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The Martini model, a coarse‐grained force field for molecular dynamics simulations, has been around for nearly two decades. Originally developed for lipid‐based systems by the groups of Marrink and Tieleman, the Martini model has over the years been extended as a community effort to the current level of a general‐purpose force field. Apart from the obvious benefit of a reduction in computational cost, the popularity of the model is largely due to the systematic yet intuitive building‐block approach that underlies the model, as well as the open nature of the development and its continuous validation. The easy implementation in the widely used Gromacs software suite has also been instrumental. Since its conception in 2002, the Martini model underwent a gradual refinement of the bead interactions and a widening scope of applications. In this review, we look back at this development, culminating with the release of the Martini 3 version in 2021. The power of the model is illustrated with key examples of recent important findings in biological and material sciences enabled with Martini, as well as examples from areas where coarse‐grained resolution is essential, namely high‐throughput applications, systems with large complexity, and simulations approaching the scale of whole cells. This article is categorized under:Software > Molecular ModelingMolecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo MethodsStructure and Mechanism > Computational Materials ScienceStructure and Mechanism > Computational Biochemistry and Biophysics [ABSTRACT FROM AUTHOR]

Certain pathogenic bacteria produce and release toxic peptides to ensure either nutrient availability or evasion from the immune system. These peptides are also toxic to the producing bacteria that utilize dedicated ABC transporters to provide self-immunity. The ABC transporter McjD exports the antibacterial peptide MccJ25 in Escherichia coli. Our previously determined McjD structure provided some mechanistic insights into antibacterial peptide efflux. In this study, we have determined its structure in a novel conformation, apo inward-occluded and a new nucleotide-bound state, high-energy outward-occluded intermediate state, with a defined ligand binding cavity. Predictive cysteine cross-linking in E. coli membranes and PELDOR measurements along the transport cycle indicate that McjD does not undergo major conformational changes as previously proposed for multi-drug ABC exporters. Combined with transport assays and molecular dynamics simulations, we propose a novel mechanism for toxic peptide ABC exporters that only requires the transient opening of the cavity for release of the peptide. We propose that shielding of the cavity ensures that the transporter is available to export the newly synthesized peptides, preventing toxic-level build-up. [ABSTRACT FROM AUTHOR]

The high brilliance of third-generation synchrotron sources increases the demand for faster detectors to utilize the available flux. The Maia detector is an advanced imaging scheme for energy-dispersive detection realising dwell times per image-pixel as low as 50 µs and count rates higher than 10 × 106 s−1. In this article the integration of such a Maia detector in the Microprobe setup of beamline P06 at the storage ring PETRA III at the Deutsches Elektronen-Synchrotron (DESY) in Hamburg, Germany, is described. The analytical performance of the complete system in terms of rate-dependent energy resolution, scanning-speed-dependent spatial resolution and lower limits of detection is characterized. The potential of the Maia-based setup is demonstrated by key applications from materials science and chemistry, as well as environmental science with geological applications and biological questions that have been investigated at the P06 beamline. [ABSTRACT FROM AUTHOR]

The Vertically Integrated Photon Imaging Chip (VIPIC) was custom-designed for X-ray photon correlation spectroscopy, an application in which occupancy per pixel is low but high time resolution is needed. VIPIC operates in a sparsified streaming mode in which each detected photon is immediately read out as a time- and position-stamped event. This event stream can be fed directly to an autocorrelation engine or accumulated to form a conventional image. The detector only delivers non-zero data (sparsified readout), greatly reducing the communications overhead typical of conventional frame-oriented detectors such as charge-coupled devices or conventional hybrid pixel detectors. This feature allows continuous acquisition of data with timescales from microseconds to hours. In this work VIPIC has been used to measure X-ray photon correlation spectroscopy data on polystyrene latex nano-colliodal suspensions in glycerol and on colloidal suspensions of silica spheres in water. Relaxation times of the nano-colloids have been measured for different temperatures. These results demonstrate that VIPIC can operate continuously in the microsecond time frame, while at the same time probing longer timescales. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of laryngeal mask airway (LMA) ventilation in obese patients with airway stenosis.Study Design: A retrospective chart review was conducted in an academic practice in a tertiary care center.Methods: We retrospectively reviewed our experience using LMA ventilation in obese patients with airway stenosis. Lowest intraoperative O2 saturation and maximum-end tidal carbon dioxide (CO2 ) levels were recorded. Complications including intubation, unplanned admission, re-admission, postoperative pain, dysphonia, oral trauma, pneumothorax, pneumomediastinum, and tracheostomy were recorded.Results: Fourteen bronchoscopies with laser incisions and dilation were performed in patients with airway stenosis exclusively using LMA ventilation. Thirteen of 14 procedures were performed on patients who had body mass index (BMI) > 30 kg/m2 . Mean BMI was noted to be 38 kg/m2 (range 25-54). All patients underwent successful laser incisions and dilation via LMA anesthesia without major or minor adverse events. The mean lowest O2 saturation level was noted to be 92%; the mean highest CO2 level was noted to be 56 mm Hg; and no patients required endotracheal intubation.Conclusion: In this small series of obese patients with airway stenosis, LMA anesthesia was effectively used without major or minor complications.Level Of Evidence: 4. Laryngoscope, 127:2582-2584, 2017. [ABSTRACT FROM AUTHOR]

