Pathophysiological Mechanisms of Premature Ventricular Complexes

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia. Despite the high prevalence, the cause of PVCs remains elusive in most patients. A better understanding of the underlying pathophysiological mechanism may help to steer future research. This review aims to provide an overview of the potential pathophysiological mechanisms of PVCs and their differentiation

The functional role of the intracellular effectors of the diacylglycerol pathway and new opportunities for their pharmacological modulations

A másodlagos messenger molekula diacil-glicerol (DAG) és intracelluláris effektorai (a C1 domént tartalmazó szignál-proteinek) meghatározó szerepet játszanak olyan jelátviteli folyamatok szabályozásában, mint a sejtproliferáció, a differenciálódás, az apoptózis és a tumorgenezis. A Disszertáció első részében a protein kináz C (PKC) rendszer (az egyik legfontosabb DAG-effektor molekulacsalád) tagjainak izoforma-specifikus és antagonisztikus szerepét elemeztük a faggyúmirigy biológiai folyamatainak szabályozásában. A PKC rendszer forbol-észter (PMA) általi aktivációja fokozta a humán sebocyták lipidszintézisét, amely a sejtek terminális differenciálódásának indikátora. Farmakológiai módszerek (PKC inhibitorok felhasználása), valamint sejt- és molekuláris biológiai technikák segítségével megállapítottuk, hogy a sebocytákban expresszálódó öt PKC izoforma (cPKCα, nPKCδ, ε, η és aPKCζ) közül a PMA hatásának közvetítésében a cPKCα és az nPKCδ izoformák vesznek részt. További fontos megfigyelésünk volt emellett, hogy az nPKCδ részt vesz az ismert gyulladásos prekurzor, az arachidonsav lipidszintézist fokozó és apoptózist indukáló celluláris hatásainak szignáltranszdukciós útvonalában is. Az aPKCζ-ról emellett bebizonyosodott, hogy konstitutív enzimaktivitásával visszaszorítja a terminális differenciálódás (lipidfelhalmozás) és az apoptózis sejtfolyamatait. A Disszertáció második részében a sokoldalú intracelluláris szignáltranszducer, a Vav1 molekula ligandkötési sajátosságait elemeztük. A DAG-felismerő intramolekuláris alegységként funkcionáló C1 domén a Vav1 molekulában is megtalálható és központi szerepet játszik a guanin nukleotid cserélő enzimaktivitás szabályozásában. A forbol-észter-kötés hiánya miatt ugyanakkor az atípusos C1 domének közé lett besorolva annak ellenére, hogy a domén ligandkötőhelyének geometriai felépítése gyakorlatilag teljesen homológ a PKC enzimek típusos C1 doménjával (amelyek nagy affinitással kötnek forbol-észtert). Rekombináns géntechnológia és irányított mutagenezis segítségével sikerült azonosítanunk öt aminosavat (Glu9, Glu10, Thr11, Thr24 és Tyr26) a kötőzseb peremén, amelyek kumulatív módon csökkentik a ligandaffinitást. Molekuláris modellezés felhasználásával megállapítottuk továbbá, hogy ezen inkompatibilis aminosavak lecsökkentik a kötőhely csúcsának hidrofóbicitását, miáltal a kötőhely membránasszociációja zavart szenved és gátlódik a ligand-C1-domén-membrán hármas komplexének kialakulása. A szerkezeti sajátosságok felhasználásával olyan DAG-analóg molekulák (DAG-laktonok) kifejlesztését kezdtük el, amelyek a Vav1 C1-specifikus aminosavak targetálásán keresztül szelektíven befolyásolhatják az enzimatikus funkciót. The lipophilic second messenger diacylglycerol (DAG) and its intracellular effectors (C1 domain containing proteins) play a substantial role in signaling events controling cell proliferation, differentiation, apoptosis and tumor formation. In the first part of the Dissertation, we demonstrate the pivotal, isoform-specific, differential and antagonistic role of protein kinase C (PKC), one the most important family of DAG-effector molecules, in the regulation of sebaceous gland biology. We report that the phorbol-ester-(PMA)-driven activation of the PKC system stimulates the lipid synthesis (hallmark of terminal differentiation of sebocytes) of human sebocytes. Our pharmacological (using PKC inhibitors) as well as cell and molecular biological approaches revealed that, among the five isoforms (cPKCα, nPKCδ, ε, η and aPKCζ) expressed by the sebocytes, the activation of cPKCα and nPKCδ participate in mediating the lipogenic effects of the PKC activator. Of further importance, using the above mentioned methods, nPKCδ was also found to play a major role in the cellular transduction of the lipogenic and apoptosis-inducing effects of arachidonic acid (a well-known inflammatory precursor). Finally, endogenous aPKCζ activity was shown to constitutively suppress basal lipid synthesis and apoptosis. In the second part of our studies, we characterized the ligand binding properties of the C1 domain (highly conserved intramolecular recognition motif of DAG) of Vav1, a versatile signal transducer with guanine nucleotide exchange activity toward small GTPases. The C1 domain of Vav1, which plays a key role in the regulation of Vav activity, is classified as atypical (non-phorbol-responsive), despite the fact that it retains a binding pocket geometry homologous to that of the typical (phorbol-responsive) C1 domains of PKCs. Using recombinant gene technology and site-directed mutagenesis approaches, we have clarified the basis for its failure to bind ligands and have identified five crucial residues (Glu9, Glu10, Thr11, Thr24 and Tyr26) along the rim of the binding pocket, which weaken binding potency in a cumulative fashion. With the help of computer modeling, we predicted that these unique residues in Vav1 decrease the hydrophobicity of the rim of the binding cleft, impairing membrane association and thereby preventing formation of the ternary C1-ligand-membrane binding complex. Initial design of DAG-lactones to exploit these Vav1-unique residues showed enhanced selectivity for C1 domains incorporating these residues, suggesting a strategy for the development of ligands targeting Vav1 activity

Investigating Condensation Heat Transfer during Vapour Phase Soldering on Round-Shaped PCB Plates

The paper presents new results in the simplified modelling of Vapour Phase Soldering (VPS) heat transfer process, where the prepared Printed Circuit Board (PCB) is assumed as a horizontal plate during the process. The paper focuses on previously not investigated round-shaped PCB plates. An explicit modelling method (based on Nusselt theory) was modified and used to investigate the heat transfer on the different sized PCBs. For verification, measurements were performed in an experimental VPS oven. Different models and introduced corrections were used for the calculations, where the final results showed acceptable error values compared to measurement data. The results point out that a specific modelling case provides the best result, without any dependence on the size of the PCB plates. It was also found that in special cases, rounded PCB corners can be neglected during calculations with rectangular PCBs

Impact of electromigration and isothermal ageing on lead-free solder joints of chip-sized SMD components

This paper presents the effect of electromigration and isothermal ageing in lead-free SAC305 (Sn3Ag0.5Cu) solder joints of chip-size surface mounted (SMD) components, where different track-to-pad joining angles define the current density in the joint. The samples were based on 0402 and 0603 size components and were loaded for an extensive period of 4000 h with 2 and 2.5 A, respectively, in an increased temperature environment (40 °C). The solder joint reliability was assessed at selected times during the loading, with shear tests and cross-section analysis on metallurgic structures. Optical and scanning electron microscopy were used to analyse the microstructure of the solder joints. The shear strength of the solder joints was found to decrease with the increasing loading times. Intermetallic compound (IMC) was found on the 4000 h current stressed samples fracture surface, contrary to the other samples. The IMC layer thickness increased with the loading times and was slightly higher for the anode side of the current stressed components. The current stressing resulted in extensive copper dissolution from the pad and IMC layer accumulation at the component metallisation at the cathode side, affecting the reliability of the joints and pointing to electromigration

TRP channels as novel players in the pathogenesis and therapy of itch

AbstractItch (pruritus) is a sensory phenomenon characterized by a (usually) negative affective component and the initiation of a special behavioral act, i.e. scratching. Older studies predominantly have interpreted itch as a type of pain. Recent neurophysiological findings, however, have provided compelling evidence that itch (although it indeed has intimate connections to pain) rather needs to be understood as a separate sensory modality. Therefore, a novel pruriceptive system has been proposed, within which itch-inducing peripheral mediators (pruritogens), itch-selective receptors (pruriceptors), sensory afferents and spinal cord neurons, and defined, itch-processing central nervous system regions display complex, layered responses to itch. In this review, we begin with a current overview on the neurophysiology of pruritus, and distinguish it from that of pain. We then focus on the functional characteristics of the large family of transient receptor potential (TRP) channels in skin-coupled sensory mechanisms, including itch and pain. In particular, we argue that – due to their expression patterns, activation mechanisms, regulatory roles, and pharmacological sensitivities – certain thermosensitive TRP channels are key players in pruritus pathogenesis. We close by proposing a novel, TRP-centered concept of pruritus pathogenesis and sketch important future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch