Metabolic Cost of Exercise Initiation in Patients With Heart Failure With Preserved Ejection Fraction vs Community-Dwelling Adults.

Importance: Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions. Objective: To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences. Design, Setting, and Participants: This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020. Exposures: Internal work (IW), a measure of work equivalents required to initiate movement. Main Outcomes and Measures: Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures. Results: Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW. Conclusions and Relevance: This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.

Adaptive shape control of wavefront-preserving X-ray mirrors with active cooling and heating.

This article describes the development and testing of a novel, water-cooled, active optic mirror system (called "REAL: Resistive Element Adjustable Length") that combines cooling with applied auxiliary heating, tailored to the spatial distribution of the thermal load generated by the incident beam. This technique is theoretically capable of sub-nanometer surface figure error control even at high power density. Tests conducted in an optical metrology laboratory and at synchrotron X-ray beamlines showed the ability to maintain the mirror profile to the level needed for the next generation storage rings and FEL mirrors.

Multiplexed, high-throughput measurements of cell contraction and endothelial barrier function.

Vascular leakage, protein exudation, and edema formation are events commonly triggered by inflammation and facilitated by gaps that form between adjacent endothelial cells (ECs) of the vasculature. In such paracellular gap formation, the role of EC contraction is widely implicated, and even therapeutically targeted. However, related measurement approaches remain slow, tedious, and complex to perform. Here, we have developed a multiplexed, high-throughput screen to simultaneously quantify paracellular gaps, EC contractile forces, and to visualize F-actin stress fibers, and VE-cadherin. As proof-of-principle, we examined barrier-protective mechanisms of the Rho-associated kinase inhibitor, Y-27632, and the canonical agonist of the Tie2 receptor, Angiopoietin-1 (Angpt-1). Y-27632 reduced EC contraction and actin stress fiber formation, whereas Angpt-1 did not. Yet both agents reduced thrombin-, LPS-, and TNFα-induced paracellular gap formation. This unexpected result suggests that Angpt-1 can achieve barrier defense without reducing EC contraction, a mechanism that has not been previously described. This insight was enabled by the multiplex nature of the force-based platform. The high-throughput format we describe should accelerate both mechanistic studies and the screening of pharmacological modulators of endothelial barrier function.

Gain in polycrystalline Nd-doped alumina: leveraging length scales to create a new class of high-energy, short pulse, tunable laser materials.

Traditionally accepted design paradigms dictate that only optically isotropic (cubic) crystal structures with high equilibrium solubilities of optically active ions are suitable for polycrystalline laser gain media. The restriction of symmetry is due to light scattering caused by randomly oriented anisotropic crystals, whereas the solubility problem arises from the need for sufficient active dopants in the media. These criteria limit material choices and exclude materials that have superior thermo-mechanical properties than state-of-the-art laser materials. Alumina (Al2O3) is an ideal example; it has a higher fracture strength and thermal conductivity than today's gain materials, which could lead to revolutionary laser performance. However, alumina has uniaxial optical proprieties, and the solubility of rare earths (REs) is two-to-three orders of magnitude lower than the dopant concentrations in typical RE-based gain media. We present new strategies to overcome these obstacles and demonstrate gain in a RE-doped alumina (Nd:Al2O3) for the first time. The key insight relies on tailoring the crystallite size to other important length scales-the wavelength of light and interatomic dopant distances, which minimize optical losses and allow successful Nd doping. The result is a laser gain medium with a thermo-mechanical figure of merit of R s~19,500 Wm-1 a 24-fold and 19,500-fold improvements over the high-energy-laser leaders Nd:YAG (R s~800 Wm-1) and Nd:Glass (R s~1 Wm-1), respectively. Moreover, the emission bandwidth of Nd:Al2O3 is broad: ~13 THz. The successful demonstration of gain and high bandwidth in a medium with superior R s can lead to the development of lasers with previously unobtainable high-peak powers, short pulses, tunability, and high-duty cycles.

Retraction: A photon thermal diode.

This corrects the article DOI: 10.1038/ncomms6446.

Unjamming and cell shape in the asthmatic airway epithelium.

From coffee beans flowing in a chute to cells remodelling in a living tissue, a wide variety of close-packed collective systems-both inert and living-have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed-to-jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, the collapse of critical scaling predicts a counter-intuitive relationship between jamming, cell shape and cell-cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role.

A 3 omega method to measure an arbitrary anisotropic thermal conductivity tensor.

Previous use of the 3 omega method has been limited to materials with thermal conductivity tensors that are either isotropic or have their principal axes aligned with the natural cartesian coordinate system defined by the heater line and sample surface. Here, we consider the more general case of an anisotropic thermal conductivity tensor with finite off-diagonal terms in this coordinate system. An exact closed form solution for surface temperature has been found for the case of an ideal 3 omega heater line of finite width and infinite length, and verified numerically. We find that the common slope method of data processing yields the determinant of the thermal conductivity tensor, which is invariant upon rotation about the heater line's axis. Following this analytic result, an experimental scheme is proposed to isolate the thermal conductivity tensor elements. Using two heater lines and a known volumetric heat capacity, the arbitrary 2-dimensional anisotropic thermal conductivity tensor can be measured with a low frequency sweep. Four heater lines would be required to extend this method to measure all 6 unknown tensor elements in 3 dimensions. Experiments with anisotropic layered mica are carried out to demonstrate the analytical results.

