Cyclic nucleotides and mitogen-activated protein kinases: regulation of simvastatin in platelet activation

<p>Abstract</p> <p>Background</p> <p>3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been widely used to reduce cardiovascular risk. These statins (i.e., simvastatin) may exert other effects besides from their cholesterol-lowering actions, including inhibition of platelet activation. Platelet activation is relevant to a variety of coronary heart diseases. Although the inhibitory effect of simvastatin in platelet activation has been studied; the detailed signal transductions by which simvastatin inhibit platelet activation has not yet been completely resolved.</p> <p>Methods</p> <p>The aim of this study was to systematically examine the detailed mechanisms of simvastatin in preventing platelet activation. Platelet aggregation, flow cytometric analysis, immunoblotting, and electron spin resonance studies were used to assess the antiplatelet activity of simvastatin.</p> <p>Results</p> <p>Simvastatin (20-50 μM) exhibited more-potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists (i.e., thrombin). Simvastatin inhibited collagen-stimulated platelet activation accompanied by [Ca²⁺]i mobilization, thromboxane A₂(TxA₂) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinases (i.e., p38 MAPK, JNKs) phosphorylation in washed platelets. Simvastatin obviously increased both cyclic AMP and cyclic GMP levels. Simvastatin markedly increased NO release, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and endothelial nitric oxide synthase (eNOS) expression. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the simvastatin-mediated inhibitory effects on platelet aggregation, PLCγ2 and p38 MAPK phosphorylation, and simvastatin-mediated stimulatory effects on VASP and eNOS phosphorylation.</p> <p>Conclusion</p> <p>The most important findings of this study demonstrate for the first time that inhibitory effect of simvastatin in platelet activation may involve activation of the cyclic AMP-eNOS/NO-cyclic GMP pathway, resulting in inhibition of the PLCγ2-PKC-p38 MAPK-TxA₂cascade, and finally inhibition of platelet aggregation.</p

Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation

Chimeric antigen receptor (CAR) T-cell therapy represents a major advancement for hematologic malignancies, with some patients achieving long-term remission. However, the majority of treated patients still die of their disease. A consistent predictor of response is tumor quantity, wherein a higher disease burden before CAR T-cell therapy portends a worse prognosis. Focal radiation to bulky sites of the disease can decrease tumor quantity before CAR T-cell therapy, but whether this strategy improves survival is unknown. We find that substantially reducing systemic tumor quantity using high-dose radiation to areas of bulky disease, which is commonly done clinically, is less impactful on overall survival in mice achieved by CAR T cells than targeting all sites of disease with low-dose total tumor irradiation (TTI) before CAR T-cell therapy. This finding highlights another predictor of response, tumor quality, the intrinsic resistance of an individual patient\u27s tumor cells to CAR T-cell killing. Little is known about whether or how an individual tumor\u27s intrinsic resistance may change under different circumstances. We find a transcriptional death receptor score that reflects a tumor\u27s intrinsic sensitivity to CAR T cells can be temporarily increased by low-dose TTI, and the timing of this transcriptional change correlates with improved in vivo leukemia control by an otherwise limited number of CAR T cells. This suggests an actionable method for potentially improving outcomes in patients predicted to respond poorly to this promising therapy and highlights that intrinsic tumor attributes may be equally or more important predictors of CAR T-cell response as tumor burden

A study on auditors’ emotional labor management

[[abstract]]Personality trait

Structural and surface characterizations of 2D β-In2Se3/3D β-Ga2O3 heterostructures grown on c-Sapphire substrates by molecular beam epitaxy

Abstract Integrating two-dimensional (2D) layered materials with wide bandgap β-Ga2O3 has unveiled impressive opportunities for exploring novel physics and device concepts. This study presents the epitaxial growth of 2D β-In2Se3/3D β-Ga2O3 heterostructures on c-Sapphire substrates by plasma-assisted molecular beam epitaxy. Firstly, we employed a temperature-dependent two-step growth process to deposit Ga2O3 and obtained a phase-pure $$(\overline{2 }01)$$ ( 2 ¯ 01 ) β-Ga2O3 film on c-Sapphire. Interestingly, the in-situ reflective high-energy electron diffraction (RHEED) patterns observed from this heterostructure revealed the in-plane ‘b’ lattice constant of β-Ga2O3 ~ 3.038Å. In the next stage, for the first time, 2D In2Se3 layers were epitaxially realized on 3D β-Ga2O3 under varying substrate temperatures (Tsub) and Se/In flux ratios (RVI/III). The deposited layers exhibited (00l) oriented β-In2Se3 on $$(\overline{2 }01)$$ ( 2 ¯ 01 ) β-Ga2O3/c-Sapphire with the epitaxial relationship of $$[11\overline{2 }0]$$ [ 11 2 ¯ 0 ] β-In2Se3 || [010] β-Ga2O3 and $$[10\overline{1 }0]$$ [ 10 1 ¯ 0 ] β-In2Se3 || [102] β-Ga2O3 as observed from the RHEED patterns. Also, the in-plane ‘a’ lattice constant of β-In2Se3 was determined to be ~ 4.027Å. The single-phase β-In2Se3 layers with improved structural and surface quality were achieved at a Tsub ~ 280 °C and RVI/III ~ 18. The microstructural and detailed elemental analysis further confirmed the epitaxy of 2D layered β-In2Se3 on 3D β-Ga2O3, a consequence of the quasi-van der Waals epitaxy. Furthermore, the β-Ga2O3 with an optical bandgap (Eg) of ~ 5.04 eV (deep ultraviolet) when integrated with 2D β-In2Se3, Eg ~ 1.43eV (near infra-red) can reveal potential applications in the optoelectronic field

