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In calling for both honest, engaged conversation and structural, material change, including redistribution of power and resources, Sadek offers an orienting vision for racial justice within psychoanalytic communities. Engaging with these ideas, this paper considers how dialogue and structural change, as well as integration in both an intrapsychic and a social, structural sense, might be linked with, and build on, each other. Drawing in part from personal experience, I also reflect on the role that sustained, collaborative work across racial difference – with a pragmatic focus on building something new together at an institutional level, as well as an attentiveness to process at an internal and interpersonal level – might play in fostering the kinds of integration and change Sadek advocates. [ABSTRACT FROM AUTHOR]

Classical atomistic simulations of biomolecules play an increasingly important role in molecular life science. The structure of current computing architectures favors methods that run multiple trajectories at once without requiring extensive communication between them. Many advanced sampling strategies in the field fit this mold. These approaches often rely on an adaptive logic and create ensembles of comparatively short trajectories whose starting points are not distributed according to the correct Boltzmann weights. This type of bias is notoriously difficult to remove, and Markov state models (MSMs) are one of the few strategies available for recovering the correct kinetics and thermodynamics from these ensembles of trajectories. In this contribution, we analyze the performance of MSMs in the thermodynamic reweighting task for a hierarchical set of systems. We show that MSMs can be rigorous tools to recover the correct equilibrium distribution for systems of sufficiently low dimensionality. This is conditional upon not tampering with local flux imbalances found in the data. For a real-world application, we find that a pure likelihood-based inference of the transition matrix produces the best results. The removal of the bias is incomplete, however, and for this system, all tested MSMs are outperformed by an alternative albeit less general approach rooted in the ideas of statistical resampling. We conclude by formulating some recommendations for how to address the reweighting issue in practice. [ABSTRACT FROM AUTHOR]

Background Prosthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention. Methods The patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient's isolate and determined by safranin staining. Results Phage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P  = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections. [ABSTRACT FROM AUTHOR]

We consider a 2D vorticity configuration where vorticity is highly concentrated around a curve and exponentially decaying away from it: the intensity of the vorticity is O(1/ε) on the curve while it decays on an O(ε) distance from the curve itself. We prove that, if the initial datum is of vortex‐layer type, Euler solutions preserve this structure for a time that does not depend on ε. Moreover, the motion of the center of the layer is well approximated by the Birkhoff‐Rott equation. © 2020 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This paper examines the problem of white liberal guilt from a Kleinian perspective, considering both the reparative potential of guilt in the depressive position, as well as the ways in which racial guilt can become diverted to an internal experience focused more on the self than on the harmed other, inspiring ways of thinking and acting that have little to do with repair. Drawing especially from the Kleinian concept of persecutory guilt, which describes the form guilt can take "when reparation is felt to be impossible", I examine the consequences of white liberal guilt as expressed in the United States today. In particular, I argue that white liberal self-idealization and self-reproach – positions summarized as "this is not who we are" and "this is all that we are" – can function as two sides of a coin, grounded in splitting and in divergent yet related forms of exceptionalism. As an alternative, I propose thinking about reparation within the realm of the ordinary, and consider what this might entail. [ABSTRACT FROM AUTHOR]

Responding to these deeply thoughtful commentaries at a moment of urgency, in the United States and globally, around the impact of racial violence, this reply reflects on the limits and potential of psychoanalysis to address these vast social problems. I discuss the confrontation this moment entails for white people; the importance of resisting the urge to respond to this confrontation by "leaving" in any of the ways elaborated by Cyrus, Davids and Swartz (this issue); and the fantasies of control contained within the liberal idea of "giving up" privilege, as critiqued by Swartz. Drawing on the respondents' insights, I revisit the psychoanalytic concept of rupture and repair and its limits within a context of ongoing structural violence; and reconsider how questions of agency and subjecthood are constructed in the idea of reparation, suggesting that what is in fact impossible may not be reparation itself, but reparation as an action of white people, seen as subjects, toward people of color, seen as objects. [ABSTRACT FROM AUTHOR]

Signal fragmentation is the (approximate) representation of a signal as a sum of signal fragments, each of which has compact support. It has been proposed as a method for transmitting a low frequency signal over an array of small antennas. We present a mathematical analysis of signal fragmentation for an idealized model of antenna transmission. In the simplest form of signal fragmentation, each fragment has the same waveform, but the nth fragment has an amplitude an and is shifted in time by an amount tn = nΔ. We analyze the spectral leakage (i.e., the error in the Fourier representation) and energy efficiency of signal fragmentation. For a special choice of wavelet the spectral leakage can be eliminated for sinusoidal signals. We also formulate a measure of energy efficiency and perform a scaling analysis of the efficiency with a large number of fragments. Although the efficiency is poor for the original wavelet expansion, an alternative form of fragmentation has efficiency that scales well with the number of fragments. We then find the fragment waveform that optimizes the energy efficiency for a given choice of support size, and we generalize some of these results to AM signals. [ABSTRACT FROM AUTHOR]

The rate of protein folding is governed by the transition state so that a detailed characterization of its structure is essential for understanding the folding process. In vitro experiments have provided a coarse-grained description of the folding transition state ensemble (TSE) of small proteins. Atomistic details could be obtained by molecular dynamics (MD) simulations but it is not straightforward to extract the TSE directly from the MD trajectories, even for small peptides. Here, the structures in the TSE are isolated by the cut-based free-energy profile (cFEP) using the network whose nodes and links are configurations sampled by MD and direct transitions among them, respectively. The cFEP is a barrier-preserving projection that does not require arbitrarily chosen progress variables. First, a simple two-dimensional free-energy surface is used to illustrate the successful determination of the TSE by the cFEP approach and to explain the difficulty in defining boundary conditions of the Markov state model for an entropically stabilized free-energy minimum. The cFEP is then used to extract the TSE of a β-sheet peptide with a complex free-energy surface containing multiple basins and an entropic region. In contrast, Markov state models with boundary conditions defined by projected variables and conventional histogram-based free-energy profiles are not able to identify the TSE of the β-sheet peptide. [ABSTRACT FROM AUTHOR]

