Interferon-β-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF

AbstractIFN-β is induced via a c-fos dependent mechanism that is present downstream of the receptor activator of NF-κB ligand (RANKL)-RANK signal transduction cascade during osteoclast differentiation. Increased production of IFN-β in turn inhibits osteoclastogenesis. However, the mechanism by which IFN-β exerts its suppressive function remains unclear. In the present study, we found that miR-155, an IFN-β-induced miRNA, mediated the suppressive effect of IFN-β on osteoclast differentiation by targeting SOCS1 and MITF, two essential regulators of osteoclastogenesis. These findings have not only demonstrated that miR-155 inhibits osteoclast differentiation, but also provided a new therapeutic target for treatment of osteoclast-mediated diseases

Optimal design and performance analysis of a hybrid system combing a floating wind platform and wave energy converters

Combined floating offshore wind platform and Wave Energy Converters (WECs) systems have the potential to provide a cost-effective solution to offshore power supply and platform protection. The objective of this paper is to optimize the size and layout of WECs within the hybrid system under a given sea state with a numerical study. The numerical model was developed based on potential flow theory with viscous correction in frequency domain to investigate the hydrodynamic performance of a hybrid system consisting of a floating platform and multiple heaving WECs. A non-dimensional method was presented to determine a series of variables, including radius, draft, and layout of the cylindrical WEC at a typical wave frequency as the initial design. WECs with larger diameter to draft ratio were found to experience relatively smaller viscous effects, and achieve more wave power, larger effective frequency range and similar wave power per unit weight compared with those with the smaller diameter to draft ratio in the same sea state. The addition of WECs reduced the maximum horizontal force and pitch moment on the platform, whereas the maximum vertical force increased due to the increasing power take-off force, especially at low frequencies. The results presented in this paper provide guidance for the optimized design of WECs and indicate the potential for synergies between wave and wind energy utilization on floating platforms

Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport

Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4T804M mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis

Jump-Diffusion Long-Run Risks Models, Variance Risk Premium and Volatility Dynamics

Bank of Canada working papers are theoretical or empirical works-in-progress on subjects in economics and finance. The views expressed in this paper are those of the author. No responsibility for them should 2 be attributed to the Bank of Canada

A radial basis function based ghost cell method with improved mass conservation for complex moving boundary flows

A sharp interface immersed boundary method is presented for simulating flows around moving boundaries with arbitrary complex geometries. A time semi-implicit finite difference method is used to solve the incompressible Navier–Stokes equations on a fixed, staggered Cartesian grid. The boundary conditions at the immersed interface are enforced by a ghost cell method. Tracking complex moving boundaries and suppressing pressure oscillations are two major challenges in the sharp interface method. In this work, a polynomial radial basis function (PRBF) is introduced to the ghost cell method to implicitly represent and reconstruct the arbitrary immersed boundaries. In addition, a simple and robust signed identification strategy is used to determine the phase state of the grid cells. To suppress violent pressure oscillations on the moving boundaries, a fractional area representation (FAR) method, together with a mass force term, is introduced to the pressure Poisson equation. This FAR method not only retains the desirable property of consistent discretization in the ghost cell method but also takes advantage of the mass conservation property of the cut cell method. The proposed method is validated using five test cases, including the flow around a hydrofoil, in-line oscillation of a cylinder in a static fluid, uniform flows around a transversely oscillating cylinder, twin oscillating cylinders, and a pitching hydrofoil. The present results are in good agreement with the reference results, which validates the accuracy and capability of the proposed method.</p

Designing a flow-controlled STA-MCA anastomosis based on the Hagen–Poiseuille law for preventing postoperative hyperperfusion in adult moyamoya disease

Background: Technical improvements for preventing postoperative symptomatic cerebral hyperperfusion (CHP) during superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis for moyamoya disease (MMD) were seldom reported. Objectives: The aim of this study was to investigate the significance of application of a novel flow-controlled concept which voluntarily reduces the hemodynamic difference between the donor and recipient arteries based on the Hagen–Poiseuille law when performing direct anastomoses of recipient parasylvian cortical arteries (PSCAs) with anterograde hemodynamic sources from the MCA (M-PSCAs) in adult MMD. Design: This was a retrospective observational study. Methods: Direct anastomoses of recipient M-PSCAs were performed on 89 symptomatic hemispheres in 82 adult MMD patients in our hospital from January 2020 to June 2021. They were divided into the flow-controlled group (patients who received direct anastomosis under designed flow-controlled principles) and non-flow-controlled group (patients who received conventional direct anastomosis to obtain maximum flow). The patients’ basic characteristics and incidence of postoperative CHP were compared between the two groups. Risk factors for occurrence of postoperative CHP were analyzed. Results: Overall, 36 hemispheres were included in the non-flow-controlled group and 53 in flow-controlled group. The incidences of postoperative focal (22.6%) and symptomatic CHP (5.7%) in the flow-controlled group were significantly lower than those (focal, 52.8%; symptomatic, 25.0%) in the non-flow-controlled group ( p  = 0.003 and 0.009, respectively). Multivariate analysis revealed that the flow-controlled concept was significantly associated with the development of focal ( p  = 0.005) and symptomatic ( p  = 0.012) CHP. Conclusion: The flow-controlled STA-MCA anastomosis can significantly decrease the incidence of postoperative CHP during direct anastomoses of recipient M-PSCAs in adult MMD

Gradient-augmented level set two-phase flow method with pretreated reinitialization for three-dimensional violent sloshing

A three-dimensional (3D) gradient-augmented level set (GALS) two-phase flow model with a pretreated reinitialization procedure is developed to simulate violent sloshing in a cuboid tank. Based on a two-dimensional (2D) GALS method, 3D Hermite, and 3D Lagrange polynomial schemes are derived to interpolate the level set function and the velocity field at arbitrary positions over a cell, respectively. A reinitialization procedure is performed on a 3D narrow band to treat the strongly distorted interface and improve computational efficiency. In addition, an identification-correction technique is proposed and incorporated into the reinitialization procedure to treat the tiny droplet which can distort the free surface shape, even lead to computation failure. To validate the accuracy of the present GALS method and the effectiveness of the proposed identification correction technique, a 3D velocity advection case is first simulated. The present method is validated to have better mass conservation property than the classical level set and original GALS methods. Also, distorted and thin interfaces are well captured on all grid resolutions by the present GALS method. Then, sloshing under coupled surge and sway excitation, sloshing under rotational excitation are simulated. Good agreements are obtained when the present wave and pressure results are compared with the experimental and numerical results. In addition, the highly nonlinear free surface is observed, and the relationship between the excitation frequency and the impulsive pressure is investigated

Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch&rsquo;s membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models