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Mafic and ultramafic rocks intercalated with metamorphosed deep-marine sediments in the Glenelg River Complex of SE Australia comprise variably tectonized fragments of an interpreted late Neoproterozoic-earliest Cambrian hyper-extended continental margin that was dismembered and thrust westwards over the adjacent continental margin during the Cambro-Ordovician Delamerian Orogeny. Ultramafic rocks include serpentinized harzburgite of inferred subcontinental lithospheric origin that had already been exhumed at the seafloor before sedimentation commenced, whereas mafic rocks exhibit mainly enriched- and normal-type mid-ocean ridge basalt (E- and N-MORB) compositions consistent with emplacement in an oceanic setting. These lithologies and their metasedimentary host rocks predate deposition of the Cambrian Kanmantoo Group and are more likely to represent temporal equivalents of the older Normanville Group or underlying Neoproterozoic Adelaide Supergroup. The Kanmantoo Group is host to basaltic rocks with higher degrees of crustal contamination and yields detrital zircon populations dominated by 600-500 Ma ages. Except for quartz greywacke confined to the uppermost part of the sequence, metasedimentary rocks in the Glenelg River Complex are devoid of detrital zircon, and are interstratified with subordinate amounts of metachert and carbonaceous dolomitic slate suggestive of deposition in a deep-marine environment far removed from any continental margin. Seismic reflection data support the idea that the Glenelg River Complex is underlain by mafic and ultramafic rocks, and preclude earlier interpretations based on aeromagnetic data that the continental margin incorporates a thick pile of seawards-dipping basaltic flows analogous to those of volcanic margins in the North Atlantic. Correlative hyper-extended continental rift margins to the Glenelg River Complex occur along strike in formerly contiguous parts of Antarctica.Supplementary material:: Geochemical data for mafic and ultramafic rocks in the Glenelg River Complex and correlative terranes, and U-Th-Pb data for western Victoria gabbros are available at http://www.geolsoc.org.uk/SUP18821.

Fetal hypoxia results in a fetal blood acidosis (pH

In this paper, we study vision-based localization for robots. We anticipate that numerous mobile robots will serve or interact with humans in indoor scenarios such as healthcare, entertainment, and public service. Such scenarios entail accurate and scalable indoor visual robot localization, the subject of this work. Most existing vision-based localization approaches suffer from low localization accuracy and scalability issues due to visual environmental features’ limited effective range and detection accuracy. In light of infrastructural cameras’ wide indoor deployment, this paper proposes BRIDGELOC, a novel vision-based indoor robot localization system that integrates both robots’ and infrastructural cameras. BRIDGELOC develops three key technologies: robot and infrastructural camera view bridging, rotation symmetric visual tag design, and continuous localization based on robots’ visual and motion sensing. Our system bridges robots’ and infrastructural cameras’ views to accurately localize robots. We use visual tags with rotation symmetric patterns to extend scalability greatly. Our continuous localization enables robot localization in areas without visual tags and infrastructural camera coverage. We implement our system and build a prototype robot using commercial off-the-shelf hardware. Our real-world evaluation validates BRIDGELOC’s promise for indoor robot localization.

In this research, we conduct a comprehensive measurement study on the predictability of human mobility with respect to demographic differences. We leverage an extensive WLAN dataset collected on a large university campus. Specifically, our dataset includes over 41 million WLAN entries gathered from over 5,000 students (with demographic information) during a four-month period in 2015. We observed surprising patterns on large increases of long-term mobility entropy by age, and the impact of academic majors on students long-term mobility entropy. The distribution of long-term entropy follows a bimodal distribution, which is different from previous studies. We also find that the predictability of students' short-term (daily or weekly) mobility varies on different days of the week and with student gender. Because of the large campus size, our results can mimic people's mobility patterns in metropolitan areas. We also anticipate that our results will provide insight that guides academic administrators' decisions regarding facilities planning, emergency management, etc. on campus.

Responses to angiotensin II (Ang II) were investigated in anaesthetised CD1 mice. Injections of Ang II caused dose-related increases in systemic arterial pressure that were antagonised by candesartan. Responses to Ang II were not altered by PD 123319. At the lowest dose studied (20 µg/kg i.v.), the inhibitory effects of candesartan were competitive, whereas at the highest dose (100 µg/kg i.v.), the dose-response curve for Ang II was shifted to the right in a non-parallel manner. The inhibitory effects of candesartan were selective and were similar in animals pretreated with enalaprilat to reduce endogenous Ang II production. Pressor responses to Ang II were not altered by propranolol, phentolamine or atropine, but were enhanced by hexamethonium. Increases in total peripheral resistance were inhibited by the AT1-receptor antagonist (ARB) but were not altered by AT2-receptor, alpha- or beta-receptor antagonists. These results suggest that pressor responses to Ang II are mediated by AT 1-receptors, are buffered by the baroreceptors, are not modulated by effects on AT2receptors, and that activation of the sympathetic nervous system plays little role in mediating rapid haemodynamic responses to the peptide in anaesthetised mice.

How and when continents grew and plate tectonics started on Earth remain poorly con- strained. Most researchers apply the modern plate tectonic paradigm to problems of ancient crustal formation, but these are unsatisfactory because diagnostic criteria and actualistic plate configur- ations are lacking. Here, we show that 3.5-3.2 Ga continental nuclei in the Pilbara Craton, Aus- tralia, and the eastern Kaapvaal Craton, southern Africa, formed as thick volcanic plateaux built on a substrate of older continental lithosphere and did not accrete through horizontal tectonic pro- cesses. These nuclei survived because of the contemporaneous development of buoyant, non- subductable mantle roots. This plateau-type of Archean continental crust is distinct from, but complementary to, Archean gneiss terranes formed over shallowly dipping zones of intraoceanic underplating (proto-subduction) on a vigorously convecting early Earth with smaller plates and primitive plate tectonics.

Pulmonary arterial hypertension is a progressive disorder in which endothelial dysfunction and vascular remodeling obstruct small pulmonary arteries, resulting in increased pulmonary vascular resistance and pulmonary pressures. This leads to reduced cardiac output, right heart failure, and ultimately death. In this review, we attempt to answer some important questions commonly asked by patients diagnosed with pulmonary arterial hypertension pertaining to the disease, and aim to provide an explanation in terms of classification, diagnosis, pathophysiology, genetic causes, demographics, and prognostic factors. Furthermore, important molecular pathways that are central to the pathogenesis of pulmonary arterial hypertension are reviewed, including nitric oxide, prostacyclin, endothelin-1, reactive oxygen species, and endothelial and smooth muscle proliferation.

BackgroundHIV-infected individuals are at increased risk for pulmonary hypertension and cardiomyopathy, portending a poor prognosis. Right ventricular (RV) dysfunction is associated with worse outcomes in these conditions, yet its prevalence is poorly defined in HIV. We sought to determine the prevalence of RV dysfunction in an outpatient HIV cohort.MethodsEchocardiograms were evaluated from 104 HIV-infected adults. Measurements included estimated pulmonary arterial systolic pressure (PASP) and several measures of RV function, including tricuspid annular plane systolic excursion (TAPSE), RV longitudinal myocardial strain (RVLMS), RV fractional area change (RVFAC), and myocardial performance index (MPI).ResultsSixteen subjects (15%) had PASP >35mm Hg, yet RV function did not differ significantly from those with normal estimated PASP. RV dysfunction defined by RVFAC 35mm Hg and LV dysfunction, but these findings did not cosegregate. RV dysfunction in HIV-infected individuals may be a separate entity from LV/global cardiomyopathy or pulmonary hypertension and deserves further study.

Krüppel-like factor 4 (KLF4) is a transcription factor expressed in the vascular endothelium, where it promotes anti-inflammatory and anticoagulant states, and increases endothelial nitric oxide synthase expression. We examined the role of endothelial KLF4 in pulmonary arterial (PA) hypertension (PAH). Mice with endothelial KLF4 knockdown were exposed to hypoxia for 3 weeks, followed by measurement of right ventricular and PA pressures, pulmonary vascular muscularization, and right ventricular hypertrophy. The effect of KLF4 on target gene expression was assessed in lungs from these mice, verified in vitro by small interfering RNA (siRNA) knockdown of KLF4, and further studied at the promoter level with cotransfection experiments. KLF4 expression was measured in lung tissue from patients with PAH and normal control subjects. We found that, after hypoxia, right ventricular and PA pressures were significantly higher in KLF4 knockdown animals than controls. Knockdown animals also had more severe pulmonary vascular muscularization and right ventricular hypertrophy. KLF4 knockdown resulted in increased pulmonary expression of endothelin-1 and decreased expression of endothelial nitric oxide synthase, endothelin receptor subtype B, and prostacyclin synthase. Concordant findings were observed in vitro, both with siRNA knockdown of KLF4 and promoter activity assays. Finally, KLF4 expression was reduced in lungs from patients with PAH. In conclusion, endothelial KLF4 regulates the transcription of genes involved in key pathways implicated in PAH, and its loss exacerbates pulmonary hypertension in response to chronic hypoxia in mice. These results introduce a novel transcriptional modulator of PAH, with the potential of becoming a new therapeutic target.

Pulmonary arterial hypertension is a severe progressive disease with marked morbidity and high mortality in which right ventricular (RV) failure is the major cause of death. Thus knowledge of the mechanisms underlying RV failure is an area of active interest. Previous studies suggest a role of NADPH oxidase in cardiomyocyte dysfunction in the left heart. Here we postulate that acute pressure overload induced by pulmonary artery banding (PAB) leads to a Nox4-initiated increase in reactive oxygen species (ROS) in mouse RV that may lead to feed-forward induction of Nox2. To test our hypothesis, ROS production was measured in RV and left ventricle homogenates. The data show that hydrogen peroxide (H2O2), but not superoxide anion (O2·−), was increased in the early phases (within 6 h) of PAB in RV and that this increase was diminished by catalase and diphenyleneiodonium chloride but not by SOD, Nω-nitro-l-arginin methyl ester, febuxostat, or indomethacin. H2O2 production in RV was not attenuated in Nox2 null mice subjected to 6 h PAB. Moreover, we observed an upregulation of Nox4 mRNA after 1 h of PAB and an increase in mitochondrial Nox4 protein 6 h post-PAB. In contrast, we observed an increase in Nox2 mRNA 1 day post-PAB. Expression of antioxidant enzymes SOD, catalase, and glutathione peroxidase did not change, but catalase activity increased 6 h post-PAB. Taken together, these findings show a role of mitochondria-localized Nox4 in the early phase of PAB and suggest an involvement of this isozyme in early ROS generation possibly contributing to progression of RV dysfunction and failure.

© 2019 Elsevier Ltd We consider three-dimensional (3D) localization in wireless multimedia sensor networks (WMSNs) and seek optimal localization accuracy in order to ensure real-time data fusion of mobile robots in WMSNs. To this end, we propose a real-time 3D localization algorithm realized by a distributed architecture with various smart devices to overcome network instability and the bottleneck channel at the coordinator. We then employ the recursive least squares (RLS) algorithm to fuse the 2D image coordinates from multiple views synchronously in WMSNs and determine the mobile robot's 3D location in an indoor environment. To minimize wireless data transmission, we also develop a distributed architecture that combines various smart devices by defining the data content transmitted from multiple wireless visual sensors. Moreover, we analyze the factors influencing the network instability of various smart devices, and factors influencing the localization performance of mobile robots in a multiple-view system. Experimental results show the proposed algorithm can achieve reliable, efficient, and real-time 3D localization in indoor WMSNs.

Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O2 (•-)) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor- and serum-independent proliferation, upregulation of matrix genes, and increased O2 (•-) production compared with control cells. Histologic analysis of SCD-associated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an α1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in end-stage SCD-associated PAH.

Review and analysis of initial lead isotope ratios from Archean volcanic-hosted massive sulfide (VHMS) and lode gold deposits and of neodymium isotopes from igneous rocks from the geologic provinces that host these deposits identifies systematic spatial and temporal patterns, both within and between the provinces. The Abitibi-Wawa subprovince of the Superior province is characterized by highly juvenile lead and neodymium. Most other Archean provinces, however, are characterized by more evolved isotopes, although domains within them can be characterized by juvenile isotope ratios. The analysis indicates that the endowment (measured as the quantity of metal contained in geologic resources per unit surface area) of VHMS and komatiite-associated nickel sulfide deposits is related to the isotopic character and, therefore, the tectonic history of provinces that host these deposits. Provinces with extensive juvenile crust have significantly higher endowment of VHMS deposits, possibly as a consequence of higher heat flow and extension-related faults. Provinces with evolved crust have higher endowment of komatiite-associated nickel sulfide deposits, possibly because such crust provided either a source of sulfur or a stable substrate for komatiite emplacement. In any case, initial radiogenic isotope ratios can be useful in predicting the endowment of Archean terranes for VHMS and komatiite-associated nickel sulfide deposits. Limited data suggest similar relationships may hold in younger terranes. Lead isotope data may provide constraints on supercraton reconstructions in the Archean as lead isotope systematics appear to be highly provincial. Similar isotope systematics between the Superior province and the Eastern Goldfields superterrane may indicate a linkage during the Neoarchean, consistent with the similar geologic and metallogenic histories of these provinces.

Current evidence and theory suggests that emotional eating resulting from attempts to manage psychological distress, such as anxiety, depression, and stress, is considered to be a major contributor to obesity. Mindfulness has been shown to be related to disordered eating behaviours. Employing a non-clinical sample of 42 males and 115 females, the present study investigated the contribution of mindfulness as a potential moderator between psychological distress and engagement in emotional eating, while controlling for the effects of gender and general nutrition knowledge. Consistent with predictions, psychological distress was positively associated with engagement in emotional eating, while mindfulness was found to share an inverse relationship. Moreover, after controlling for gender and general nutrition knowledge, the interaction between psychological distress and mindfulness was found to significantly predict the tendency to engage in emotional eating over and above the individual effects of these variables. The findings from the current study add to the current literature supporting the use of mindfulness-based interventions for treatment of emotional eating practices in individuals experiencing anxiety, stress, and lower levels of depression.

Small talk is an important social lubricant that helps people, especially strangers, initiate conversations and make friends with each other in physical proximity. However, due to difficulties in quickly identifying significant topics of common interest, real-world small talk tends to be superficial. The mass popularity of mobile phones can help improve the effectiveness of small talk. In this paper, we present E-SmallTalker, a distributed mobile communications system that facilitates social networking in physical proximity. It automatically discovers and suggests topics such as common interests for more significant conversations. We build on Bluetooth Service Discovery Protocol (SDP) to exchange potential topics by customizing service attributes to publish nonservice-related information without establishing a connection. We propose a novel iterative Bloom filter (IBF) protocol that encodes topics to fit in SDP attributes and achieves a low false positive rate. We have implemented the system in Java ME for ease of deployment. Our experiments on real-world phones show that it is efficient enough at the system level to facilitate social interactions among strangers in physical proximity. To the best of our knowledge, E-SmallTalker is the first distributed mobile system to achieve the same purpose.

Moderately to strongly fractionated S-type granites crop out extensively (> 2500 km2) in the central and eastern parts of the Hodgkinson Province, north Queensland, Australia. The granites have been subdivided in two major supersuites: the garnet-bearing Whypalla and cordierite-bearing Cooktown Supersuites; and a number of minor suites—including the extremely fractionated Wangetti and Mount Alto Suites. Early formed magmatic tourmaline is a feature of the Wangetti and Mount Alto granites. Almost all of the S-type granites contain metasedimentary enclave material, while microdioritic enclaves are mostly notably absent. The S-type granites are felsic with a moderate SiO2 range (68–77%). Most elements are negatively correlated with increasing differentiation, including TiO2, FeOtot, MgO, CaO, Ba, Sr, Th, LREE, Eu, Zr, Hf, and ratios such as K/Rb; many decrease to very low levels. There are very few positively correlated elements: Rb, U, and to some extent Na2O. Geochemical differences between supersuites include higher CaO, Ba, Sr, Pb, and lower Rb, Sn, B, V in the Whypalla Supersuite. Geochemical variation within the granites is largely due to extensive crystal fractionation. Some of the S-type granites have FeO* and MgO contents of 2.5–3.0% or more indicating they do not represent simple sedimentary melts, but rather represent the presence of both cumulate and restitic material. Variable Nd and Sr signatures (eNd between − 2 and − 6.5; initial Sr ratios between 0.709 and 0.715), suggest multiple components. The S-type granites intrude a very extensive, siliciclastic turbidite sequence that is isotopically evolved (e.g., eNd mostly − 12.0 to − 15.0 at 270 Ma), and generally too mature (too CaO poor) to produce S-type granites. Isotopic and chemical modeling show that although magma-mixing is permissible, the levels permissible (

Rationale: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries. Objective: We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium. Methods and Results: RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r 2 =0.838 and r 2 =0.818, respectively; P −7,−6,−5 mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner ( P Conclusions: Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.

Accurate indoor localization is a key enabling technology for numerous applications such as indoor navigation, mobile social networking, and augmented reality. Despite major effort from the research community, state-of-the-art indoor localization performance remains unsatisfactory. Current approaches using radio frequency entail tedious site surveys and have limited accuracy. While vision-based localization techniques are promising, they struggle with human recognition and changing environments. This paper proposes Flash-Loc, an accurate indoor localization system leveraging flashes of light to localize people carrying mobile phones in areas with deployed surveillance cameras. A person's mobile phone emits a sequence of flashes that uniquely “represents” the person from the cameras' view. Flash-Loc develops three key mechanisms that distinguish people while avoiding long irritating flashes: adaptive-length flash coding, pulse width modulation based flash generation, and image subtraction based flash localization. Further, we design a system in which Flash-Loc cooperates with fingerprinting and dead reckoning for accurate human localization. We implement Flash-Loc on commercial off-the-shelf equipment. Our real-world experiments show Flash-Loc achieves accurate indoor localization by itself and in cooperation with other localization technology. In particular, Flash-Loc can localize a user 45 m away from the camera with sub-meter accuracy.

Aims Thrombospondin-1 (TSP1) is a ligand for CD47 and TSP1−/− mice are protected from pulmonary hypertension (PH). We hypothesized the TSP1–CD47 axis is upregulated in human PH and promotes pulmonary arterial vasculopathy. Methods and results We analyzed the molecular signature and functional response of lung tissue and distal pulmonary arteries (PAs) from individuals with ( n = 23) and without ( n = 16) PH. Compared with controls, lungs and distal PAs from PH patients showed induction of TSP1–CD47 and endothelin-1/endothelin A receptor (ET-1/ETA) protein and mRNA. In control PAs, treatment with exogenous TSP1 inhibited vasodilation and potentiated vasoconstriction to ET-1. Treatment of diseased PAs from PH patients with a CD47 blocking antibody improved sensitivity to vasodilators. Hypoxic wild type (WT) mice developed PH and displayed upregulation of pulmonary TSP1, CD47, and ET-1/ETA concurrent with down regulation of the transcription factor cell homolog of the v-myc oncogene (cMyc). In contrast, PH was attenuated in hypoxic CD47−/− mice while pulmonary TSP1 and ET-1/ETA were unchanged and cMyc was overexpressed. In CD47−/− pulmonary endothelial cells cMyc was increased and ET-1 decreased. In CD47+/+ cells, forced induction of cMyc suppressed ET-1 transcript, whereas suppression of cMyc increased ET-1 signaling. Furthermore, disrupting TSP1–CD47 signaling in pulmonary smooth muscle cells abrogated ET-1-stimulated hypertrophy. Finally, a CD47 antibody given 2 weeks after monocrotaline challenge in rats upregulated pulmonary cMyc and improved aberrations in PH-associated cardiopulmonary parameters. Conclusions In pre-clinical models of PH CD47 targets cMyc to increase ET-1 signaling. In clinical PH TSP1–CD47 is upregulated, and in both, contributes to pulmonary arterial vasculopathy and dysfunction.

