Modulation of TGF-beta signaling by proinflammatory cytokines in articular chondrocytes.

OBJECTIVE: The normal structure and function of articular cartilage are the result of a precisely balanced interaction between anabolic and catabolic processes. The transforming growth factor-beta (TGF-beta) family of growth factors generally exerts an anabolic or repair response; in contrast, proinflammatory cytokines such as interleukin 1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) exert a strong catabolic effect. Recent evidence has shown that IL-1beta, and TNF-alpha, and the TGF-beta signaling pathways share an antagonistic relationship. The aim of this study was to determine whether the modulation of the response of articular chondrocytes to TGF-beta by IL-1beta or TNF-alpha signaling pathways occurs through regulation of activity and availability of mothers against DPP (Drosophila) human homologue (Smad) proteins. METHODS: Human articular chondrocytes isolated from knee joints from patients with osteoarthritis (OA) or normal bovine chondrocytes were cultured in suspension in poly-(2-hydroxyethyl methacrylate)-coated dishes with either 10% fetal bovine serum media or serum-deprived media 6h before treatment with IL-1beta alone, TNF-alpha alone or IL-1beta followed by TGF-beta. Nuclear extracts were examined by electrophoretic mobility-shift assays (EMSA) for nuclear factor-kappa B (NF-kappaB) and Smad3/4 deoxyribonucleic acid (DNA) binding. Nuclear extracts were also subjected to the TranSignal Protein/DNA array (Panomics, Redwood City, CA) enabling the simultaneous semiquantitative assessment of DNA-binding activity of 54 different transcription factors. Nuclear phospho-Smad2/3 and total Smad7 protein expression in whole cell lysates were studied by Western blot. Cytoplasmic Smad7, type II collagen alpha 1 (COL2A1), aggrecan and SRY-related high mobility group-Box gene 9 (SOX-9) mRNA expression were measured by real-time polymerase chain reaction (PCR). RESULTS: The DNA-binding activity of Smad3/4 in the TranSignal Protein/DNA array was downregulated by TNF-alpha (46%) or IL-1beta treatment (42%). EMSA analysis showed a consistent reduction in Smad3/4 DNA-binding activity in human articular chondrocytes treated with IL-1beta or TNF-alpha. TGF-beta-induced Smad3/4 DNA-binding activity and Smad2/3 phosphorylation were also reduced following pretreatment with IL-1beta in human OA and bovine chondrocytes. Real-time PCR and Western blot analysis showed that IL-1beta partially reversed the TGF-beta stimulation of Smad7 mRNA and protein levels in TGF-beta-treated human OA cells. In contrast, TGF-beta-stimulated COL2A1, aggrecan, and SOX-9 mRNA levels were abrogated by IL-1beta. CONCLUSIONS: IL-1beta or TNF-alpha exerted a suppressive effect on Smad3/4 DNA-binding activity in human articular chondrocytes, as well as on TGF-beta-induced stimulation of Smad3/4 DNA-binding activity and Smad2/3 phosphorylation in human OA and bovine articular chondrocytes. IL-1beta partially reversed the increase in TGF-beta-stimulated Smad7 mRNA or protein levels suggesting that Smad7 may not be involved in the suppression of TGF-beta signaling induced by IL-1beta or TNF-alpha in articular chondrocytes. The balance between the IL-1beta or TNF-alpha and the TGF-beta signaling pathways is crucial for maintenance of articular cartilage homeostasis and its disruption likely plays a substantial role in the pathogenesis of OA

How Peclet number affects microstructure and transient cluster aggregation in sedimenting colloidal suspensions

We study how varying the P \'eclet number (Pe) affects the steady state sedimentation of colloidal particles that interact through short-ranged attractions. By employing a hybrid molecular dynamics simulation method we demonstrate that the average sedimentation velocity changes from a non- monotonic dependence on packing fraction {\phi} at low Pe numbers, to a monotonic decrease with {\phi} at higher Pe numbers. At low Pe number the pair correlation functions are close to their equilibrium values, but as the Pe number increases, important deviations from equilibrium forms are observed. Although the attractive forces we employ are not strong enough to form permanent clusters, they do induce transient clusters whose behaviour is also affected by Pe number. In particular, clusters are more likely to fragment and less likely to aggregate at larger Pe numbers, and the probability of finding larger clusters decreases with increasing Pe number. Interestingly, the life-time of the clusters is more or less independent of Pe number in the range we study. Instead, the change in cluster distribution occurs because larger clusters are less likely to form with increasing Pe number. These results illustrate some of the subtleties that occur in the crossover from equilibrium like to purely non-equilibrium behaviour as the balance between convective and thermal forces changes.Comment: 8 page

