Magnetotelluric imaging of anisotropic crust near Fort McMurray, Alberta: implications for engineered geothermal system development

Viability for the development of an engineered geothermal system (EGS) in the oilsands region near Fort McMurray, Alberta, is investigated by studying the structure of the Precambrian basement rocks with magnetotellurics (MT). MT data were collected at 94 broad-band stations on two east–west profiles. Apparent resistivity and phase data showed little variation along each profile. The short period MT data detected a 1-D resistivity structure that could be identified as the shallow sedimentary basin underlain by crystalline basement rocks to a depth of 4–5 km. At lower frequencies a strong directional dependence, large phase splits, and regions of out-of-quadrant (OOQ) phase were detected. 2-D isotropic inversions of these data failed to produce a realistic resistivity model. A detailed dimensionality analysis found links between large phase tensor skews (∼15°), azimuths, OOQ phases and tensor decomposition strike angles at periods greater than 1 s. Low magnitude induction vectors, as well as uniformity of phase splits and phase tensor character between the northern and southern profiles imply that a 3-D analysis is not necessary or appropriate. Therefore, 2-D anisotropic forward modelling was used to generate a resistivity model to interpret the MT data. The preferred model was based on geological observations of outcropping anisotropic mylonitic basement rocks of the Charles Lake shear zone, 150 km to the north, linked to the study area by aeromagnetic and core sample data. This model fits all four impedance tensor elements with an rms misfit of 2.82 on the southern profile, and 3.3 on the northern. The conductive phase causing the anisotropy is interpreted to be interconnected graphite films within the metamorphic basement rocks. Characterizing the anisotropy is important for understanding how artificial fractures, necessary for EGS development, would form. Features of MT data commonly interpreted to be 3-D (e.g. out of OOQ phase and large phase tensor skew) are shown to be interpretable with this 2-D anisotropic model

Platelet signaling: a complex interplay between inhibitory and activatory networks

The role of platelets in hemostasis and thrombosis is dependent on a complex balance of activatory and inhibitory signaling pathways. Inhibitory signals released from the healthy vasculature suppress platelet activation in the absence of platelet receptor agonists. Activatory signals present at a site of injury initiate platelet activation and thrombus formation; subsequently, endogenous negative signaling regulators dampen activatory signals to control thrombus growth. Understanding the complex interplay between activatory and inhibitory signaling networks is an emerging challenge in the study of platelet biology and necessitates a systematic approach to utilize experimental data effectively. In this review, we will explore the key points of platelet regulation and signaling that maintain platelets in a resting state, mediate activation to elicit thrombus formation or provide negative feedback. Platelet signaling will be described in terms of key signaling molecules that are common to the pathways activated by platelet agonists and can be described as regulatory nodes for both positive and negative regulators. This article is protected by copyright. All rights reserved

Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction

The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy

PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signalling and platelet function through upregulation of protein kinase A activity

BACKGROUND: Agonists for the peroxisome proliferator activated receptor PPARγ, have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. OBJECTIVES: Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signalling. Both GPVI and GPCR signalling pathways lead to αIIbβ3 activation, and signalling through αIIbβ3 plays a critical role in platelet function and normal haemostasis. METHODS: The effects of PPARγ agonists on the regulation of αIIbβ3 outside-in signalling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signalling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by western blotting. RESULTS: Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signalling, including the integrin β3 subunit, Syk, PLCγ2, FAK and Akt was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was a due to an increase in PKA activity following treatment with PPARγ receptor agonists. CONCLUSIONS: This study provides further evidence for anti-platelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside-in signalling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation

Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen

OBJECTIVE: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH AND RESULTS: By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. CONCLUSIONS: These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis

The master builders: LAIRAH research on good practice in the construction of digital humanities projects

Although many digital humanities resources are being developed for online use, there is little understanding of why some become popular, whilst others are neglected. Through log analysis techniques, the LAIRAH project identified twenty-one popular and well-used digital humanities projects, and in order to ascertain the factors they had in common, which predisposed them to be well used, conducted in-depth interviews with the creators of these resources. This article presents the findings of the study, highlighting areas that developers should be aware of, and providing a set of recommendations for both funders and creators, which should ensure that a digital humanities resource will have the best possible chance of being used in the long term

Expression of adrenomedullin and its receptor during embryogenesis suggests autocrine or paracrine modes of action

The present study reports the developmental patterns of expression of adrenomedullin (AM) in rat and mouse embryos. AM is a novel multifunctional peptide recently isolated from a human pheochromocytoma, which has been shown to promote growth in a variety of mammalian cell lines. We have applied several techniques to investigate the localization of both the AM peptide and its receptor throughout development. Immunocytochemical detection has been performed using different specific antibodies against AM and its gene-related peptide pro-AM N-terminal 20 peptide. In situ hybridization showed the localization of the messenger RNAs for AM and its receptor. Western blot analysis together with reverse transcription-PCR gave further support to the localization of AM and its receptor in a variety of embryonic tissues. The localization of the receptor paralleled that of AM itself, suggesting an autocrine or paracrine mode of action. The spatio-temporal pattern of expression of AM in cardiovascular, neural, and skeletal-forming tissues as well as in the main embryonic internal organs is described. The primitive placenta, especially the giant trophoblastic cells, shows high levels of AM and AM receptor. The heart is the first organ that expresses AM during development. The kidney, lung, and developing tooth, in which epithelial-mesenchymal interactions are taking place, show specific patterns of AM expression. In several regions of the embryo, the patterns of AM expression correspond to the degree of differentiation. The possible involvement of AM in the control of embryonic invasion, proliferation, and differentiation is discussed