[EN] The KM3NeT research infrastructure, currently under construction in the Mediterranean Sea, will host neutrino telescopes for the identification of neutrino sources in the Universe and for studies of the neutrino mass hierarchy. These telescopes will house hundreds of thousands of photomultiplier tubes that will have to be operated in a stable and reliable fashion. In this context, the stability of the dark counts has been investigated for photomultiplier tubes with negative high voltage on the photocathode and held in insulating support structures made of 3D printed nylon material. Small gaps between the rigid support structure and the photomultiplier tubes in the presence of electric fields can lead to discharges that produce dark count rates that are highly variable. A solution was found by applying the same insulating varnish as used for the high voltage bases directly to the outside of the photomultiplier tubes. This transparent conformal coating provides a convenient and inexpensive method of insulation., The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02), France; The General Secretariat of Research and Technology (GSRT), Greece; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Italy; Agence de l'Oriental and CNRST, Morocco; Stichting voor Fundamenteel Onderzoek der Materie (FOM), Nederlandse organisatie voorWetenschappelijk Onderzoek (NWO), the Netherlands; National Authority for Scientific Research (ANCS), Romania; Plan Estatal de Investigacion (refs. FPA2015-65150-C3-1-P, -2-P and -3-P, (MINECO/FEDER)), Severo Ochoa Centre of Excellence and MultiDark Consolider (MINECO), and Prometeo and Grisolia programs (Generalitat Valenciana), Spain.

The authors would like to thank D Allard, A Esmaili, G Fogli, O Mena, K Murase, S Palomares Ruiz, E Parizot, S T Petcov, S Razzaque, D Semikoz, A Yu Smirnov, F L Villante, F Vissani and R Zukanovich Funchal for their support and valuable discussions and suggestions in preparing this Letter of Intent., The main objectives of the KM3NeT Collaboration are (i) the discovery and subsequent observation of high-energy neutrino sources in the Universe and (ii) the determination of the mass hierarchy of neutrinos. These objectives are strongly motivated by two recent important discoveries, namely: (1) the highenergy astrophysical neutrino signal reported by IceCube and (2) the sizable contribution of electron neutrinos to the third neutrino mass eigenstate as reported by Daya Bay, Reno and others. To meet these objectives, the KM3NeT Collaboration plans to build a new Research Infrastructure consisting of a network of deep-sea neutrino telescopes in the Mediterranean Sea. A phased and distributed implementation is pursued which maximises the access to regional funds, the availability of human resources and the synergistic opportunities for the Earth and sea sciences community. Three suitable deep-sea sites are selected, namely off-shore Toulon (France), Capo Passero (Sicily, Italy) and Pylos (Peloponnese, Greece). The infrastructure will consist of three so-called building blocks. A building block comprises 115 strings, each string comprises 18 optical modules and each optical module comprises 31 photo-multiplier tubes. Each building block thus constitutes a threedimensional array of photo sensors that can be used to detect the Cherenkov light produced by relativistic particles emerging from neutrino interactions. Two building blocks will be sparsely configured to fully explore the IceCube signal with similar instrumented volume, different methodology, improved resolution and complementary field of view, including the galactic plane. One building block will be densely configured to precisely measure atmospheric neutrino oscillations., The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commission Européenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cité (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02), France; The General Secretariat of Research and Technology (GSRT), Greece; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell'Istruzione, dell’Universitàe della Ricerca (MIUR), Italy; Agence de l’Oriental and CNRST, Morocco; Stichting voor Fundamenteel Onderzoek der Materie (FOM), Nederlandseorganisatie voor Wetenschappelijk Onderzoek (NWO), The Netherlands; National Authority for Scientific Research (ANCS), Romania; Plan Estatal de Investigación (refs. FPA2015-65150-C3-1-P, -2-P and -3-P, (MINECO/FEDER)), Severo Ochoa Centre of Excellence and MultiDark Consolider (MINECO), and Prometeo and Grisolía programs (Generalitat Valenciana), Spain. The KM3NeT collaboration has received funding from the European Community Sixth Framework Programme under Contract 011937 and the Seventh Framework Programme under Grant Agreement 212525.

A prototype detection unit of the KM3NeT deep-sea neutrino telescope has been installed at 3500m depth 80 km offshore the Italian coast. KM3NeT in its final configuration will contain several hundreds of detection units. Each detection unit is a mechanical structure anchored to the sea floor, held vertical by a submerged buoy and supporting optical modules for the detection of Cherenkov light emitted by charged secondary particles emerging from neutrino interactions. This prototype string implements three optical modules with 31 photomultiplier tubes each. These optical modules were developed by the KM3NeT Collaboration to enhance the detection capability of neutrino interactions. The prototype detection unit was operated since its deployment in May 2014 until its decommissioning in July 2015. Reconstruction of the particle trajectories from the data requires a nanosecond accuracy in the time calibration. A procedure for relative time calibration of the photomultiplier tubes contained in each optical module is described. This procedure is based on the measured coincidences produced in the sea by the $$^{40}$$40K background light and can easily be expanded to a detector with several thousands of optical modules. The time offsets between the different optical modules are obtained using LED nanobeacons mounted inside them. A set of data corresponding to 600 h of livetime was analysed. The results show good agreement with Monte Carlo simulations of the expected optical background and the signal from atmospheric muons. An almost background-free sample of muons was selected by filtering the time correlated signals on all the three optical modules. The zenith angle of the selected muons was reconstructed with a precision of about 3$$^circ $$∘.

The media has the ability to affect public opinion and policy direction. Prevalence of morbid obesity in Canada is increasing; as is the only effective long-term treatment, weight loss surgery (WLS). Limited research has explored media re/presentations of WLS. The purpose of this study was to examine national online news coverage (and reader comments) of WLS using content analysis. We sought to understand the dominant messages being conveyed within the news texts and reader comments, specifically whose voice was represented, who was the intended audience and what was the overall tone. Articles and comments were retrieved from the Canadian Broadcasting Corporation news web site and analysed using line-by-line techniques. Articles were predominantly 'positive/supportive' (63%) in tone and frequently presented the voices and opinions of 'experts' conveying a biomedical perspective. Comments were overwhelmingly 'negative' (56%) and often derogatory including such language as 'piggy' and 'fatty'. Comments were almost exclusively anonymous (99%) and were frequently directed at other commenters (33%) and 'fat' people (6%). The potentially problematic nature of media framing and reader comments, particularly as they could relate to weight-based stigmatization and discrimination is discussed.