On differential systems related to generalized Meixner and deformed Laguerre orthogonal polynomials

In this paper we present a connection between systems of differential equations for the recurrence coefficients of polynomials orthogonal with respect to the generalized Meixner and the deformed Laguerre weights. It is well-known that the recurrence coefficients of both generalized Meixner and deformed Laguerre orthogonal polynomials can be expressed in terms of solutions of the fifth Painlevé equation but no explicit relation between systems of differential equations for the recurrence coefficients was known. We also present certain limits in which the recurrence coefficients can be expressed in terms of solutions of the Painlevé XXXIV equation, which in the deformed Laguerre case extends previous studies and in the generalized Meixner case is a new result

Pan African Sanctuary Alliance: securing a future for the African great apes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145498/1/izy12174.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145498/2/izy12174_am.pd

Acoustic waves: should they be propagated forward in time, or forward in space?

The evolution of acoustic waves can be evaluated in two ways: either as a temporal, or a spatial propagation. Propagating in space provides the considerable advantage of being able to handle dispersion and propagation across interfaces with remarkable efficiency; but propagating in time is more physical and gives correctly behaved reflections and scattering without effort. Which should be chosen in a given situation, and what compromises might have to be made? Here the natural behaviors of each choice of propagation are compared and contrasted for an ordinary second order wave equation, the time-dependent diffusion wave equation, an elastic rod wave equation, and the Stokes'/ van Wijngaarden's equations, each case illuminating a characteristic feature of the technique. Either choice of propagation axis enables a partitioning the wave equation that gives rise to a directional factorization based on a natural "reference" dispersion relation. The resulting exact coupled bidirectional equations then reduce to a single unidirectional first-order wave equation using a simple "slow evolution" assumption that minimizes effect of subsequent approximations, while allowing a direct term-to-term comparison between exact and approximate theories.Comment: 12 pages, v2 correcte

Thin-film flow in helically wound rectangular channels with small torsion

Laminar gravity-driven thin-film flow down a helically-wound channel of rectangular cross-section with small torsion in which the fluid depth is small is considered. Neglecting the entrance and exit regions we obtain the steady-state solution that is independent of position along the axis of the channel, so that the flow, which comprises a primary flow in the direction of the axis of the channel and a secondary flow in the cross-sectional plane, depends only on position in the two-dimensional cross-section of the channel. A thin-film approximation yields explicit expressions for the fluid velocity and pressure in terms of the free-surface shape, the latter satisfying a non-linear ordinary differential equation that has a simple exact solution in the special case of a channel of rectangular cross-section. The predictions of the thin-film model are shown to be in good agreement with much more computationally intensive solutions of the small-helix-torsion Navier–Stokes equations. The present work has particular relevance to spiral particle separators used in the mineral-processing industry. The validity of an assumption commonly used in modelling flow in spiral separators, namely that the flow in the outer region of the separator cross-section is described by a free vortex, is shown to depend on the problem parameters

Hamiltonian structure for a differential system from a modified Laguerre weight via the geometry of the modified third Painlevé equation

Recurrence coefficients of semi-classical orthogonal polynomials are often related to the solutions of special nonlinear second-order differential equations known as the Painlevé equations. Each Painlevé equation can be written in a standard form as a non-autonomous Hamiltonian system, so it is natural to ask whether differential systems satisfied by the recurrence coefficients also possess Hamiltonian structures. We consider recurrence coefficients for a modified Laguerre weight which satisfy a differential system known to be related to the modified third Painlevé equation and identify a Hamiltonian structure for it by constructing its space of initial conditions. We also discuss a transformation from this system to the modified third Painlevé equation which simultaneously identifies a discrete system for the recurrence coefficients with a discrete Painlevé equation

Generation of two-color polarization-entangled optical beams with a self-phase-locked two-crystal Optical Parametric Oscillator

A new device to generate polarization-entangled light in the continuous variable regime is introduced. It consists of an Optical Parametric Oscillator with two type-II phase-matched non-linear crystals orthogonally oriented, associated with birefringent elements for adjustable linear coupling. We give in this paper a theoretical study of its classical and quantum properties. It is shown that two optical beams with adjustable frequencies and well-defined polarization can be emitted. The Stokes parameters of the two beams are entangled. The principal advantage of this setup is the possibility to directly generate polarization entangled light without the need of mixing four modes on beam splitters as required in current experimental setups. This device opens new directions for the study of light-matter interfaces and generation of multimode non-classical light and higher dimensional phase space