On the mechanism of TASK channel inhibition by G-Protein coupled receptors

Background K+ conductance TASK channels belong to the family of two pore domain potassium channels. They are involved in regulation of neuronal excitability, cardiovascular homeostasis and endocrine activity. TASK channel activity is down-regulated by activation Gq-protein coupled receptors (GqPCR). In various tissues this regulatory mechanism is crucial for proper organ function. Well studied examples of GqPCR mediated TASK channel inhibition are the cholinergic inhibition of IK,SO in cerebellar granule neurons, angiotensin II stimulated aldosterone secretion in adrenal zona-glomerulosa cells and vasoconstriction of the pulmonary artery by endothelin-1. Despite intense research, the mechanism underlying this inhibition remains elusive. Strong evidence exists for two competing hypotheses: TASK channels could be either blocked directly by the Gq-alpha subunit released on GqPCR activation, or their closure could be a direct consequence of Phospholipase C (PLC)-mediated phosphatidyl-inositol(4,5)-bis-phosphate (PtdIns(4,5)P2) depletion. In the present study I investigated the role of PLC mediated phosphoinositide cleavage in the process of TASK channel regulation by GqPCR in the intact cell. Recently developed genetically encoded switchable phosphoinositide-phosphatases were used to specifically deplete PtdIns(4,5)P2. Additionally, I interfered with PtdIns(4,5)P2 resynthesis and PLC activity. I found that blockage of PLC results in abolishment of GqPCR induced TASK inhibition. However depletion of the PLC substrate PtdIns(4,5)P2 alone was not sufficient to inhibit TASK. These results show that PLC activation is an indispensable step in TASK channel inhibition. They further demonstrate that the depletion of PtdIns(4,5)P2 does not directly inhibit TASK and therefore suggest that a regulatory mechanism downstream of PtdIns(4,5)P2-hydrolysis mediates TASK channel inhibition

Fermionic WIMPs and Vacuum Stability in the Scotogenic Model

We demonstrate that the condition of vacuum stability severely restricts scenarios with fermionic WIMP dark matter in the scotogenic model. The sizable Yukawa couplings that are required to satisfy the dark matter constraint via thermal freeze-out in these scenarios tend to destabilise the vacuum at scales below that of the heaviest singlet fermion, rendering the model inconsistent from a theoretical point of view. By means of a scan over the parameter space, we study the impact of these renormalisation group effects on the viable regions of this model. Our analysis shows that a fraction of more than 90% of the points compatible with all known experimental constraints - including neutrino masses, the dark matter density, and lepton flavour violation - is actually inconsistent.Comment: 8 pages, 6 figures; content matches published versio

Hairpin-Wicklungen für elektrische Fahrantriebe

Dieser Beitrag beschäftigt sich mit den zunehmend Verbreitung findenden Hairpin-Wicklungen unter den besonderen Randbedingungen elektrischer Fahrantriebe. Dabei wird bewusst auf den in der Literatur bekannten Vergleich zu konventionellen Wicklungen hinsichtlich Nutfüllfaktor und Kühlanbindung verzichtet. Stattdessen konzentriert sich der Beitrag zunächst auf die Stromverdrängung, ihre Abhängigkeiten sowie Möglichkeiten zur Reduzierung des Effekts, wobei ausschließlich Maßnahmen vorgestellt werden, die zum Stand der Technik großserientauglich sind. Darüber hinaus werden Potentiale im Layout der Spulenseiten und Wickelköpfe aufgezeigt, die weit über die Optionen von aus Endlosdraht hergestellten Wicklungen hinausgehen.This paper examines the increasingly popular hairpin windings under the dedicated boundary conditions of electrical drivetrains. A comparison to conventional windings regarding slot filling and cooling link will consciously be omitted since it is well known from literature. Instead, the paper concentrates on current displacement, its dependencies and possibilities for its reduction – with only measures being considered that state-of-the-art are suitable for mass-production. Furthermore, potentials in the layout of coil sides and end-windings are shown, which are far beyond the options of windings manufactured from continuous wire

Reconstruction and subsurface lattice distortions in the (2 × 1)O-Ni(110) structure: A LEED analysis

LEED analysis of the reconstructed (2 × 1)O-Ni(110) system clearly favors the “missing row” structure over the “saw-tooth” and “buckled row” models. By using a novel computational procedure 8 structural parameters could be refined simultaneously, leading to excellent R-factors (RZJ = 0.09, RP = 0.18). The adsorbed O atoms are located 0.2 Å above the long bridge sites in [001] direction, presumably with a slight displacement ( 0.1 Å) in [1 0] direction to an asymmetric adsorption site. The nearest-neighbor Ni---O bond lengths (1.77 Å) are rather short. The separation between the topmost two Ni layers is expanded to 1.30 Å (bulk value 1.25 Å), while that between the second and third layer is slightly contracted to 1.23 Å. The third layer is, in addition, slightly buckled (±0.05 Å). The results are discussed on the basis of our present general knowledge about the structure of adsorbate covered metallic surfaces