A photon thermal diode.

A thermal diode is a two-terminal nonlinear device that rectifies energy carriers (for example, photons, phonons and electrons) in the thermal domain, the heat transfer analogue to the familiar electrical diode. Effective thermal rectifiers could have an impact on diverse applications ranging from heat engines to refrigeration, thermal regulation of buildings and thermal logic. However, experimental demonstrations have lagged far behind theoretical proposals. Here we present the first experimental results for a photon thermal diode. The device is based on asymmetric scattering of ballistic energy carriers by pyramidal reflectors. Recent theoretical work has predicted that this ballistic mechanism also requires a nonlinearity in order to yield asymmetric thermal transport, a requirement of all thermal diodes arising from the second Law of Thermodynamics, and realized here using an 'inelastic thermal collimator' element. Experiments confirm both effects: with pyramids and collimator the thermal rectification is 10.9 ± 0.8%, while without the collimator no rectification is detectable (<0.3%).

Glassy dynamics, cell mechanics, and endothelial permeability.

A key feature of all inflammatory processes is disruption of the vascular endothelial barrier. Such disruption is initiated in part through active contraction of the cytoskeleton of the endothelial cell (EC). Because contractile forces are propagated from cell to cell across a great many cell-cell junctions, this contractile process is strongly cooperative and highly nonlocal. We show here that the characteristic length scale of propagation is modulated by agonists and antagonists that impact permeability of the endothelial barrier. In the presence of agonists including thrombin, histamine, and H2O2, force correlation length increases, whereas in the presence of antagonists including sphingosine-1-phosphate, hepatocyte growth factor, and the rho kinase inhibitor, Y27632, force correlation length decreases. Intercellular force chains and force clusters are also evident, both of which are reminiscent of soft glassy materials approaching a glass transition.

Protein Structure Prediction: The Next Generation.

Over the last 10-15 years a general understanding of the chemical reaction of protein folding has emerged from statistical mechanics. The lessons learned from protein folding kinetics based on energy landscape ideas have benefited protein structure prediction, in particular the development of coarse grained models. We survey results from blind structure prediction. We explore how second generation prediction energy functions can be developed by introducing information from an ensemble of previously simulated structures. This procedure relies on the assumption of a funneled energy landscape keeping with the principle of minimal frustration. First generation simulated structures provide an improved input for associative memory energy functions in comparison to the experimental protein structures chosen on the basis of sequence alignment.

Associative memory Hamiltonians for structure prediction without homology: alpha/beta proteins.

We describe a method for predicting the structure of alpha beta class proteins in the absence of information from homologous structures. The method is based on an associative memory model for short to intermediate range in sequence contacts and a contact potential for long range in sequence contacts. The coefficients in the energy function are chosen to maximize the ratio of the folding temperature to the glass transition temperature. We use the resulting optimized model to predict the structure of three alpha beta protein domains ranging in length from 81 to 115 residues. The resulting predictions align with low rms deviations to large portions of the native state. We have also calculated the free energy as a function of similarity to the native state for one of these three domains, and we show that, as expected from the optimization criteria, the free energy surface resembles a rough funnel to the native state. Finally, we briefly demonstrate the effect of roughness in the energy landscape on the dynamics.

Ab initio protein structure prediction.

Steady progress has been made in the field of ab initio protein folding. A variety of methods now allow the prediction of low-resolution structures of small proteins or protein fragments up to approximately 100 amino acid residues in length. Such low-resolution structures may be sufficient for the functional annotation of protein sequences on a genome-wide scale. Although no consistently reliable algorithm is currently available, the essential challenges to developing a general theory or approach to protein structure prediction are better understood. The energy landscapes resulting from the structure prediction algorithms are only partially funneled to the native state of the protein. This review focuses on two areas of recent advances in ab initio structure prediction-improvements in the energy functions and strategies to search the caldera region of the energy landscapes.

Folding funnels: the key to robust protein structure prediction.

Natural proteins fold because their free energy landscapes are funneled to their native states. The degree to which a model energy function for protein structure prediction can avoid the multiple minima problem and reliably yield at least low-resolution predictions is also dependent on the topography of the energy landscape. We show that the degree of funneling can be quantitatively expressed in terms of a few averaged properties of the landscape. This allows us to optimize simplified energy functions for protein structure prediction even in the absence of homology information. Here we outline the optimization procedure in the context of associative memory energy functions originally introduced for tertiary structure recognition and demonstrate that even partially funneled landscapes lead to qualitatively correct, low-resolution predictions.