BACKGROUND AND PURPOSE Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a bifunctional protein comprising a TRP ion channel segment linked to an α‐type protein kinase ...domain. TRPM7 is essential for proliferation and cell growth. Up‐regulation of TRPM7 function is involved in anoxic neuronal death, cardiac fibrosis and tumour cell proliferation. The goal of this work was to identify non‐toxic inhibitors of the TRPM7 channel and to assess the effect of blocking endogenous TRPM7 currents on the phenotype of living cells.
EXPERIMENTAL APPROACH We developed an aequorin bioluminescence‐based assay of TRPM7 channel activity and performed a hypothesis‐driven screen for inhibitors of the channel. The candidates identified were further assessed electrophysiologically and in cell biological experiments.
KEY RESULTS TRPM7 currents were inhibited by modulators of small conductance Ca2+‐activated K+ channels (KCa2.1–2.3; SK) channels, including the antimalarial plant alkaloid quinine, CyPPA, dequalinium, NS8593, SKA31 and UCL 1684. The most potent compound NS8593 (IC50 1.6 µM) specifically targeted TRPM7 as compared with other TRP channels, interfered with Mg2+‐dependent regulation of TRPM7 channel and inhibited the motility of cultured cells. NS8593 exhibited full and reversible block of native TRPM7‐like currents in HEK 293 cells, freshly isolated smooth muscle cells, primary podocytes and ventricular myocytes.
CONCLUSIONS AND IMPLICATIONS This study reveals a tight overlap in the pharmacological profiles of TRPM7 and KCa2.1–2.3 channels. NS8593 acts as a negative gating modulator of TRPM7 and is well‐suited to study functional features and cellular roles of endogenous TRPM7.
•Amyloid aggregates at pH 2 and pH 3.5 differed in their building blocks.•All aggregate building blocks changed towards smaller peptides after >48 h incubation.•Apparent dityrosine oxidation reached ...a maximum after 5 h incubation.•Protein carbonyls were not significantly increased during the first 5 h of fibril preparation.•The amyloid aggregates were deteriorated after 72 h incubation.
Although the connection between protein oxidation, amyloid aggregation and diseases such as Alzheimer’s is well known there is no information on such effects during preparation of beta-lactoglobulin fibrils. Different morphologies of amyloid aggregates of beta-lactoglobulin were prepared by incubation at pH 2 or pH 3.5 for up to 72 h. After 5 h, amyloid aggregates at pH 2 formed typical fibrils, which consisted of peptides. At pH 3.5, the amyloid aggregates were worm-like and consisted of intact protein. After 72 h, the building blocks at both pH values changed towards smaller peptides. The apparent tyrosine oxidation reached a maximum after 5 h at both pH values, whereas N-formylkynurenine and carbonyls increased continuously during 72 h. In case amyloid structures are used as edible material, the health related effects caused by protein oxidation needs to be considered.
The corrosion behavior of an electroless Ni–P coating on low-Cr X20CrMoV12-1 steel as a cost-efficient substrate-coating combination is investigated in molten NaNO3–KNO3 nitrates at 600 °C. Results ...indicated that the as-deposited Ni–P coating was transformed to a thermally treated diffusion coating upon exposure to the molten salt without additional heat treatment prior to the exposure. Detailed evolution of the Ni–P coating and the oxidation behavior during the 1000-h immersion test is discussed. Results showed competitive corrosion resistance of the coating system compared to that of the sophisticated Ni alloy 230, with the advantage of an inherent barrier against Cr dissolution form the substrate. The significant corrosion resistance of the electroless plated Ni–P coating is attributed in part to the protective Ni--rich oxide scale and in other part to the in-situ formed Ni3P barrier at the oxide-substrate interphase boundary.
-Electroless Ni–P coating was developed on a low-cost X20CrMoV12-1 substrate-Interdiffusion occurred during the immersion test at 600 °C-The as-coated substrate required no additional heat treatment prior to the molten salt exposure-An outer Ni–Cr rich oxide scale and an inner Ni3P layer formed during the immersion test-The Ni–Cr scale and Ni3P layer protected the substrate against molten salt corrosion and Cr-dissolution
Molten chlorides are promising heat transfer fluids (HTF) and thermal energy storage (TES) materials for third-generation concentrated solar power (CSP) plants. Despite their low cost and wide ...operating temperature ranges (400–800 °C), structural materials experience severe corrosion in commercially available chloride salts. The understanding of the corrosion mechanisms is therefore critical for successful plant design to ensure constant power generation over the 30 years of expected lifetime. This work investigates the corrosion behavior of ferritic-martensitic P91 steel and Inconel 600 nickel-based alloy in molten NaCl-KCl-MgCl2 (24.5-20.5-55.0 wt%) under isothermal conditions at 700 °C in Ar. For both alloys, the corrosion attack is associated with the selective dissolution of Cr and the removal of Cr-rich carbides from the alloy matrix leaving subsurface voids. The initial “impurity-driven” corrosion mechanism associated with the cathodic reduction of MgOH+ impurities leads to the formation of insoluble MgO on the substrates’ surface. Compositional and microstructural features of the alloys, especially the distribution of Cr-rich carbides as well as the solubility and mobility of carbon within the metallic matrix, are found to significantly affect their corrosion resistance. The experimental observations indicate, that the formation of galvanic pairs and solid-state diffusion mechanisms play a major role regarding the corrosion attack of the alloys. The systematic corrosion experiments conducted in this study indicate a lower corrosiveness of NaCl-KCl-MgCl2 ternary mixture than that of NaCl-KCl binary mixture in static conditions at 700 °C under Ar. This work gives significant insights into corrosion issues that may be expected in third-generation industrial CSP plants.
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•The impurity-driven corrosion mechanisms in molten chlorides are unveiled.•Cathodic reduction of MgOH+ forms insoluble MgO scales on the alloys' surfaces.•Corrosion attack associated with the precipitation/dissolution of Cr-rich phases.•The microstructural instability of the alloys influences their corrosion behavior.•Theoretical calculations and Raman data on the MgO:Cr3+ fluorescence bands are given.
Chronic pelvic pain accounts for approximately 10% of outpatient gynecologic visits and among the varied causes, pelvic congestion syndrome is second only to endometriosis in frequency. ...Manifestations may include pelvic pain, dyspareunia, dysuria, and dysmenorrhea as well as external varices and a number of psychosocial symptoms. Although a variety of treatments have been proposed-including pharmacologic ovarian suppression, hysterectomy with or without oophorectomy, and ovarian vein resection-transcatheter embolization is the least invasive and most efficacious management option. Complete or partial symptom improvement has been reported in 68.2-100% of patients and there has been a consistent reduction in visual analog pain scores after treatment. Based upon these results, recommendation of either pharmacotherapy or other surgical procedures is difficult to justify. However, it is also clear that 6-31.8% of patients do not get substantial relief from pelvic venous embolization. Potential explanations for an inadequate response to treatment include patient variability, procedural variability, and inadequate outcome measures. The latter are particularly important and future investigation should focus on the development of disease-specific quality of life measures as well as identifying those aspects of the procedure, such as choice of embolic agents and extent of embolization, associated with the best clinical outcomes.
Trade booms, trade busts, and trade costs Jacks, David S.; Meissner, Christopher M.; Novy, Dennis
Journal of international economics,
03/2011, Volume:
83, Issue:
2
Journal Article
Peer reviewed
Open access
What has driven trade booms and trade busts in the past and present? We employ a micro-founded measure of trade frictions consistent with leading trade theories to gauge the importance of bilateral ...trade costs in determining international trade flows. We construct a new balanced sample of bilateral trade flows for 130 country pairs across the Americas, Asia, Europe, and Oceania for the period from 1870 to 2000 and demonstrate an overriding role for declining trade costs in the pre-World War I trade boom. In contrast, for the post-World War II trade boom we identify changes in output as the dominant force. Finally, the entirety of the interwar trade bust is explained by increases in trade costs.
Common dolphins, Delphinus sp., are one of the marine mammal species tourism operations in New Zealand focus on. While effects of cetacean-watching activities have previously been examined in coastal ...regions in New Zealand, this study is the first to investigate effects of commercial tourism and recreational vessels on common dolphins in an open oceanic habitat. Observations from both an independent research vessel and aboard commercial tour vessels operating off the central and east coast Bay of Plenty, North Island, New Zealand were used to assess dolphin behaviour and record the level of compliance by permitted commercial tour operators and private recreational vessels with New Zealand regulations. Dolphin behaviour was assessed using two different approaches to Markov chain analysis in order to examine variation of responses of dolphins to vessels. Results showed that, regardless of the variance in Markov methods, dolphin foraging behaviour was significantly altered by boat interactions. Dolphins spent less time foraging during interactions and took significantly longer to return to foraging once disrupted by vessel presence. This research raises concerns about the potential disruption to feeding, a biologically critical behaviour. This may be particularly important in an open oceanic habitat, where prey resources are typically widely dispersed and unpredictable in abundance. Furthermore, because tourism in this region focuses on common dolphins transiting between adjacent coastal locations, the potential for cumulative effects could exacerbate the local effects demonstrated in this study. While the overall level of compliance by commercial operators was relatively high, non-compliance to the regulations was observed with time restriction, number or speed of vessels interacting with dolphins not being respected. Additionally, prohibited swimming with calves did occur. The effects shown in this study should be carefully considered within conservation management plans, in order to reduce the risk of detrimental effects on common dolphins within the region.
Sources of magnetic fields-magnetic monopoles-have so far proven elusive as elementary particles. Condensed-matter physicists have recently proposed several scenarios of emergent quasiparticles ...resembling monopoles. A particularly simple proposition pertains to spin ice on the highly frustrated pyrochlore lattice. The spin-ice state is argued to be well described by networks of aligned dipoles resembling solenoidal tubes-classical, and observable, versions of a Dirac string. Where these tubes end, the resulting defects look like magnetic monopoles. We demonstrated, by diffuse neutron scattering, the presence of such strings in the spin ice dysprosium titanate (Dy2Ti2O7). This is achieved by applying a symmetry-breaking magnetic field with which we can manipulate the density and orientation of the strings. In turn, heat capacity is described by a gas of magnetic monopoles interacting via a magnetic Coulomb interaction.
Mapping semi-natural grassland has become increasingly important with regard to climate variability, invasive species, and the intensification of land use. At the same time, adequate field data ...collection is of pivotal importance for national and international reporting obligations, such as the European Habitats Directive. We present a remote-sensing-based monitoring framework for a Natura 2000 site with a heterogeneous composition of different grassland communities, using the Random Forest algorithm. Automated training data selection was successfully implemented based on the Random Forest proximity measure (Overall Accuracy ranging from 77.5-86.5%). RapidEye acquisitions originating from the onset of vegetation (prespring and first spring) and senescence (late summer and first autumn) were identified as important phenological phases for mapping semi-natural grassland communities. The derived probability maps of occurrences for each grassland class captured transitions between grassland communities and are therefore a better approximation of real-world conditions compared to classical, discrete maps.
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