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Now showing items 145 - 160 of 12819

  • Anmerkung zu OLG K?ln, Hinweisbeschl. v. 24.2.2015 – 5 U 156/14 (LG Bonn)

    Schmidt-Recla   Adrian  

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  • Anmerkung zu OVG Sachsen-Anhalt, Urt. v. 19.7.2012 – 1 K 75/11

    Dr. iur. Karsten Scholz  

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  • Control of Sleep Onset by Shal/K(v)4 Channels in Drosophila Circadian Neurons

    Feng, Ge   Zhang, Jiaxing   Li, Minzhe   Shao, Lingzhan   Yang, Luna   Song, Qian   Ping, Yong  

    Sleep is highly conserved across animal species. Both wake- and sleep-promoting neurons are implicated in the regulation of wake-sleep transition at dusk in Drosophila. However, little is known about how they cooperate and whether they act via different mechanisms. Here, we demonstrated that in female Drosophila, sleep onset was specifically delayed by blocking the Shaker cognate L channels [Shal; also known as voltage-gated K+ channel 4 (K(v)4)] in wake-promoting cells, including large ventral lateral neurons (l-LNvs) and pars intercerebralis (PI), but not in sleep-promoting dorsal neurons (DN1s). Delayed sleep onset was also observed in males by blocking K(v)4 activity in wake- promoting neurons. Electrophysiological recordings show that K(v)4 channels contribute A-type currents in LNvs and PI cells, but are much less conspicuous in DN1s. Interestingly, blocking K(v)4 in wake- promoting neurons preferentially increased firing rates at dusk similar to ZT13, when the resting membrane potentials and firing rates were at lower levels. Furthermore, pigment-dispersing factor (PDF) is essential for the regulation of sleep onset by K(v)4 in l-LNvs, and downregulation of PDF receptor (PDFR) in PI neurons advanced sleep onset, indicating K(v)4 controls sleep onset via regulating PDF/PDFR signaling in wake-promoting neurons. We propose that K(v)4 acts as a sleep onset controller by suppressing membrane excitability in a clock-dependent manner to balance the wake-sleep transition at dusk. Our results have important implications for the understanding and treatment of sleep disorders such as insomnia.
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  • Identification of Novel and Selective K(V)2 Channel Inhibitors

    Herrington, James   Solly, Kelli   Ratliff, Kevin S.   Li, Nina   Zhou, Yun-Ping   Howard, Andrew   Kiss, Laszlo   Garcia, Maria L.   McManus, Owen B.   Deng, Qiaolin   Desai, Ranjit   Xiong, Yusheng   Kaczorowski, Gregory J.  

    Identification of selective ion channel inhibitors represents a critical step for understanding the physiological role that these proteins play in native systems. In particular, voltage-gated potassium (K(V)2) channels are widely expressed in tissues such as central nervous system, pancreas, and smooth muscle, but their particular contributions to cell function are not well understood. Although potent and selective peptide inhibitors of K(V)2 channels have been characterized, selective small molecule K(V)2 inhibitors have not been reported. For this purpose, high-throughput automated electrophysiology (IonWorks Quattro; Molecular Devices, Sunnyvale, CA) was used to screen a 200,000-compound mixture (10 compounds per sample) library for inhibitors of K(V)2.1 channels. After deconvolution of 190 active samples, two compounds (A1 and B1) were identified that potently inhibit K(V)2.1 and the other member of the K(V)2 family, K(V)2.2 (IC 50, 0.1-0.2 mu M), and that possess good selectivity over K(V)1.2 (IC 50 > 10 mu M). Modeling studies suggest that these compounds possess a similar three-dimensional conformation. Compounds A1 and B1 are > 10-fold selective over Na(V) channels and other K(V) channels and display weak activity (5-9 mu M) on Ca(V) channels. The biological activity of compound A1 on native K(V)2 channels was confirmed in electrophysiological recordings of rat insulinoma cells, which are known to express K(V)2 channels. Medicinal chemistry efforts revealed a defined structure-activity relationship and led to the identification of two compounds (RY785 and RY796) without significant CaV channel activity. Taken together, these newly identified channel inhibitors represent important tools for the study of K(V)2 channels in biological systems.
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  • Jahresberichte 2010 und 2011 des K?lnischen Geschichtsvereins e. V.