A deep crustal seismic reflection and magnetotelluric survey, conducted in 2007, established the architecture and geodynamic framework of north Queensland, Australia. Results based on the interpretation of the deep seismic data include the discovery of a major, west-dipping, Paleoproterozoic (or older) crustal boundary, considered to be an ancient suture zone, separating relatively nonreflective, thick crust of the Mount Isa Province from thinner, two layered crust to the east. Farther to the east, a second major crustal boundary also dips west or southwest, offsetting the Moho and extending below it, and is interpreted as a fossil subduction zone. Across the region, the lower crust is mostly highly reflective and is subdivided into three mappable seismic provinces, but they have not been tracked to the surface. In the east, the Greenvale and Charters Towers Provinces, part of the Thomson Orogen, have been mapped on the surface as two discrete provinces, but the seismic interpretation raises the possibility that these two provinces are continuous in the subsurface, and also extend northwards to beneath the Hodgkinson Province, originally forming part of an extensive Neoproterozoic–Cambrian passive margin. Continuation of the Thomson Orogen at depth beneath the Hodgkinson and Broken River Provinces suggests that these provinces (which formed in an oceanic environment, possibly as an accretionary wedge at a convergent margin) have been thrust westwards onto the older continental passive margin. The Tasman Line, originally defined to represent the eastern limit of Precambrian rocks in Australia, has a complicated geometry in three dimensions, which is related to regional deformational events during the Paleozoic. Overall, the seismic data show evidence for a continental margin with a long history (Paleoproterozoic to early Mesozoic) but showing only limited outward growth by crustal accretion, because of a repeated history of overthrust shortening during repeated phases of orogenesis.

Although right-ventricular function is an important determinant of cardio-pulmonary performance in health and disease, right ventricular myocardium mechanical behaviour has received relatively little attention. We present a novel experimental method for quantifying the mechanical behaviour of transmurally intact, viable right-ventricular myocardium. Seven murine right ventricular free wall (RVFW) specimens were isolated and biaxial mechanical behaviour measured, along with quantification of the local transmural myofibre and collagen fibre architecture. We developed a complementary strain energy function based method to capture the average biomechanical response. Overall, murine RVFW revealed distinct mechanical anisotropy. The preferential alignment of the myofibres and collagen fibres to the apex-to-outflow-tract direction was consistent with this also being the mechanically stiffer axis. We also observed that the myofibre and collagen fibre orientations were remarkably uniform throughout the entire RVFW thickness. Thus, our findings indicate a close correspondence between the tissue microstructure and biomechanical behaviour of the RVFW myocardium, and are a first step towards elucidating the structure–function of non-contracted murine RVFW myocardium in health and disease.

Right ventricular (RV) function is the major determinant of mortality in pulmonary arterial hypertension and male sex is a strong predictor of mortality in this disease. The effects of testosterone on RV structure and function in load stress are presently unknown. We tested whether testosterone levels affect RV hypertrophic responses, fibrosis, and function. Male C57BL/6 mice underwent castration or sham followed by pulmonary artery banding (PAB) or sham. After recovery, testosterone pellets were placed in a subset of the castrated mice and mice were maintained for at least two weeks, when they underwent hemodynamic measurements and tissues were harvested. Plasma levels of testosterone were reduced by castration and repleted by testosterone administration. In PAB, castration resulted in lower right ventricle/left ventricle + septum (RV/LV+S), and myocyte diameter (P < 0.05). Replacement of testosterone normalized these parameters and increased RV fibrosis (P < 0.05). Two weeks of PAB resulted in increased RV systolic pressure in all groups with decreased markers of RV systolic and diastolic function, specifically reduced ejection fraction and increased time constant, and dPdt minimum (P < 0.05), though there was minimal effect of testosterone on hemodynamic parameters. Survival was improved in mice that underwent castration with PAB compared with PAB alone (P < 0.05). Testosterone affects RV hypertrophic response to load stress through increased myocyte size and increased fibrosis in mice. Castration and testosterone replacement are not accompanied by significant alterations in RV in vivo hemodynamics, but testosterone deprivation appears to improve survival in PAB. Further study of the role of testosterone in RV dysfunction is warranted to better understand these findings in the context of human disease.

A database of 1075 high-precision geochemical analyses of least-altered ultramafic–mafic units, predominantly flows, was compiled for the Eastern Goldfields Superterrane. Samples are divided into a high-Mg population at MgO≥10–24 wt% and a basaltic population where 4≤MgO

Caveolin-1 (Cav-1)−/− mice develop mild pulmonary hypertension as they age. In this study, we sought to determine the effect of chronic hypoxia, an established model of pulmonary hypertension, on young Cav-1−/− mice with no measurable signs of pulmonary hypertension. Exposure of Cav-1−/− mice to chronic hypoxia resulted in an initial rise in right ventricular (RV) systolic pressure (RVSP) similar to wild-type (WT) mice. By three weeks RVSP decreased in the Cav-1−/− mice, whereas it was maintained in WT mice. The drop in RVSP in Cav-1−/− mice was accompanied by decreased cardiac output, increased RV hypertrophy, RV interstitial fibrosis, decreased RV sarco(endo)plasmic reticulum Ca2+-ATPase 2a mRNA and decreased RV function compared with WT mice. Importantly, minimal differences were noted in pulmonary vascular remodeling between WT and Cav-1−/− mice, and left ventricular function was normal in hypoxic Cav-1−/− mice. Mechanistically, increased endothelial nitric oxide synthase uncoupling and increased tyrosine nitration of protein kinase G were detected in the RV of Cav-1−/− mice. These hemodynamic, histological, and molecular changes were prevented in Cav-1−/− mice expressing an endothelial-specific Cav-1 transgene or by nitric oxide synthase inhibition. These data suggest that, in Cav-1−/− mice, increased oxidative/nitrosative stress due to endothelial nitric oxide synthase uncoupling modifies the response of the RV to pressure overload, accelerating the deterioration of RV function.

Pulmonary vessel constriction results from an imbalance between vasodilator and vasoconstrictor factors released by the endothelium including nitric oxide, endothelin, prostanoids, and reactive oxygen species (ROS). ROS, generated by a variety of enzymatic sources (such as mitochondria and NADPH oxidases, a.k.a. Nox), appear to play a pivotal role in vascular homeostasis, whereas elevated levels effect vascular disease. The pulmonary circulation is very sensitive to changes in the partial pressure of oxygen and differs from the systemic circulation in its response to this change. In fact, the pulmonary vessels contract in response to low oxygen tension, whereas systemic vessels dilate. Growing evidence suggests that ROS production and ROS-related pathways may be key factors that underlie this differential response to oxygen tension. A major emphasis of our laboratory is the role of Nox isozymes in cardiovascular disease. In this review, we will focus our attention on the role of Nox-derived ROS in the control of pulmonary vascular tone.

Arginase expression and activity have been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-(S)-amino-6-boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation were measured in all cohorts. The cavernous nerve was stimulated with a graded electrical stimulus, and the intracavernosal/mean arterial pressure ratios and total intracavernosal pressure were recorded. Arginase activity was elevated in the aged rats compared with young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P.05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function.

The geological evolution of Australia is closely linked to supercontinent cycles that have characterised the tectonic evolution of Earth, with most geological and metallogenic events relating to supercontinent/supercraton assembly and breakup. Australia mainly grew from W-E, with two major Archean cratons, the Yilgarn and Pilbara cratons, forming the oldest part of the continent in the West Australian Element. The centre of the continent consists of the mainly Paleoproterozoic-Mesoproterozoic North and South Australian elements, whereas the E is dominated by the Neoproterozoic-Mesozoic Tasman Element. The West, North and South Australian elements initially assembled during the Paleoproterozoic amalgamation of Nuna, and the Tasman Element formed mostly as a Paleozoic accretionary margin during the assembly of Gondwana-Pangea. Australia's present position as a relatively stable continent resulted from the breakup of Gondwana. Australia is currently moving northward toward SE Asia, probably reflecting the earliest stages of the assembly of the next supercontinent, Amasia. Australia's resources, both mineral and energy, are linked to its tectonic evolution and the supercontinent cycle. Australia's most important Au province is the product of the assembly of Kenorland, whereas its major Zn-Pb-Ag deposits and iron oxide-Cu-Au deposits formed as Nuna broke up. The diverse metallogeny of the Tasman Element is a product of Pangea-Gondwana assembly and most of Australia's hydrocarbon resources are a consequence of the breakup of this supercontinent.

Background— Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly upregulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH. Methods and Results— Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced downregulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease. Conclusions— These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.

As a result of recent welfare state transformations, and most notably the reorientation of welfare states towards activation, the internal fragmentation of social security systems has emerged as a key policy problem in many western European countries. The types of response that have been adopted, however, vary substantially across countries, ranging from the encouragement of inter-agency collaboration to the outright merger of agencies. The purpose of this exploratory article is twofold. First, by proposing the concept of coordination initiatives, it tries to develop a better conceptualization of the cross-national diversity in responses to the fragmentation problem. Second, starting from existing theories of welfare state development and policy change, it presents first hypotheses accounting for the variation observed in coordination initiatives.

Active worms have posed a major security threat to the Internet and many research efforts have focused on them. However, defending against them remains challenging due to their continuous evolution. In this paper, we study a new class of defense-oriented evolved worms, the Varying Scan Rate worm (the VSR worm in short). In order to circumvent detection by existing worm detection schemes, the VSR worm deliberately varies its scan rate according to these schemes' weaknesses. To counteract the VSR worm, we design a new worm-detection scheme, the attack-target Distribution Entropy-based Dynamic detection scheme (DED detection for short). DED detection utilizes the attack-target distribution and robust statistical feature in conjunction with dynamic decision adaptation to distinguish worm-scan traffic from non-worm-scan traffic. We present a comparatively complete space of detection schemes and conduct extensive performance evaluations on the DED detection scheme compared with other schemes, using real-world Internet traces as background scan traffic. Our data clearly demonstrate the effectiveness of the DED detection scheme in detecting both the VSR worm and the traditional worm.

Although medical therapies for pulmonary arterial hypertension have greatly improved, it remains a chronic and fatal disease. For patients who are refractory to medical therapy, lung transplantation is an important treatment option. This review discusses issues pertaining to indications for transplant, preparation for transplant and listing, operative issues, and outcomes for patients with pulmonary arterial hypertension.

The operation and extent of modern-style plate tectonics in the Archean and Paleoproterozoic are controversial, although subduction and terrane accretion models have been proposed for most Archean cratons in the world, including both the Yilgarn and Pilbara Cratons of Western Australia. The recognition of ancient island arcs can be used to infer convergent plate margin processes, and in this paper we present evidence for the existence of several intraoceanic island arcs now preserved in Australia. Beginning in the Archean, Australia evolved to its present configuration through the accretion and assembly of several continental blocks, by convergent plate margin processes. In Australia, possibly the best example of an Archean island arc (or primitive continental arc) is preserved within the Mesoarchean (ca. 3130–3112 Ma) Whundo Group in the Sholl Terrane of the West Pilbara Superterrane. Two younger, Neoarchean, island arc terranes, and associated accretion, have also been proposed for the Yilgarn Craton: the Saddleback island arc (ca. 2714–2665 Ma) in the southwest Yilgarn Craton and the Kurnalpi island arc (ca. 2719–2672 Ma) in the eastern Yilgarn Craton. In the early Proterozoic, in the Central Zone of the Halls Creek Orogen, northern Western Australia, the Tickalara Metamorphics (ca. 1865–1850 Ma) have been interpreted to represent an island arc. In the southwest Gawler Craton in South Australia, the St Peter Suite (ca. 1631–1608 Ma), of juvenile I-type calcalkaline tonalite to granodiorite, possibly represents an island arc. In the Musgrave Province in central Australia, age and geochemical constraints are poor due to later overprinting tectonic events, but felsic orthogneisses (ca. 1607–1565 Ma) possibly represent juvenile felsic crust which was emplaced though subduction-related processes into an oceanic island arc. The arcs are volumetrically insignificant, but important, in that they separate much larger tracts of, usually older, continental crust, often of different composition and geological history. The arcs were sutured to continental crust during arc–continent collisional events, which eventually resulted in the assembly of much of present-day Australia. The arcs, thus, indicate lost oceanic crust. The recognition of island arcs in the ancient rock record indicates that subduction processes, similar in many ways to modern day processes at convergent plate margins, were operating on Earth by at least 3100 Ma ago.

Background— Lymphocytic myocarditis is a clinically important condition that is difficult to diagnose and distinguish. We hypothesized that the transcriptome obtained from an endomyocardial biopsy would yield clinically relevant and accurate molecular signatures. Methods and Results— Microarray analysis was performed on samples from patients with histologically proven lymphocytic myocarditis (n=16) and idiopathic dilated cardiomyopathy (n=32) to develop accurate diagnostic transcriptome-based biomarkers using multiple classification algorithms. We identified 9878 differentially expressed genes in lymphocytic myocarditis versus idiopathic dilated cardiomyopathy (fold change >1.2; false discovery rate Conclusions— Together, these findings demonstrate that transcriptomic biomarkers from a single endomyocardial biopsy can improve the clinical detection of patients with inflammatory diseases of the heart. This approach advances the clinical management and treatment of cardiac disorders with highly variable outcome.

Aims It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. Methods and results We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Conclusion Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.

Pulmonary hypertension (PH) commonly results as a complication of left heart failure (systolic or nonsystolic dysfunction). It is important to note that there is a distinct difference between PH as a whole and pulmonary arterial hypertension (PAH), which have the same criteria with regard to mean pulmonary artery pressure (mPAP) as PAH with the critical difference of the pulmonary capillary wedge pressure (PCWP) measurement. Table 1 shows the most common causes of RV dysfunction. The issue of management of right ventricular (RV) failure has recently become more important with increased awareness of RV failure symptoms in the setting of PH. Moreover, with growing consideration for surgical left ventricular support (left ventricular assist device, LVAD) and the need for RV functional competence, the need to better understand the role of RV function is becoming more paramount.

