1,721,062 research outputs found
Kinematic FE homogenized limit analysis model for masonry curved structures strengthened by near surface mounted FRP bars
No full textMasonry curved structures, as for instance arches, domes and vaults, are very diffused in historical and existing structures and usually require seismic upgrading and/or rehabilitation.
Where FRP external strips cannot be applied for some reasons, the utilization of FRP bars embedded near the external surface becomes a very interesting and effective alternative.
In this paper, a kinematic Finite Element limit analysis model to predict collapse loads and failure mechanisms of masonry curved structures reinforced with near surface mounted FRP bars regularly distributed is presented. Reinforced masonry homogenized failure surfaces are obtained by means of a compatible identification procedure, where a central brick is supposed interacting with its neighbors by means of finite thickness mortar joints, filler epoxy resin and FRP rods. In the model, it is required only that the curved structure results from a periodic disposition of bricks, mortar and FRP bars. Therefore, any pattern (multi-leaf, multi-head and single leaf) may be potentially investigated with the procedure proposed. In the framework of the kinematic theorem of limit analysis, a simple constrained minimization problem is obtained on the unit cell, suitable to estimate – with a very limited computational effort – reinforced masonry homogenized failure surfaces.
A FE strategy is adopted to solve the homogenization problem at a cell level, modeling joints, bricks, filler and FRP rods by means of 8-noded infinitely resistant parallelepiped elements. A possible jump of velocities is assumed at the interfaces between contiguous elements, where plastic dissipation occurs.
For mortar and bricks interfaces, a frictional behavior with possible limited tensile and compressive strength is assumed, whereas for epoxy resin and FRP bars some formulas available in the literature are adopted in order to take into account in an approximate but effective way, the delamination of the bar from the epoxy and the failure of the filler at the interface with the joint.
In order to validate the model proposed, two numerical examples are analyzed, consisting of a circular masonry arch and a hemispherical dome. For both the examples presented, comparisons with experimental evidences, where available, and alternative non-linear FE procedures are reported.
Reliable predictions of collapse loads and failure mechanisms are obtained with the model proposed for all the cases analyzed, meaning that the approach may be used by practitioners for a fast and reliable evaluation of the effectiveness of a strengthening intervention
Inhibitory action of ivabradine on hHCN4 channel
No full textInhibitory action of ivabradine on hHCN4 channe
The cardiac pacemaker current
No full textIn mammals cardiac rate is determined by the duration of the diastolic depolarization of sinoatrial node (SAN) cells which is mainly determined by the pacemaker I-f current I-f-channels are encoded by four members of the hyperpolarization-activated cyclic nucleotide-gated gene (HCN1-4) family. HCN4 is the most abundant isoform in the SAN, and its relevance to pacemaking has been further supported by the discovery of four loss-of-function mutations in patients with mild or severe forms of cardiac rate disturbances. Due to its selective contribution to pacemaking, the I-f current is also the pharmacological target of a selective heart rate-reducing agent (ivabradine) currently used in the clinical practice. Albeit to a minor extent, the I-f current is also present in other spontaneously active myocytes of the cardiac conduction system (atrioventricular node and Purkinje fibres). In working atrial and ventricular myocytes f-channels are expressed at a very low level and do not play any physiological role; however in certain pathological conditions over-expression of HCN proteins may represent an arrhythmogenic mechanism. In this review some of the most recent findings on f/HCN channels contribution to pacemaking are described
I-f modulation: perspectives in clinical medicine
No full textAs opposed to a number of other pharmacological agents, ivabradine expresses high selectivity and specificity for its target. Ivabradine exerts a unique action on cardiac pacemaker activity, based on its block of the hyperpolarization-activated, cyclic nucleotide-gated channels that pass the pacemaker current, If. In doing so, it suppresses but does not stop the sinoatrial pacemaker's rate of firing. In the following pages, we will review the mechanisms of normal pacemaker activity in the heart, discuss ivabradine's mechanism of action, and then review the advantages of heart rate reduction in clinical settings as well as other potential applications of the drug
Physiology and pharmacology of the cardiac pacemaker ("funny") current
No full textFirst described over a quarter of a century ago, the cardiac pacemaker funny (I(f)) current has been extensively characterized since, and its role in cardiac pacemaking has been thoroughly demonstrated. A similar current, termed I(h), was later described in different types of neurons, where it has a variety of functions and contributes to the control of cell excitability and plasticity. I(f) is an inward current activated by both voltage hyperpolarization and intracellular cAMP. In the heart, as well as generating spontaneous activity, f-channels mediate autonomic-dependent modulation of heart rate: beta-adrenergic stimulation accelerates, and vagal stimulation slows, cardiac rate by increasing and decreasing, respectively, the intracellular cAMP concentration and, consequently, the f-channel degree of activation. Four isoforms of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels have been cloned more recently and shown to be the molecular correlates of native f-channels in the heart and h-channels in the brain. Individual HCN isoforms have kinetic and modulatory properties which differ quantitatively. A comparison of their biophysical properties with those of native pacemaker channels provides insight into the molecular basis of the pacemaker current properties and, together with immunolabelling and other detection techniques, gives information on the pattern of HCN isoform distribution in different tissues. Because of their relevance to cardiac pacemaker activity, f-channels are a natural target of drugs aimed at the pharmacological control of heart rate. Several agents developed for their ability to selectively reduce heart rate act by a specific inhibition of f-channel function; these substances have a potential for the treatment of diseases such as angina and heart failure. In the near future, devices based on the delivery of f-channels in situ, or of a cellular source of f-channels (biological pacemakers), will likely be developed for use in therapies for diseases of heart rhythm with the aim of replacing electronic pacemakers
Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels
No full textIvabradine is a 'heart rate-reducing' agent able to slow heart rate, without complicating side-effects. Its action results from a selective and specific block of pacemaker f-channels of the cardiac sinoatrial node (SAN). Investigation has shown that block by ivabradine requires open f-channels, is use dependent, and is affected by the direction of current flow. The constitutive elements of native pacemaker channels are the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, of which four isoforms (HCN1-4) are known; in rabbit SAN tissue HCN4 is expressed strongly, and HCN1 weakly. In this study we have investigated the blocking action of ivabradine on mouse (m) HCN1 and human (h) HCN4 channels heterologously expressed in HEK 293 cells. Ivabradine blocked both channels in a dose-dependent way with half-block concentrations of 0.94 μ for mHCNI and 2.0 μM for hHCN4.Properties of block changed substantially for the two channels. Block of hHCN4 required open channels, was strengthened by depolarization and was relieved by hyperpolarization. Block of mHCN1 did not occur, nor was it relieved, when channels were in the open state during hyperpolarization; block required channels to be either closed, or in a transitional state between open and closed configurations. The dependence of block upon current flow was limited for hHCN4, and not significant for mHCN1 channels. In summary our results indicate that ivabradine is an 'open-channel' blocker of hHCN4, and a 'closed-channel' blocker of mHCN1 channels. The mode of action of ivabradine on the two channels is discussed by implementing a simplified version of a previously developed model of f-channel kinetics
Toward a better understanding of HCN4 inhibition by the heart rate reducing agent ivabradine
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