Computer simulations offer a valuable way to study membrane systems, from simple lipid bilayers to large transmembrane protein complexes and lipid-nucleic acid complexes for drug delivery. Their accuracy depends on the quality of the force field parameters used to describe the components of a particular system. We have implemented the widely used CHARMM22 and CHARMM27 force fields in the GROMACS simulation package to (i) combine the CHARMM22 protein force field with two sets of united-atom lipids parameters; (ii) allow comparisons of the lipid CHARMM27 force field with other lipid force fields or lipid-protein force field combinations. Our tests do not show any particular issue with the combination of the all-atom CHARMM22 force field with united-atoms lipid parameters, although pertinent experimental data are lacking to assess the quality of the lipid-protein interactions. The conversion utilities allow automatic generation of GROMACS simulation files with CHARMM nucleic acids and protein parameters and topologies, starting from pdb files using the standard GROMACS pdb2gmx method. CMAP is currently not implemented. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

While there is evidence that other ABC transporters can tell between empty and loaded substrate binding protein, reconstitution experiments suggest otherwise for the Escherichia coli vitamin B12 importer BtuCD-F. Here, we address the question of BtuCD-F substrate sensitivity in a combined protein-protein docking and molecular dynamics simulation approach. Starting from the BtuCD and holo-BtuF crystal structures, we model two holo-BtuCD-F docking complexes differing by a 180° orientation of BtuF. One of these is similar to the apo-BtuCD-F crystal structure. Both docking complexes were embedded in a lipid/water environment to investigate their dynamics and BtuCD's conformational response to the presence and absence of BtuF, vitamin B12, and Mg-ATP in a series of 28 independent MD simulations. We find holo-BtuF stabilizing the open conformation of BtuCD, whereas the transporter begins to close again when BtuF or vitamin B12 is removed-suggesting BtuCD-F is capable of substrate sensitivity. We identified BtuC transmembrane helices 3 and 5, the L-loops and the adjacent helices comprised of BtuC residues 170-180 as hotspots of conformational change. We propose the latter to act as substrate sensors. BtuF-Trp44 appears to act as a lid on the vitamin B12 binding cleft in BtuF X-ray structures and protrudes into the BtuCD transport channel in one of our simulations, which might represent an initial step in vitamin B12 uptake. On an average, we observe subunit motions where the nucleotide binding domains approach each other while the transmembrane domains display an opening trend toward the periplasm. Proteins 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The shuttling of substrates across a cellular membrane frequently requires a specialized ATP-binding cassette (ABC) transporter, which couples the energy of ATP binding and hydrolysis to substrate transport. Due to its importance in immunity, the ABC transporter associated with antigen processing (TAP) has been studied extensively and is an excellent model for other ABC transporters. The TAP protein pumps cytosolic peptides into the endoplasmic reticulum for loading onto class I major histocompatibility complex (MHC) for subsequent immune Surveillance. Here, we outline a potential mechanism for the TAP protein with supporting evidence from bacterial transporter structures. The similarities and differences between TAP and other transporters support the notion that ABC transporters in general have adapted around a universal transport mechanism. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations of the RN24 peptide, which includes a diverse set of structurally heterogeneous states, are carried out in explicit solvent. Two approaches are employed and compared directly under identical simulation conditions. Specifically, we examine sampling by two individual long trajectories (microsecond timescale) and many shorter (MS) uncoupled trajectories. Statistical analysis of the structural properties indicates a qualitative agreement between these approaches. Microsecond timescale sampling gives large uncertainties on most structural metrics, while the shorter timescale of MS simulations results in slight structural memory for beta-structure starting states. Additionally, MS sampling detects numerous transitions on a relatively short timescale that are not observed in microsecond sampling, while long simulations allow for detection of a few transitions on significantly longer timescales. A correlation between the complex free energy landscape and the kinetics of the equilibrium is highlighted by principal component analysis on both simulation sets. This report highlights the increased precision of the MS approach when studying the kinetics of complex conformational change, while revealing the complementary insight and qualitative agreement offered by far fewer individual simulations on significantly longer timescales. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [ABSTRACT FROM AUTHOR]

