Generalized Born Implicit Solvent Models Do Not Reproduce Secondary Structures of De Novo Designed Glu/Lys Peptides

[Image: see text] We test a range of standard generalized Born (GB) models and protein force fields for a set of five experimentally characterized, designed peptides comprising alternating blocks of glutamate and lysine, which have been shown to differ significantly in α-helical content. Sixty-five combinations of force fields and GB models are evaluated in >800 μs of molecular dynamics simulations. GB models generally do not reproduce the experimentally observed α-helical content, and none perform well for all five peptides. These results illustrate that these models are not usefully predictive in this context. These peptides provide a useful test set for simulation methods

Characteristics of Lightning Within Electrified Snowfall Events Using Total Lightning Measurements

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Characteristics of Lightning Within Electrified Snowfall Events Using Lightning Mapping Arrays

This study examined 34 lightning flashes within four separate thundersnow events derived from lightning mapping arrays (LMAs) in northern Alabama, central Oklahoma, and Washington, DC. The goals were to characterize the in-cloud component of each lightning flash, as well as the correspondence between the LMA observations and lightning data taken from national lightning networks like the National Lightning Detection Network (NLDN). Individual flashes were examined in detail to highlight several observations within the dataset. The study results demonstrated that the structures of these flashes were primarily normal polarity. The mean area encompassed by this set of flashes is 375 square kilometers, with a maximum flash extent of 2300 square kilometers, a minimum of 3 square kilometers, and a median of 128 square kilometers. An average of 2.29 NLDN flashes were recorded per LMA-derived lightning flash. A maximum of 11 NLDN flashes were recorded in association with a single LMA-derived flash on 10 January 2011. Additionally, seven of the 34 flashes in the study contain zero NLDN identified flashes. Eleven of the 34 flashes initiated from tall human-made objects (e.g., communication towers). In at least six lightning flashes, the NLDN detected a return stroke from the cloud back to the tower and not the initial upward leader. This study also discusses lightning's interaction with the human built environment and provides an example of lightning within heavy snowfall observed by GOES-16's Geostationary Lightning Mapper

Patients With Generalized Joint Hypermobility Have Thinner Superior Hip Capsules and Greater Hip Internal Rotation on Physical Examination

PURPOSE: To compare preoperative hip range of motion (ROM), hip capsular thickness on magnetic resonance imaging (MRI), and bony morphology on radiographs and computed tomography (CT) between patients with and without joint hypermobility as measured by the Beighton Test score (BTS), with subanalysis based on sex and age. METHODS: Consecutive patients who underwent hip arthroscopy for a diagnosis of femoroacetabular impingement syndrome with or without dysplasia were retrospectively reviewed. Patient BTS, hip ROM, demographics, surgical data, morphologic measures on radiographs and CT, and MRI findings including hip capsule thickness at various locations were compiled. Multiple statistical tests were performed, including multivariable linear or logistic regression models, while controlling for BTS, age, and sex. RESULTS: In total, 99 patients were included with a mean age of 29 ± 9.9 years; 62 (62.6%), were female. Forty patients (40.4%) had a BTS ≥4. Female patients (P \u3c .001) and younger patients (26.7 vs 30.9 years, P = .030) were more likely to have a BTS ≥4. Male patients had significantly thicker superior capsules (3.4 mm vs. 2.8 mm, P = .034). BTS was not associated with capsular thickness when controlling for sex. On CT, femoral version (18.9° vs 11.4°, P \u3c .001), and McKibben index (37.8° vs. 28.2°, P \u3c .001) were significantly greater in those with a BTS ≥4. Patients with a BTS ≥4 had more hip internal rotation at 90° of flexion (15.0° vs 10.0°, P \u3c .001), when prone (30.0° vs 20.0°, P = .004), and in extension (10.0° vs. 5.0°, P \u3c .001). CONCLUSIONS: All female patients, regardless of Beighton score, and all patients with a BTS ≥4 indicated for primary hip arthroscopy for femoroacetabular impingement syndrome with or without dysplasia were more likely to have thinner superior hip capsules on MRI and greater hip internal rotation on exam. Bony morphologic differences exist between sexes and between patients with and without hypermobility, likely contributing to differences in ROM. LEVEL OF EVIDENCE: III, retrospective cohort study

Structural resolution of switchable states of a de novo peptide assembly

De novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By placing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally

Sudden cardiac death in patients with ischemic heart failure undergoing coronary artery bypass grafting results from the STICH randomized clinical trial (Surgical Treatment for Ischemic Heart Failure)

Background—The risk of sudden cardiac death (SCD) in patients with heart failure following CABG has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing and clinical predictors of SCD after CABG. Methods—Patients enrolled in the Surgical Treatment of Ischemic Heart Failure (STICH) trial who underwent CABG with or without surgical ventricular reconstruction (SVR) were included. We excluded patients with prior ICD and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results—Over a median follow-up of 46 months, 113 patients of 1411 patients who received CABG without (n = 934) or with SVR (n = 477) had SCD; 311 died of other causes. The mean LVEF at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than those who died for reasons other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-90 day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy and LV function, ESVI and BNP were most strongly associated with SCD. Conclusions—The monthly risk of SCD shortly after CABG among patients with a low LVEF is highest between the first and third month, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative ESVI and/or BNP