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  • Behavioural and functional characterization of K(v)10.1 (Eag1) knockout mice

    Ufartes, Roser   Schneider, Tomasz   Mortensen, Lena Suenke   de Juan Romero, Camino   Hentrich, Klaus   Knoetgen, Hendrik   Beilinson, Vadim   Moebius, Wiebke   Tarabykin, Victor   Alves, Frauke   Pardo, Luis A.   Rawlins, J. Nicholas P.   Stuehmer, Walter  

    K(v)10.1 (Eag1), member of the K(v)10 family of voltage-gated potassium channels, is preferentially expressed in adult brain. The aim of the present study was to unravel the functional role of K(v)10.1 in the brain by generating knockout mice, where the voltage sensor and pore region of K(v)10.1 were removed to render non-functional proteins through deletion of exon 7 of the KCNH1 gene using the '3 Lox P strategy'. K(v)10.1-deficient mice show no obvious alterations during embryogenesis and develop normally to adulthood; cortex, hippocampus and cerebellum appear anatomically normal. Other tests, including general health screen, sensorimotor functioning and gating, anxiety, social behaviour, learning and memory did not show any functional aberrations in K(v)10.1 null mice. K(v)10.1 null mice display mild hyperactivity and longer-lasting haloperidol-induced catalepsy, but there was no difference between genotypes in amphetamine sensitization and withdrawal, reactivity to apomorphine and haloperidol in the prepulse inhibition tests or to antidepressants in the haloperidol-induced catalepsy. Furthermore, electrical properties of K(v)10.1 in cerebellar Purkinje cells did not show any difference between genotypes. Bearing in mind that K(v)10.1 is overexpressed in over 70 of all human tumours and that its inhibition leads to a reduced tumour cell proliferation, the fact that deletion of K(v)10.1 does not show a marked phenotype is a prerequisite for utilizing K(v)10.1 blocking and/or reduction techniques, such as siRNA, to treat cancer.
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  • 4-Cycle decompositions of\\(( \\lambda +m)K_{v+u} {\\setminus } \\lambda K_v\\)

    Newman   N. A.  

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  • Tun und K?nnen || Die kausale Dimension von Verm?gen (V 12, IX 1)

    Jansen   Ludger  

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  • Vereinsbericht: Jahresbericht 2009 des K?lnischen Geschichtsvereins e. V.

    Wunsch   Stefan  

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  • K(v)7.1 surface expression is regulated by epithelial cell polarization

    Andersen, Martin N.   Olesen, Soren-Peter  

    Andersen MN, Olesen SP, Rasmussen HB. K(v)7.1 surface expression is regulated by epithelial cell polarization. Am J Physiol Cell Physiol 300: C814-C824, 2011. First published January 12, 2011; doi:10.1152/ajpcell.00390.2010.-The potassium channel K(V)7.1 is expressed in the heart where it contributes to the repolarization of the cardiac action potential. In addition, K(V)7.1 is expressed in epithelial tissues where it plays a role in salt and water transport. Mutations in the kcnq1 gene can lead to long QT syndrome and deafness, and several mutations have been described as trafficking mutations. To learn more about the basic mechanisms that regulate K(V)7.1 surface expression, we have investigated the trafficking of K(V)7.1 during the polarization process of the epithelial cell line Madin-Darby Canine Kidney (MDCK) using a modified version of the classical calcium switch. We discovered that K(V)7.1 exhibits a very dynamic localization pattern during the calcium switch. When MDCK cells are kept in low calcium medium, K(V)7.1 is mainly observed at the plasma membrane. During the first hours of the switch, K(V)7.1 is removed from the plasma membrane and an intracellular accumulation in the endoplasmic reticulum (ER) is observed. The channel is retained in the ER until the establishment of the lateral membranes at which point K(V)7.1 is released from the ER and moves to the plasma membrane. Our data furthermore suggest that while the removal of K(V)7.1 from the cell surface and its accumulation in the ER could involve activation of protein kinase C, the subsequent release of K(V)7.1 from the ER depends on phosphoinositide 3-kinase (PI3K) activation. In conclusion, our results demonstrate that K(V)7.1 surface expression is regulated by signaling mechanisms involved in epithelial cell polarization in particular signaling cascades involving protein kinase C and PI3K.
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  • Outer membrane protein K as a subunit vaccine against V. anguillarum

    Mohammed Abdullatif Hamod   Muliya Sankappa Nithin   Yassamin Nahil Shukur   Iddya Karunasagar   Indrani Karunasagar  

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  • In Vitro Folding of KvAP, a Voltage-Gated K+ Channel

    Devaraneni, Prasanna K.   Devereaux, Jordan J.   Valiyaveetil, Francis I.  

