Sodium channel selectivity filter regulates antiarrhythmic drug binding

Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel’s selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle Na+ channel (μ1) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the Na+ channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment.

The 74th (Yeomanry) Division in Syria and France,

Mode of access: Internet.

The 56th Division (1st London territorial division) /

Includes index.

Annotated record and chemical analysis of manganese nodules from R/V Moana Wave Cruise Mn-74-01 and Mn-74-02 stations

Cruise Mn-74-02 of the R/V MOANA WAVE was the second part of the field work of the NSF/IDOE Inter-University Ferromanganese Research Program in 1974, and we gratefully acknowledge the support of the office for the International Decade of Ocean Exploration and the Office of Oceanographic Facilities and Support. This program was designed to investigate the origin, growth, and distribution of copper/nickel-rich manganese nodules in the Pacific Ocean. The field effort was designed to satisfy sample requirements of the fifteen principal investigators, while increasing general knowledge of the copper/nickel-rich nodule deposits of the equatorial Pacific. This report is the second of a series of cruise reports designed to assist sample requests for documented nodules, sediment, and water samples so that laboratory results can be realistically compared and related to the environment of nodule growth. Nodule samples and bathymetric and navigational data are archived at the Hawaii Institute of Geophysics, University of Hawaii. Bulk chemical analyses of nodules and reduction of survey data were carried out at Hawaii. Sediment cores were stored at the University of Hawaii and at Scripps Institution of Oceanography. The SIO analytical facility provided stratigraphic data on sediment chemistry.

Memorial addresses on the life and character of Dudley C. Haskell (a representative from Kansas), delivered in the House of representatives and in the Senate, Forty-eighth Congress, first session.

Pub. by order of Congress.

Topographical survey for the estate of Mr. H.C. Dudley; Duluth, Minnesota

Blueprint, pencil; proposed residence sketched in; Morell & Nichols, landscape architects; unsigned. 85x68 cm. Scale: 1"=20' [from photographic copy by Lance Burgharrdt]

Water and drainage plan for the estate of Mr. H.C. Dudley; Duluth, Minnesota

Yellow, green, black ink on linen; colored lines indicate sewer, water pipes; number "3" in lower right; signed. 93x60 cm. Scale: 1"=50' [from photographic copy by Lance Burgharrdt]

A grading plan showing sections for the estate of Mr. H.C. Dudley; Duluth, Minnesota

Ink on linen; four cross-sections showing grades for sections of estate, with elevations; sketches depict trees, pools and residence; number "4" in lower right; signed. 89x59 cm. No scale. [from photographic copy by Lance Burgharrdt]

A planting plan for the gardens. Mr. H.C. Dudley estate; Duluth, Minnesota. Revised August 1926

Ink on linen; with selected elevations, location, type of plantings, location of walkways; number "2A" in lower right; unsigned. 102x63 cm. Scale: 1"=10' [from photographic copy by Lance Burgharrdt]

The CMCC Eddy-permitting Global Ocean Physical Reanalysis (C-GLORS v5, 1980-2014), links to NetCDF files

The CMCC Global Ocean Physical Reanalysis System (C-GLORS) is used to simulate the state of the ocean in the last decades. It consists of a variational data assimilation system (OceanVar), capable of assimilating all in-situ observations along with altimetry data, and a forecast step performed by the ocean model NEMO coupled with the LIM2 sea-ice model. KEY STRENGTHS: - Data are available for a large number of ocean parameters - An extensive validation has been conducted and is freely available - The reanalysis is performed at high resolution (1/4 degree) and spans the last 30 years KEY LIMITATIONS: - Quality may be discontinuos and depend on observation coverage - Uncertainty estimates are simply derived through verification skill scores

The Wye tour, or Gilpin on the Wye, with picturesque additions, from Wheatley, Price, &c. and archaeological illustrations.

Mode of access: Internet.