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Heart failure with reduced ejection fraction is a syndrome consisting of symptoms (dyspnoea, fatigue, swelling) and/or signs of congestion (pulmonary crackles, oedema). It is caused by structural and/or functional pathologies, most commonly ischaemic heart disease, entailing elevated cardiac filling pressures and can result in low cardiac output. Medical treatment has evolved during the recent decades as outlined in this review, and a 4-pillar treatment strategy is recommended including a renin-angiotensin-aldosterone system blocker or sacubitril/valsartan, a betablocker, a mineralocorticoid antagonist, and an SGLT2 inhibitor., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Stimulated by informal conversations at the XVII International Small Angle Scattering (SAS) conference (Traverse City, 2017), an international team of experts undertook a round-robin exercise to produce a large dataset from proteins under standard solution conditions. These data were used to generate consensus SAS profiles for xylose isomerase, urate oxidase, xylanase, lysozyme and ribonuclease A. Here, we apply a new protocol using maximum likelihood with a larger number of the contributed datasets to generate improved consensus profiles. We investigate the fits of these profiles to predicted profiles from atomic coordinates that incorporate different models to account for the contribution to the scattering of water molecules of hydration surrounding proteins in solution. Programs using an implicit, shell-type hydration layer generally optimize fits to experimental data with the aid of two parameters that adjust the volume of the bulk solvent excluded by the protein and the contrast of the hydration layer. For these models, we found the error-weighted residual differences between the model and the experiment generally reflected the subsidiary maxima and minima in the consensus profiles that are determined by the size of the protein plus the hydration layer. By comparison, all-atom solute and solvent molecular dynamics (MD) simulations are without the benefit of adjustable parameters and, nonetheless, they yielded at least equally good fits with residual differences that are less reflective of the structure in the consensus profile. Further, where MD simulations accounted for the precise solvent composition of the experiment, specifically the inclusion of ions, the modelled radius of gyration values were significantly closer to the experiment. The power of adjustable parameters to mask real differences between a model and the structure present in solution is demonstrated by the results for the conformationally dynamic ribonuclease A and calculations with pseudo-experimental data. This study shows that, while methods invoking an implicit hydration layer have the unequivocal advantage of speed, care is needed to understand the influence of the adjustable parameters. All-atom solute and solvent MD simulations are slower but are less susceptible to false positives, and can account for thermal fluctuations in atomic positions, and more accurately represent the water molecules of hydration that contribute to the scattering profile., (open access.)

We review the GPAW open-source Python package for electronic structure calculations. GPAW is based on the projector-augmented wave method and can solve the self-consistent density functional theory (DFT) equations using three different wave-function representations, namely real-space grids, plane waves, and numerical atomic orbitals. The three representations are complementary and mutually independent and can be connected by transformations via the real-space grid. This multi-basis feature renders GPAW highly versatile and unique among similar codes. By virtue of its modular structure, the GPAW code constitutes an ideal platform for the implementation of new features and methodologies. Moreover, it is well integrated with the Atomic Simulation Environment (ASE), providing a flexible and dynamic user interface. In addition to ground-state DFT calculations, GPAW supports many-body GW band structures, optical excitations from the Bethe-Salpeter Equation, variational calculations of excited states in molecules and solids via direct optimization, and real-time propagation of the Kohn-Sham equations within time-dependent DFT. A range of more advanced methods to describe magnetic excitations and non-collinear magnetism in solids are also now available. In addition, GPAW can calculate non-linear optical tensors of solids, charged crystal point defects, and much more. Recently, support for graphics processing unit (GPU) acceleration has been achieved with minor modifications to the GPAW code thanks to the CuPy library. We end the review with an outlook, describing some future plans for GPAW., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

AMPA-type ionotropic glutamate receptors (AMPARs) are central to various neurological processes, including memory and learning. They assemble as homo- or heterotetramers of GluA1, GluA2, GluA3, and GluA4 subunits, each consisting of an N-terminal domain (NTD), a ligand-binding domain, a transmembrane domain, and a C-terminal domain. While AMPAR gating is primarily controlled by reconfiguration in the ligand-binding domain layer, our study focuses on the NTDs, which also influence gating, yet the underlying mechanism remains enigmatic. In this investigation, we employ molecular dynamics simulations to evaluate the NTD interface strength in GluA1, GluA2, and NTD mutants GluA2-H229N and GluA1-N222H. Our findings reveal that GluA1 has a significantly weaker NTD interface than GluA2. The NTD interface of GluA2 can be weakened by a single point mutation in the NTD dimer-of-dimer interface, namely H229N, which renders GluA2 more GluA1-like. Electrophysiology recordings demonstrate that this mutation also leads to slower recovery from desensitization. Moreover, we observe that lowering the pH induces more splayed NTD states and enhances desensitization in GluA2. We hypothesized that H229 was responsible for this pH sensitivity; however, GluA2-H229N was also affected by pH, meaning that H229 is not solely responsible and that protons exert their effect across multiple domains of the AMPAR. In summary, our work unveils an allosteric connection between the NTD interface strength and AMPAR desensitization., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

In this issue of Structure, Hall et al. 1 investigate the binding modes of anillin-like Mid1. During cytokinesis, Mid1 connects the contractile ring to the plasma membrane. Using computer simulations, the authors demonstrated how this connection is established via the L3 loop of the C2 domain., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Shape2SAS is a web application that allows researchers and students to build intuition about and understanding of small-angle scattering. It is available at https://somo.chem.utk.edu/shape2sas. The user defines a model of arbitrary shape by combining geometrical subunits, and Shape2SAS then calculates and displays the scattering intensity and the pair distance distribution, as well as a visualization of the user-defined shape. Simulated data with realistic noise are also generated. Here, it is demonstrated how Shape2SAS can calculate and display the different scattering patterns for various geometrical shapes, such as spheres and cylinders. It is also shown how the effect of structure factors can be visualized. Finally, it is indicated how multi-contrast particles can readily be generated, and how the calculated scattering may be used to validate and visualize analytical models generated in analysis software for fitting small-angle scattering data., (© Andreas Haahr Larsen et al. 2023.)

