Molecular determinants of drug access to the receptor site for antiarrhythmic drugs in the cardiac Na+ channel.

The clinical efficacy of local anesthetic and antiarrhythmic drugs is due to their voltage- and frequency-dependent block of Na+ channels. Quaternary local anesthetic analogs such as QX-314, which are permanently charged and membrane-impermeant, effectively block cardiac Na+ channels when applied from either side of the membrane but block neuronal Na+ channels only from the intracellular side. This difference in extracellular access to QX-314 is retained when rat brain rIIA Na+ channel alpha subunits and rat heart rH1 Na+ channel alpha subunits are expressed transiently in tsA-201 cells. Amino acid residues in transmembrane segment S6 of homologous domain IV (IVS6) of Na+ channel alpha subunits have important effects on block by local anesthetic drugs. Although five amino acid residues in IVS6 differ between brain rIIA and cardiac rH1, exchange of these amino acid residues by site-directed mutagenesis showed that only conversion of Thr-1755 in rH1 to Val as in rIIA was sufficient to reduce the rate and extent of block by extracellular QX-314 and slow the escape of drug from closed channels after use-dependent block. Tetrodotoxin also reduced the rate of block by extracellular QX-314 and slowed escape of bound QX-314 via the extracellular pathway in rH1, indicating that QX-314 must move through the pore to escape. QX-314 binding was inhibited by mutation of Phe-1762 in the local anesthetic receptor site of rH1 to Ala whether the drug was applied extracellularly or intracellularly. Thus, QX-314 binds to a single site in the rH1 Na+ channel alpha subunit that contains Phe-1762, whether it is applied from the extracellular or intracellular side of the membrane. Access to that site from the extracellular side of the pore is determined by the amino acid at position 1755 in the rH1 cardiac Na+ channel.

[Admittatur of Ephraim Abbott (Harvard AB 1806)], 1802 September 24

Printed copy of an undated abstract of the laws and regulations with the admittatur of undergraduate Ephraim Abbott signed by President Joseph Willard on September 24, 1802.

[Admittatur of Thomas Wigglesworth], 1829 August 24

Printed copy of an undated abstract of laws and regulations with the admittatur of undergraduate Thomas Wigglesworth signed by President Josiah Quincy on August 24, 1829.

[Admittatur of John Capen], 1836

Printed copy of the 1833 abstract of laws and regulations with the admittatur of undergraduate John Capen signed by President Josiah Quincy on August 30, 1836. The admittatur also includes a certificate of removal from probation signed December 20, 1836.

[Admittatur of W. O. White], 1836 August 30

Printed copy of the 1833 abstract of laws and regulations with the admittatur of undergraduate W. O. White signed by President Josiah Quincy on August 30, 1836.

[Admittatur of Samuel F. McCleary], 1837 August 28

Printed copy of the 1833 abstract of laws and regulations with the admittatur of undergraduate Samuel F. McCleary signed by President Josiah Quincy on August 28, 1837.

[Admittatur of Isaac F. Shepard], 1838 August 28

Printed copy of an undated abstract of laws and regulations with the admittatur of undergraduate Isaac F. Shepard signed by President Josiah Quincy on August 28, 1837.

[Admittatur of Thomas Bartlett Hall], 1840 August 25

Printed copy of an undated abstract of laws and regulations with the admittatur of undergraduate Thomas B. Hall signed by President Josiah Quincy on August 25, 1840. The admittatur identifies Hall as a freshman.

[Certificate of admission of Thomas B. Hall], 1840 August 27

Printed copy of an undated abstract of laws and regulations with the admittatur of undergraduate Thomas Bartlett Hall to the Sophomore class on probation signed by President Josiah Quincy on August 27, 1840. The admittatur identifies Hall as a sophomore.

[Certificate of admission of Justin Winsor], 1849 July 20

Printed copy of an undated abstract of laws and regulations with the admittatur of undergraduate Justin Winsor signed by President Jared Sparks on July 20, 1849.

[Certificate of admission of Charles Ammi Cutter], 1851 July 15

Photocopy of an abstract of laws and regulations, and the certificate of admission of undergraduate Charles Ammi Cutter signed by President Jared Sparks on July 15, 1851.

[Certificate of admission of Elihu Chauncey], 1857 September 4

Printed copy of an abstract of laws and regulations, and the certificate of admission of undergraduate Elihu Chauncey signed by President James Walker on September 4, 1857.

[Certificate of admission of W. P. Alexander], 1866 July 17

Printed copy of an abstract of laws and regulations, and the certificate of admission of undergraduate W. P. Alexander signed by President Thomas Hill on July 17, 1866.

[Certificate of admission of F. H. Viaux], 1866-1867

Printed copy of an abstract of laws and regulations, and the certificate of admission of undergraduate F. H. Viaux signed by President Thomas Hill on July 17, 1866, and a Certificate of Matriculation signed by President Hill on January 28, 1867.

The Visegrad group and Germany: towards a new paradigm. CEPS Commentary, 28 November 2013

In surveying the strategic realignment now underway in Central Europe among the four members of the Visegrad Group, Michal Simecka observes in a new CEPS Commentary that it is hard to think of another point in modern history that permitted a scenario of Germany and its eastern neighbours working together to constructively shape Europe.