The myeloperoxidase-derived oxidant HOSCN inhibits protein tyrosine phosphatases and modulates cell signalling via the mitogen-activated protein kinase (MAPK) pathway in macrophages

MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by hydrogen peroxide to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid) respectively. Specificity constants indicate that SCN− is a major substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. While HOCl and HOBr are powerful oxidizing agents, HOSCN is a less reactive, but more specific, oxidant which targets thiols and especially low pKa species. In the present study we show that HOSCN targets cysteine residues present in PTPs (protein tyrosine phosphatases) with this resulting in a loss of PTP activity for the isolated enzyme, in cell lysates and intact J774A.1 macrophage-like cells. Inhibition also occurs with MPO-generated HOCl and HOBr, but is more marked with MPO-generated HOSCN, particularly at longer incubation times. This inhibition is reversed by dithiothreitol, particularly at early time points, consistent with the reversible oxidation of the active site cysteine residue to give either a cysteine–SCN adduct or a sulfenic acid. Inhibition of PTP activity is associated with increased phosphorylation of p38a and ERK2 (extracellular-signal-regulated kinase 2) as detected by Western blot analysis and phosphoprotein arrays, and results in altered MAPK (mitogen-activated protein kinase) signalling. These data indicate that the highly selective targeting of some protein thiols by HOSCN can result in perturbation of cellular phosphorylation and altered cell signalling. These changes occur with (patho)physiological concentrations of SCN− ions, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage, particularly in smokers who have elevated plasma levels of SCN−

Earthquake Excited Base-Isolated Structures Protected by Tuned Liquid Column Dampers: Design Approach and Experimental Verification

In this contribution a direct approach for optimal design of a Tuned Liquid Column Damper (TLCD) device attached to the base slab of a base-isolated structure is presented, aiming at reducing the seismic displacement demand of the base-isolation subsystem. Assuming white noise base excitation, for a wide parameter range a direct optimization procedure yields design charts for optimal TLCD quantities. The performance of the base-isolated structure equipped with optimally tuned TLCD device in comparison to the simple base-isolated one is evaluated both numerically and experimentally. In a numerical study the system is subjected to the 44 records of the FEMA P-695 far-field ground motion set. The experimental studies are conducted on a three-story small-scale base-isolated shear frame model. From the results it can be concluded that a TLCD effectively controls the seismic response of earthquake excited low-damped base-isolated structures

Nonlinear mechanical model of a fluid inerter

Dynamic vibration control devices provided with inertance, such as Tuned Inerter Dampers, Tuned Mass Damper Inerters or Tuned Liquid Column Damper Inerters, have been shown in numerous numerical studies to have superior vibration mitigation performance compared to conventional devices, such as Tuned Mass Dampers. One possible way to produce this inertance effect is by means of a moving fluid. In this study, the dynamic performance of such a fluid inerter is analyzed experimentally. The considered small-scale prototype consists of a hydraulic cylinder, and the inertance is generated by the flow of the working fluid in an external channel attached to the cylinder itself. In a first step, the dry configuration, i.e. without fluid, is investigated, revealing a nonlinear dissipation force. In a corresponding mechanical model, this force is represented by a variant of the well-known Stribeck effect. Subsequent experiments on the complete configuration, i.e. with fluid, reveal a further nonlinear effect. This effect is attributed to the compressibility of the working fluid as well as air trapped in the channel. Once the parameters of the mechanical model are retrieved, comparative studies are carried out. These show a remarkable agreement between numerical and experimental outcomes, thus enabling the mechanical model to be used in dynamic vibration control devices, as stated above