Phosphatase and tensin homologue (PTEN) and SH2-containing inositol 5'-phosphatase 2 (SHIP2) are structurally and functionally similar. They both consist of a phosphatase (Ptase) domain and an adjacent C2 domain, and both proteins dephosphorylate phosphoinositol-tri(3,4,5)phosphate, PI(3,4,5)P 3 ; PTEN at the 3-phophate and SHIP2 at the 5-phosphate. Therefore, they play pivotal roles in the PI3K/Akt pathway. Here, we investigate the role of the C2 domain in membrane interactions of PTEN and SHIP2, using molecular dynamics simulations and free energy calculations. It is generally accepted that for PTEN, the C2 domain interacts strongly with anionic lipids and therefore significantly contributes to membrane recruitment. In contrast, for the C2 domain in SHIP2, we previously found much weaker binding affinity for anionic membranes. Our simulations confirm the membrane anchor role of the C2 domain in PTEN, as well as its necessity for the Ptase domain in gaining its productive membrane-binding conformation. In contrast, we identified that the C2 domain in SHIP2 undertakes neither of these roles, which are generally proposed for C2 domains. Our data support a model in which the main role of the C2 domain in SHIP2 is to introduce allosteric interdomain changes that enhance catalytic activity of the Ptase domain.

Different amphiphilic co-polymers have been introduced to produce polymer-lipid particles with nanodisc structure composed of an inner lipid bilayer and polymer chains self-assembled as an outer belt. These particles can be used to stabilize membrane proteins in solution and enable their characterization by means of biophysical methods, including small-angle X-ray scattering (SAXS). Some of these co-polymers have also been used to directly extract membrane proteins together with their associated lipids from native membranes. Styrene/maleic acid and diisobutylene/maleic acid are among the most commonly used co-polymers for producing polymer-lipid particles, named SMALPs and DIBMALPs, respectively. Recently, a new co-polymer, named Glyco-DIBMA, was produced by partial amidation of DIBMA with the amino sugar N -methyl-d-glucosamine. Polymer-lipid particles produced with Glyco-DIBMA, named Glyco-DIBMALPs, exhibit improved structural properties and stability compared to those of SMALPs and DIBMALPs while retaining the capability of directly extracting membrane proteins from native membranes. Here, we characterize the structure and lipid composition of Glyco-DIBMALPs produced with either 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine (POPC) or 1,2-dimyristoyl- sn -glycero-3-phosphocholine (DMPC). Glyco-DIBMALPs were also prepared with mixtures of either POPC or DMPC and cholesterol at different mole fractions. We estimated the lipid content in the Glyco-DIBMALPs and determined the particle structure and morphology by SAXS. We show that the Glyco-DIBMALPs are nanodisc-like particles whose size and shape depend on the polymer/lipid ratio. This is relevant for designing nanodisc particles with a tunable diameter according to the size of the membrane protein to be incorporated. We also report that the addition of >20 mol % cholesterol strongly perturbed the formation of Glyco-DIBMALPs. Altogether, we describe a detailed characterization of the Glyco-DIBMALPs, which provides relevant inputs for future application of these particles in the biophysical investigation of membrane proteins.

The canonical members of the Jagged/Serrate and Delta families of transmembrane ligands have an extracellular, amino-terminal C2 domain that binds to phospholipids and is required for optimal activation of the Notch receptor. Somatic mutations that cause amino substitutions in the C2 domain in human JAGGED1 (JAG1) have been identified in tumors. We found in reporter cell assays that mutations affecting an N-glycosylation site reduced the ligand's ability to activate Notch. This N-glycosylation site located in the C2 domain is conserved in the Jagged/Serrate family but is lacking in the Delta family. Site-specific glycan analysis of the JAG1 amino terminus demonstrated that occupancy of this site by either a complex-type or high-mannose N-glycan was required for full Notch activation in reporter cell assays. Similarly to JAG1 variants with defects in Notch binding, N-glycan removal, either by mutagenesis of the glycosylation site or by endoglycosidase treatment, reduced receptor activation. The N-glycan variants also reduced receptor activation in a Notch signaling-dependent vascular smooth muscle cell differentiation assay. Loss of the C2 N-glycan reduced JAG1 binding to liposomes to a similar extent as the loss of the entire C2 domain. Molecular dynamics simulations suggested that the presence of the N-glycan limits the orientation of JAG1 relative to the membrane, thus facilitating Notch binding. These data are consistent with a critical role for the N-glycan in promoting a lipid-binding conformation that is required to orient Jagged at the cell membrane for full Notch activation.

Eukaryotic cells contain membranes with various curvatures, from the near-plane plasma membrane to the highly curved membranes of organelles, vesicles, and membrane protrusions. These curvatures are generated and sustained by curvature-inducing proteins, peptides, and lipids, and describing these mechanisms is an important scientific challenge. In addition to that, some molecules can sense membrane curvature and thereby be trafficked to specific locations. The description of curvature sensing is another fundamental challenge. Curved lipid membranes and their interplay with membrane-associated proteins can be investigated with molecular dynamics (MD) simulations. Various methods for simulating curved membranes with MD are discussed here, including tools for setting up simulation of vesicles and methods for sustaining membrane curvature. The latter are divided into methods that exploit scaffolding virtual beads, methods that use curvature-inducing molecules, and methods applying virtual forces. The variety of simulation tools allow researcher to closely match the conditions of experimental studies of membrane curvatures.

Aims: Persistent cardiac symptoms are an increasingly reported phenomenon following COVID-19. However, the underlying cause of cardiac symptoms is unknown. This study aimed to identify the underlying causes, if any, of these symptoms 1 year following acute COVID-19 infection., Methods and Results: 22 individuals with persistent cardiac symptoms were prospectively investigated using echocardiography, cardiovascular magnetic resonance (CMR), 6-min walking test, cardio-pulmonary exercise testing and electrocardiography. A median of 382 days (IQR 368, 442) passed between diagnosis of COVID-19 and investigation. As a cohort their echocardiography, CMR, 6-min walking test and exercise testing results were within the normal ranges. There were no differences in left ventricular ejection fraction (61.45 ± 6.59 %), global longitudinal strain (19.80 ± 3.12 %) or tricuspid annular plane systolic excursion (24.96 ± 5.55 mm) as measured by echocardiography compared to a healthy control group. VO2 max (2045.00 ± 658.40 ml/min), % expected VO2 max (114.80 ± 23.08 %) and 6-minute distance walked (608.90 ± 54.51 m) exceeded that expected for the patient cohort, whilst Troponin I (5.59 ± 6.59 ng/l) and Nt-proBNP (88.18 ± 54.27 ng/l) were normal., Conclusion: Among a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary fitness 1 year following COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wood, Kirkevang, Agergaard, Leth, Hansen, Laustsen, Larsen, Jensen, Østergaard, Bøtker, Poulsen and Kim.)

Peripheral membrane proteins (PMPs) can reversibly and specifically bind to biological membranes to carry out functions such as cell signalling, enzymatic activity, or membrane remodelling. Structures of these proteins and of their lipid-binding domains are typically solved in a soluble form, sometimes with a lipid or lipid headgroup at the binding site. To provide a detailed molecular view of PMP interactions with the membrane, computational methods such as molecular dynamics (MD) simulations can be applied. Here, we outline recent attempts to characterise these binding interactions, focusing on both intracellular proteins, such as phosphatidylinositol phosphate (PIP)-binding domains, and extracellular proteins such as glycolipid-binding bacterial exotoxins. We compare methods used to identify and analyse lipid-binding sites from simulation data and highlight recent work characterising the energetics of these interactions using free energy calculations. We describe how improvements in methodologies and computing power will help MD simulations to continue to contribute to this field in the future., (© 2022 The Author(s).)

The generation and sensing of membrane curvature by proteins has become of increasing interest to researchers with multiple mechanisms, from hydrophobic insertion to protein crowding, being identified. However, the role of charged lipids in the membrane curvature-sensing process is still far from understood. Many proteins involved in endocytosis bind phosphatidylinositol 4,5-bisphosphate (PIP2) lipids, allowing these proteins to accumulate at regions of local curvature. Here, using coarse-grained molecular dynamics simulations, we study the curvature-sensing behavior of the ANTH domain, a protein crucial for endocytosis. We selected three ANTH crystal structures containing either an intact, split, or truncated terminal amphipathic helix. On neutral membranes, the ANTH domain has innate curvature-sensing ability. In the presence of PIP2, however, only the domain with an intact helix senses curvature. Our work sheds light on the role of PIP2 and its modulation of membrane curvature sensing by proteins.

Aims: Myocardial external efficiency (MEE) is the ratio of cardiac work in relation with energy expenditure. We studied MEE in patients with different aetiologies and stages of heart failure (HF) to discover the role and causes of deranged MEE. In addition, we explored the impact of patient characteristics such as sex, body mass index (BMI), and age on myocardial energetics., Methods and Results: Cardiac energetic profiles were assessed with 11C-acetate positron emission tomography (PET) and left ventricular ejection fraction (LVEF) was acquired with echocardiography. MEE was studied in 121 participants: healthy controls (n = 20); HF patients with reduced (HFrEF; n = 25) and mildly reduced (HFmrEF; n = 23) LVEF; and patients with asymptomatic (AS-asymp; n = 38) and symptomatic (AS-symp; n = 15) aortic stenosis (AS). Reduced MEE coincided with symptoms of HF irrespective of aetiology and declined in tandem with deteriorating LVEF. Patients with AS-symp and HFmrEF had reduced MEE as compared with controls (22.2 ± 4.9%, P = 0.041 and 20.0 ± 4.2%, P < 0.001 vs. 26.1 ± 5.8% in controls) and a further decline was observed in patients with HFrEF (14.7 ± 6.3%, P < 0.001). Disproportionate left ventricular hypertrophy was a major cause of reduced MEE. Female sex (P < 0.001), a lower BMI (P = 0.001), and advanced age (P = 0.03) were associated with a lower MEE., Conclusion: MEE was reduced in patients with HFrEF, HFmrEF, and HF due to pressure overload and MEE may therefore constitute a treatment target in HF. Patients with LVH, advanced age, female sex, and low BMI had more pronounced reduction in MEE and personalized treatment within these patient subgroups could be relevant., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

The CorA family of proteins regulates the homeostasis of divalent metal ions in many bacteria, archaea, and eukaryotic mitochondria, making it an important target in the investigation of the mechanisms of transport and its functional regulation. Although numerous structures of open and closed channels are now available for the CorA family, the mechanism of the transport regulation remains elusive. Here, we investigated the conformational distribution and associated dynamic behaviour of the pentameric Mg 2+ channel CorA at room temperature using small-angle neutron scattering (SANS) in combination with molecular dynamics (MD) simulations and solid-state nuclear magnetic resonance spectroscopy (NMR). We find that neither the Mg 2+ -bound closed structure nor the Mg 2+ -free open forms are sufficient to explain the average conformation of CorA. Our data support the presence of conformational equilibria between multiple states, and we further find a variation in the behaviour of the backbone dynamics with and without Mg 2+ . We propose that CorA must be in a dynamic equilibrium between different non-conducting states, both symmetric and asymmetric, regardless of bound Mg 2+ but that conducting states become more populated in Mg 2+ -free conditions. These properties are regulated by backbone dynamics and are key to understanding the functional regulation of CorA., Competing Interests: NJ, MB, TB, AL, FT, MP, PH, JB, TD, NY, AM, TP, AB, MS, MR, RC, TS, KL, GP, LA No competing interests declared, (© 2022, Johansen et al.)

C2 domains facilitate protein interactions with lipid bilayers in either a Ca 2+ -dependent or -independent manner. We used molecular dynamics (MD) simulations to explore six Ca 2+ -independent C2 domains, from KIBRA, PI3KC2α, RIM2, PTEN, SHIP2, and Smurf2. In coarse-grained MD simulations these C2 domains formed transient interactions with zwitterionic bilayers, compared with longer-lived interactions with anionic bilayers containing phosphatidylinositol bisphosphate (PIP 2 ). Type I C2 domains bound non-canonically via the front, back, or side of the β sandwich, whereas type II C2 domains bound canonically, via the top loops. C2 domains interacted strongly with membranes containing PIP 2 , causing bound anionic lipids to cluster around the protein. Binding modes were refined via atomistic simulations. For PTEN and SHIP2, CG simulations of their phosphatase plus C2 domains with PIP 2 -containing bilayers were also performed, and the roles of the two domains in membrane localization compared. These studies establish a simulation protocol for membrane-recognition proteins., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Early Endosomal Antigen 1 (EEA1) is a key protein in endosomal trafficking and is implicated in both autoimmune and neurological diseases. The C-terminal FYVE domain of EEA1 binds endosomal membranes, which contain phosphatidylinositol-3-phosphate (PI(3)P). Although it is known that FYVE binds PI(3)P specifically, it has not previously been described of how FYVE attaches and binds to endosomal membranes. In this study, we employed both coarse-grained (CG) and atomistic (AT) molecular dynamics (MD) simulations to determine how FYVE binds to PI(3)P-containing membranes. CG-MD showed that the dominant membrane binding mode resembles the crystal structure of EEA1 FYVE domain in complex with inositol-1,3-diphospate (PDB ID 1JOC). FYVE, which is a homodimer, binds the membrane via a hinge mechanism, where the C-terminus of one monomer first attaches to the membrane, followed by the C-terminus of the other monomer. The estimated total binding energy is ~70 kJ/mol, of which 50-60 kJ/mol stems from specific PI(3)P-interactions. By AT-MD, we could partition the binding mode into two types: (i) adhesion by electrostatic FYVE-PI(3)P interaction, and (ii) insertion of amphipathic loops. The AT simulations also demonstrated flexibility within the FYVE homodimer between the C-terminal heads and coiled-coil stem. This leads to a dynamic model whereby the 200 nm long coiled coil attached to the FYVE domain dimer can amplify local hinge-bending motions such that the Rab5-binding domain at the other end of the coiled coil can explore an area of 0.1 μm2 in the search for a second endosome with which to interact., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism., Methods: Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55-68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity., Results: Compared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, - 0.2%; 95% CI - 0.3 to 0.0; p = 0.03), reduced body weight (- 2.8 kg; 95% CI - 5.0 to - 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol L -1 ; 95% CI 0.4 to 6.0; p = 0.03). No changes were observed in whole-body insulin sensitivity, endogenous glucose production, and peripheral glucose disposal or oxidation with metformin. Equally, resting energy expenditure, lipid and urea turnover, and skeletal muscle mitochondrial respiratory capacity remained unaltered., Conclusion: Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes., Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT02810132. Date of registration: June 22, 2016.

Electronic circular dichroism (ECD) is a powerful spectroscopy method for investigating chiral properties at the molecular level. ECD calculations with the commonly used linear-response time-dependent density functional theory (LR-TDDFT) framework can be prohibitively costly for large systems. To alleviate this problem, we present here an ECD implementation within the projector augmented-wave method in a real-time-propagation TDDFT framework in the open-source GPAW code. Our implementation supports both local atomic basis sets and real-space finite-difference representations of wave functions. We benchmark our implementation against an existing LR-TDDFT implementation in GPAW for small chiral molecules. We then demonstrate the efficiency of our local atomic basis set implementation for a large hybrid nanocluster and discuss the chiroptical properties of the cluster.

Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, noncompetitive (i.e., negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 Å resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly results in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site. DATABASE: The atomic coordinates and structure factors from the crystal structure determination have been deposited in the Protein Data Bank under accession code https://doi.org/10.2210/pdb6RUQ/pdb. The electron microscopy 3D reconstruction volumes have been deposited in EMDB (EMD-4875: Apo; EMD-4920: ZK200775/GYKI53655; EMD-4921: AMPA compact; EMD-4922: AMPA/GYKI53655 bulgy; EMD-4923: GYKI53655; EMD-4924: AMPA bulgy; EMD-4925: AMPA/GYKI53655 compact)., (© 2020 Federation of European Biochemical Societies.)

Objectives: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT)., Methods: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years., Results: As of May 2020, 296 patients have been randomized at 20 centers in Denmark., Conclusion: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Apolipoproteins are vital to lipid metabolism and cholesterol transport in the human body. Here we present a structural study of the lipid-bound particles formed by ApoE3 in a full-length and a truncated version. The particles are formed with, respectively, POPC and DMPC and investigated by small-angle X-ray scattering and negative stain electron microscopy. We find that lipid-bound ApoE3 particles are elliptical, disc-shaped particles composed of a central lipid bilayer encircled by two amphipathic ApoE3 proteins. We went on to investigate a truncated form of ApoE3 containing only residue 80 to 255 (ApoE3 80-255 ), which is the central helical repeat segment of ApoE3. The lipid-bound ApoE3 80-255 particles are found to have the same morphology as the particles with full-length ApoE3. However, they are larger, and form more heterogeneous discoidal structures with four proteins per particle. This behavior is in contrast to ApoA1 where the highly similar helical repeat domain determines the size and stoichiometry of the formed particles both in the case of full-length and truncated ApoA1. Our data hence points towards different mechanisms for lipid bilayer structural modulation by ApoA1 and ApoE3 due to different roles of the non-repeat segments., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to investigate the preoperative prevalence, relation to symptoms, and prognostic implications of elevated left ventricular (LV) apical-to-basal strain ratio (ABr) in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement., Methods: A total of 499 contemporary consecutive patients with AS treated with transcatheter aortic valve replacement were retrospectively included. Patients were included if they underwent preoperative echocardiography with adequate image quality for assessment of LV global longitudinal strain. Baseline clinical and echocardiographic data were collected and analyzed in ABr subgroups. From two-dimensional echocardiographic apical images, ABr was calculated as mean longitudinal strain of the five LV apical segments divided by the mean of the six basal segments., Results: Median follow-up time was 743 days. Mean age was 79.8 ± 7 years. The prevalence of severely increased ABr ≥4 was 16% (n = 78). Patients with ABr ≥4 had higher preoperative New York Heart Association functional class; 77% of those with ABr ≥4 were in New York Heart Association functional class III or IV compared with 59% of those with ABr of 0 to 1.9 (P < .01). Median preoperative N-terminal pro-brain natriuretic peptide level in patients with ABr ≥4 was 1,781 pmol/L, compared with 876 pmol/L in those with ABr of 0 to 1.9 (P = .003). N-terminal pro-brain natriuretic peptide levels at 3-month follow-up remained considerably elevated in patients with ABr ≥4 (the median in patients with ABr ≥4 was 1,262 pmol/L vs 645 pmol/L in those with ABr of 0 to 1.9, P < .01). AS severity was comparable across ABr subgroup levels. Overall, increased ABr ≥4 was associated with poor survival, as overall 3-year survival was 67% among patients with ABr ≥4 compared with 83% in those with ABr of 2 to 3.9 and 86% in those with ABr of 0 to 1.9 (P = .04)., Conclusion: Among patients with increased ABr ≥4, pre- and postoperative New York Heart Association functional class, serum N-terminal pro-brain natriuretic peptide level, and mortality were significantly increased, and ABr may thus serve as a new echocardiographic marker of high mortality risk among patients with AS treated with transcatheter aortic valve replacement., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Aims: The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes., Methods and Results: Thirty-six HFrEF patients (ejection fraction 37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by 11 C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 ± 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg·mL·m -2 ·10 6 ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O 2 ·100 g -1 ·min -1 ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups., Conclusion: Metformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes., (© 2019 European Society of Cardiology.)

