Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines

Objective - Although inflammation is a recognized feature of atherosclerosis, the impact of inflammation on cellular cholesterol homeostasis is unclear. This study focuses on the molecular mechanisms by which inflammatory cytokines disrupt low-density lipoprotein (LDL) receptor regulation.Methods and Results - IL-1 beta enhanced transformation of vascular smooth muscle cells into foam cells by increasing uptake of unmodified LDL via LDL receptors and by enhancing cholesterol esterification as demonstrated by Oil Red O staining and direct assay of intracellular cholesterol concentrations. In the absence of IL-1 beta, a high concentration of LDL decreased LDL receptor promoter activity, mRNA synthesis and protein expression. However, IL-1 beta enhanced LDL receptor expression, overriding the suppression usually induced by a high concentration of LDL and inappropriately increasing LDL uptake. Exposure to IL-1 beta also caused overexpression of the sterol regulatory element binding protein ( SREBP) cleavage-activating protein ( SCAP), and enhanced its translocation from the endoplasmic reticulum to the Golgi, where it is known to cleave SREBP, thereby enhancing LDL receptor gene expression.Conclusions - These observations demonstrate that IL-1 beta disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam cell formation. The implication of these findings is that inflammatory cytokines may contribute to intracellular LDL accumulation without previous modification of the lipoprotein

Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children

Extracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes

Modelling chemical abundance distributions for dwarf galaxies in the Local Group: the impact of turbulent metal diffusion

We investigate stellar metallicity distribution functions (MDFs), including Fe and ${\alpha}$-element abundances, in dwarf galaxies from the Feedback in Realistic Environments (FIRE) project. We examine both isolated dwarf galaxies and those that are satellites of a Milky Way-mass galaxy. In particular, we study the effects of including a sub-grid turbulent model for the diffusion of metals in gas. Simulations that include diffusion have narrower MDFs and abundance ratio distributions, because diffusion drives individual gas and star particles toward the average metallicity. This effect provides significantly better agreement with observed abundance distributions of dwarf galaxies in the Local Group, including the small intrinsic scatter in [${\alpha}$/Fe] vs. [Fe/H] (less than 0.1 dex). This small intrinsic scatter arises in our simulations because the interstellar medium (ISM) in dwarf galaxies is well-mixed at nearly all cosmic times, such that stars that form at a given time have similar abundances to within 0.1 dex. Thus, most of the scatter in abundances at z = 0 arises from redshift evolution and not from instantaneous scatter in the ISM. We find similar MDF widths and intrinsic scatter for satellite and isolated dwarf galaxies, which suggests that environmental effects play a minor role compared with internal chemical evolution in our simulations. Overall, with the inclusion of metal diffusion, our simulations reproduce abundance distribution widths of observed low-mass galaxies, enabling detailed studies of chemical evolution in galaxy formation.Comment: 19 pages, 13 figures, published in MNRA

Targeting tumor cell motility as a strategy against invasion and metastasis

Advances in diagnosis and treatment have rendered most solid tumors largely curable if they are diagnosed and treated before dissemination. However, once they spread beyond the initial primary location, these cancers are usually highly morbid, if not fatal. Thus, current efforts focus on both limiting initial dissemination and preventing secondary spread. There are two modes of tumor dissemination – invasion and metastasis – each leading to unique therapeutic challenges and likely to be driven by distinct mechanisms. However, these two forms of dissemination utilize some common strategies to accomplish movement from the primary tumor, establishment in an ectopic site, and survival therein. The adaptive behaviors of motile cancer cells provide an opening for therapeutic approaches if we understand the molecular, cellular, and tissue biology that underlie them. Herein, we review the signaling cascades and organ reactions that lead to dissemination, as these are non-genetic in nature, focusing on cell migration as the key to tumor progression. In this context, the cellular phenotype will also be discussed because the modes of migration are dictated by quantitative and physical aspects of the cell motility machinery.National Institute of General Medical Sciences (U.S.)National Cancer Institute (U.S.

Discrete Effects in Stellar Feedback: Individual Supernovae, Hypernovae, and IMF Sampling in Dwarf Galaxies

Using high-resolution simulations from the FIRE-2 (Feedback In Realistic Environments) project, we study the effects of discreteness in stellar feedback processes on the evolution of galaxies and the properties of the interstellar medium (ISM). We specifically consider the discretization of supernovae (SNe), including hypernovae (HNe), and sampling the initial mass function (IMF). We study these processes in cosmological simulations of dwarf galaxies with $z=0$ stellar masses $M_{\ast}\sim 10^{4}-3\times10^{6}\,M_\odot$ (halo masses $\sim 10^{9}-10^{10}\,M_\odot$). We show that the discrete nature of individual SNe (as opposed to a model in which their energy/momentum deposition is continuous over time, similar to stellar winds) is crucial in generating a reasonable ISM structure and galactic winds and in regulating dwarf stellar masses. However, once SNe are discretized, accounting for the effects of IMF sampling on continuous mechanisms such as radiative feedback and stellar mass-loss (as opposed to adopting IMF-averaged rates) has weak effects on galaxy-scale properties. We also consider the effects of rare HNe events with energies $\sim 10^{53}\,{\rm erg}$. The effects of HNe are similar to the effects of clustered explosions of SNe -- which are already captured in our default simulation setup -- and do not quench star formation (provided that the HNe do not dominate the total SNe energy budget), which suggests that HNe yield products should be observable in ultra-faint dwarfs today.Comment: 9 pages, 4 figure

