Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a

Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximate to50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.

The role of putative phosphorylation sites in the targeting and shuttling of the aquaporin-2 water channel

In renal collecting ducts, a vasopressin-induced cAMP increase results in the phosphorylation of aquaporin-2 (AQP2) water channels at Ser-256 and its redistribution from intracellular vesicles to the apical membrane. Hormones that activate protein kinase C (PKC) proteins counteract this process. To determine the role of the putative kinase sites in the trafficking and hormonal regulation of human AQP2, three putative casein kinase II (Ser-148, Ser-229, Thr-244), one PKC (Ser-231), and one protein kinase A (Ser-256) site were altered to mimic a constitutively non-phosphorylated/phosphorylated state and were expressed in Madin-Darby canine kidney cells. Except for Ser-256 mutants, seven correctly folded AQP2 kinase mutants trafficked as wild-type AQP2 to the apical membrane via forskolin-sensitive intracellular vesicles. With or without forskolin, AQP2-Ser-256A was localized in intracellular vesicles, whereas AQP2-S256D was localized in the apical membrane. Phorbol 12-myristate 13-acetate-induced PKC activation following forskolin treatment resulted in vesicular distribution of all AQP2 kinase mutants, while all were still phosphorylated at Ser-256. Our data indicate that in collecting duct cells, AQP2 trafficking to vasopressin-sensitive vesicles is phosphorylation-independent, that phosphorylation of Ser-256 is necessary and sufficient for expression of AQP2 in the apical membrane, and that PMA-induced PKC-mediated endocytosis of AQP2 is independent of the AQP2 phosphorylation state.

Acoustic analysis of speech through a hearing aid: perceptual effects of changes with two-channel compression

Compression amplification significantly alters the acoustic speech signal in comparison to linear amplification. The central hypothesis of the present study was that the compression settings of a two-channel aid that best preserved the acoustic properties of speech compared to linear amplification would yield the best perceptual results, and that the compression settings that most altered the acoustic properties of speech compared to linear would yield significantly poorer speech perception. On the basis of initial acoustic analysis of the test stimuli recorded through a hearing aid, two different compression amplification settings were chosen for the perceptual study. Participants were 74 adults with mild to moderate sensorineural hearing impairment. Overall, the speech perception results supported the hypothesis. A further aim of the study was to determine if variation in participants' speech perception with compression amplification (compared to linear amplification) could be explained by the individual characteristics of age, degree of loss, dynamic range, temporal resolution, and frequency selectivity; however, no significant relationships were found.

Structure of the HERG K+ channel S5P extracellular linker - Role of an amphipathic alpha-helix in C-type inactivation

The HERG K+ channel has very unusual kinetic behavior that includes slow activation but rapid inactivation. These features are critical for normal cardiac repolarization as well as in preventing lethal ventricular arrhythmias. Mutagenesis studies have shown that the extracellular peptide linker joining the fifth transmembrane domain to the pore helix is critical for rapid inactivation of the HERG K+ channel. This peptide linker is also considerably longer in HERG K+ channels, 40 amino acids, than in most other voltage-gated K+ channels. In this study we show that a synthetic 42-residue peptide corresponding to this linker region of the HERG K+ channel does not have defined structural elements in aqueous solution; however, it displays two well defined helical regions when in the presence of SDS micelles. The helices correspond to Trp(585)-Ile(593) and Gly(604)-Tyr(611) of the channel. The Trp(585)-Ile(593) helix has distinct hydrophilic and hydrophobic surfaces. The Gly(604)-Tyr(611) helix corresponds to an N-terminal extension of the pore helix. Electrophysiological studies of HERG currents following application of exogenous S5P peptides show that the amphipathic helix in the S5P linker interacts with the pore region of the channel in a voltage-dependent manner.

ClC-5 chloride channel and kidney stones : what is the link?

Nephrolithiasis is one of the most common diseases in the Western world. The disease manifests itself with intensive pain, sporadic infections, and, sometimes, renal failure. The symptoms are due to the appearance of urinary stones (calculi) which are formed mainly by calcium salts. These calcium salts precipitate in the renal papillae and/or within the collecting ducts. Inherited forms of nephrolithiasis related to chromosome X (X-linked hypercalciuric nephrolithiasis or XLN) have been recently described. Hypercalciuria, nephrocalcinosis, and male predominance are the major characteristics of these diseases. The gene responsible for the XLN forms of kidney stones was cloned and characterized as a chloride channel called ClC-5. The ClC-5 chloride channel belongs to a superfamily of voltage-gated chloride channels, whose physiological roles are not completely understood. The objective of the present review is to identify recent advances in the molecular pathology of nephrolithiasis, with emphasis on XLN. We also try to establish a link between a chloride channel like ClC-5, hypercalciuria, failure in urine acidification and protein endocytosis, which could explain the symptoms exhibited by XLN patients.

Improving a Cluster Based Directional Channel Model in Realistic Macro-Cell Environment

In this paper a realistic directional channel model that is an extension of the COST 273 channel model is presented. The model uses a cluster of scatterers and visibility region generation based strategy with increased realism, due to the introduction of terrain and clutter information. New approaches for path-loss prediction and line of sight modeling are considered, affecting the cluster path gain model implementation. The new model was implemented using terrain, clutter, street and user mobility information for the city of Lisbon, Portugal. Some of the model's outputs are presented, mainly path loss and small/large-scale fading statistics.

Phototransistor with nanocrystalline Si/amorphous Si bilayer channel

We report a field-effect phototransistor with a channel comprising a thin nanocrystalline silicon transport layer and a thicker hydrogenated amorphous silicon absorption layer. The semiconductor and dielectric layers were deposited by radio-frequency plasma enhanced chemical vapor deposition. The phototransistor with channel length of 24 microns and photosensitive area of 1.4 mm(2) shows an off-current of about 1 pA, and high photoconductive gain in the subthreshold region. Measurements of the quantum efficiency at different incident light intensities and biasing conditions, along with spectral-response characteristics, and threshold voltage stability characterization demonstrate the feasibility of the phototransistor for low light level detection.

Magma flow, exsolution processes and rock metasomatism in the Great Messejana-Plasencia dyke (Iberian Peninsula)

Magma flow in dykes is still not well understood; some reported magnetic fabrics are contradictory and the potential effects of exsolution and metasomatism processes on the magnetic properties are issues open to debate. Therefore, a long dyke made of segments with different thickness, which record distinct degrees of metasomatism, the Messejana-Plasencia dyke (MPD), was studied. Oriented dolerite samples were collected along several cross-sections and characterized by means of microscopy and magnetic analyses. The results obtained show that the effects of metasomatism on rock mineralogy are important, and that the metasomatic processes can greatly influence anisotropy degree and mean susceptibility only when rocks are strongly affected by metasomatism. Petrography, scanning electron microscopy (SEM) and bulk magnetic analyses show a high-temperature oxidation-exsolution event, experienced by the very early Ti-spinels, during the early stages of magma cooling, which was mostly observed in central domains of the thick dyke segments. Exsolution reduced the grain size of the magnetic carrier (multidomain to single domain transformation), thus producing composite fabrics involving inverse fabrics. These are likely responsible for a significant number of the 'abnormal' fabrics, which make the interpretation of magma flow much more complex. By choosing to use only the 'normal' fabric for magma flow determination, we have reduced by 50 per cent the number of relevant sites. In these sites, the imbrication angle of the magnetic foliation relative to dyke wall strongly suggests flow with end-members indicating vertical-dominated flow (seven sites) and horizontal-dominated flow (three sites).

Paleomagnetic study of the Great Foum Zguid dyke (southern Morocco): A positive contact test related to metasomatic processes

When a paleomagnetic pole is sought for in an igneous body, the host rocks should be subjected to a contact test to assure that the determined paleopole has the age of the intrusion. If the contact test is positive, it precludes the possibility that the measured magnetization is a later effect. Therefore, we investigated the variations of the remanent magnetization along cross-sections of rocks hosting the Foum Zguid dyke (southern Morocco) and the dyke itself. A positive contact test was obtained, but it is mainly related with Chemical/Crystalline Remanent Magnetization due to metasomatic processes in the host-rocks during magma intrusion and cooling, and not only with Thermo-Remanent Magnetization as ordinarily assumed in standard studies. Paleomagnetic data obtained within the dyke then reflect the Earth magnetic field during emplacement of this well-dated (196.9 +/- 1.8 Ma) intrusion.

Preliminary results of a study of magnetic properties in the Foum-Zguid dyke (Morocco)

This work focuses on the study of flow and propagation of magma using rock magnetic analyses along sections across the thick Jurassic dyke of Foum-Zguid (Southern Morocco). Thermomagnetic data show that Ti-poor titanomagnetite is the main magnetic carrier. Petrographic analysis shows that the main Ti phase (ilmenite) occurs either as lamellae within spinel (center of the dyke) or as isolated grains (dyke margin). Bulk magnetic properties display distinct behavior according to the distance to the dyke margin; grain size of the main magnetic carrier decreases towards the center of the dyke, while the natural remanent magnetization and the bulk magnetic susceptibility increase. Only the magnetic susceptibility ellipsoid close to the dyke margin corresponds to that usually found in thin dykes, with the magnetic foliation sub parallel to dyke margins. Maximum principal axis is in most cases either parallel or perpendicular to the intersection between the planes of magnetic foliation and dyke wall. Moreover, when this axis is perpendicular to the intersection it is associated with a more oblate magnetic susceptibility ellipsoid shape, indicating the presence of complex magnetic fabrics. The studied magnetic properties show that, in this 100 m wide thick dyke, flow structures related with dyke propagation are only preserved close to the quickly cooled dyke margins.

Thick dyke emplacement and internal flow: A structural and magnetic fabric study of the deep-seated dolerite dyke of Foum Zguid (southern Morocco)

Knowledge on forced magma injection and magma flow in dykes is crucial for the understanding of how magmas migrate through the crust to the Earth's surface. Because many questions still persist, we used the long, thick, and deep-seated Foum Zguid dyke (Morocco) to investigate dyke emplacement and internal flow by means of magnetic methods, structural analysis, petrography, and scanning electron microscopy. We also investigated how the host rocks accommodated the intrusion. Regarding internal flow: 1. Important variations of the rock magnetic properties and magnetic fabric occur with distance from dyke wall; 2. anisotropy of anhysteretic remanent magnetization reveals that anisotropy of magnetic susceptibility (AMS) results mainly from the superposition of subfabrics with distinct coercivities and that the imbrication between magnetic foliation and dyke plane is more reliable to deduce flow than the orientation of the AMS maximum principal axis; and 3. a dominant upward flow near the margins can be inferred. The magnetic fabric closest to the dyke wall likely records magma flow best due to fast cooling, whereas in the core the magnetic properties have been affected by high-temperature exsolution and metasomatic effects due to slow cooling. Regarding dyke emplacement, this study shows that the thick forceful intrusion induced deformation by homogeneous flattening and/or folding of the host sedimentary strata. Dewatering related to heat, as recorded by thick quartz veins bordering the dyke in some localities, may have also helped accommodating dyke intrusion. The spatial arrangement of quartz veins and their geometrical relationship with the dyke indicate a preintrusive to synintrusive sinistral component of strike slip.

Variation of magnetic properties in sedimentary rocks hosting the Foum Zguid dyke (southern Morocco): Combined effects of re-crystallization and Fe-metasomatism

The effects of dyke intrusion on the magnetic properties of host sedimentary rocks are still poorly understood. Therefore, we have evaluated bulk magnetic parameters of standard palaeomagnetic samples collected along several sections across the sediments hosting the Foum Zguid dyke in southern Morocco. The study has been completed with the evaluation of the magnetic fabric after laboratory application of sequential heating experiments. The present study shows that: (1) close to Fourn Zguid dykes, the variations of the bulk magnetic parameters and of the magnetic fabric is strongly related with re-crystallization and Fe-metasomatism intensity. (2) The thermal experiments on AMS of samples collected farther from the dyke and, thus, less affected by heating during dyke emplacement, indicate that 300-400 degrees C is the minimum experimental temperature necessary to trigger appreciable transformations of the pre-existing magnetic fabrics. For temperatures higher than ca. 580 degrees C, the magnetic fabric transformations are fully realized, with complete transposition of the initial fabric to a fabric similar to that of samples collected close to the dyke. Therefore, measured variations of the magnetic fabric can be used to evaluate re-crystallization temperatures experienced by the host sedimentary rock during dyke emplacement. The distinct magnetic behaviour observed along the cross-sections strongly suggests that samples collected farther from the dyke margins did not experience thermal episodes with temperatures higher than 300 degrees C after dyke emplacement. (3) AMS data shows a gradual variation of the magnetic fabric with distance from the dyke margin, from sub-horizontal K-3 away from the dyke to vertical K3 close to the dyke. Experimental heating shows that heat alone can be responsible for this strong variation. Therefore, such orientation changes should not be unequivocally interpreted as the result of a stress field (resulting from the emplacement of the dyke, for instance). (4) Magnetic studies prove to be a very sensitive tool to assess rock magnetic transformations, thermally and chemically induced by dyke intrusion in hosting sediments.

Paleomagnetic study of the Messejana Plasencia dyke (Portugal and Spain): A lower Jurassic paleopole for the Iberian plate

The only Iberian lower Jurassic palcomagnetic pole come from the "Central Atlantic Magmatic Province"-related Messejana Plasencia dyke, but the age and origin of its remanence have been a matter of discussion. With the aim of solving this uncertainty, and to go further into a better understanding of its emplacement and other possible tectonic features, a systematic paleomagnetic investigation of 40 sites (625 specimens) distributed all along the 530 kin of the Messejana Plasencia dyke has been carried out. Rock magnetic experiments indicate PSD low Ti-titanomagnetite and magnetite as the minerals carrying the NRM. The samples were mostly thermally demagnetized. Most sites exhibit a characteristic remanent component of normal polarity with the exception of two sites, where samples with reversed polarities have been observed. The paleomagnetic pole derived from a total of 35 valid sites is representative of the whole structure of the dyke, and statistically well defined, with values of PLa = 70.4 degrees N, PLo = 237.6 degrees E, K= 47.9 and A(95) = 3.5 degrees. Paleomagnetic data indicates that: (i) there is no evidence of a Cretaceous remagnetization in the dyke, as it was suggested; (ii) most of the dyke had a brief emplacement time; furthermore, two dyke intrusion events separated in time from it by at least 10,000 y have been detected; (iii) the high grouping of the VGPs directions suggests no important tectonic perturbations of the whole structure of the dyke since its intrusion time; (iv) the pole derived from this study is a good quality lower Jurassic paleopole for the Iberian plate; and (v) the Messejana Plasencia dyke paleopole for the Iberian plate is also in agreement with quality-selected European and North American lower Jurassic paleopoles and the magnetic anomalies data sets that are available for rotate them to Iberia.

Bi-Dimensional Characterization of a Wimax Radio Channel at 3.5GHz

This paper presents the characterization of an indoor Wimax radio channel using the Finite-Difference Time-Domain (FDTD) [1] method complemented with the Convolutional Perfect Matched Layer (CPML) technique [2]. An indoor 2D scenario is simulated in the 3.5GHz band (IEEE 802.16d-2004 and IEEE 802.16e-2005 [3]). In this study, we used two complementary techniques in both analysis, technique A and B for fading based on delay spread and technique C and D for fading based on Doppler spread. Both techniques converge to the same result. Simulated results define the channel as flat, slow and without inter-symbolic interference (ISI), making the application of the spatial diversity the most appropriate scheme.

Directional Moving Target Indication for Civil Traffic Monitoring Using Single Channel SAR

This paper presents a novel moving target indicator which is selective with respect to a direction of interest. Preliminary results indicate that the obtained selectivity may have high interest in civil traffic monitoring using single channel SAR data.