First-principles electronic structure calculations are now accessible to a very large community of users across many disciplines, thanks to many successful software packages, some of which are described in this special issue. The traditional coding paradigm for such packages is monolithic, i.e., regardless of how modular its internal structure may be, the code is built independently from others, essentially from the compiler up, possibly with the exception of linear-algebra and message-passing libraries. This model has endured and been quite successful for decades. The successful evolution of the electronic structure methodology itself, however, has resulted in an increasing complexity and an ever longer list of features expected within all software packages, which implies a growing amount of replication between different packages, not only in the initial coding but, more importantly, every time a code needs to be re-engineered to adapt to the evolution of computer hardware architecture. The Electronic Structure Library (ESL) was initiated by CECAM (the European Centre for Atomic and Molecular Calculations) to catalyze a paradigm shift away from the monolithic model and promote modularization, with the ambition to extract common tasks from electronic structure codes and redesign them as open-source libraries available to everybody. Such libraries include "heavy-duty" ones that have the potential for a high degree of parallelization and adaptation to novel hardware within them, thereby separating the sophisticated computer science aspects of performance optimization and re-engineering from the computational science done by, e.g., physicists and chemists when implementing new ideas. We envisage that this modular paradigm will improve overall coding efficiency and enable specialists (whether they be computer scientists or computational scientists) to use their skills more effectively and will lead to a more dynamic evolution of software in the community as well as lower barriers to entry for new developers. The model comes with new challenges, though. The building and compilation of a code based on many interdependent libraries (and their versions) is a much more complex task than that of a code delivered in a single self-contained package. Here, we describe the state of the ESL, the different libraries it now contains, the short- and mid-term plans for further libraries, and the way the new challenges are faced. The ESL is a community initiative into which several pre-existing codes and their developers have contributed with their software and efforts, from which several codes are already benefiting, and which remains open to the community.

Many proteins contain multiple folded domains separated by flexible linkers, and the ability to describe the structure and conformational heterogeneity of such flexible systems pushes the limits of structural biology. Using the three-domain protein TIA-1 as an example, we here combine coarse-grained molecular dynamics simulations with previously measured small-angle scattering data to study the conformation of TIA-1 in solution. We show that while the coarse-grained potential (Martini) in itself leads to too compact conformations, increasing the strength of protein-water interactions results in ensembles that are in very good agreement with experiments. We show how these ensembles can be refined further using a Bayesian/Maximum Entropy approach, and examine the robustness to errors in the energy function. In particular we find that as long as the initial simulation is relatively good, reweighting against experiments is very robust. We also study the relative information in X-ray and neutron scattering experiments and find that refining against the SAXS experiments leads to improvement in the SANS data. Our results suggest a general strategy for studying the conformation of multi-domain proteins in solution that combines coarse-grained simulations with small-angle X-ray scattering data that are generally most easy to obtain. These results may in turn be used to design further small-angle neutron scattering experiments that exploit contrast variation through 1H/2H isotope substitutions., Competing Interests: The authors have declared that no competing interests exist.

Over the last few years, extraordinary advances in experimental and theoretical tools have allowed us to monitor and control matter at short time and atomic scales with a high degree of precision. An appealing and challenging route toward engineering materials with tailored properties is to find ways to design or selectively manipulate materials, especially at the quantum level. To this end, having a state-of-the-art ab initio computer simulation tool that enables a reliable and accurate simulation of light-induced changes in the physical and chemical properties of complex systems is of utmost importance. The first principles real-space-based Octopus project was born with that idea in mind, i.e., to provide a unique framework that allows us to describe non-equilibrium phenomena in molecular complexes, low dimensional materials, and extended systems by accounting for electronic, ionic, and photon quantum mechanical effects within a generalized time-dependent density functional theory. This article aims to present the new features that have been implemented over the last few years, including technical developments related to performance and massive parallelism. We also describe the major theoretical developments to address ultrafast light-driven processes, such as the new theoretical framework of quantum electrodynamics density-functional formalism for the description of novel light-matter hybrid states. Those advances, and others being released soon as part of the Octopus package, will allow the scientific community to simulate and characterize spatial and time-resolved spectroscopies, ultrafast phenomena in molecules and materials, and new emergent states of matter (quantum electrodynamical-materials).

Molecular simulations and biophysical experiments can be used to provide independent and complementary insights into the molecular origin of biological processes. A particularly useful strategy is to use molecular simulations as a modeling tool to interpret experimental measurements, and to use experimental data to refine our biophysical models. Thus, explicit integration and synergy between molecular simulations and experiments is fundamental for furthering our understanding of biological processes. This is especially true in the case where discrepancies between measured and simulated observables emerge. In this chapter, we provide an overview of some of the core ideas behind methods that were developed to improve the consistency between experimental information and numerical predictions. We distinguish between situations where experiments are used to refine our understanding and models of specific systems, and situations where experiments are used more generally to refine transferable models. We discuss different philosophies and attempt to unify them in a single framework. Until now, such integration between experiments and simulations have mostly been applied to equilibrium data, and we discuss more recent developments aimed to analyze time-dependent or time-resolved data., (© 2020 Elsevier Inc. All rights reserved.)

A necessary first step in the development of technologies such as artificial photosynthesis is understanding the photoexcitation process within the basic building blocks of naturally occurring light harvesting complexes (LHCs). The most important of these building blocks in biological LHCs such as LHC II from green plants are the chlorophyll a (Chl a) and chlorophyll b (Chl b) chromophores dispersed throughout the protein matrix. However, efforts to describe such systems are still hampered by the lack of computationally efficient and accurate methods that are able to describe optical absorption in large biomolecules. In this work, we employ a highly efficient linear combination of atomic orbitals (LCAOs) to represent the Kohn-Sham (KS) wave functions at the density functional theory (DFT) level and perform time-dependent density functional theory (TDDFT) calculations in either the reciprocal space and frequency domain (LCAO-TDDFT-k-ω) or real space and time domain (LCAO-TDDFT-r-t) of the optical absorption spectra of Chl a and b monomers and dimers. We find that our LCAO-TDDFT-k-ω and LCAO-TDDFT-r-t calculations reproduce results obtained with a plane-wave (PW) representation of the KS wave functions (PW-TDDFT-k-ω) but with a significant reduction in computational effort. Moreover, by applying the Gritsenko, van Leeuwen, van Lenthe, and Baerends solid and correlation derivative discontinuity correction Δ x to the KS eigenenergies, with both LCAO-TDDFT-k-ω and LCAO-TDDFT-r-t methods, we are able to semiquantitatively reproduce the experimentally measured photoinduced dissociation results. This work opens the path to first principles calculations of optical excitations in macromolecular systems.