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  • Differential Effects of ICA-27243 on Cloned K(V)7 Channels

    Blom, Sigrid Marie   Schmitt, Nicole  

    Background/Aims: The neuronal K(V)7 family members (K(V)7.2-5) are important regulators of neuronal excitability. K(V)7 channel openers are therefore attractive drug candidates for the treatment of several hyperexcitability disorders. While most described K(V)7 channel openers discriminate poorly between K(V)7.2-5, Icagen's N-(6-chloropyridin-3-yl)-3,4-difluorobenzamide (ICA-27243) is more potent at K(V)7.2/3 than at K(V)7.4 and K(V)7.3/5 and offers some progress towards subtype selectivity. We have investigated its mode of action on K(V)7.2 and K(V)7.4, compared its effect to that of retigabine and studied the combinatorial effect of retigabine and ICA-27243, as these two compounds recognize different binding sites in the channels. Methods: The effects of ICA-27243 and retigabine were studied using voltage-clamp electrophysiology in Xenopus laevis oocytes and rubidium flux in Chinese hamster ovary cells. Results: We found that in contrast to retigabine's voltage-dependent action on K(V)7.2, ICA-27243 induced a voltage-independent current on this subtype, which was not observed on K(V)7.4. Additionally, the combined treatment of K(V)7.2 and K(V)7.4 with retigabine and ICA-27243 revealed that the effect of ICA-27243 on K(V)7.2 dominates that of retigabine, while the compounds act additively and synergistically on K(V)7.4. Conclusions: These results offer further detailed insight into pharmacological activation of K(V)7 channels and offer evidence of differential functional and subtype-specific effects by activation of different binding sites in the K(V)7 channels. Copyright (C) 2010 S. Karger AG, Basel
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  • Implication of K(v)7 Channels in the Spinal Antinociceptive Actions of Celecoxib

    Vicente-Baz, Jorge   Lopez-Garcia, Jose A.   Rivera-Arconada, Ivan  

    Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat pain conditions in humans. In addition to its blocking activity on cyclooxygenase (COX) enzymes, several other targets could contribute to its analgesic activity. Here we explore the spinal antinociceptive actions of celecoxib and the potential implication of K(v)7 channels in mediating its effects. Spinal cord in vitro preparations from hind paw-inflamed animals were used to assess the segmental sensory-motor and the early sensory processing of nociceptive information. Electrophysiological recordings of ventral roots and dorsal horn neurones were obtained, and the effects of celecoxib and K(v)7 modulators on responses to repetitive dorsal root stimulation at C-fiber intensity were assessed. Celecoxib applied at clinically relevant concentrations produced depressant effects on responses to dorsal root stimulation recorded from both ventral roots and individual dorsal horn neurones; by contrast, the non-nociceptive monosynaptic reflex was unaffected. The NSAID indomethacin had no effect on spinal reflexes, but further coapplication of celecoxib still produced depressant effects. The depressant actions of celecoxib were abolished after K(v)7 channel block-ade and mimicked by its structural analog dimethyl-celecoxib, which lacks COX-blocking activity. The present results identify K(v)7 channels as novel central targets for celecoxib, which may be relevant to its analgesic effect. This finding contributes to better understand the pharmacology of celecoxib and reinforces both the role of K(v)7 channels in modulating the excitability of central pain pathways and its validity as target for the design of analgesics.
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  • Reduction for primitive flag-transitive (v,k, 4)-symmetric designs

    Eugenia O’Reilly-Regueiro  

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  • Anmerkung zu VG Neustadt an der Weinstra?e, Urt. v. 15.11.2017 – 1 K 232/17.NW

    Rosset   Christoph  

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