ABSTRACT
Plate tectonics successfully describes the surface of Earth as a mosaic of moving lithospheric plates. But it is not clear what happens at the base of the plates, the lithosphere-asthenosphere boundary (LAB). The LAB has been well imaged with converted teleseismic waves, whose 10-40-kilometre wavelength controls the structural resolution. Here we use explosion-generated seismic waves (of about 0.5-kilometre wavelength) to form a high-resolution image for the base of an oceanic plate that is subducting beneath North Island, New Zealand. Our 80-kilometre-wide image is based on P-wave reflections and shows an approximately 15° dipping, abrupt, seismic wave-speed transition (less than 1 kilometre thick) at a depth of about 100 kilometres. The boundary is parallel to the top of the plate and seismic attributes indicate a P-wave speed decrease of at least 8 ± 3 per cent across it. A parallel reflection event approximately 10 kilometres deeper shows that the decrease in P-wave speed is confined to a channel at the base of the plate, which we interpret as a sheared zone of ponded partial melts or volatiles. This is independent, high-resolution evidence for a low-viscosity channel at the LAB that decouples plates from mantle flow beneath, and allows plate tectonics to work.
ABSTRACT
AIMS: The use of mechanical restraint is a challenging area for psychiatry. Although mechanical restraint remains accepted as standard practice in some regions, there are ethical, legal and medical reasons to minimise or abolish its use. These concerns have intensified following the Convention on the Rights of Persons with Disabilities. Despite national policies to reduce use, the reporting of mechanical restraint has been poor, hampering a reasonable understanding of the epidemiology of restraint. This paper aims to develop a consistent measure of mechanical restraint and compare the measure within and across countries in the Pacific Rim. METHODS: We used the publicly available data from four Pacific Rim countries (Australia, New Zealand, Japan and the United States) to compare and contrast the reported rates of mechanical restraint. Summary measures were computed so as to enable international comparisons. Variation within each jurisdiction was also analysed. RESULTS: International rates of mechanical restraint in 2017 varied from 0.03 (New Zealand) to 98.9 (Japan) restraint events per million population per day, a variation greater than 3000-fold. Restraint in Australia (0.17 events per million) and the United States (0.37 events per million) fell between these two extremes. Variation as measured by restraint events per 1000 bed-days was less extreme but still substantial. Within all four countries there was also significant variation in restraint across districts. Variation across time did not show a steady reduction in restraint in any country during the period for which data were available (starting from 2003 at the earliest). CONCLUSIONS: Policies to reduce or abolish mechanical restraint do not appear to be effecting change. It is improbable that the variation in restraint within the four examined Pacific Rim countries is accountable for by psychopathology. Greater efforts at reporting, monitoring and carrying out interventions to achieve the stated aim of reducing restraint are urgently needed.
Subject(s)
Hospitals, Psychiatric/statistics & numerical data , Patient Isolation/statistics & numerical data , Restraint, Physical/statistics & numerical data , Adolescent , Adult , Aged , Australia , Coercion , Cross-Cultural Comparison , Epidemiologic Studies , Humans , Japan , Mental Disorders/epidemiology , Mental Disorders/therapy , Middle Aged , New Zealand , United StatesABSTRACT
Treatment of isolated mitochondria with Ca2+ and inorganic phosphate (Pi) induces an inner membrane permeability that appears to be mediated through a cyclosporin A (CsA)-inhibitable Ca(2+)-dependent pore. Isolated mitochondria during inner membrane permeability undergo rapid efflux of matrix solutes such as glutathione as GSH and Ca2+, loss of coupled functions, and large amplitude swelling. Permeability transition without large amplitude swelling, a parameter often used to assess inner membrane permeability, has been observed. The addition of either oligomycin, antimycin, or sulfide to incubation buffer containing Ca2+ and Pi abolished large amplitude swelling of mitochondria. The GSH status during a Ca(2+)- and Pi-dependent mechanism of mitochondrial GSH release in isolated mitochondria was influenced significantly by metabolic inhibitors of the respiratory chain but did not prevent inner membrane permeability as demonstrated by the release of mitochondrial GSH and Ca2+. The release of GSH was inhibited by the addition of CsA, a potent inhibitor of permeability transition. Under these conditions we did not find GSSG; however, rapid oxidation of pyridine nucleotides and depletion of ATP and ADP with conversion to AMP occurred. The addition of CsA, prevented the oxidation of pyridine nucleotides and depletion of ATP and ADP. Since NADH and NADPH were extensively oxidized, protection against oxidative stress is reflected in maintenance of GSH and not observable lipid peroxidation. Evidence from transmission electron microscopy analysis, combined with the GSH release data, indicate that permeability transition can be observed in the absence of large amplitude swelling.
Subject(s)
Glutathione/metabolism , Intracellular Membranes/metabolism , Mitochondria, Liver/metabolism , Adenine Nucleotides/metabolism , Animals , Antimycin A/analogs & derivatives , Antimycin A/pharmacology , Calcium/pharmacology , Cyclosporine/pharmacology , Intracellular Membranes/drug effects , Intracellular Membranes/ultrastructure , Male , Microscopy, Electron , Mitochondria, Liver/drug effects , Mitochondria, Liver/ultrastructure , NAD/metabolism , NADP/metabolism , Oligomycins/pharmacology , Permeability , Phosphates/pharmacology , Rats , Rats, Sprague-Dawley , Sulfides/pharmacologyABSTRACT
The Ugi protein inhibitor of uracil-DNA glycosylase encoded by bacteriophage PBS2 inactivates human uracil-DNA glycosylases (UDG) by forming a tight enzyme:inhibitor complex. To create human cells that are impaired for UDG activity, the human glioma U251 cell line was engineered to produce active Ugi protein. In vitro assays of crude cell extracts from several Ugi-expressing clonal lines showed UDG inactivation under standard assay conditions as compared to control cells, and four of these UDG defective cell lines were characterized for their ability to conduct in vivo uracil-DNA repair. Whereas transfected plasmid DNA containing either a U:G mispair or U:A base pairs was efficiently repaired in the control lines, uracil-DNA repair was not evident in the lines producing Ugi. Experiments using a shuttle vector to detect mutations in a target gene showed that Ugi-expressing cells exhibited a 3-fold higher overall spontaneous mutation frequency compared to control cells, due to increased C:G to T:A base pair substitutions. The growth rate and cell cycle distribution of Ugi-expressing cells did not differ appreciably from their parental cell counterpart. Further in vitro examination revealed that a thymine DNA glycosylase (TDG) previously shown to mediate Ugi-insensitive excision of uracil bases from DNA was not detected in the parental U251 cells. However, a Ugi-insensitive UDG activity of unknown origin that recognizes U:G mispairs and to a lesser extent U:A base pairs in duplex DNA, but which was inactive toward uracil residues in single-stranded DNA, was detected under assay conditions previously shown to be efficient for detecting TDG.
Subject(s)
DNA Glycosylases , DNA Repair , Mutagenesis , N-Glycosyl Hydrolases/antagonists & inhibitors , Viral Proteins/biosynthesis , Bacillus Phages/enzymology , Cell Cycle , Enzyme Inhibitors , Genetic Vectors , Glioma/genetics , Humans , Recombinant Proteins/biosynthesis , Tumor Cells, Cultured , Uracil-DNA Glycosidase , Viral Proteins/geneticsABSTRACT
Treatment of isolated mitochondria with calcium and inorganic phosphate induces inner membrane permeability that is thought to be mediated through a non-selective, calcium-dependent pore. The inner membrane permeability results in the rapid efflux of small matrix solutes such as glutathione and calcium, loss of coupled functions, and large amplitude swelling. We have identified conditions of permeability transition without large amplitude swelling, a parameter often used to assess inner membrane permeability. The addition of either oligomycin, antimycin, or sulfide to incubation buffer containing calcium and inorganic phosphate abolished large-amplitude swelling of mitochondria but did not prevent inner membrane permeability as demonstrated by the release of mitochondrial glutathione and calcium. The release of both glutathione and calcium was inhibited by the addition of cyclosporin A, a potent inhibitor of permeability transition. Transmission electron microscopy analysis, combined with the glutathione and calcium release data, indicate that permeability transition can be observed in the absence of large-amplitude swelling. Permeability transition occurring both with and without large-amplitude swelling was accompanied by a collapse of the membrane potential. We conclude that cyclosporin A-sensitive permeability transition can occur without obvious morphological changes such as large-amplitude swelling. Monitoring the cyclosporin A-sensitive release of concentrated endogenous matrix solutes, such as GSH, may be a sensitive and useful indicator of permeability transition.
Subject(s)
Calcium/metabolism , Cyclosporine/pharmacology , Glutathione/metabolism , Mitochondria, Liver/drug effects , Mitochondrial Swelling/physiology , Animals , Antimycin A/analogs & derivatives , Antimycin A/pharmacology , Biological Transport , Calcium/pharmacology , Male , Microscopy, Electron , Mitochondria, Liver/metabolism , Mitochondria, Liver/ultrastructure , Oligomycins/pharmacology , Onium Compounds/metabolism , Permeability , Phosphates/pharmacology , Rats , Rats, Sprague-Dawley , Sulfides/pharmacology , Time Factors , Trityl Compounds/metabolismABSTRACT
We have examined the pyridine and adenine nucleotide status during calcium- and inorganic phosphate-induced permeability transition. Calcium- and inorganic phosphate-induced permeability transition is accompanied by the rapid oxidation of pyridine nucleotides and depletion of ATP and ADP with conversion to AMP. The addition of cyclosporin A, a potent inhibitor of the permeability transition prevented the oxidation of pyridine nucleotides and depletion of ATP and ADP.
Subject(s)
Adenine Nucleotides/metabolism , Calcium/pharmacology , Mitochondria/metabolism , NADP/metabolism , NAD/metabolism , Phosphates/pharmacology , Animals , Cyclosporine/pharmacology , Energy Metabolism/drug effects , Intracellular Membranes/metabolism , Male , Mitochondria/drug effects , Permeability , Rats , Rats, Sprague-DawleyABSTRACT
The status of glutathione (GSH) was studied in isolated rat liver mitochondria under conditions which induce a permeability transition. This transition, which is inhibited by cyclosporin A (CyA), requires the presence of Ca2+ and an inducing agent such as near physiological levels (3 mM) of inorganic phosphate (Pi). The transition is characterized by an increased inner membrane permeability to some low molecular weight solutes and by large amplitude swelling under some experimental conditions. Addition of 70 microM Ca2+ and 3 mM Pi to mitochondria resulted in mitochondrial swelling and extensive release of GSH that was recovered in the extramitochondrial medium as GSH. Both swelling and the efflux of mitochondrial GSH were prevented by CyA. Incubation of mitochondria in the presence of Ca2+, Pi, and GSH followed by addition of CyA provided a mechanism to load mitochondria with exogenous GSH that was greater than the rate of uptake by untreated mitochondria. Thus, GSH efflux from mitochondria may occur under toxicological and pathological conditions in which mitochondria are exposed to elevated Ca2+ in the presence of near physiological concentrations of Pi through a nonspecific pore. Cyclical opening and closing of the pore could also provide a mechanism for uptake of GSH by mitochondria.