Myocardial deformation assessed by speckle tracking echocardiography (STE) is increasingly used for diagnosis, monitoring and prognosis in patients with clinical and pre-clinical cardiovascular diseases. Feature tracking cardiac magnetic resonance (FT-CMR) also allows myocardial deformation analysis. To clarify whether the two modalities can be used interchangeably, we compared myocardial deformation analysis by FT-CMR with STE in patients with a variety of cardiovascular diseases and healthy subjects. We included 40 patients and 10 healthy subjects undergoing cardiac magnetic resonance and echocardiographic examination for left ventricular volumetric assessment. We studied patients with heart failure and reduced ejection fraction (n = 10), acute perimyocarditis (n = 10), aortic valve stenosis (n = 10), and previous heart transplantation (n = 10) by global longitudinal (GLS), radial (GRS) and circumferential strain (GCS). Myocardial deformation analysis by FT-CMR was feasible in all but one participant. While GLS, GRS and GCS measured by FT-CMR correlated overall with STE (r = 0.74 and p < 0.001, r = 0.58 and p < 0.001, and r = 0.76 and p < 0.001), the correlations were not consistent within subgroups. GLS was systematically lower, whereas GRS and GCS were higher by FT-CMR compared to STE (p = 0.04 and p < 0.0001). Inter- and intra-observer reproducibility were comparable for FT-CMR and STE overall and across subgroups. In conclusion, myocardial deformation can be evaluated using FT-CMR applied to routine cine-CMR images in patients with a variety of cardiovascular diseases. However, correlation between FT-CMR and STE was modest and agreement was not optimal due to systematic bias regarding GLS and GCS. Consequently, FT-CMR and STE should not be used interchangeably for myocardial strain evaluation.

Background: There are no standardized therapy guidelines for rehabilitation of calcaneus fractures. While there is consensus on non or partial weight-bearing, the use of supporting devices such as specific foot ankle orthosis is still a matter of debate. Recently, a heel-unloading orthosis ("Settner shoe") was introduced for aftercare of these fractures, allowing walking by shifting the load to the middle-foot and forefoot. This orthosis enables early mobilization of patients suffering from either one-sided or two-sided fractures. The Settner shoe can be applied in non-operative therapy and after surgery. Specifically in calcaneus fractures, early regain of physical activity has been highlighted as one of the key factors for quality of life and the ability to return to work. Thus, we hypothesize that mobilization with the Settner shoe results in improved quality of life and greater physical activity within the first 3 months., Methods: This is going to be analyzed by a randomized controlled study comparing treatment with and without this specific orthosis. The secondary outcome measure is the time point of return to work in patients aged between 18 and 60 years, with calcaneus fracture. Furthermore, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, a 3-dimensional gait analysis, and the Euroqol-5 dimension-3 level (EQ-5D-3 L) questionnaire for quality of life are assessed., Discussion: This is the first trial applying a standardized rehabilitation protocol in patients with calcaneus fractures, aiming to improve the non-operative part of treatment by use of an orthosis., Trial Registration: ClinicalTrials.gov, NCT03572816 . Registered on 27 July 2018.

The bacterial Sec translocon, SecYEG, associates with accessory proteins YidC and the SecDF-YajC subcomplex to form the bacterial holo-translocon (HTL). The HTL is a dynamic and flexible protein transport machine capable of coordinating protein secretion across the membrane and efficient lateral insertion of nascent membrane proteins. It has been hypothesized that a central lipid core facilitates the controlled passage of membrane proteins into the bilayer, ensuring the efficient formation of their native state. By performing small-angle neutron scattering on protein solubilized in "match-out" deuterated detergent, we have been able to interrogate a "naked" HTL complex, with the scattering contribution of the surrounding detergent micelle rendered invisible. Such an approach has allowed the confirmation of a lipid core within the HTL, which accommodates between 8 and 29 lipids. Coarse-grained molecular dynamics simulations of the HTL also demonstrate a dynamic, central pool of lipids. An opening at this lipid-rich region between YidC and the SecY lateral gate may provide an exit gateway for newly synthesized, correctly oriented, membrane protein helices, or even small bundles of helices, to emerge from the HTL., (Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The AMPA receptor GluA2 belongs to the family of ionotropic glutamate receptors, which are responsible for most of the fast excitatory neuronal signalling in the central nervous system. These receptors are important for memory and learning, but have also been associated with brain diseases such as Alzheimer's disease and epilepsy. Today, one drug is on the market for the treatment of epilepsy targeting AMPA receptors, i.e. a negative allosteric modulator of these receptors. Recently, crystal structures and cryo-electron microscopy (cryo-EM) structures of full-length GluA2 in the resting (apo), activated and desensitized states have been reported. Here, solution structures of full-length GluA2 are reported using small-angle neutron scattering (SANS) with a novel, fully matched-out detergent. The GluA2 solution structure was investigated in the resting state as well as in the presence of AMPA and of the negative allosteric modulator GYKI-53655. In solution and at neutral pH, the SANS data clearly indicate that GluA2 is in a compact form in the resting state. The solution structure resembles the crystal structure of GluA2 in the resting state, with an estimated maximum distance ( D max ) of 179 ± 11 Å and a radius of gyration ( R g ) of 61.9 ± 0.4 Å. An ab initio model of GluA2 in solution generated using DAMMIF clearly showed the individual domains, i.e. the extracellular N-terminal domains and ligand-binding domains as well as the transmembrane domain. Solution structures revealed that GluA2 remained in a compact form in the presence of AMPA or GYKI-53655. At acidic pH only, GluA2 in the presence of AMPA adopted a more open conformation of the extracellular part (estimated D max of 189 ± 5 Å and R g of 65.2 ± 0.5 Å), resembling the most open, desensitized class 3 cryo-EM structure of GluA2 in the presence of quisqualate. In conclusion, this methodological study may serve as an example for future SANS studies on membrane proteins.

Background: The aims of the present study were to determine left ventricular (LV) myocardial contractile reserve during exercise stress testing in healthy adults and to evaluate the effects of gender and age on exercise LV global longitudinal strain (GLS)., Methods: The study population consisted of 67 healthy adults (age range, 23-80 years; 49% women). Subjects were analyzed with respect to gender and predefined age groups (age < 35 years, n = 18; age 35-55 years, n = 24; age > 55 years, n = 25). All subjects underwent comprehensive echocardiographic assessment at rest and during symptom-limited semisupine exercise test. LV GLS was determined using two-dimensional speckle-tracking echocardiography., Results: LV GLS magnitude during peak stress was 25.4 ± 2.0%. The average absolute numeric LV GLS increase was 5.3%, equivalent to a relative 26.7% increase of LV GLS. LV GLS magnitude at peak exercise was without clinically significant differences between age groups (P = .07). No significant difference was found in peak exercise LV GLS between genders (P = .48). Linear regression analysis revealed a significant but weak correlation between peak LV GLS and age (r = -0.30, P = .02), whereas peak LV GLS was independent of maximal heart rate (r = 0.23, P = .07), peak mean arterial blood pressure (r = -0.11, P = .38), body mass index (r = 0.15, P = .22), and peak pulsed Doppler-derived cardiac index (r = -0.06, P = .67)., Conclusions: LV GLS increases significantly during exercise stress in a healthy population. A dose-response relationship was found between LV GLS and exercise level independent of gender, and the influence of age appeared marginal. The technique is feasible, with low intra- and interobserver variability., (Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

A novel and generally applicable method for determining structures of membrane proteins in solution via small-angle neutron scattering (SANS) is presented. Common detergents for solubilizing membrane proteins were synthesized in isotope-substituted versions for utilizing the intrinsic neutron scattering length difference between hydrogen and deuterium. Individual hydrogen/deuterium levels of the detergent head and tail groups were achieved such that the formed micelles became effectively invisible in heavy water (D 2 O) when investigated by neutrons. This way, only the signal from the membrane protein remained in the SANS data. We demonstrate that the method is not only generally applicable on five very different membrane proteins but also reveals subtle structural details about the sarco/endoplasmatic reticulum Ca 2+ ATPase (SERCA). In all, the synthesis of isotope-substituted detergents makes solution structure determination of membrane proteins by SANS and subsequent data analysis available to nonspecialists., (© 2017 Federation of European Biochemical Societies.)

Background: The aim of the present study was to evaluate the clinical importance of echocardiographic coronary flow velocity reserve (CFVR), resting and exercise left ventricular global longitudinal strain (LVGLS), and myocardial work efficiency (MWE) in patients with cardiac amyloidosis (CA)., Methods: The study population comprised 69 subjects: group A, 27 patients with CA confirmed by endomyocardial biopsy (CA positive); group B, 42 healthy control subjects. The amyloid phenotype in group A was as follows: patients with wild-type transthyretin-related amyloidosis (n = 10), carriers of the Danish familial transthyretin amyloidosis mutation with cardiac involvement (n = 5), and patients with amyloid light chain amyloidosis with cardiac involvement (n = 12). All subjects underwent comprehensive echocardiographic evaluation during rest and during symptom-limited, semisupine exercise testing. Furthermore, CFVR was assessed using Doppler echocardiography., Results: Patients with CA had significantly lower CFVR (1.7 ± 0.6 vs 3.9 ± 0.8, P < .0001), MWE (1.9 ± 1.0 vs 3.0 ± 0.7, P < .0001), and LVGLS magnitude (11% [10%-14%] vs 20% [18%-21%], P < .0001) than control subjects. Patients with CA showed severely reduced deformation and efficiency reserve compared with control subjects (ΔLVGLS 0.9 ± 2.8% vs 5.6 ± 2.3%, P < .0001; ΔMWE 2.5 ± 2.8 vs 8.8 ± 2.6, P < .0001). In patients with CA, a strong relation was seen between physical capacity by the metabolic equivalent of tasks test and CFVR (r = 0.55, P < .01), peak exercise LVGLS (r = 0.64, P < .0001), and peak exercise MWE (r = 0.60, P < .01)., Conclusions: Patients with CA had a profound lack of CFVR and longitudinal myocardial deformation reserve compared with healthy control subjects. Both parameters were significantly associated with exercise capacity and may prove useful for evaluating cardiac performance in patients with CA., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

We present a review of different computational methods to describe time-dependent phenomena in open quantum systems and their extension to a density-functional framework. We focus the discussion on electron emission processes in atoms and molecules addressing excited-state lifetimes and dissipative processes. Initially we analyze the concept of an electronic resonance, a central concept in spectroscopy associated with a metastable state from which an electron eventually escapes (electronic lifetime). Resonances play a fundamental role in many time-dependent molecular phenomena but can be rationalized from a time-independent context in terms of scattering states. We introduce the method of complex scaling, which is used to capture resonant states as localized states in the spirit of usual bound-state methods, and work on its extension to static and time-dependent density-functional theory. In a time-dependent setting, complex scaling can be used to describe excitations in the continuum as well as wave packet dynamics leading to electron emission. This process can also be treated by using open boundary conditions which allow time-dependent simulations of emission processes without artificial reflections at the boundaries (i.e., borders of the simulation box). We compare in detail different schemes to implement open boundaries, namely transparent boundaries using Green functions, and absorbing boundaries in the form of complex absorbing potentials and mask functions. The last two are regularly used together with time-dependent density-functional theory to describe the electron emission dynamics of atoms and molecules. Finally, we discuss approaches to the calculation of energy and angle-resolved time-dependent pump-probe photoelectron spectroscopy of molecular systems.

Real-space grids are a powerful alternative for the simulation of electronic systems. One of the main advantages of the approach is the flexibility and simplicity of working directly in real space where the different fields are discretized on a grid, combined with competitive numerical performance and great potential for parallelization. These properties constitute a great advantage at the time of implementing and testing new physical models. Based on our experience with the Octopus code, in this article we discuss how the real-space approach has allowed for the recent development of new ideas for the simulation of electronic systems. Among these applications are approaches to calculate response properties, modeling of photoemission, optimal control of quantum systems, simulation of plasmonic systems, and the exact solution of the Schrödinger equation for low-dimensionality systems.

In this paper, we use density functional theory (DFT) calculations on highly parallel computing resources to study size-dependent changes in the chemical and electronic properties of platinum (Pt) for a number of fixed freestanding clusters ranging from 13 to 1415 atoms, or 0.7-3.5 nm in diameter. We find that the surface catalytic properties of the clusters converge to the single crystal limit for clusters with as few as 147 atoms (1.6 nm). Recently published results for gold (Au) clusters showed analogous convergence with size. However, this convergence happened at larger sizes, because the Au d-states do not contribute to the density of states around the Fermi-level, and the observed level fluctuations were not significantly damped until the cluster reached ca. 560 atoms (2.7 nm) in size.

We have studied the effect of nanostructuring in Pt monolayer model electrocatalysts on a Rh(111) single-crystal substrate on the adsorption strength of chemisorbed species. In situ high energy resolution fluorescence detection X-ray absorption spectroscopy at the Pt L(3) edge reveals characteristic changes of the shape and intensity of the "white-line" due to chemisorption of atomic hydrogen (H(ad)) at low potentials and oxygen-containing species (O/OH(ad)) at high potentials. On a uniform, two-dimensional Pt monolayer grown by Pt evaporation in ultrahigh vacuum, we observe a significant destabilization of both H(ad) and O/OH(ad) due to strain and ligand effects induced by the underlying Rh(111) substrate. When Pt is deposited via a wet-chemical route, by contrast, three-dimensional Pt islands are formed. In this case, strain and Rh ligand effects are balanced with higher local thickness of the Pt islands as well as higher defect density, shifting H and OH adsorption energies back toward pure Pt. Using density functional theory, we calculate O adsorption energies and corresponding local ORR activities for fcc 3-fold hollow sites with various local geometries that are present in the three-dimensional Pt islands.

