Mechanism of Ca(v)1.2 channel modulation by the amino terminus of cardiac beta2-subunits

L-type calcium channels are composed of a pore, alpha1c (Ca(V)1.2), and accessory beta- and alpha2delta-subunits. The beta-subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five beta2-subunits isoforms expressed in human heart (beta(2a-e)) on the single L-type calcium channel current. These splice variants differ only by amino-terminal length and amino acid composition. Single-channel modulation by beta2-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All beta2-subunits increased open probability, availability, and peak current with a highly consistent rank order (beta2a approximately = beta2b > beta2e approximately = beta2c > beta2d). We show graded modulation of some transition rates within and between deep-closed and inactivated states. The extent of modulation correlates strongly with the length of amino-terminal domains. Two mutant beta2-subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.

The Amplifier - v. 8,(a-2) no. 2

In this issue...Anaconda Scholarships, homecoming, David Rovig, Berkeley Pit, National Reactor Testing Station, Anaconda Company, Wesley Club, Star Lanes Bowling

Comparison of Newer-Generation Drug-Eluting With Bare-Metal Stents in Patients With Acute ST-Segment Elevation Myocardial Infarction: A Pooled Analysis of the EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial INfArcTION) and COMFORTABLE-AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction) Trials

OBJECTIVES This study sought to study the efficacy and safety of newer-generation drug-eluting stents (DES) compared with bare-metal stents (BMS) in an appropriately powered population of patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Among patients with STEMI, early generation DES improved efficacy but not safety compared with BMS. Newer-generation DES, everolimus-eluting stents, and biolimus A9-eluting stents, have been shown to improve clinical outcomes compared with early generation DES. METHODS Individual patient data for 2,665 STEMI patients enrolled in 2 large-scale randomized clinical trials comparing newer-generation DES with BMS were pooled: 1,326 patients received a newer-generation DES (everolimus-eluting stent or biolimus A9-eluting stent), whereas the remaining 1,329 patients received a BMS. Random-effects models were used to assess differences between the 2 groups for the device-oriented composite endpoint of cardiac death, target-vessel reinfarction, and target-lesion revascularization and the patient-oriented composite endpoint of all-cause death, any infarction, and any revascularization at 1 year. RESULTS Newer-generation DES substantially reduce the risk of the device-oriented composite endpoint compared with BMS at 1 year (relative risk [RR]: 0.58; 95% confidence interval [CI]: 0.43 to 0.79; p = 0.0004). Similarly, the risk of the patient-oriented composite endpoint was lower with newer-generation DES than BMS (RR: 0.78; 95% CI: 0.63 to 0.96; p = 0.02). Differences in favor of newer-generation DES were driven by both a lower risk of repeat revascularization of the target lesion (RR: 0.33; 95% CI: 0.20 to 0.52; p < 0.0001) and a lower risk of target-vessel infarction (RR: 0.36; 95% CI: 0.14 to 0.92; p = 0.03). Newer-generation DES also reduced the risk of definite stent thrombosis (RR: 0.35; 95% CI: 0.16 to 0.75; p = 0.006) compared with BMS. CONCLUSIONS Among patients with STEMI, newer-generation DES improve safety and efficacy compared with BMS throughout 1 year. It remains to be determined whether the differences in favor of newer-generation DES are sustained during long-term follow-up.

A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents.

BACKGROUND Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. OBJECTIVE To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). METHODS All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. RESULTS Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. CONCLUSION Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.

Beitrag zur Geschichte der Verfolgung der Juden im 19ten Jahrhundert durch Schriftsteller : ein Sendschreiben an die Frau Kammerherrin von der Recke, geb. Gräfin v. Medem

von David Friedländer

Briefe über die Moral des Handels : (voran ein Gewissensfall im Handel, nebst einem Schreiben v. Mendelssohn)

geschrieben im Jahr 1785 von David Friedländer

Dāv��r ṭôv : ʿal šemê šem qôdeš ... di teḥine der nun fun roš ha-šone we-jom kiper biz nach hešaine rabe ...

Digitalisat der Ausg. Fjurda, [1766/67]

Advanced Physical Chemistry Problems (V), Thermodynamics (ThermoChemistry)

This is a set of P. Chem. problems posed at a slightly higher level than the normal textbook level, for students who are continuing in the study of this subject.

Die Religions-Philosophie des R. Abraham ben David ha -Levi : nach dessen noch ungedruckter Schrift "Emuna rama" in ihrem innern und historischen Zusammenhange entwickelt

von Joseph Gugenheimer

Na 1 Nachlass Max Horkheimer, 455 - Korrespondenzen u.a. mit Margo H. Wolff und Karl August Wittfogel (p. V 173, 210-429)

19 Briefe zwischen Lisa Witherell (geb. Richter) und Max Horkheimer, 1963-1971; 2 Briefe zwischen Werner Wittayer (stud. phil.) und Max Horkheimer, 1964; 4 Drucksachen vom Landtagspräsidenten Otto Witte an Max Horkheimer, 1952-1954; 2 Briefe an Otto Witte von Max Horkheimer, 1952-1953; 1 Todesanzeige, 1963; 4 Briefe zwischen der Studentin Ulrike Wittenberg und Max Horkheimer, 1972-1973; 4 Briefe zwischen dem Professor Karl A. Wittfogel und Max Horkheimer, 1972; 3 Briefe zwischen dem Oberstudiendirektor Dr. Kurt Debus und Max Horkheimer, 1967; 3 Briefe zwischen David Wodlinger und Max Horkheimer, 1960; 2 Briefe zwischen Dr. Herman Wohlstein und Max Horkheimer, 1965; 16 Briefe an Johanna Woitschach von Max Horkheimer, 1970-1973 (die Briefe an Max Horkheimer wurden zurückverlangt); 1 Brief von Ernst Wolf an Max Horkheimer, San Francisco, 1954; 3 Briefe zwischen dem Diplom-Psychologen Heinz E. Wolf und Max Horkheimer, 1958; 13 Briefe zwischen dem Oberstudiendirektor Oskar Wolfenstädter und Max Horkheimer, 1968-1969; 4 Briefe zwischen der Ordensschwester Katherine Wolff und Max Horkheimer, 1970-1971; 25 Briefe zwischen Margo H. Wolff und Max Horkheimer, 1962-1973; 11 Briefe zwischen dem Professor Max Wolff und Max Horkheimer, 1960; 3 Briefe zwischen dem Professor Manfred Wolfson und Max Horkheimer, 1971; 6 Briefe von der Physiotherapeutin Helga Wolk an Max Horkheimer, 1970-1971; 13 Briefe zwischen Hedwig G. de Wollenberger und Max Horkheimer, 1966-1970; 1 Brief an den Professor Günther Wollheim von Max Horkheimer, 1965; 4 Briefe zwischen Johanna Wopperer-Ege und Max Horkheimer, 1970; 5 Briefe zwischen Anton Wopperer und Max Horkheimer, 1969-1970; 3 Briefe an die World Future Society von Max Horkheimer, 1969-1973; 2 Briefe zwischen dem World Jewish Congress und Max Horkheimer, 1970; 2 Briefe zwischen dem Professor Theodor Würtenberger und Max Horkheimer, 1964; 3 Briefe zwischen der Würtembergischen Landesbibliothek und Max Horkheimer, 1969; 16 Briefe zwischen Rösle Wüstholz und Max Horkheimer, 1951-1959; 2 Briefe zwischen Christoph Wulf und Max Horkheimer, 1973; 1 Brief an Jssy Wygoda von Max Horkheimer, 1964; 2 Briefe zwischen Dr. Hans von Wyl und Max Horkheimer, 1971; 2 Briefe zwischen Jacques Wyler und Max Horkheimer, 1973; 1 Brief von Gisela Wysocki an Max Horkheimer, o.J. (1973?);