Granite-cored domes are associated with many of the larger gold deposits of the Archaean Eastern Yilgarn Craton of Western Australia. The Scotia-Kanowna Dome is eroded to sufficiently deep levels to provide insights into the role granite-cored domes play in controlling fluid flow and gold deposition. At the centre of the Scotia-Kanowna Dome is a granite batholith, which is surrounded by outward-dipping greenstone belts and associated shear zones. This upper-crustal dome sits above mid-crustal domes, providing a series of stacked geometries favourable to focussed fluid flow. A number of small- to medium-sized gold deposits occur on the limbs and the centre of the dome, and the world-class Kanowna Belle gold mine occurs on the nose of the dome. At least three separate gold mineralising events are defined, each of regional significance, which can be correlated with other well known gold deposits of the Eastern Yilgarn Craton. The palaeostress across this region was dominated by both maximum contractional and extensional vectors oriented perpendicular to the north-northwest trending grain. The resultant strain is seen in the architecture of the Scotia-Kanowna Dome, with its margins and associated shear zones controlling the distribution of stratigraphy, which is relatively linear and parallel to the margin. Throughout most of the tectonic history, the flanking shear zones were high-strain domains that recorded multiple stages of contraction, with thrust and mostly sinistral strike-slip shear kinematics. In contrast, the dome nose region was a relatively low-strain domain as it was located in the strain shadow of the regional contractional events. For example, the early extensional record has been preserved at the nose, with late-stage basins formed in the hangingwall to the extensional faults, adding to the stratigraphic complexity of the local region. These late basins also may have contributed to the fluid budget. In contrast, along the flanks of the domes there is no record of these late basins or the extensional faults that controlled their deposition. The architecture of the dome played an important role in controlling mineralisation during a significant deviation in the maximum contractional stress vector to an east-southeast-west-southwest orientation. At this time, basins in the nose region underwent inversion, with thrusting to the north and northwest. Shortening was accommodated along the dome flanks by sinistral strike-slip shearing, which was relatively free to move due to the mostly linear stratigraphy, combined with limited anisotropy and perturbations along the flank. However, the stratigraphic and geometrical complexity around the dome nose resulted in localised maximum dilation and gold deposition at this time. The dome nose area was also a favoured locus for gold-enriched, dominantly Mafic-type magmas, which are seen as the extensive porphyry swarms in the region. These felsic-intermediate rocks also may have contributed to the complex fluid budget and are considered as indicators of particular fertility for gold. They may have been the primary source for much of the metal endowment. The architecture of granite-cored domes has played a critical role in focussing magma as well as mineralising fluids into regions of maximum dilation. They did this by virtue of their inherent competence, and by influencing the position and geometry of shear zones (fluid pathways) and hence distribution of stratigraphy (depositional sites) across the region. The Scotia-Kanowna Dome is a good example of this effect, and inferences can be made in favour of similar controls by concealed domes, such as beneath Kalgoorlie.

A new structural evolution consisting of both extensional and contractional events has been defined for the St Ives Goldfield in the south-central Kalgoorlie Terrane of the eastern Yilgarn Craton in Western Australia. These events shaped the development of the fault architecture, which controlled the location of the regional anticlines, the magmatic centres, and the deposition of the Archaean greenstone successions. The fundamental grain of the St Ives Goldfield is north-northwest-trending. This trend is marked by faults which developed during D1 extension, which was oriented east-northeast–west-southwest. Across these faults we map major stratigraphic changes in the thickness and composition of units, especially of the previously undivided Black Flag Group volcaniclastic rocks. The centre of the St Ives Goldfield is dominated by the Kambalda Anticline. This north-northwest-trending regional fold was likely established early during the D1 extensional history, and was fully established during subsequent east-northeast-oriented D2 contraction. The regional anticline is an important architectural element because (1) magmatism and gold mineralising fluids were focussed into this domed region, and (2) deformation was partitioned across the limbs and crest of this structure. The D3 event involved regional uplift and extension, resulting in the formation of late basins (Merougil Conglomerate locally) and the emplacement of granitoids sourced from a metasomatised mantle wedge (Mafic-type porphyries). The most significant gold event in terms of endowment occurred during D4b sinistral strike-slip shearing and associated thrusting (e.g., Tramways and Republican thrusts). These thrusts were previously interpreted as the first contractional structures to deform the area (‘D1’), but are here reinterpreted as relatively late (D4b). In this D4b event, the north-northwest-trending faults underwent sinistral strike-slip shearing and were linked across the Kambalda Anticline by accommodation structures represented by generally east- to east-northeast-trending thrusts. Reactivation of D1 transfer structures may have influenced the location of these later accommodation structures. Late-stage mineralisation during D5 was the result of dextral strike-slip brittle shearing.

World-class mineral systems, such as those found in the Archaean eastern Yilgarn Craton, are the product of enormous energy and mass-flux systems driven by lithospheric-scale processes. These processes can create big footprints or signatures in the lithosphere, which can be observed at a range of scales and via a variety of methods: including geophysics, isotopes, tectonostratigraphy and geochemistry. We use these datasets to describe both the architecture (structure) of world-class gold systems of the Yilgarn Craton and the signatures of their formation. By applying an understanding of the most critical elements of the process, and their signatures, new areas, especially undercover, may be targeted more predictably than before. Knowledge of the major architectural elements of the Yilgarn Craton has increased greatly over the last decade, through the collection of a wide range of geophysical, geochemical and isotopic data. These data range in scale from (1) lithospheric-scale, which provide information on the entire craton and their underlying volumes down to depths in excess of 350 km, through; (2) regional-scale, which provide information at the province scale and to depths of 30–40 km, to; (3) mine- and camp-scale, which provide information on the top few kilometres of the crust. The architecture (structure) in the upper mantle and lower crust can be inferred from broadband seismic tomography and analysis of long-wavelength gravity data. Geophysical data, such as magnetotellurics and deep-crustal reflection seismic, also provide evidence for the signatures of the flow of fluids through this architecture (the pathways) and they illustrate that the scale of the system is many orders of magnitude larger than the immediate deposit itself. Of particular importance is the role of deep-crustal-penetrating shear zones or faults which link the mantle with domes in the upper crust. Together, these data provide first-order insights into the physical and chemical properties of the Yilgarn Craton. These insights provide geodynamic clues and constraints as to why the Yilgarn is so well endowed in metals such as gold ( Groves et al., 1989 ). The intersection of favourable architectural features provides connections between the mantle and the upper crust in the Kalgoorlie region, possibly explaining why this area is so well endowed in comparison to others.

