scholarly journals A mathematical model relates intracellular TLR4 oscillations to sepsis progression

2017 ◽  
Author(s):  
Razvan C. Stan ◽  
Francisco G. Soriano ◽  
Maristela M. de Camargo
Keyword(s):  
Sepsis Syndrome ◽  
Signaling Cascades ◽  
Hospital Data ◽  
Cell Organelles ◽  
Toll Like Receptor 4 ◽  
Downstream Signaling ◽  
Fixed Point Attractor ◽  
Point Attractor ◽  
Bacterial Stimulation ◽  
Concentration Changes

AbstractOscillations drive many biological processes and their modulation is determinant for various pathologies. In sepsis syndrome, Toll-like receptor 4 (TLR4) is a key sensor for signaling the presence of Gram-negative bacteria. Its expression and activity, along with its intracellular trafficking rates shift the equilibrium between the pro‐ and anti-inflammatory downstream signaling cascades, leading to either the physiological resolution of the bacterial stimulation or to sepsis. We hypothesize that the initial tlr4 expression in patients diagnosed with sepsis and TLR4 dynamic concentration changes on the cell membrane or intracellularly, dictates how the sepsis syndrome is initiated. Using a set of three differential equations, we defined the TLR4 flux between relevant cell organelles. We obtained three different regions in the phase space: 1. a limit-cycle describing unstimulated physiological oscillations, 2. a fixed-point attractor resulting from moderate LPS stimulation that is resolved and 3. a double-attractor resulting from sustained LPS stimulation that leads to sepsis. We tested the models against hospital data of sepsis patients and we correctly evaluate the clinical outcome of these patients.

Interrupting the FGF19-FGFR4 Axis to Therapeutically Disrupt Cancer Progression

2018 ◽  
Vol 19 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Liwei Lang ◽  
Austin Y. Shull ◽  
Yong Teng
Keyword(s):  
Cancer Progression ◽  
Therapeutic Strategy ◽  
Tumor Development ◽  
Vital Role ◽  
Signaling Cascades ◽  
Cancer Cell Proliferation ◽  
Clinical Use ◽  
Fibroblast Growth ◽  
Apoptosis Resistance ◽  
Downstream Signaling

Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.

scholarly journals Spinal BDNF-induced phrenic motor facilitation requires PKCθ activity

2017 ◽  
Vol 118 (5) ◽  
pp. 2755-2762 ◽  
Author(s):  
Ibis M. Agosto-Marlin ◽  
Gordon S. Mitchell
Keyword(s):  
Motor Neurons ◽  
Akt Signaling ◽  
Signaling Cascades ◽  
Receptor Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Inhibitory Peptide ◽  
Downstream Signaling ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Necessary And Sufficient

Spinal brain-derived neurotrophic factor (BDNF) is necessary and sufficient for certain forms of long-lasting phrenic motor facilitation (pMF). BDNF elicits pMF by binding to its high-affinity receptor, tropomyosin receptor kinase B (TrkB), on phrenic motor neurons, potentially activating multiple downstream signaling cascades. Canonical BDNF/TrkB signaling includes the 1) Ras/RAF/MEK/ERK MAP kinase, 2) phosphatidylinositol 3‐kinase (PI3K)/Akt, and 3) PLCγ/PKC pathways. Here we demonstrate that spinal BDNF-induced pMF requires PLCγ/PKCθ in normal rats but not MEK/ERK or PI3K/Akt signaling. Cervical intrathecal injections of MEK/ERK (U0126) or PI3K/Akt (PI-828; 100 μM, 12 μl) inhibitor had no effect on BDNF-induced pMF (90 min after BDNF; U0126 + BDNF: 59 ± 14%, PI-828 + BDNF: 59 ± 8%, inhibitor vehicle + BDNF: 56 ± 7%; all P ≥ 0.05). In contrast, PKCθ inhibition with theta inhibitory peptide (TIP; 0.86 mM, 12 μl) prevented BDNF-induced pMF (90 min after BDNF; TIP + BDNF: −2 ± 2%; P ≤ 0.05 vs. other groups). Thus BDNF-induced pMF requires downstream PLCγ/PKCθ signaling, contrary to initial expectations. NEW AND NOTEWORTHY We demonstrate that BDNF-induced pMF requires downstream signaling via PKCθ but not MEK/ERK or PI3K/Akt signaling. These data are essential to understand the sequence of the cellular cascade leading to BDNF-dependent phrenic motor plasticity.