A Fast Diagnosis Method for Both IGBT Faults and Current Sensor Faults in Grid-Tied Three-Phase Inverters With Two Current Sensors

© 1986-2012 IEEE. This article considers fault detection in the case of a three-phase three-wire (3P3W) inverter, when only two current sensors are used to save cost or due to a faulty current sensor. With two current sensors, there is no current method addressing the diagnosis of both IGBT open-circuit (OC) faults and current sensor faults. In order to solve this problem, this article proposes a method which innovatively combines two kinds of diagnosis variables, line voltage deviations and phase voltage deviations. The unique faulty characteristics of diagnosis variables for each fault are extracted and utilized to distinguish the fault. Using an average model, the method only needs the signals already available in the controller. Both IGBT OC faults and current sensor faults can be detected quickly in inverter mode and rectifier mode, so that the converter can be protected in a timely way to avoid further damages. In addition, error-adaptive thresholds are adopted to make the method robust. Effects such as system unbalance are analyzed to ensure that the method is robust and feasible. Simulation and experimental results are used to verify and validate the effectiveness of the method

Distributed Consensus of Linear Multi-Agent Systems with Adaptive Dynamic Protocols

This paper considers the distributed consensus problem of multi-agent systems with general continuous-time linear dynamics. Two distributed adaptive dynamic consensus protocols are proposed, based on the relative output information of neighboring agents. One protocol assigns an adaptive coupling weight to each edge in the communication graph while the other uses an adaptive coupling weight for each node. These two adaptive protocols are designed to ensure that consensus is reached in a fully distributed fashion for any undirected connected communication graphs without using any global information. A sufficient condition for the existence of these adaptive protocols is that each agent is stabilizable and detectable. The cases with leader-follower and switching communication graphs are also studied.Comment: 17 pages, 5 figue

Experimental delayed-choice entanglement swapping

Motivated by the question, which kind of physical interactions and processes are needed for the production of quantum entanglement, Peres has put forward the radical idea of delayed-choice entanglement swapping. There, entanglement can be "produced a posteriori, after the entangled particles have been measured and may no longer exist". In this work we report the first realization of Peres' gedanken experiment. Using four photons, we can actively delay the choice of measurement-implemented via a high-speed tunable bipartite state analyzer and a quantum random number generator-on two of the photons into the time-like future of the registration of the other two photons. This effectively projects the two already registered photons onto one definite of two mutually exclusive quantum states in which either the photons are entangled (quantum correlations) or separable (classical correlations). This can also be viewed as "quantum steering into the past"

An inhomogeneous toy-model of the quantum gravity with explicitly evolvable observables

An inhomogeneous (1+1)-dimensional model of the quantum gravity is considered. It is found, that this model corresponds to a string propagating against some curved background space. The quantization scheme including the Wheeler-DeWitt equation and the "particle on a sphere" type of the gauge condition is suggested. In the quantization scheme considered, the "problem of time" is solved by building of the quasi-Heisenberg operators acting in a space of solutions of the Wheeler-DeWitt equation and the normalization of the wave function corresponds to the Klein-Gordon type. To analyze the physical consequences of the scheme, a (1+1)-dimensional background space is considered for which a classical solution is found and quantized. The obtained estimations show the way to solution of the cosmological constant problem, which consists in compensation of the zero-point oscillations of the matter fields by the quantum oscillations of the scale factor. Along with such a compensation, a slow global evolution of a background corresponding to an universe expansion exists.Comment: 18 page

Topological Schr\"odinger cats: Non-local quantum superpositions of topological defects

Topological defects (such as monopoles, vortex lines, or domain walls) mark locations where disparate choices of a broken symmetry vacuum elsewhere in the system lead to irreconcilable differences. They are energetically costly (the energy density in their core reaches that of the prior symmetric vacuum) but topologically stable (the whole manifold would have to be rearranged to get rid of the defect). We show how, in a paradigmatic model of a quantum phase transition, a topological defect can be put in a non-local superposition, so that - in a region large compared to the size of its core - the order parameter of the system is "undecided" by being in a quantum superposition of conflicting choices of the broken symmetry. We demonstrate how to exhibit such a "Schr\"odinger kink" by devising a version of a double-slit experiment suitable for topological defects. Coherence detectable in such experiments will be suppressed as a consequence of interaction with the environment. We analyze environment-induced decoherence and discuss its role in symmetry breaking.Comment: 7 pages, 4 figure