On Charged Black Holes in Anti-de Sitter Space

We study the region inside the event horizon of charged black holes in five dimensional asymptotically anti-de Sitter space, using as a probe two-sided correlators which are dominated by spacelike geodesics penetrating the horizon. The spacetimes we investigate include the Reissner-Nordstrom black hole and perturbations thereof. The perturbed spacetimes can be found exactly, enabling us to perform a local scan of the region between the inner and outer horizons. Surprisingly, the two-sided correlators we calculate seem to be geometrically protected from the instability of the inner horizon.Comment: 1+37 pages, 20 ps and eps figures, LaTeX. References added and changes made to section

Use of hydroxyethyl starch in leukocytapheresis procedures does not increase renal toxicity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134412/1/trf13795.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134412/2/trf13795_am.pd

Iron Abundances in Lunar Impact Basin Melt Sheets From Orbital Magnetic Field Data

International audienceMagnetic field data acquired from orbit shows that the Moon possesses many magnetic anomalies. Though most of these are not associated with known geologic structures, some are found within large impact basins within the interior peak ring. The primary magnetic carrier in lunar rocks is metallic iron, but indigenous lunar rocks are metal poor and cannot account easily for the observed field strengths. The projectiles that formed the largest impact basins must have contained a significant quantity of metallic iron, and a portion of this iron would have been retained on the Moon's surface within the impact melt sheet. Here we use orbital magnetic field data to invert for the magnetization within large impact basins using the assumption that the crust is unidirectionally magnetized. We develop a technique based on laboratory thermoremanent magnetization acquisition to quantify the relationship between the strength of the magnetic field at the time the rock cooled and the abundance of metal in the rock. If we assume that the magnetized portion of the impact melt sheet is 1 km thick, we find average abundances of metallic iron ranging from 0.11% to 0.45 wt %, with an uncertainty of a factor of about 3. This abundance is consistent with the metallic iron abundances in sampled lunar impact melts and the abundance of projectile contamination in terrestrial impact melts. These results help constrain the composition of the projectile, the impact process, and the time evolution of the lunar dynamo

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

Background and PurposeTo further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR‐101 (PD132301‐02).Experimental ApproachWe compared the effects of ATR‐101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC‐derived cell lines. We examined the effects of these compounds in combination with methyl‐β‐cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds.Key ResultsATR‐101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC‐derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl‐β‐cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR‐101. ATR‐101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR‐101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR‐101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR‐101. ATR‐101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation.Conclusions and ImplicationsInhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR‐101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/1/bph13951-sup-0001-supplementary_material.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/2/bph13951_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/3/bph13951.pd

High content live cell imaging for the discovery of new antimalarial marine natural products

<p>Abstract</p> <p>Background</p> <p>The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, <it>Plasmodium falciparum</it>.</p> <p>Methods</p> <p>A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown <it>in vitro </it>in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.</p> <p>Results</p> <p>Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.</p> <p>Conclusion</p> <p>Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.</p

Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies

Active fixturing: literature review and future research directions

Fixtures are used to fixate, position and support workpieces and represent a crucial tool in manufacturing. Their performance determines the result of the whole manufacturing process of a product. There is a vast amount of research done on automatic fixture layout synthesis and optimisation and fixture design verification. Most of this work considers fixture mechanics to be static and the fixture elements to be passive. However, a new generation of fixtures has emerged that has actuated fixture elements for active control of the part–fixture system during manufacturing operations to increase the end product quality. This paper analyses the latest studies in the field of active fixture design and its relationship with flexible and reconfigurable fixturing systems. First, a brief introduction is given on the importance of research of fixturing systems. Secondly, the basics of workholding and fixture design are visited, after which the state-of-the-art in active fixturing and related concepts is presented. Fourthly, part–fixture dynamics and design strategies which take these into account are discussed. Fifthly, the control strategies used in active fixturing systems are examined. Finally, some final conclusions and prospective future research directions are presented

The Confrontation between General Relativity and Experiment

The status of experimental tests of general relativity and of theoretical frameworks for analysing them is reviewed. Einstein's equivalence principle (EEP) is well supported by experiments such as the Eotvos experiment, tests of special relativity, and the gravitational redshift experiment. Future tests of EEP and of the inverse square law are searching for new interactions arising from unification or quantum gravity. Tests of general relativity at the post-Newtonian level have reached high precision, including the light deflection, the Shapiro time delay, the perihelion advance of Mercury, and the Nordtvedt effect in lunar motion. Gravitational-wave damping has been detected in an amount that agrees with general relativity to better than half a percent using the Hulse-Taylor binary pulsar, and other binary pulsar systems have yielded other tests, especially of strong-field effects. When direct observation of gravitational radiation from astrophysical sources begins, new tests of general relativity will be possible.Comment: 89 pages, 8 figures; an update of the Living Review article originally published in 2001; final published version incorporating referees' suggestion

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability