may ultimately permit the temporal and spatial mapping of the chalcophile metallogenic budget of the lithospheric mantle, providing a blueprint for assessing regional metallogenic potential. Abbreviations: NAC, North Atlantic Craton; GGF, Great Glen Fault; NAIP, North Atlantic Igneous Province; BPIP, British Palaeogene Igneous Province; SCLM, subcontinental lithospheric mantle; PGE, platinum-group elements; HSE, highly siderophile elements; BMS, base metal sulphid

Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice.

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury

Gold-catalyzed conversion of lignin to low molecular weight aromatics

A heterogeneous catalyst system, employing Au nanoparticles (NPs) and Li-Al (1:2) layered double hydroxide (LDH) as support, showed excellent activity in aerobic oxidation of the benzylic alcohol group in β-O-4 linked lignin model dimers to the corresponding carbonyl products using molecular oxygen under atmospheric pressure. The synergistic effect between Au NPs and the basic Li-Al LDH support induces further reaction of the oxidized model compounds, facilitating facile cleavage of the β-O-4 linkage. Extension to oxidation of γ-valerolactone (GVL) extracted lignin and kraft lignin using Au/Li-Al LDH under similar conditions produced a range of aromatic monomers in high yield. Hydrolysis of the Au/Li-Al LDH oxidized lignin was found to increase the degree of lignin depolymerization, with monomer yields reaching 40% for GVL extracted lignin. Based on these results, the Au/Li-Al LDH + O2 catalyst system shows potential to be an environmentally friendly means of depolymerizing lignin to low molecular weight aromatics under mild conditions

Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension.

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death