Over the last decade there have been significant advances in our understanding of the stratigraphy, magmatism, deformation, metamorphism and timing of mineralisation, in the eastern Yilgarn Craton (EYC) of Western Australia. The integration of these disciplines has enabled a holistic review of the tectonic history of the EYC which favours a paraautochthonous tectonic model. A significant advance has been the recognition of a ∼2810 Ma rifting event off the eastern margin of the Youanmi Terrane which set up the north-northwest trending architecture of the EYC. Rifting was followed by a ∼100 Myr long phase of tectonic activity initiated by the establishment of a convergent margin at 2715 Ma characterised by a west-dipping subduction zone to the east of the EYC. Subduction was associated with the deposition of 2715–2670 Ma volcanic stratigraphy and the emplacement of voluminous tonalite-trondhjemite-granodiorite magmatism, which resulted in magmatic thickening of the crust. Volcanism was terminated by a ∼5 Myr pulse of east-northeast contraction followed by mid-orogenic extension possibly linked to lithospheric and lower crustal delamination. The lack of ultra-high pressure metamorphism and the presence of high geothermal gradients preclude this contractional event from recording continent–continent collision. Mid-orogenic extension at 2665 Ma resulted in the introduction of metasomatised mantle melts (mafic-granites and syenites), deposition of siliciclastic basins (which record metamorphic anticlockwise PTt paths) and the start of significant economic gold mineralisation in the EYC. High stretching factors and/or delamination associated with this extension event resulted in significant heat input into the base of the crust, which eventually led to the emplacement of Low-Ca (crustal melt) granites and cratonisation of the EYC. Major gold mineralisation postdates mid-orogenic extension, and was associated with renewed compression-transpression (∼2650 Ma) and the development of steep predominantly north-northwest striking sinistral and later north to north-northeast striking dextral strike–slip faults during Low-Ca granite emplacement.

Background Emerging evidence suggests that phosphoinositide 3-kinase (PI3K) may modulate cardiac inotropy; however, the underlying mechanism remains elusive. We hypothesized that β(2)-adrenergic receptor (AR)-coupled PI3K constrains increases in cardiac inotropy through cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) activation. Methods We tested the effects of PI3K and PDE4 inhibition on myocardial contractility by using isolated murine cardiac myocytes to study physiologic functions (sarcomere shortening [SS] and intracellular Ca(+) transients), as well as cAMP and PDE activity. Results PI3K inhibition with the reversible inhibitor LY294002 (LY) resulted in a significant increase in SS and Ca(2+) handling, indicating enhanced contractility. This response depended on G(iα) protein activity, because incubation with pertussis toxin (an irreversible G(iα) inhibitor) abolished the LY-induced hypercontractility. In addition, PI3K inhibition had no greater effect on SS than both a PDE3,4 inhibitor (milrinone) and LY combined. Furthermore, LY decreased PDE4 activity in a concentration-dependent manner (58.0% of PDE4 activity at LY concentrations of 10 μM). Notably, PI3K(γ) coimmunoprecipitated with PDE4D. The β(2)-AR inverse agonist, ICI 118,551 (ICI), abolished induced increases in contractility. Conclusions PI3K modulates myocardial contractility by a cAMP-dependent mechanism through the regulation of the catalytic activity of PDE4. Furthermore, basal agonist-independent activity of the β(2)-AR and its resultant cAMP production and enhancement of the catalytic activity of PDE4 through PI3K represents an example of integrative cellular signaling, which controls cAMP dynamics and thereby contractility in the cardiac myocyte. These results help to explain the mechanism by which milrinone is able to increase myocardial contractility in the absence of direct β-adrenergic stimulation and why it can further augment contractility in the presence of maximal β-adrenergic stimulation.

The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13Rα1 is the canonical IL-13 signaling receptor, whereas IL-13Rα2 is a competitive nonsignaling decoy receptor. Wild-type, IL-13Rα1−/−, and IL-13Rα2−/− C57BL/6J mice were percutaneously infected with S. mansoni cercariae, followed by i.v. injection of eggs. We assessed PH with right ventricular catheterization, histological evaluation of pulmonary vascular remodeling, and detection of IL-13 and transforming growth factor-β signaling. Infected mice developed pulmonary peri-egg granulomas and arterial remodeling involving predominantly the vascular media. In addition, gain-of-function IL-13Rα2−/− mice had exacerbated vascular remodeling and PH. Mice with loss of IL-13Rα1 function did not develop PH and had reduced pulmonary vascular remodeling. Moreover, the expression of resistin-like molecule-α, a target of IL-13 signaling, was increased in infected wild-type and IL-13Rα2−/− but not IL-13Rα1−/− mice. Phosphorylated Smad2/3, a target of transforming growth factor-β signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relies on up-regulated IL-13 signaling.

Following PHA's 9th International Pulmonary Hypertension Conference and Scientific Sessions, Karen Fagan, MD, guest editor of this issue of Advances, convened a call with Nicholas Hill, MD, Chief of the Division of Pulmonary, Critical Care, and Sleep Medicine at Tufts Medical Center, Boston, and Hunter Champion, MD, PhD, associate professor of medicine in the Division of Pulmonology, Allergy and Critical Care, the Vascular Medicine Institute, and the Cardiovascular Institute at the University of Pittsburgh, to discuss their perceptions of this and past meetings and the contributions they make to progress in basic and clinical science in the care of patients with pulmonary hypertension.

Rationale: Pulmonary arterial hypertension (PAH) related to systemic sclerosis (SSc) has a poorer prognosis compared with other forms of PAH for reasons that remain unexplained. Objectives: To identify risk factors of mortality in a well-characterized cohort of patients with PAH related to systemic sclerosis (SSc-PAH). Methods: Seventy-six consecutive patients with SSc (64 women and 12 men; mean age 61 ± 11 yr) were diagnosed with PAH by heart catheterization in a single center, starting in January 2000, and followed over time. Kaplan-Meier estimates were calculated and mortality risk factors were analyzed. Measurements and Main Results: Forty (53%) patients were in World Health Organization functional class III or IV. Mean pulmonary artery pressure was 41 ± 11 mm Hg, pulmonary vascular resistance (PVR) was 8.6 ± 5.6 Wood units, and cardiac index was 2.4 ± 0.7 L/min/m2. Median follow-up time was 36 months, with 42 deaths observed. Survival estimates were 85%, 72%, 67%, 50%, and 36% at 1, 2, 3, 4, and 5 years, respectively. Multivariate analysis identified PVR (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03–1.18; P < 0.01), stroke volume index (HR, 0.94; 95% CI, 0.89–0.99; P = 0.02), and pulmonary arterial capacitance (HR, 0.43; 95% CI, 0.20–0.91; P = 0.03) as strong predictors of survival. An estimated glomerular filtration rate less than 60 ml/min/1.73 m2 portended a threefold risk of mortality. Conclusions: Our results suggest that specific components of right ventricular dysfunction and renal impairment contribute to increased mortality in SSc-PAH. Understanding the mechanisms of right ventricular dysfunction in response to increased afterload should lead to improved targeted therapy in these patients.

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.