A diagnosis of Myofascial Pain Syndrome (MPS) requires palpation for the identification of at least one clinically relevant trigger point (TP). However, few comparable, high quality studies currently exist from which to draw firm conclusions regarding the robustness of TP examination. An inter-observer agreement study was conducted using two experienced and two inexperienced clinicians. All performed standardized palpation of the upper Trapezius musculature, judging the clinical relevance of TP(s) using clinician global assessment (GA). A random case mix of 81 female participants was examined, 14 asymptomatic and the remainder suffering from neck/shoulder pain. Examiners received psychomotor skills training and video feedback analysis to improve protocol standardization. Kappa co-efficient calculations indicated good agreement between the experienced pairing (κ = 0.63), moderate agreement between the mixed pairings (κ = 0.35 and 0.47) and poor agreement between the inexperienced pairing (κ = 0.22). Inter-observer agreement was not stable with the experienced pairing exhibiting a sharp decline in agreement during the latter portion of the study. Identification of clinically relevant TPs of the upper Trapezius musculature is reproducible when performed by two experienced clinicians, however, a mixed observer pairing can yield acceptable agreement. A protracted period of data collection may be detrimental to inter-observer agreement; more investigation is needed in this regard., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Electronic structure calculations have become an indispensable tool in many areas of materials science and quantum chemistry. Even though the Kohn-Sham formulation of the density-functional theory (DFT) simplifies the many-body problem significantly, one is still confronted with several numerical challenges. In this article we present the projector augmented-wave (PAW) method as implemented in the GPAW program package (https://wiki.fysik.dtu.dk/gpaw) using a uniform real-space grid representation of the electronic wavefunctions. Compared to more traditional plane wave or localized basis set approaches, real-space grids offer several advantages, most notably good computational scalability and systematic convergence properties. However, as a unique feature GPAW also facilitates a localized atomic-orbital basis set in addition to the grid. The efficient atomic basis set is complementary to the more accurate grid, and the possibility to seamlessly switch between the two representations provides great flexibility. While DFT allows one to study ground state properties, time-dependent density-functional theory (TDDFT) provides access to the excited states. We have implemented the two common formulations of TDDFT, namely the linear-response and the time propagation schemes. Electron transport calculations under finite-bias conditions can be performed with GPAW using non-equilibrium Green functions and the localized basis set. In addition to the basic features of the real-space PAW method, we also describe the implementation of selected exchange-correlation functionals, parallelization schemes, ΔSCF-method, x-ray absorption spectra, and maximally localized Wannier orbitals.

Chronic pain and psychosocial distress are generally thought to be associated in chronic musculoskeletal disorders such as non-specific neck pain. However, it is unclear whether a raised level of anxiety is necessarily a feature of longstanding, intense pain amongst patient and general population sub-groups. In a cohort of 70 self-selected female, non-specific neck pain sufferers, we observed relatively high levels of self-reported pain of 4.46 (measured on the 11 point numerical pain rating scale (NRS-101)) and a longstanding duration of symptoms (156 days/year). However, the mean anxiety scores observed (5.49), fell well below the clinically relevant threshold of 21 required by the Beck Anxiety Inventory. The cohort was stratified to further distinguish individuals with higher pain intensity (NRS>6) and longer symptom duration (>90 days). Although a highly statistically significant difference (p = 0.000) was subsequently observed with respect to pain intensity, in the resulting sub-groups, none such a difference was noted with respect to anxiety levels. Our results indicate that chronic, intense pain and anxiety do not always appear to be related. Explanations for these findings may include that anxiety is not triggered in socially functional individuals, that individual coping strategies have come into play or in some instances that a psychological disorder like alexithymia could be a confounder. More studies are needed to clarify the specific role of anxiety in chronic non-specific musculoskeletal pain before general evidence-driven clinical extrapolations can be made.

Stair walking is an important functional movement task that may require considerable amounts of muscle strength/power. This study aimed to perform a descriptive biomechanical analysis of maximal stair ascent in elderly women and to examine the relationship between mechanical muscle function and maximal stair ascending velocity (MAV). Seventeen healthy elderly women (age 72.4 +/- 6.4) were tested for MAV, maximal multi-joint counter movement jumping (CMJ), and maximal single-joint isokinetic/isometric muscle moment. Peak knee joint power during MAV was the single independent parameter that explained most of the variation in MAV (50%), however, combining knee and ankle parameters in a multiple regression analysis mean joint power explained 82.4% of the variation in MAV. Generally, multi-joint CMJ parameters showed stronger correlations with MAV than single-joint isokinetic/isometric muscle strength parameters. MAV appeared to be highly dependent upon knee and ankle power and to a lesser extent on joint moment and range of motion. Furthermore, CMJ assessment seemed well applicable in healthy elderly individuals to distinguish between differentiated levels of maximal stair walking capacity.

We present a computational screening study of ternary metal borohydrides for reversible hydrogen storage based on density functional theory. We investigate the stability and decomposition of alloys containing 1 alkali metal atom, Li, Na, or K (M(1)); and 1 alkali, alkaline earth or 3d/4d transition metal atom (M(2)) plus two to five (BH(4))(-) groups, i.e., M(1)M(2)(BH(4))(2-5), using a number of model structures with trigonal, tetrahedral, octahedral, and free coordination of the metal borohydride complexes. Of the over 700 investigated structures, about 20 were predicted to form potentially stable alloys with promising decomposition energies. The M(1)(Al/Mn/Fe)(BH(4))(4), (Li/Na)Zn(BH(4))(3), and (Na/K)(Ni/Co)(BH(4))(3) alloys are found to be the most promising, followed by selected M(1)(Nb/Rh)(BH(4))(4) alloys.

Unlabelled: Stair walking is a demanding task in old age. Ground reaction force (GRF) analysis, relative EMG activation, and muscular coactivation were performed during stair walking. The aim was to investigate the ageing effect on GRF distribution and muscle antagonist coactivation during stair walking, at varied speed. During ascending at maximal velocity old subjects demonstrated reduced GRF in all examined phases (range: 28-35%), whereas muscle coactivation only was elevated for the Entire stance phase (18.5%). GRF parameters during ascent and descent at freely chosen speed demonstrated differences between age groups (5-28%). Furthermore, muscle coactivation was elevated in old subjects (e.g. Entire stance phase (17-19%)) along with greater EMG activation in all muscles (16-65%). At standardized gait velocity only minor differences in GRF were observed between age groups. However, elderly subjects showed elevated muscular coactivation (e.g. loading phase and entire stance phase (18-22%)) along with greater EMG activation (35-66%)., Conclusions: Differences between age groups in neuromotor and kinetic stair walking strategy do not depend upon the age-related decline in velocity alone, but rather reflect a uniform alteration. This needs to be considered during rehabilitation and/or clinical settings at old age.