Protective Function of STAT3 in CVB3-Induced Myocarditis

The transcription factor signal transducer and activator of transcription 3 (STAT3) is an important mediator of the inflammatory process. We investigated the role of STAT3 in viral myocarditis and its possible role in the development to dilated cardiomyopathy. We used STAT3-deficent mice with a cardiomyocyte-restricted knockout and induced a viral myocarditis using Coxsackievirus B3 (CVB3) which induced a severe inflammation during the acute phase of the viral myocarditis. A complete virus clearance and an attenuated inflammation were examined in both groups WT and STAT3 KO mice 4 weeks after infection, but the cardiac function in STAT3 KO mice was significantly decreased in contrast to the infected WT mice. Interestingly, an increased expression of collagen I was detected in STAT3 KO mice compared to WT mice 4 weeks after CVB3 infection. Furthermore, the matrix degradation was reduced in STAT3 KO mice which might be an explanation for the observed matrix deposition. Consequently, we here demonstrate the protective function of STAT3 in CVB3-induced myocarditis. Since the cardiomyocyte-restricted knockout leads to an increased fibrosis, it can be assumed that STAT3 signalling in cardiomyocytes protects the heart against increased fibrosis through paracrine effects

Probing alternative cosmologies through the inverse distance ladder

We study the implications of a combined analysis of cosmic standard candles and standard rulers on the viability of cosmological models beyond the cosmological concordance model. To this end, we employ data in the form of the joint light-curve analysis supernova compilation, baryon acoustic oscillations, cosmic microwave background data, and a recently proposed set of Quasars as objects of known brightness. The advantage of including the latter is that they extend the local distance measures to redshifts which have previously been out of reach and we investigate how this allows one to test cosmologies beyond $\Lambda$CDM. We focus on two particular modifications: One is the theory of a massive tensor field interacting with the standard metric of gravity, so-called bigravity, and the other conformal gravity, a theory of gravity that has no knowledge of fundamental length scales. The former of the two constitutes a veritable extension of General Relativity, given that it adds to the metric tensor of gravity a second dynamical tensor field. The resulting dynamics have been proposed as a self-accelerating cosmology. Conformal gravity on the other hand is a much more drastic change of the underlying gravitational theory. Its ignorance towards fundamental length scales offers a completely different approach to late time acceleration and the so-called cosmological constant problem. In this sense, both models offer - in one way or another - an explanation for the cosmological constant problem. We perform a combined cosmological fit which provides strong constraints on some of these extensions, while some alternative cosmologies are in fact favoured by the data. We also briefly comment on the implications of the long-standing $H_0$-tension.Comment: 36 pages, 15 figure

Differential Expression of Matrix Metalloproteases in Human Fibroblasts with Different Origins

Fibroblasts are widely distributed cells and are responsible for the deposition of extracellular matrix (ECM) components but also secrete ECM-degrading matrix metalloproteases. A finely balanced equilibrium between deposition and degradation of ECM is essential for structural integrity of tissues. In the past, fibroblasts have typically been understood as a uniform cell population with comparable functions regardless of their origin. Here, we determined growth curves of fibroblasts derived from heart, skin, and lung and clearly show the lowest proliferation rate for cardiac fibroblasts. Furthermore, we examined basal expression levels of collagen and different MMPs in these three types of fibroblasts and compared these concerning their site of origin. Interestingly, we found major differences in basal mRNA expression especially for MMP1 and MMP3. Moreover, we treated fibroblasts with TNF-α and observed different alterations under these proinflammatory conditions. In conclusion, fibroblasts show different properties in proliferation and MMP expression regarding their originated tissue

Electro-mechanical whole-heart digital twins: A fully coupled multi-physics approach

Mathematical models of the human heart are evolving to become a cornerstone of precision medicine and support clinical decision making by providing a powerful tool to understand the mechanisms underlying pathophysiological conditions. In this study, we present a detailed mathematical description of a fully coupled multi-scale model of the human heart, including electrophysiology, mechanics, and a closed-loop model of circulation. State-of-the-art models based on human physiology are used to describe membrane kinetics, excitation-contraction coupling and active tension generation in the atria and the ventricles. Furthermore, we highlight ways to adapt this framework to patient specific measurements to build digital twins. The validity of the model is demonstrated through simulations on a personalized whole heart geometry based on magnetic resonance imaging data of a healthy volunteer. Additionally, the fully coupled model was employed to evaluate the effects of a typical atrial ablation scar on the cardiovascular system. With this work, we provide an adaptable multi-scale model that allows a comprehensive personalization from ion channels to the organ level enabling digital twin modeling

Taxonomy of Trust-Relevant Failures and Mitigation Strategies

We develop a taxonomy that categorizes HRI failure types and their impact on trust to structure the broad range of knowledge contributions. We further identify research gaps in order to support fellow researchers in the development of trustworthy robots. Studying trust repair in HRI has only recently been given more interest and we propose a taxonomy of potential trust violations and suitable repair strategies to support researchers during the development of interaction scenarios. The taxonomy distinguishes four failure types: Design, System, Expectation, and User failures and outlines potential mitigation strategies. Based on these failures, strategies for autonomous failure detection and repair are presented, employing explanation, verification and validation techniques. Finally, a research agenda for HRI is outlined, discussing identified gaps related to the relation of failures and HR-trust