Ion channel gene variants predisposing to severe human ventricular arrhythmias

Congenital long QT syndrome (LQTS) with an estimated prevalence of 1:2000-1:10 000 manifests with prolonged QT interval on electrocardiogram and risk for ventricular arrhythmias and sudden death. Several ion channel genes and hundreds of mutations in these genes have been identified to underlie the disorder. In Finland, four LQTS founder mutations of potassium channel genes account for up to 40-70% of genetic spectrum of LQTS. Acquired LQTS has similar clinical manifestations, but often arises from usage of QT-prolonging medication or electrolyte disturbances. A prolonged QT interval is associated with increased morbidity and mortality not only in clinical LQTS but also in patients with ischemic heart disease and in the general population. The principal aim of this study was to estimate the actual prevalence of LQTS founder mutations in Finland and to calculate their effect on QT interval in the Finnish background population. Using a large population-based sample of over 6000 Finnish individuals from the Health 2000 Survey, we identified LQTS founder mutations KCNQ1 G589D (n=8), KCNQ1 IVS7-2A>G (n=1), KCNH2 L552S (n=2), and KCNH2 R176W (n=16) in 27 study participants. This resulted in a weighted prevalence estimate of 0.4% for LQTS in Finland. Using a linear regression model, the founder mutations resulted in a 22- to 50-ms prolongation of the age-, sex-, and heart rate-adjusted QT interval. Collectively, these data suggest that one of 250 individuals in Finland may be genetically predisposed to ventricular arrhythmias arising from the four LQTS founder mutations. A KCNE1 D85N minor allele with a frequency of 1.4% was associated with a 10-ms prolongation in adjusted QT interval and could thus identify individuals at increased risk of ventricular arrhythmias at the population level. In addition, the previously reported associations of KCNH2 K897T, KCNH2 rs3807375, and NOS1AP rs2880058 with QT interval duration were confirmed in the present study. In a separate study, LQTS founder mutations were identified in a subgroup of acquired LQTS, providing further evidence that congenital LQTS gene mutations may underlie acquired LQTS. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by exercise-induced ventricular arrhythmias in a structurally normal heart and results from defects in the cardiac Ca2+ signaling proteins, mainly ryanodine receptor type 2 (RyR2). In a patient population of typical CPVT, RyR2 mutations were identifiable in 25% (4/16) of patients, implying that noncoding variants or other genes are involved in CPVT pathogenesis. A 1.1 kb RyR2 exon 3 deletion was identified in two patients independently, suggesting that this region may provide a new target for RyR2-related molecular genetic studies. Two novel RyR2 mutations showing a gain-of-function defect in vitro were identified in three victims of sudden cardiac death. Extended pedigree analyses revealed some surviving mutation carriers with mild structural abnormalities of the heart and resting ventricular arrhythmias suggesting that not all RyR2 mutations lead to a typical CPVT phenotype, underscoring the relevance of tailored risk stratification of a RyR2 mutation carrier.

Hydrographic observations and model simulation of the Bay of Bengal freshwater plume

Hydrographic observations were taken along two coastal sections and one open ocean section in the Bay of Bengal during the 1999 southwest monsoon, as a part of the Bay of Bengal Monsoon Experiment (BOBMEX). The coastal section in the northwestern Bay of Bengal, which was occupied twice, captured a freshwater plume in its two stages: first when the plume was restricted to the coastal region although separated from the coast, and then when the plume spread offshore. Below the freshwater layer there were indications of an undercurrent. The coastal section in the southern Bay of Bengal was marked by intense coastal upwelling in a 50 km wide band. In regions under the influence of the freshwater plume, the mixed layer was considerably thinner and occasionally led to the formation of a temperature inversion. The mixed layer and isothermal layer were of similar depth for most of the profiles within and outside the freshwater plume and temperature below the mixed layer decreased rapidly till the top of seasonal thermocline. There was no barrier layer even in regions well under the influence of the freshwater plume. The freshwater plume in the open Bay of Bengal does not advect to the south of 16 degrees N during the southwest monsoon. A model of the Indian Ocean, forced by heat, momentum and freshwater fluxes for the year 1999, reproduces the freshwater plume in the Bay of Bengal reasonably well. Model currents as well as the surface circulation calculated as the sum of geostrophic and Ekman drift show a southeastward North Bay Monsoon Current (NBMC) across the Bay, which forms the southern arm of a cyclonic gyre. The NBMC separates the very low salinity waters of the northern Bay from the higher salinities in the south and thus plays an important role in the regulation of near surface stratification. (c) 2007 Elsevier Ltd. All rights reserved.

Hydrographic observations and model simulation of the Bay of Bengal freshwater plume

Hydrographic observations were taken along two coastal sections and one open ocean section in the Bay of Bengal during the 1999 southwest monsoon, as a part of the Bay of Bengal Monsoon Experiment (BOBMEX). The coastal section in the northwestern Bay of Bengal, which was occupied twice, captured a freshwater plume in its two stages: first when the plume was restricted to the coastal region although separated from the coast, and then when the plume spread offshore. Below the freshwater layer there were indications of an undercurrent. The coastal section in the southern Bay of Bengal was marked by intense coastal upwelling in a 50 km wide band. In regions under the influence of the freshwater plume, the mixed layer was considerably thinner and occasionally led to the formation of a temperature inversion. The mixed layer and isothermal layer were of similar depth for most of the profiles within and outside the freshwater plume and temperature below the mixed layer decreased rapidly till the top of seasonal thermocline. There was no barrier layer even in regions well under the influence of the freshwater plume. The freshwater plume in the open Bay of Bengal does not advect to the south of 16 degrees N during the southwest monsoon. A model of the Indian Ocean, forced by heat, momentum and freshwater fluxes for the year 1999, reproduces the freshwater plume in the Bay of Bengal reasonably well. Model currents as well as the surface circulation calculated as the sum of geostrophic and Ekman drift show a southeastward North Bay Monsoon Current (NBMC) across the Bay, which forms the southern arm of a cyclonic gyre. The NBMC separates the very low salinity waters of the northern Bay from the higher salinities in the south and thus plays an important role in the regulation of near surface stratification. (c) 2007 Elsevier Ltd. All rights reserved.

Average-Delay Optimal Policies for the Point-to-Point Channel

Average-delay optimal scheduflng of messages arriving to the transmitter of a point-to-point channel is considered in this paper. We consider a discrete time batch-arrival batch-service queueing model for the communication scheme, with service time that may be a function of batch size. The question of delay optimality is addressed within the semi-Markov decision-theoretic framework. Approximations to the average-delay optimal policy are obtained.

Numerical studies on channel formation and growth during solidification: Effect of process parameters

In the present work, solidification of a hyper-eutectic ammonium chloride solution in a bottom-cooled cavity (i.e. with stable thermal gradient) is numerically studied. A Rayleigh number based criterion is developed, which determines the conditions favorable for freckles formation. This criterion, when expressed in terms of physical properties and process parameters, yields the condition for plume formation as a function of concentration, liquid fraction, permeability, growth rate of a mushy layer and thermophysical properties. Subsequently, numerical simulations are performed for cases with initial and boundary conditions favoring freckle formation. The effects of parameters, such as cooling rate and initial concentration, on the formation and growth of freckles are investigated. It was found that a high cooling rate produced larger and more defined channels which are retained for a longer durations. Similarly, a lower initial concentration of solute resulted in fewer but more pronounced channels. The number and size of channels are also found to be related to the mushy zone thickness. The trends predicted with regard to the variation of number of channels with time under different process conditions are in accordance with the experimental observations reported in the literature.

Effects of membrane channel-forming polypeptides on mitochondrial oxidative phosphorylation. A comparison of alamethicin, gramicidin A, melittin and tetraacetyl melittin

Transmembrane channel-forming polypeptides can function as uncouplers of mitochondrial oxidative phosphorylation. The observed effects are dependent on the phosphate ion (Pi) concentration in the medium. At low Pi (2.5 mM) the order of uncoupling efficiencies is gramicidin A much greater than alamethicin greater than tetraacetyl melittin greater than melittin. The remarkably high activity of gramicidin A suggests insertion of preformed channel dimers into the membrane. It is also suggested that lipid phase association of peptides is necessary in the other cases. At Pi = 100 mM inhibitory effects are observed for alamethicin and tetraacetyl melittin. Less pronounced inhibition is seen for melittin, while no such effect is noted for gramicidin A. The site of inhibition is shown to be complex IV, and the differences in the behavior of the peptides are rationalized in terms of channel structures.

Effects of membrane channel-forming polypeptides on mitochondrial oxidative phosphorylation. A comparison of alamethicin, gramicidin A, melittin and tetraacetyl melittin.

Transmembrane channel-forming polypeptides can function as uncouplers of mitochondrial oxidative phosphorylation. The observed effects are dependent on the phosphate ion (Pi) concentration in the medium. At low Pi (2.5 mM) the order of uncoupling efficiencies is gramicidin A much greater than alamethicin greater than tetraacetyl melittin greater than melittin. The remarkably high activity of gramicidin A suggests insertion of preformed channel dimers into the membrane. It is also suggested that lipid phase association of peptides is necessary in the other cases. At Pi = 100 mM inhibitory effects are observed for alamethicin and tetraacetyl melittin. Less pronounced inhibition is seen for melittin, while no such effect is noted for gramicidin A. The site of inhibition is shown to be complex IV, and the differences in the behavior of the peptides are rationalized in terms of channel structures.

Ion channel formation by zervamicin-IIB. A molecular modelling study.

Zervamicin-IIB (Zrv-IIB) is a 16 residue peptaibol which forms voltage-activated, multiple conductance level channels in planar lipid bilayers. A molecular model of Zrv-IIB channels is presented. The structure of monomeric Zrv-IIB is based upon the crystal structure of Zervamicin-Leu. The helical backbone is kinked by a hydroxyproline residue at position 10. Zrv-IIB channels are modelled as helix bundles of from 4 to 8 parallel helices surrounding a central pore. The monomers are packed with their C-terminal helical segments in close contact, and the bundles are stabilized by hydrogen bonds between glutamine 11 and hydroxyproline 10 of adjacent helices. Interaction energy profiles for movement of three different probes species (K+, Cl- and water) through the central pore are analyzed. The conformations of: (a) the sidechain of glutamine 3; (b) the hydroxyl group of hydroxyproline 10; and (c) the C-terminal hydroxyl group are "optimized" in order to maximize favourable interactions between the channel and the probes, resulting in favourable interaction energy profiles for all three. This suggests that conformational flexibility of polar sidechains enables the channel lining to mimic an aqueous environment.

Delay optimal control algorithm for a multiaccess fading channel with peak power constraint

We consider an optimal power and rate scheduling problem for a multiaccess fading wireless channel with the objective of minimising a weighted sum of mean packet transmission delay subject to a peak power constraint. The base station acts as a controller which, depending upon the buffer lengths and the channel state of each user, allocates transmission rate and power to individual users. We assume perfect channel state information at the transmitter and the receiver. We also assume a Markov model for the fading and packet arrival processes. The policy obtained represents a form of Indexability.

Measurement of the top quark mass in the dilepton channel using mT2 at CDF

We present measurements of the top quark mass using the \mT2, a variable related to the transverse mass in events with two missing particles. We use the template method applied to t\tbar dilepton events produced in p\pbar collisions at Fermilab's Tevatron and collected by the CDF detector. From a data sample corresponding to an integrated luminosity of 3.4 \invfb, we select 236 t\tbar candidate events. Using the \mT2 distribution, we measure the top quark mass to be M_{Top} = 168.0^{+4.8}_{-4.0} $\pm$ {2.9} GeV/c^{2}. By combining the \mT2 with the reconstructed top mass distributions based on a neutrino weighting method, we measure M_{top}=169.3 $\pm$ 2.7 $\pm$ 3.2 GeV/c^{2}. This is the first application of the \mT2 variable in a mass measurement at a hadron collider.

Search for the associated production of the standard-model Higgs boson in the all-hadronic channel

"We report on a search for the standard-model Higgs boson in pp collisions at s=1.96 TeV using an integrated luminosity of 2.0 fb(-1). We look for production of the Higgs boson decaying to a pair of bottom quarks in association with a vector boson V (W or Z) decaying to quarks, resulting in a four-jet final state. Two of the jets are required to have secondary vertices consistent with B-hadron decays. We set the first 95% confidence level upper limit on the VH production cross section with V(-> qq/qq('))H(-> bb) decay for Higgs boson masses of 100-150 GeV/c(2) using data from run II at the Fermilab Tevatron. For m(H)=120 GeV/c(2), we exclude cross sections larger than 38 times the standard-model prediction."

Search for new physics in the μμ+e/μ+E̸T channel with a low-pT lepton threshold at the Collider Detector at Fermilab

A search for new physics using three-lepton (trilepton) data collected with the CDF II detector and corresponding to an integrated luminosity of 976 pb-1 is presented. The standard model predicts a low rate of trilepton events, which makes some supersymmetric processes, such as chargino-neutralino production, measurable in this channel. The mu+mu+l signature is investigated, where l is an electron or a muon, with the additional requirement of large missing transverse energy. In this analysis, the lepton transverse momenta with respect to the beam direction (pT) are as low as 5 GeV/c, a selection that improves the sensitivity to particles which are light as well as to ones which result in leptonically decaying tau leptons. At the same time, this low-p_T selection presents additional challenges due to the non-negligible heavy-quark background at low lepton momenta. This background is measured with an innovative technique using experimental data. Several dimuon and trilepton control regions are investigated, and good agreement between experimental results and standard-model predictions is observed. In the signal region, we observe one three-muon event and expect 0.4+/-0.1 mu+mu+l events

Inclusive Search for Standard Model Higgs Boson Production in the WW Decay Channel using the CDF II Detector

We present a search for standard model (SM) Higgs boson production using ppbar collision data at sqrt(s) = 1.96 TeV, collected with the CDF II detector and corresponding to an integrated luminosity of 4.8 fb-1. We search for Higgs bosons produced in all processes with a significant production rate and decaying to two W bosons. We find no evidence for SM Higgs boson production and place upper limits at the 95% confidence level on the SM production cross section (sigma(H)) for values of the Higgs boson mass (m_H) in the range from 110 to 200 GeV. These limits are the most stringent for m_H > 130 GeV and are 1.29 above the predicted value of sigma(H) for mH = 165 GeV.