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Correlated diffusion in lipid bilayers
Lipid membranes are complex quasi–two-dimensional fluids, whose importance in biology and unique physical/materials properties have made them a major target for biophysical research. Recent single-molecule tracking experiments in membranes have caused some controversy, calling the venerable Saffman–Delbrück model into question and suggesting that, perhaps, current understanding of membrane hydrodynamics is imperfect. However, single-molecule tracking is not well suited to resolving the details of hydrodynamic flows; observations involving correlations between multiple molecules are superior for this purpose. Here dual-color molecular tracking with submillisecond time resolution and submicron spatial resolution is employed to reveal correlations in the Brownian motion of pairs of fluorescently labeled lipids in membranes. These correlations extend hundreds of nanometers in freely floating bilayers (black lipid membranes) but are severely suppressed in supported lipid bilayers. The measurements are consistent with hydrodynamic predictions based on an extended Saffman–Delbrück theory that explicitly accounts for the two-leaflet bilayer structure of lipid membranes.
Journal Article
Batman, the brave and the bold : the Bronze Age
\"The late '60s marked the height of Batmania, when fans of the Batman television series and the comic books couldn't get enough of the Caped Crusader. His appearances on covers meant higher sales, so it was decreed Batman would take up permanent residence in THE BRAVE AND THE BOLD. His courage was never questioned, and he fearlessly teamed up with the most daring partners from across the DC Universe at a time when such crossovers were rare. These groundbreaking stories featured some of Batman's greatest team-ups with such legendary characters as Wonder Woman, the Flash, Deadman, Green Arrow, Green Lantern, the Teen Titans and others, all by some of the foremost comics talent of the Bronze Age--Neal Adams, Jim Aparo, Bob Haney, Dick Giordano and Dennis O'Neil, to name a few.\"-- Provided by publisher.
Book
Continuum simulations of biomembrane dynamics and the importance of hydrodynamic effects
Traditional particle-based simulation strategies are impractical for the study of lipid bilayers and biological membranes over the longest length and time scales (microns, seconds and longer) relevant to cellular biology. Continuum-based models developed within the frameworks of elasticity theory, fluid dynamics and statistical mechanics provide a framework for studying membrane biophysics over a range of mesoscopic to macroscopic length and time regimes, but the application of such ideas to simulation studies has occurred only relatively recently. We review some of our efforts in this direction with emphasis on the dynamics in model membrane systems. Several examples are presented that highlight the prominent role of hydrodynamics in membrane dynamics and we argue that careful consideration of fluid dynamics is key to understanding membrane biophysics at the cellular scale.
Journal Article
Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40
Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design.
Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40–MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.
Journal Article
A Consistent Model for Thermal Fluctuations and Protein-Induced Deformations in Lipid Bilayers
We present an elastic Hamiltonian for membrane energetics that captures bilayer undulation and peristaltic deformations over all wavelengths, including the short wavelength protrusion regime. The model implies continuous functional forms for thermal undulation and peristaltic amplitudes as a function of wavelength and predicts previously overlooked relationships between these curves. Undulation and peristaltic spectra display excellent agreement with data from both atomistic and coarse-grained models over all simulated length scales. Additionally, the model accurately predicts the bilayer’s response to a cylindrical protein inclusion as observed in coarse-grained simulation. This elastic response provides an explanation for gramicidin ion channel lifetime versus membrane thickness data that requires no fit constants. The physical parameters inherent to this picture may be expressed in terms of familiar material properties associated with lipid monolayers. Inclusion of a finite monolayer spontaneous curvature is essential to obtain fully consistent agreement between theory and the full range of available simulation/experimental data.
Journal Article
Contributions of Gaussian Curvature and Nonconstant Lipid Volume to Protein Deformation of Lipid Bilayers
An elastic model for membrane deformations induced by integral membrane proteins is presented. An earlier theory is extended to account for nonvanishing saddle splay modulus within lipid monolayers and perturbations to lipid volume proximal to the protein. Analytical results are derived for the deformation profile surrounding a single cylindrical protein inclusion, which compare favorably to coarse-grained simulations over a range of protein sizes. Numerical results for multi-protein systems indicate that membrane-mediated interactions between inclusions are strongly affected by Gaussian curvature and display nonpairwise additivity. Implications for the aggregation of proteins are discussed.
Journal Article
High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery
Perioperative myocardial infarction (MI) is a serious complication after noncardiac surgery. We hypothesized that preoperative cardiac troponin T detected with a novel high-sensitivity (hs-cTnT) assay will identify patients at risk for acute MI and long-term mortality after major noncardiac surgery.
This was a prospective cohort study within the VINO trial (n = 608). Patients had been diagnosed with or had multiple risk factors for coronary artery disease and underwent major noncardiac surgery. Cardiac troponin I (contemporary assay) and troponin T (high-sensitivity assay) and 12-lead electrocardiograms were obtained before and immediately after surgery and on postoperative days 1, 2, and 3.
At baseline before surgery, 599 patients (98.5%) had a detectable hs-cTnT concentration, and 247 (41%) were >14 ng/L (99th percentile). After surgery, 497 patients (82%) had a rise in hs-cTnT (median change in hs-cTnT +2.7 ng/L [interquartile range 0.7-6.8]). During the first 3 postoperative days, there were 9 patients (2.5%) with a preoperative hs-cTnT <14 ng/L with acute MI, compared with 21 patients (8.6%) with a preoperative hs-cTnT >14 ng/L (odds ratio 3.67, 95% CI 1.65-8.15). During long-term follow-up, 80 deaths occurred. The 3-year mortality rate was 11% in patients with a preoperative hs-cTnT concentration <14 ng/L compared with 25% in patients with a preoperative hs-cTnT >14 ng/L (adjusted hazard ratio 2.17, 95% CI 1.19-3.96).
In this cohort of high-risk patients, preoperative hs-cTnT concentrations were significantly associated with postoperative MI and long-term mortality after noncardiac surgery.
Journal Article
Characteristics Associated with Hospitalization Among Patients with COVID-19 — Metropolitan Atlanta, Georgia, March–April 2020
The first reported U.S. case of coronavirus disease 2019 (COVID-19) was detected in January 2020 (1). As of June 15, 2020, approximately 2 million cases and 115,000 COVID-19-associated deaths have been reported in the United States.* Reports of U.S. patients hospitalized with SARS-CoV-2 infection (the virus that causes COVID-19) describe high proportions of older, male, and black persons (2-4). Similarly, when comparing hospitalized patients with catchment area populations or nonhospitalized COVID-19 patients, high proportions have underlying conditions, including diabetes mellitus, hypertension, obesity, cardiovascular disease, chronic kidney disease, or chronic respiratory disease (3,4). For this report, data were abstracted from the medical records of 220 hospitalized and 311 nonhospitalized patients aged ≥18 years with laboratory-confirmed COVID-19 from six acute care hospitals and associated outpatient clinics in metropolitan Atlanta, Georgia. Multivariable analyses were performed to identify patient characteristics associated with hospitalization. The following characteristics were independently associated with hospitalization: age ≥65 years (adjusted odds ratio [aOR] = 3.4), black race (aOR = 3.2), having diabetes mellitus (aOR = 3.1), lack of insurance (aOR = 2.8), male sex (aOR = 2.4), smoking (aOR = 2.3), and obesity (aOR = 1.9). Infection with SARS-CoV-2 can lead to severe outcomes, including death, and measures to protect persons from infection, such as staying at home, social distancing (5), and awareness and management of underlying conditions should be emphasized for those at highest risk for hospitalization with COVID-19. Measures that prevent the spread of infection to others, such as wearing cloth face coverings (6), should be used whenever possible to protect groups at high risk. Potential barriers to the ability to adhere to these measures need to be addressed.
Journal Article