Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models

BACKGROUND: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a rationally designed immunosuppressive drug. The current study investigates the effect of MMF on key pattern of restenosis in a cascade of in vitro and ex vivo models. METHODS: Part I of the study investigated in northern blot and cytoflow studies the effect of MMF (50, 100, 150, 200, 250, and 300 μg/mL) on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary medial smooth muscle cells (HCMSMC). Part II of the study applied a human coronary 3D model of leukocyte attack, the 3DLA-model. HCAEC and HCMSMC were cultured on both sides of a polycarbonate filters, mimicking the internal elastic membrane. Leukocyte attack (LA) was carried out by adding human monocytes (MC) on the endothelial side. The effect of MMF (50 μg/mL) on adhesion and chemotaxis (0.5, 1, 2, 3, 4, 6, and 24 h after LA) and the effect on proliferation of co-cultured HCMSMC (24 h after LA) was studied. In part III of the study a porcine coronary organ culture model of restenosis (POC-model) was used. After ex vivo ballooning MMF (50 μg/mL) was added to the cultures for a period of 1, 2, 3, 4, 5, 6, and 7 days. The effect on reactive cell proliferation and neointimal thickening was studied at day 7 and day 28 after ballooning. RESULTS: Expression of ICAM-1 in northern blot and cytoflow studies was neither clearly inhibited nor stimulated after administration of MMF in the clinical relevant concentration of 50 μg/mL. In the 3DLA-model 50 μg/mL of MMF caused a significant antiproliferative effect (p < 0.001) in co-cultured HCMSMC but had no effect on MC-adhesion and MC-chemotaxis. In the ex vivo POC-model neighter reactive cell proliferation at day 7 nor neointimal hyperplasia at day 28 were significantly inhibited by MMF (50 μg/mL). CONCLUSION: Thus, the data demonstrate a significant antiproliferative effect of clinical relevant levels of MMF (50 μg/mL) in the 3DLA-model. The antiproliferative effect was a direct antiproliferative effect that was not triggered via reduced expression of ICAM-1 or via an inhibition of MC-adhesion and chemotaxis. Probably due to technical limitations (as e.g. the missing of perfusion) the antiproliferative effect of MMF (50 μg/mL) could not be reproduced in the coronary organ culture model. A cascade of focused in vitro and ex vivo models may help to gather informations on drug effects before large experimental studies are initiated

An eclipsing binary distance to the Large Magellanic Cloud accurate to 2 per cent

In the era of precision cosmology it is essential to determine the Hubble Constant with an accuracy of 3% or better. Currently, its uncertainty is dominated by the uncertainty in the distance to the Large Magellanic Cloud (LMC) which as the second nearest galaxy serves as the best anchor point of the cosmic distance scale. Observations of eclipsing binaries offer a unique opportunity to precisely and accurately measure stellar parameters and distances. The eclipsing binary method was previously applied to the LMC but the accuracy of the distance results was hampered by the need to model the bright, early-type systems used in these studies. Here, we present distance determinations to eight long-period, late- type eclipsing systems in the LMC composed of cool giant stars. For such systems we can accurately measure both the linear and angular sizes of their components and avoid the most important problems related to the hot early-type systems. Our LMC distance derived from these systems is demonstrably accurate to 2.2 % (49.97 +/- 0.19 (statistical) +/- 1.11 (systematic) kpc) providing a firm base for a 3 % determination of the Hubble Constant, with prospects for improvement to 2 % in the future.Comment: 34 pages, 5 figures, 13 tables, published in the Nature, a part of our data comes from new unpublished OGLE-IV photometric dat

Biomass and Burning Characteristics of Sugar Pine Cones

We investigated the physical and burning characteristics of sugar pine (Pinus lambertiana Douglas) cones and their contribution to woody surface fuel loadings. Field sampling was conducted at the Yosemite Forest Dynamics Plot (YFDP), a 25.6 ha mapped study plot in Yosemite National Park, California, USA. We developed a classification system to describe sugar pine cones of different sizes and decay conditions, and examined differences among cone classes in biomass, bulk density, flame length, burning time, consumption, and relative contribution to surface fuel loads. Sugar pine cones comprised 601 kg ha-1 of surface fuels. Mature cones comprised 54% of cone biomass, and aborted juvenile cones accounted for 44%. Cone biomass, diameter, and bulk density differed among cone condition classes, as did burning characteristics (one-way ANOVA, P \u3c 0.001 in all cases). Flame lengths ranged from 5 cm to 94 cm for juvenile cones, and 71 cm to 150 cm for mature cones. Our results showed that the developmental stage at which sugar pine cones become surface fuels determines their potential contribution to surface fire behavior in Sierra Nevada mixed-conifer forests. Sugar pine cones burn with greater flame lengths and flame times than the cones of other North American fire-tolerant pine species studied to date, indicating that cones augment the surface fire regime of sugar pine forests, and likely do so to a greater degree than do cones of other pine species

Socio-Economic Instability and the Scaling of Energy Use with Population Size

The size of the human population is relevant to the development of a sustainable world, yet the forces setting growth or declines in the human population are poorly understood. Generally, population growth rates depend on whether new individuals compete for the same energy (leading to Malthusian or density-dependent growth) or help to generate new energy (leading to exponential and super-exponential growth). It has been hypothesized that exponential and super-exponential growth in humans has resulted from carrying capacity, which is in part determined by energy availability, keeping pace with or exceeding the rate of population growth. We evaluated the relationship between energy use and population size for countries with long records of both and the world as a whole to assess whether energy yields are consistent with the idea of an increasing carrying capacity. We find that on average energy use has indeed kept pace with population size over long time periods. We also show, however, that the energy-population scaling exponent plummets during, and its temporal variability increases preceding, periods of social, political, technological, and environmental change. We suggest that efforts to increase the reliability of future energy yields may be essential for stabilizing both population growth and the global socio-economic system

Facial expressions depicting compassionate and critical emotions: the development and validation of a new emotional face stimulus set

Attachment with altruistic others requires the ability to appropriately process affiliative and kind facial cues. Yet there is no stimulus set available to investigate such processes. Here, we developed a stimulus set depicting compassionate and critical facial expressions, and validated its effectiveness using well-established visual-probe methodology. In Study 1, 62 participants rated photographs of actors displaying compassionate/kind and critical faces on strength of emotion type. This produced a new stimulus set based on N = 31 actors, whose facial expressions were reliably distinguished as compassionate, critical and neutral. In Study 2, 70 participants completed a visual-probe task measuring attentional orientation to critical and compassionate/kind faces. This revealed that participants lower in self-criticism demonstrated enhanced attention to compassionate/kind faces whereas those higher in self-criticism showed no bias. To sum, the new stimulus set produced interpretable findings using visual-probe methodology and is the first to include higher order, complex positive affect displays

False discovery rate estimation and heterobifunctional cross-linkers

<div><p>False discovery rate (FDR) estimation is a cornerstone of proteomics that has recently been adapted to cross-linking/mass spectrometry. Here we demonstrate that heterobifunctional cross-linkers, while theoretically different from homobifunctional cross-linkers, need not be considered separately in practice. We develop and then evaluate the impact of applying a correct FDR formula for use of heterobifunctional cross-linkers and conclude that there are minimal practical advantages. Hence a single formula can be applied to data generated from the many different non-cleavable cross-linkers.</p></div

Synthesis of Bio-Compatible SPION–based Aqueous Ferrofluids and Evaluation of RadioFrequency Power Loss for Magnetic Hyperthermia

Bio-compatible magnetic fluids having high saturation magnetization find immense applications in various biomedical fields. Aqueous ferrofluids of superparamagnetic iron oxide nanoparticles with narrow size distribution, high shelf life and good stability is realized by controlled chemical co-precipitation process. The crystal structure is verified by X-ray diffraction technique. Particle sizes are evaluated by employing Transmission electron microscopy. Room temperature and low-temperature magnetic measurements were carried out with Superconducting Quantum Interference Device. The fluid exhibits good magnetic response even at very high dilution (6.28 mg/cc). This is an advantage for biomedical applications, since only a small amount of iron is to be metabolised by body organs. Magnetic field induced transmission measurements carried out at photon energy of diode laser (670 nm) exhibited excellent linear dichroism. Based on the structural and magnetic measurements, the power loss for the magnetic nanoparticles under study is evaluated over a range of radiofrequencies

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation