Effect of metabolic syndrome and aging on Ca2+ dysfunction in coronary smooth muscle and coronary artery disease severity in Ossabaw miniature swine

BACKGROUND: Metabolic syndrome (MetS) and aging are prevalent risk factors for coronary artery disease (CAD) and contribute to the etiology of CAD, including dysregulation of Ca2+ handling mechanisms in coronary smooth muscle (CSM). The current study tested the hypothesis that CAD severity and CSM Ca2+ dysregulation were different in MetS-induced CAD compared to aging-induced CAD. METHODS: Young (2.5 ± 0.2 years) and old (8.8 ± 1.2 years) Ossabaw miniature swine were fed an atherogenic diet for 11 months to induce MetS and were compared to lean age-matched controls. The metabolic profile was confirmed by body weight, plasma cholesterol and triglycerides, and intravenous glucose tolerance test. CAD was measured with intravascular ultrasound and histology. Intracellular Ca2+ ([Ca2+]i) was assessed with fura-2 imaging. RESULTS: CAD severity was similar between MetS young and lean old swine, with MetS old swine exhibiting the most severe CAD. Compared to CSM [Ca2+]i handling in lean young, the MetS young and lean old swine exhibited increased sarcoplasmic reticulum Ca2+ store release, increased Ca2+ influx through voltage-gated Ca2+ channels, and attenuated sarco-endoplasmic reticulum Ca2+ ATPase activity. MetS old and MetS young swine had similar Ca2+ dysregulation. CONCLUSIONS: Ca2+ dysregulation, mainly the SR Ca2+ store, in CSM is more pronounced in lean old swine, which is indicative of mild, proliferative CAD. MetS old and MetS young swine exhibit Ca2+ dysfunction that is typical of late, severe disease. The more advanced, complex plaques in MetS old swine suggest that the "aging milieu" potentiates effects of Ca2+ handling dysfunction in CAD

An improved algorithm for the retrieval of ocean wave spectra from synthetic aperture radar image spectra

An earlier algorithm for retrieving two-dimensional wave spectra from synthetic aperture radar (SAR) image spectra is improved by using a modified cost function and introducing an additional iteration loop in which the first-guess input spectrum is systematically updated. For this purpose a spectral partitioning scheme is applied in which the spectrum is decomposed into a finite number of distinct wave systems. At each iteration step, the individual wave systems of the partitioned nth-guess wave spectrum are adjusted to agree in mean energy, frequency, and direction with the corresponding mean values of the associated wave systems of the SAR-inverted wave spectrum. The algorithm retrieves smooth wave spectra, avoiding the discontinuities which tended to arise in the previous algorithm in the transition region near the azimuthal wavenumber cutoff of the SAR image spectrum. The azimuthal cutoff of the SAR spectrum is also reproduced more accurately. The greatest improvement of the new retrieval algorithm is obtained when the discrepancies between the initial first-guess wave spectrum and the observed SAR spectrum are large. In this case the additional updating loop for the input spectrum enables the retrieved spectrum to adjust such that the simulated SAR spectrum matches more closely the observed SAR spectrum. The overall correlation of a large set of simulated SAR spectra with the measured SAR spectra is found to be significantly higher than with the previous algorithm, indicating that the algorithm not only overcomes isolated shortcomings of the earlier algorithm but also yields retrieved wave spectra which are generally more consistent with the input SAR data. An additional practical advantage of the new algorithm is that it returns spectral partioning parameters which dan be used in SAR wave data assimilation schemes

Diffusion due to the Beam-Beam Interaction and Fluctuating Fields in Hadron Colliders

Random fluctuations in the tune, beam offsets and beam size in the presence of the beam-beam interaction are shown to lead to significant particle diffusion and emittance growth in hadron colliders. We find that far from resonances high frequency noise causes the most diffusion while near resonances low frequency noise is responsible for the large emittance growth observed. Comparison of different fluctuations shows that offset fluctuations between the beams causes the largest diffusion for particles in the beam core.Comment: 5 pages, 3 postscript figure

The characterisation of two members of the cytochrome P450 CYP150 family: CYP150A5 and CYP150A6 from Mycobacterium marinum

Background: Actinobacteria, including the Mycobacteria, have a large component of cytochrome P450 family monooxygenases. This includes Mycobacterium tuberculosis, M. ulcerans and M. marinum, and M. vanbaalenii. These enzymes can abstract CH bonds and have important roles in natural product biosynthesis. Methohds: Two members of the bacterial CYP150 family, CYP150A5 and CYP150A6 from M. marinum, were produced, purified and characterised. The potential substrate ranges of both enzymes were analysed and the monooxygenase activity of CYP150A5 was reconstituted using a physiological electron transfer partner system. CYP150A6 was structurally characterised by X-ray crystallography. Results: CYP150A5 was shown to bind various norisoprenoids and terpenoids. It could regioselectively hydroxylate β-ionol. The X-ray crystal structure of substrate-free CYP150A6 was solved to 1.5 Å. This displayed an open conformation with short F and G helices, an unresolved F-G loop region and exposed active site pocket. The active site residues could be identified and important variations were found among the CYP150A enzymes. Haem-binding azole inhibitors were identified for both enzymes. Conclusions: The structure of CYP150A6 will facilitate the identification of physiological substrates and the design of better inhibitors for members of this P450 family. Based on the observed differences in substrate binding preference and sequence variations among the active site residues, their roles are predicted to be different. General Significance: Multiple CYP150 family members were found in many bacteria and are prevalent in the Mycobacteria including several human pathogens. Inhibition and structural data are reported here for these enzymes for the first time.Stella A. Child, Kate L. Flint, John B. Bruning, Stephen G. Bel

Planning the Future of U.S. Particle Physics (Snowmass 2013): Chapter 6: Accelerator Capabilities

These reports present the results of the 2013 Community Summer Study of the APS Division of Particles and Fields ("Snowmass 2013") on the future program of particle physics in the U.S. Chapter 6, on Accelerator Capabilities, discusses the future progress of accelerator technology, including issues for high-energy hadron and lepton colliders, high-intensity beams, electron-ion colliders, and necessary R&D for future accelerator technologies.Comment: 26 page

A Magnetic Transition Probed by the Ce Ion in Square-Lattice Antiferromagnet CeMnAsO

We examined the magnetic properties of the square-lattice antiferromagnets CeMnAsO and LaMnAsO and their solid solutions La1-xCexMnAsO by resistivity, magnetic susceptibility, and heat capacity measurements below room temperature. A first-order phase transition is observed at 34.1 K, below which the ground-state doublet of the Ce ion splits by 3.53 meV. It is likely that Mn moments already ordered above room temperature are reoriented at the transition, as reported for related compounds, such as NdMnAsO and PrMnSbO. This transition generates a large internal magnetic field at the Ce site in spite of the fact that simple Heisenberg interactions should be cancelled out at the Ce site owing to geometrical frustration. The transition takes place at nearly the same temperature with the substitution of La for Ce up to 90%. The Ce moment does not undergo long-range order by itself, but is parasitically induced at the transition, serving as a good probe for detecting the magnetism of Mn spins in a square lattice.Comment: 11 pages, 5 figures, to be published in J. Phys. Soc. Jp

Hormonal Signal Amplification Mediates Environmental Conditions during Development and Controls an Irreversible Commitment to Adulthood

Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals