Spectroscopic Properties of a Biologically Relevant [Fe2(μ-O)2] Diamond Core Motif with a Short Iron-Iron Distance

Diiron cofactors in enzymes perform diverse challenging transformations. The structures of high valent intermediates (Q in methane monooxygenase and X in ribonucleotide reductase) are debated since Fe−Fe distances of 2.5–3.4 Å were attributed to “open” or “closed” cores with bridging or terminal oxido groups. We report the crystallographic and spectroscopic characterization of a FeIII2(μ-O)2 complex (2) with tetrahedral (4C) centres and short Fe−Fe distance (2.52 Å), persisting in organic solutions. 2 shows a large Fe K-pre-edge intensity, which is caused by the pronounced asymmetry at the TD FeIII centres due to the short Fe−μ−O bonds. A ≈2.5 Å Fe−Fe distance is unlikely for six-coordinate sites in Q or X, but for a Fe2(μ-O)2 core containing four-coordinate (or by possible extension five-coordinate) iron centres there may be enough flexibility to accommodate a particularly short Fe−Fe separation with intense pre-edge transition. This finding may broaden the scope of models considered for the structure of high-valent diiron intermediates formed upon O2 activation in biology

Sex-specific aspects of phospholamban cardiomyopathy:The importance and prognostic value of low-voltage electrocardiograms

Background: A pathogenic variant in the gene encoding phospholamban (PLN), a protein that regulates calcium homeostasis of cardiomyocytes, causes PLN cardiomyopathy. It is characterized by a high arrhythmic burden and can progress to severe cardiomyopathy. Risk assessment guides implantable cardioverter-defibrillator therapy and benefits from personalization. Whether sex-specific differences in PLN cardiomyopathy exist is unknown. Objective: The purpose of this study was to improve the accuracy of PLN cardiomyopathy diagnosis and risk assessment by investigating sex-specific aspects. Methods: We analyzed a multicenter cohort of 933 patients (412 male, 521 female) with the PLN p.(Arg14del) pathogenic variant following up on a recently developed PLN risk model. Sex-specific differences in the incidence of risk model components were investigated: low-voltage electrocardiogram (ECG), premature ventricular contractions, negative T waves, and left ventricular ejection fraction. Results: Sustained ventricular arrhythmias (VAs) occurred in 77 males (18.7%) and 61 females (11.7%) (P =.004). Of the 933 cohort members, 287 (31%) had ≥1 low-voltage ECG during follow-up (180 females [63%], 107 males [37%]; P =.006). Female sex, age, age at clinical presentation, and proband status predicted low-voltage ECG during follow-up (area under the curve: 0.78). Sustained VA-free survival was lowest in males with low-voltage ECG (P <.001). Conclusion: Low-voltage ECGs predict sustained VA and are a component of the PLN risk model. Low-voltage ECGs are more common in females, yet prognostic value is greater in males. Future studies should determine the impact of this difference on the risk prediction of PLN cardiomyopathy and possibly other cardiomyopathies

Plasma lens for US based super neutrino beam at either FNAL OR BNL

The plasma lens concept is examined as an alternative to focusing horns and solenoids for a neutrino beam facility. The concept is based on a combined high-current lens/target configuration. Current is fed at an electrode located downstream from the beginning of the target where pion capturing is needed. The current is carried by plasma outside the target. A second plasma lens section, with an additional current feed, follows the target. The plasma is immersed in a relatively small solenoidal magnetic field to facilitate its current profile shaping to optimize pion capture. Simulations of the not yet fully optimized configuration yielded a 25% higher neutrino flux at a detector situated at 3 km from the target than the horn system for the entire energy spectrum and a factor of 2.5 higher flux for neutrinos with energy larger than 3 GeV. A major advantage of plasma lenses is in background reduction. In antineutrino operation, neutrino background is reduced by a factor of close to 3 for the whole spectrum, and for energy larger than 3 GeV, neutrino background is reduced by a factor of 3.6. Plasma lenses have additional advantages: larger axial currents, high signal purity: minimal neutrino background in antineutrino runs. The lens medium consists of plasma, consequently, particle absorption and scattering is negligible. Withstanding high mechanical and thermal stresses in a plasma is not an issue.Comment: 4 pages, 4 figures submitted to Particle Accelerators Conference 2007 (PAC07

Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions

Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia:a landmark study

Aims:Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. Methods:We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were and results collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6–3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79–0.87) and calibration slope of 0.97. Conclusion:The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.</p

Long-term reliability of the phospholamban (PLN) p.(Arg14del) risk model in predicting major ventricular arrhythmia:a landmark study

Aims:Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. Methods:We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were and results collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6–3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79–0.87) and calibration slope of 0.97. Conclusion:The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.</p