Conformation of the Transmembrane Domain of the Anthrax Toxin Receptor

Restauració dels vitrallsFoto final, plafó a6, cara interna, amb llum a través. Geomètric

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p

A combined experimental and theoretical study of ion solvation in liquid N-methylacetamide

Most current biomolecular simulations are based on potential energy functions that treat the electrostatic energy as a sum of pairwise Coulombic interactions between effective fixed atomic charges. This approximation, in which many-body induced polarization effects are included in an average way, is expected to be satisfactory for a wide range of systems, but less accurate for processes involving the transfer and partition of ions among heterogeneous environments. The limitations of these potential energy functions are perhaps most obvious in studies of ion permeation through membrane channels. In many cases, the pore is so narrow that the permeating ion must shed most of its surrounding water molecules and the large energetic loss due to dehydration must be compensated by coordination with protein atoms. Interactions of cations with protein backbone carbonyl oxygens, in particular, play a critical role in several important biological channels. As a first step toward meeting the challenge of developing an accurate explicit accounting for induced polarization effects, the present work combines experiments and computation to characterize the interactions of alkali and halide ions with N-methylacetamide chosen to represent the peptide bond. From solubility measurements, we extract the solvation free energies of KCl and NaCl in liquid N-methylacetamide. Polarizable models based on the Drude oscillator are then developed and compared with available experimental and ab initio data. The good agreement for a range of structural and thermodynamic properties in the gas and condensed phases suggests that the polarizable models provide an accurate representation of ion−amide interactions in biological systems

Data_Sheet_2_Assessment of absolute risk of life-threatening cardiac events in long QT syndrome patients.ZIP

BackgroundRisk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time.MethodsRochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age ResultsIn Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell’s generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740–0.827) and 0.785 (95% CI: 0.721–0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610–0.790) and 0.711 (95% CI: 0.631–0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed.ConclusionThis study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient’s risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.</p

Data_Sheet_1_Assessment of absolute risk of life-threatening cardiac events in long QT syndrome patients.pdf

BackgroundRisk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time.MethodsRochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age ResultsIn Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell’s generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740–0.827) and 0.785 (95% CI: 0.721–0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610–0.790) and 0.711 (95% CI: 0.631–0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed.ConclusionThis study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient’s risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.</p

Measurement of charged-particle multiplicities in gluon and quark jets in p(p)over-bar collisions at root s=1.8 TeV

We report the first largely model independent measurement of charged particle multiplicities in quark and gluon jets, N-q and N-g, produced at the Fermilab Tevatron in p (p) over bar collisions with a center-of-mass energy of 1.8 TeV and recorded by the Collider Detector at Fermilab. The measurements are made for jets with average energies of 41 and 53 GeV by counting charged particle tracks in cones with opening angles of θ(c)=0.28, 0.36, and 0.47 rad around the jet axis. The corresponding jet hardness Q=E-jetθ(c) varies in the range from 12 to 25 GeV. At Q=19.2 GeV, the ratio of multiplicities r=N-g/N-q is found to be 1.64&PLUSMN; 0.17, where statistical and systematic uncertainties are added in quadrature. The results are in agreement with resummed perturbative QCD calculations