Abstract: We exploit the biochemical and sequence similarity between Staphylococcus aureus Sav1866 and P-glycoprotein to develop a homology model of P-glycoprotein representing an ATP-bound state, which captures the major features of the low-resolution EM structure and is consistent with cysteine mutagenesis studies. Using insights from the MalK crystal structures and BtuCD simulations, we model two nucleotide-free conformations. Conformational changes are characterized by pincering rigid-body rotations of the nucleotide-binding domains, inducing transmembrane domain reorganizations which correspond to the two lowest frequency normal modes of the protein. These conformations (see supplementary material) may characterize some of the major steps in the nucleotide catalytic cycle. [Copyright &y& Elsevier]

The hydration free energies of amino acid side chains are an important determinant of processes that involve partitioning between different environments, including protein folding, protein complex formation, and protein–membrane interactions. Several recent papers have shown that calculated hydration free energies for polar and aromatic residues (Trp, His, Tyr, Asn, Gln, Asp, Glu) in several common molecular dynamics force fields differ significantly from experimentally measured values. We have attempted to improve the hydration energies for these residues by modifying the partial charges of the OPLS-AA force field based on natural population analysis of density functional theory calculations. The resulting differences between calculated hydration free energies and experimental results for the seven side chain analogs are less than 0.1 kcal/mol. Simulations of the synthetic Trp-rich peptide Trpzip2 show that the new charges lead to significantly improved geometries for interacting Trp-side chains. We also investigated an off-plane charge model for aromatic rings that more closely mimics their electronic configuration. This model results in an improved free energy of hydration for Trp and a somewhat altered benzene–sodium potential of mean force with a more favorable energy for direct benzene–sodium contact. © 2006 Wiley Periodicals, Inc. J Comput Chem 28: 689–697, 2007 [ABSTRACT FROM AUTHOR]

1. A key function of biological membranes is to provide mechanisms for the controlled transport of ions, nutrients, metabolites, peptides and proteins between a cell and its environment. 2. We are using computer simulations to study several processes involved in transport. 3. In model membranes, the distribution of small molecules can be accurately calculated; we are making progress towards understanding the factors that determine the partitioning behaviour in the inhomogeneous lipid environment, with implications for drug distribution, membrane protein folding and the energetics of voltage gating. 4. Lipid bilayers can be simulated at a scale that is sufficiently large to study significant defects, such as those caused by electroporation. 5. Computer simulations of complex membrane proteins, such as potassium channels and ATP-binding cassette (ABC) transporters, can give detailed information about the atomistic dynamics that form the basis of ion transport, selectivity, conformational change and the molecular mechanism of ATP-driven transport. 6. This is illustrated in the present review with recent simulation studies of the voltage-gated potassium channel KvAP and the ABC transporter BtuCD. [ABSTRACT FROM AUTHOR]

The recent crystal structures of the voltage‐gated potassium channel KvAP and its isolated voltage‐sensing “paddle” (composed of segments S1 to S4) (Jiang et al., Nature 2003, 423, 33–41) challenged existing models of voltage gating and encouraged a large number of experimental and theoretical studies to answer a number of questions about the structure of the physiologically relevant states of voltage‐gated potassium channels and their gating mechanism. We describe equilibrium simulations of the KvAP crystal structure. The crystal structure of the full channel undergoes a large conformational change, localized to the S1–S4 domains, as the S1–S4 domains move into the membrane. We also present a model of the closed state, in agreement with the position of the paddle in the paddle model of voltage gating. Finally, we estimate the energetic cost of transferring a single arginine sidechain from water into an octane slab with the approximate hydrophobic thickness of a membrane. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004 [ABSTRACT FROM AUTHOR]

The recent crystal structures of the voltage-gated potassium channel KvAP and its isolated voltage-sensing ‘paddle’ (composed of segments S1–S4) challenge existing models of voltage gating and raise a number of questions about the structure of the physiologically relevant state. We investigate a possible gating mechanism based on the crystal structures in a 10 ns steered molecular dynamics simulation of KvAP in a membrane-mimetic octane layer. The structure of the full KvAP protein has been modified by restraining the S2–S4 domain to the conformation of the isolated high-resolution paddle structure. After an initial relaxation, the paddle tips are pulled through the membrane from the intracellular to the extracellular side, corresponding to a putative change from closed to open. We describe the effect of this large-scale motion on the central pore domain, which remains largely unchanged, on the protein hydrogen-bonding network and on solvent. We analyze the motion of the S3b–S4 portion of the protein and propose a possible coupling mechanism between the paddle motion and the opening of the channel. Interactions between the arginine residues in S4, solvent and chloride ions are likely to play a role in the gating charge. [Copyright &y& Elsevier]

Examines the cost effectiveness of 81 alternative manure management systems for a swine finishing operation in reducing three pollutants associated with livestock waste. Levels of the three manure residuals; Feasible reductions in residuals; Comparison of abatement costs.

The outer membrane of Gram-negative bacteria contains porins, large sieve-like proteins allowing small molecules to diffuse in and out of the periplasm. We have simulated transport of the dipolar molecules alanine and methylglucose through the OmpF porin from Escherichia coli using non-equilibrium steered molecular dynamics simulations in a realistic bilayer environment. Structural perturbation of the protein is minimal. During the permeation process, both alanine and methylglucose align strongly in the electric field in the eyelet region, where the adhesion force on the permeating molecule has a maximum. Binding of the permeating dipolar molecules in the eyelet region is not observed. [Copyright &y& Elsevier]

Psychiatric symptoms, other than dementia, are compared in two groups of mental hospital patients who came to autopsy and had complete brain examination, One group had Alzheimer brain changes with no cerebral infarction. The other group had cerebral infarction with no Alzheimer brain changes. Onset with a non-dementing paranoid illness after the age of 50 was commoner in the Alzheimer group. There was no predominance of affective symptoms in either group. Suddenness of onset of psychosis distinguished the infarct cases, even in cases where there was no neurologically evident stroke, and when there were long time intervals between onset and death. Those destined to suffer Alzheimer brain changes had a less sudden onset, fewer discharges and rehospitalizations and more frequent transition to dementia. [ABSTRACT FROM AUTHOR]

This study concerns differences between Alzheimer's disease in the old and the young. Literature differentiating Alzheimer's disease from `senile dementia' is reviewed. Two groups of mental hospital patients with Alzheimer brain changes at autopsy are compared. They comprised the 17 oldest and 17 youngest of the 56 patients with definite Alzheimer changes in a series of 212 consecutive autopsies. The younger group had been first hospitalized at later ages than the older group, and were more likely to have been demented at admission. The older group had mostly been diagnosed as schizophrenic (mainly paranoid) on admission. Neuropathologically the younger group showed more severe Alzheimer changes of all kinds. The changes in the older group tended to he limited to the hippocampus, whereas in the younger group they showed extension into the frontal and occipital cortex and were also found in subcortical gray matter. Lipofuscin was more abundant in the older group, so that a discrepancy between very severe Alzheimer changes and less abundant lipofuscin characterizes the younger cases. [ABSTRACT FROM AUTHOR]

This investigations concerns the mental changes associated with Lewy bodies, Lewy bodies are inclusion bodies found in nerve cells and are characteristic of idiopathic Parkinson's disease. It has also been suggested that they may occur as a normal ageing change. Previous literature concerning the psychiatric symptoms of Lewy body disease is reviewed. Dementia and parkinsonism-associated depression have been previously recognized. For this study the psychiatric histories of two groups of autopsied mental hospital patients were compared; one group with Lewy bodies, and one group without Lewy bodies. There were 212 autopsies. Of these, 15 had Lewy bodies and 197 did not. Clinical and neuropathological descriptions of those with Lewy bodies are given. Findings are also presented in tabulated form, and the groups are compared statistically. Clinical diagnosis of Parkinson's disease and admission with a paranoid diagnosis were the findings most associated with Lewy bodies. It is suggested that paranoia may sometimes be an early symptom of Lewy body disease. The problem of patients with psychosis who subsequently develop idiopathic Parkinson's disease is discussed. Such patients could be misidentified and mistreated because of being diagnosed as drug-induced parkinsonism. [ABSTRACT FROM AUTHOR]

Examines the specification of behavioral equations both private and public sectors that allowed comprehensive long- and short-run forecasts to be made not only of supplies, demands and prices but of the important governmental policy variables. Importance of government interventions in agricultural and food systems; Alternative frameworks in quantifying the interaction and feedback effects between public and private sectors.

Abstract An overlapping generations model of a small open economy is used to explore several policy options aimed at reducing the burden of income taxes and pay-as-you-go (PAYG) contributions on labor income so as to improve the incentives to supply labor. Including the return of funded collective (FC) pension plans in the tax base turns out to be counterproductive. Cutting PAYG benefits, in contrast, succeeds in improving efficiency in general and labor-market incentives in particular. Under specific variants of the FC plan, reducing PAYG benefits even proves to be Pareto-welfare improving. [ABSTRACT FROM AUTHOR]

Following the work of Ray Fair (1979), expectations terms in the FOCUS model are generated using predicted values from the model itself. Expectations are therefore 'consistent' with the model structure. Government expenditure multipliers are compared for the standard model and the CE version. Three further examples show the power of the technique as applied to the analysis of fiscal policy shocks. The first considers a temporary versus a permanent income tax surcharge. The second considers the possibility of an 'anticipatory recession' when pre-announced fiscal stimulus is combined with monetary restraint. The third examines the planned re-structuring of the Canadian corporate tax system. [ABSTRACT FROM AUTHOR]

Presents an empirical dynamic portfolio balance model describing the portfolio behavior of the German private sector in the period 1975.I-1990.I. Estimation of the structural parameters of the portfolio problem; Explanation of the `home bias' observed in portfolios in industrialized economies; Conclusion to study.

The article focuses on the boundaries and development of sociology. It probes into some problems of cross-national sociology. As a young science and a new profession, sociology has been approached in different ways by different nations. In the United States where social changes have taken place more rapidly than in other nations, its existence has largely been limited to the university campuses. Sociologists are only now beginning to play their part in all branches of national life. A national boundary, as the term is used in the article, does not merely refer to the demarcation lines established by international commissions as a result of political negotiations or a war between two or more states. National boundaries constitute barriers of three major types, namely: semiotic, political, and cultural. It is possible that the diversity of arguments about what should constitute the subject matter of sociology stemmed from the fact that the early American sociologists represented a variety of backgrounds ranging from the ministry to paleontology.

Reports on the synthesis of porous composites with uniform network structure through sintering of pure mixtures of dolomite and zirconia powders. Doping of dolomite and zirconia powders; Formation of strong necks between particles before completion of pyrolysis; Formation of a homogenous open-pore structure; Application as filter materials.

A flow cell has been commissioned to monitor in situ precipitation reactions under non-ambient conditions. The majority of high-pressure systems use anvils and presses to obtain high pressures around a small reaction area; however, this prototype is unique in that solutions may be examined as they flow through the cell under pressure. The cell is made of single-crystal silicon, which is capable of withstanding the high pressures created by liquid flow within the cell. With the capability of reaching pressures of up to 4 x 10[SUP7] Pa, the cell is ideal for work on geological and oilfield systems. Here it is used to examine the formation of barium sulfate scale in situ under non-ambient conditions using angle-dispersive XRD on beamline X17b1 at the NSLS. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor on the definition of neuroplastic sensitivity, used as criteria for clinical diagnosis of Lewy body disease, published in the "International Journal of Geriatric Psychiatry."

Comments on the article 'A randomized controlled trial of exercise to improve outcomes of acute hospitalization in older adults,' by H. Siebens et al published in the 'Journal of American Geriatric Society.' Reasons cited for functional decline following hospitalization of older people; Caregiver stress in demented or personality disorder patients losing their support systems.

Summary: The dTph1 transposable element family of Petunia hybrida line W138 consists of between 100 and 200 members. A strategy that allows simultaneous detection of individual elements is described. Sequences flanking dTph1 elements are amplified by means of a ligation-mediated PCR. The resulting fragments are locus-specific and can be analysed by polyacrylamide gel electrophoresis. One of the applications of Transposon Display is the isolation of dTph1-tagged genes. Fragments that co-segregate with a mutant phenotype can be extracted from the gel and reamplified, providing access to tagged genes, as demonstrated in a reconstruction experiment. Data on the molecular identification of a phenotypic mutant, isolated in a random tagging experiment is also presented. Upon sequencing, the obtained candidate fragment was found to be identical to part of the previously identified Fbp1 gene. [ABSTRACT FROM AUTHOR]

We have studied the effect of a single injection of reserpine (5 mg/kg, s.c.) on the synaptic vesicle monoamine transporter (VMAT) density in the rat striatum, using two labelling procedures: radioimmunolabelling with an antibody against VMAT, and binding of the specific ligand [(3)H]dihydrotetrabenazine ([(3)H]TBZOH). In the rostral and medial striatum, the distribution of VMAT immunoreactivity displayed the highest density in the lateral subregions. In the caudal part of the striatum, VMAT immunoreactivity showed increasing density from dorsal to ventral subregions. The VMAT immunoreactivity was not altered 2 and 30 days after the reserpine injection, whereas [(3)H]TBZOH binding site density, measured on adjacent slices, showed a dramatic decrease at day 2 and a moderate recovery at day 30, suggesting that despite a persistent blockade of [(3)H]TBZOH binding sites, VMAT protein density was unchanged.