Abstract only Objective: Neuregulin-1 (Nrg1) promotes cardiomyocyte hypertrophy, survival, and cell cycle activity through ErbB signaling. It is investigated in clinical trials as a cardioprotective ...agent; however, its therapeutic use might be limited due to its pro-neoplastic potential for non-cardiomyocytes that makes targeted approaches necessary. High-throughput screening of hypertrophic agonists found that Nrg1 induces CITED4 (C4) expression. C4 is also upregulated in both physiological and pathological cardiac growth and necessary to prevent adverse remodeling in vivo. However, how C4 regulates Nrg1-signaling in the heart is yet unknown. Methods: We combined pulsed-SILAC labeling, click-chemistry and mass spectrometry that allows to capture immediate changes in the proteome and secretome after Nrg1 (12h and 24h) stimulation in siRNA-mediated C4-knockdown (C4KD) and control (ctr) NRVM and complemented this with established cell- and molecular biology techniques to validate and investigate cellular function and molecular signaling. Results: We confirmed dose-dependent C4 mRNA upregulation in response to Nrg1 stimulation in NRVM. Nrg1 downstream signaling through AKT was hindered in C4KD. Computational analysis comparing the nascent proteome after Nrg1 stimulation in C4KD and ctr NRVM revealed that C4 significantly regulates proteins responsible for translation, RNA processing and energy derivation. Consistent with previously observed development of cardiac fibrosis in C4 knockout mice in vivo , we found significant upregulation of TGFb2 in C4KD NRVM. We next confirmed the upregulation of TGFb2 and its downstream effectors in C4KD and ctr, while adenoviral overexpression of C4 led to reduced TGFb2 expression. Additionally, we found TGFb2 secretion increased from C4KD NRVM with Nrg1 stimulation in the nascent secretome. Conditioned media from C4KD NRVM led to an increased pro-fibrotic response in cardiac fibroblasts. In conclusion, nascent proteomics and secretomics help to elucidate C4-dependent Nrg1-signaling, which may be an important contribution toward our goal to identify targetable cardioprotective pathways in the heart.
When Shil'nikov Meets Hopf in Excitable Systems Champneys, Alan R.; Kirk, Vivien; Knobloch, Edgar ...
SIAM journal on applied dynamical systems,
01/2007, Letnik:
6, Številka:
4
Journal Article
Recenzirano
This paper considers a hierarchy of mathematical models of excitable media in one spatial dimension, specifically the FitzHugh-Nagumo equation and several models of the dynamics of intracellular ...calcium. A common feature of the models is that they support solitary traveling pulse solutions which lie on a characteristic C-shaped curve of wave speed versus parameter. This C lies to the left of a U-shaped locus of Hopf bifurcations that corresponds to the onset of small-amplitude linear waves. The central question addressed is how the Hopf and solitary wave (homoclinic orbit in a moving frame) bifurcation curves interact in these "CU systems." A variety of possible codimension-two mechanisms is reviewed through which such Hopf and homoclinic bifurcation curves can interact. These include Shil'nikov-Hopf bifurcations and the local birth of homoclinic chaos from a saddle-node/Hopf (Gavrilov-Guckenheimer) point. Alternatively, there may be barriers in phase space that prevent the homoclinic curve from reaching the Hopf bifurcation. For example, the homoclinic orbit may bump into another equilibrium at a so-called T-point, or it may terminate by forming a heteroclinic cycle with a periodic orbit. This paper presents the results of detailed numerical continuation results on different CU systems, thereby illustrating various mechanisms by which Hopf and homoclinic curves interact in CU systems. Owing to a separation of time scales in these systems, considerable care has to be taken with the numerics in order to reveal the true nature of the bifurcation curves observed.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The dynamics occurring near a heteroclinic cycle between a hyperbolic equilibrium and a hyperbolic periodic orbit is analyzed. The case of interest is when the equilibrium has a one-dimensional ...unstable manifold and a two-dimensional stable manifold while the stable and unstable manifolds of the periodic orbit are both two-dimensional. A codimension-two heteroclinic cycle occurs when there are two codimension-one heteroclinic connections, with the connection from the periodic orbit to the equilibrium corresponding to a tangency between the two relevant manifolds. The results are restricted to $\mathbb{R}^3$, the lowest possible dimension in which such a heteroclinic cycle can occur, but are expected to be applicable to systems of higher dimensions as well. A geometric analysis is used to partially unfold the dynamics near such a heteroclinic cycle by constructing a leading-order expression for the Poincaré map in a full neighborhood of the cycle in both phase and parameter space. Curves of orbits homoclinic to the equilibrium are located in a generic parameter plane, as are curves of homoclinic tangencies to the periodic orbit. Moreover, it is shown how curves of folds of periodic orbits, which have different asymptotics near the homoclinic bifurcation of the equilibrium and the homoclinic bifurcation of the periodic orbit, are glued together near the codimension-two point. A simple global assumption is made about the existence of a pair of codimension-two heteroclinic cycles corresponding to a first and last tangency of the stable manifold of the equilibrium and the unstable manifold of the periodic orbit. Under this assumption, it is shown how the locus of homoclinic orbits to the equilibrium should oscillate in the parameter space, a phenomenon known as homoclinic snaking. Finally, we present several numerical examples of systems that arise in applications, which corroborate and illustrate our theory.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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