Solid Phase Epitaxy of Single Phase Two-Dimensional Layered InSe Grown by MBE

Single-phase two-dimensional (2D) indium monoselenide (γ-InSe) film is successfully grown via solid phase epitaxy in the molecular beam epitaxy (MBE) system. Having high electron mobility and high photoresponsivity, ultrathin 2D γ-InSe semiconductors are attractive for future field-effect transistor and optoelectronic devices. However, growing single-phase γ-InSe film is a challenge due to the polymorphic nature of indium selenide (γ-InSe, α-In2Se3, β-In2Se3, γ-In2Se3, etc.). In this work, the 2D α-In2Se3 film was first grown on a sapphire substrate by MBE. Then, the high In/Se ratio sources were deposited on the α-In2Se3 surface, and an γ-InSe crystal emerged via solid-phase epitaxy. After 50 min of deposition, the initially 2D α-In2Se3 phase was also transformed into a 2D γ-InSe crystal. The phase transition from 2D α-In2Se3 to γ-InSe was confirmed by Raman, XRD, and TEM analysis. The structural ordering of 2D γ-InSe film was characterized by synchrotron-based grazing-incidence wide-angle X-ray scattering (GIWAXS)

Exercise Alters Gait Pattern but Not Knee Load in Patients with Knee Osteoarthritis

Six female patients with bilateral medial knee OA and 6 healthy controls were recruited. Patients with knee OA received a 6-week physiotherapist-supervised and home-based exercise program. Outcome measures, including the Western Ontario and McMaster Universities Arthritis Index and Short Form-36 Health Survey as well as objective biomechanical indices were obtained at baseline and follow-up. After treatment, no significant difference was observed in the knee abductor moment (KAM), lever arm, and ground reaction force. We, however, observed significantly improved pain and physical function as well as altered gait patterns, including a higher hip flexor moment and hip extension angle with a faster walking speed. Although KAM was unchanged, patients with bilateral knee OA showed an improved walking speed and altered the gait pattern after 6 weeks of supervised exercise. This finding suggests that the exercise intervention improves proximal joint mechanics during walking and can be considered for patients with bilateral knee OA. Non-weight-bearing strengthening without external resistance combined with stretching exercise may be an option to improve pain and function in individuals with OA who cannot perform high resistance exercises owing to pain or other reasons

Roles of 3‑Ethylrhodanine in Attaining Highly Ordered Crystal Arrays of Ambipolar Diketopyrrolopyrrole Oligomers

Until now, only limited DPP oligomers delivered ambipolar semiconductor characteristics. To develop a facile strategy of preparing ambipolar mono-DPP oligomers, two dithienyl diketopyrrolopyrrole (DPPT) based-conjugated molecules, <b>DPPT-RD</b> and <b>DPPT-DCV</b>, which contain 3-ethylrhodanine (RD) and dicyano-2-vinyl (DCV) end substituents were synthesized. The influences of the -RD end substituents on the molecular properties, solid-state morphology, and OFET performances of the DPPT oligomer were investigated. The UV–vis absorption and CV results showed that the RD end substituents provide the DPPT oligomer suitable <i>E</i>_HOMO and <i>E</i>_LUMO for hole and electron injection from the Au source-drain electrodes. Moreover, the RD end substituents also improve the crystalline nature of the DPPT oligomer. That is, <b>DPPT-RD</b> can form crystal arrays with good lattice orientation, larger crystalline size, and without polymorphism. With those properties, <b>DPPT-RD</b> thus display ambipolar characteristic with μ_h and μ_e reaching 2.16 × 10^–2 and 7.27 × 10^–2 cm² V^–1 s^–1, respectively