scholarly journals Equivalent Electronic Circuit of a System of Oscillators Connected With Periodically Variable Stiffness

2022 ◽  
Author(s):  
Soumyajit Seth ◽  
Grzegorz Kudra ◽  
Krzysztof Witkowski ◽  
Jan Awrejcewicz
Keyword(s):  
Mechanical System ◽  
Electronic Circuit ◽  
Mechanical Design ◽  
Variable Stiffness ◽  
State Variables ◽  
Fixed Point Attractor ◽  
Point Attractor ◽  
Magnetic Resistance ◽  
Nonlinear Behaviors ◽  
Resistance Forces

In this paper, we have shown the electronic circuit equivalence of a mechanical system consists of two oscillators coupled with each other. The mechanical design has the effects of the magnetic, resistance forces and the spring constant of the system is periodically varying. We have shown that the system’s state variables, such as the displacements and the velocities, under the effects of different forces, lead to some nonlinear behaviors, like a transition from the fixed point attractor to the chaotic attractor through the periodic and quasi-periodic attractors. We have constructed the equivalent electronic circuit of this mechanical system and have verified the numerically obtained behaviors using the electronic circuit.

scholarly journals Differential YAP nuclear signaling in healthy and dystrophic skeletal muscle

2019 ◽  
Vol 317 (1) ◽  
pp. C48-C57 ◽  
Author(s):  
Shama R. Iyer ◽  
Sameer B. Shah ◽  
Christopher W. Ward ◽  
Joseph P. Stains ◽  
Espen E. Spangenburg ◽  
...  
Keyword(s):  
Muscle Development ◽  
Signaling Cascades ◽  
In Vitro Assays ◽  
Pcr Analysis ◽  
Western Blots ◽  
Downstream Signaling ◽  
Nuclear Signaling ◽  
Extracellular Matrix Stiffness

Mechanical forces regulate muscle development, hypertrophy, and homeostasis. Force-transmitting structures allow mechanotransduction at the sarcolemma, cytoskeleton, and nuclear envelope. There is growing evidence that Yes-associated protein (YAP) serves as a nuclear relay of mechanical signals and can induce a range of downstream signaling cascades. Dystrophin is a sarcolemma-associated protein, and its absence underlies the pathology in Duchenne muscular dystrophy. We tested the hypothesis that the absence of dystrophin in muscle would result in reduced YAP signaling in response to loading. Following in vivo contractile loading in muscles of healthy (wild-type; WT) mice and mice lacking dystrophin ( mdx), we performed Western blots of whole and fractionated muscle homogenates to examine the ratio of phospho (cytoplasmic) YAP to total YAP and nuclear YAP, respectively. We show that in vivo contractile loading induced a robust increase in YAP expression and its nuclear localization in WT muscles. Surprisingly, in mdx muscles, active YAP expression was constitutively elevated and unresponsive to load. Results from qRT-PCR analysis support the hyperactivation of YAP in vivo in mdx muscles, as evidenced by increased gene expression of YAP downstream targets. In vitro assays of isolated myofibers plated on substrates with high stiffness showed YAP nuclear labeling for both genotypes, indicating functional YAP signaling in mdx muscles. We conclude that while YAP signaling can occur in the absence of dystrophin, dystrophic muscles have altered mechanotransduction, whereby constitutively active YAP results in a failure to respond to load, which could be attributed to the increased state of “pre-stress” with increased cytoskeletal and extracellular matrix stiffness.

scholarly journals STAT5 is Expressed in CD34+/CD38− Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1021 ◽  
Author(s):  
Emir Hadzijusufovic ◽  
Alexandra Keller ◽  
Daniela Berger ◽  
Georg Greiner ◽  
Bettina Wingelhofer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Janus Kinase ◽  
Signaling Cascades ◽  
Nuclear Compartment ◽  
Downstream Signaling ◽  
Direct Targeting ◽  
Calr Mutations

Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, n = 10), essential thrombocythemia (ET, n = 15) and primary myelofibrosis (PMF, n = 9), and in the JAK2 V617F-positive cell lines HEL and SET-2. As assessed by immunohistochemistry, MPN cells displayed pSTAT5 in all patients examined. Phosphorylated STAT5 was also detected in putative CD34+/CD38− MPN stem cells (MPN-SC) by flow cytometry. Immunostaining experiments and Western blotting demonstrated pSTAT5 expression in both the cytoplasmic and nuclear compartment of MPN cells. Confirming previous studies, we also found that JAK2-targeting drugs counteract the expression of pSTAT5 and growth in HEL and SET-2 cells. Growth-inhibition of MPN cells was also induced by the STAT5-targeting drugs piceatannol, pimozide, AC-3-019 and AC-4-130. Together, we show that CD34+/CD38− MPN-SC express pSTAT5 and that pSTAT5 is expressed in the nuclear and cytoplasmic compartment of MPN cells. Whether direct targeting of pSTAT5 in MPN-SC is efficacious in MPN patients remains unknown.

EFFECT OF DISSIPATION ON THE HAMILTONIAN CHAOS IN COUPLED OSCILLATOR SYSTEMS

2002 ◽  
Vol 12 (04) ◽  
pp. 859-867 ◽  
Author(s):  
V. SHEEJA ◽  
M. SABIR
Keyword(s):  
Degrees Of Freedom ◽  
Chaotic Behavior ◽  
Period Doubling ◽  
Dissipation Function ◽  
Hamiltonian Chaos ◽  
Fixed Point Attractor ◽  
Point Attractor ◽  
Route To Chaos ◽  
Period Doubling Bifurcations ◽  
External Driving

We study the effect of linear dissipative forces on the chaotic behavior of coupled quartic oscillators with two degrees of freedom. The effect of quadratic Rayleigh dissipation functions, one with diagonal coefficients only and the other with nondiagonal coefficients as well are studied. It is found that the effect of Rayleigh Dissipation function with diagonal coefficients is to suppress chaos in the system and to lead the system to its equilibrium state. However, with a dissipation function with nondiagonal elements, other types of behaviors — including fixed point attractor, periodic attractors and even chaotic attractors — are possible even when there is no external driving. In such a system the route to chaos is through period-doubling bifurcations. This result contradicts the view that linear dissipation always causes decay of oscillations in oscillator models.

scholarly journals Regulation of Jak2 through the Ubiquitin-Proteasome Pathway Involves Phosphorylation of Jak2 on Y1007 and Interaction with SOCS-1

2002 ◽  
Vol 22 (10) ◽  
pp. 3316-3326 ◽  
Author(s):  
Daniela Ungureanu ◽  
Pipsa Saharinen ◽  
Ilkka Junttila ◽  
Douglas J. Hilton ◽  
Olli Silvennoinen
Keyword(s):  
Catalytic Activity ◽  
Tyrosine Kinases ◽  
Signaling Cascades ◽  
Ubiquitin Proteasome Pathway ◽  
Downstream Signaling ◽  
The Family ◽  
Ubiquitin Proteasome ◽  
Socs Proteins ◽  
Proteasome Pathway ◽  
Control Activation

ABSTRACT The family of cytoplasmic Janus (Jak) tyrosine kinases plays an essential role in cytokine signal transduction, regulating cell survival and gene expression. Ligand-induced receptor dimerization results in phosphorylation of Jak2 on activation loop tyrosine Y1007 and stimulation of its catalytic activity, which, in turn, results in activation of several downstream signaling cascades. Recently, the catalytic activity of Jak2 has been found to be subject to negative regulation through various mechanisms including association with SOCS proteins. Here we show that the ubiquitin-dependent proteolysis pathway is involved in the regulation of the turnover of activated Jak2. In unstimulated cells Jak2 was monoubiquitinated, and interleukin-3 or gamma interferon stimulation induced polyubiquitination of Jak2. The polyubiquitinated Jak2 was rapidly degraded through proteasomes. By using different Jak2 mutants we show that tyrosine-phosphorylated Jak2 is preferentially polyubiquitinated and degraded. Furthermore, phosphorylation of Y1007 on Jak2 was required for proteasomal degradation and for SOCS-1-mediated downregulation of Jak2. The proteasome inhibitor treatment stabilized the Jak2-SOCS-1 protein complex and inhibited the proteolysis of Jak2. In summary, these results indicate that the ubiquitin-proteasome pathway negatively regulates tyrosine-phosphorylated Jak2 in cytokine receptor signaling, which provides an additional mechanism to control activation of Jak2 and maintain cellular homeostasis.

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