The replica exchange molecular dynamics (REMD) approach is applied to a 20-residue three-stranded antiparallel β-sheet peptide. At physiologically relevant temperature REMD samples conformational space much more efficiently than constant temperature molecular dynamics (MD) and allows reversible folding (312 folding events during a total simulation time of 32 μs). The energetic and structural properties during the folding process are similar in REMD and conventional MD at the temperature values where there is enough statistics for the latter. The simulation results indicate that the unfolded state contains a significant amount of non-native interactions especially at low temperature. The folding events consist of a gradual replacement of non-native contacts with native ones which is coupled with an almost monotonic decrease of the REMD temperature. [ABSTRACT FROM AUTHOR]

HIGHLIGHTS • OMT Blue Clay kills human pathogens existing in free-floating and adherent states. • Clay suspension is more bioactive than the solution of clay's metal derivatives. • Species differences in past, present results allude to impact of strain variation. Abstract Clay is a substance historically utilized by indigenous cultures for the treatment of superficial wound infections. This study evaluated the effects of a recently identified clay – OMT Blue Clay – against staphylococci, streptococci, Enterobacteriaceae and non-fermenting Gram-negative bacilli. The clay and its aqueous leachate were evaluated against the bacteria in biofilm and planktonic states. Time-kill studies were used to assess planktonic activity. Biofilms on medical-grade Teflon discs were treated with a hydrated clay suspension or leachate. For the planktonic studies, clay and leachate exhibited bactericidal activity against all strains tested, with the exception of leachate against Staphylococcus aureus IDRL-6169 and USA300. All strains treated with clay suspension and leachate resulted in statistically significant biofilm population reductions compared with controls, except S. aureus IDRL-6169 and USA300 (P ≤ 0.05). OMT Blue Clay and its aqueous leachate exhibited bactericidal activity against a range of human pathogens in the planktonic and biofilm states. [ABSTRACT FROM AUTHOR]

We report on two fragment-based drug design protocols, SEED2XR and ALTA, which start by high-throughput docking. SEED2XR is a two-stage protocol for fragment-based drug design. The first stage is in silico and consists of the automatic docking of 10 3 -10 4 fragments using SEED, which requires about 1 s per fragment. SEED is a docking software developed specifically for fragment docking and binding energy evaluation by a force field with implicit solvent. In the second stage of SEED2XR, the 10-10 2 fragments with the most favorable predicted binding energies are validated by protein X-ray crystallography. The recent applications of SEED2XR to bromodomains demonstrate that the whole SEED2XR protocol can be carried out in about a week of working time, with hit rates ranging from 10% to 40%. Information on fragment-target interactions generated by the SEED2XR protocol or directly from SEED docking has been used for the discovery of hundreds of hits. ALTA is a computational protocol for screening which identifies candidate ligands that preserve the interactions between the optimal SEED fragments and the protein target. Medicinal chemistry optimization of ligands predicted by ALTA has resulted in pre-clinical candidates for protein kinases and bromodomains. The high-throughput, very low cost, sustainability, and high hit rate of the SEED-based protocols, unreachable by purely experimental techniques, make them perfectly suitable for both academic and industrial drug discovery research. [ABSTRACT FROM AUTHOR]

Recent years have witnessed rapid developments of computer-aided drug design methods, which have reached accuracy that allows their routine practical applications in drug discovery campaigns. Protein structure-based methods are useful for the prediction of binding modes of small molecules and their relative affinity. The high-throughput docking of up to 10 6 small molecules followed by scoring based on implicit-solvent force field can robustly identify micromolar binders using a rigid protein target. Molecular dynamics with explicit solvent is a low-throughput technique for the characterization of flexible binding sites and accurate evaluation of binding pathways, kinetics, and thermodynamics. In this review we highlight recent advancements in applications of ligand docking tools and molecular dynamics simulations to ligand identification and optimization. [ABSTRACT FROM AUTHOR]

Bromodomains are protein modules adopting conserved helix bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders. To interfere with or modulate these processes, it is therefore of fundamental interest to understand the molecular mechanisms by which epigenetic regulation occurs. Here, we present results from molecular dynamics simulations of a doubly acetylated histone H4 peptide bound to the bromodomain of ATAD2 (hereafter referred to as ATAD2A). These simulations revealed how the flexibility of ATAD2A's major loop, the so-called ZA loop, creates an adaptable interface that preserves the disorder of both peptide and loop in the bound state. We further demonstrate that the binding involves an almost identical average pattern of interactions irrespective of which acetyl mark is inserted into the pocket. In conjunction with a likely mechanism of electrostatically driven recruitment, our simulation results highlight how the bromodomain is built toward promiscuous binding with low specificity. In conclusion, the simulations indicate that disorder and electrostatic steering function jointly to recruit ATAD2A to the histone core and that these fuzzy interactions may promote cooperativity between nearby epigenetic marks. [ABSTRACT FROM AUTHOR]

Compressed modes are solutions of the Laplace equation with a potential and a subgradient term. The subgradient term comes from addition of an L¹ penalty in the corresponding variational principle. This paper presents an analysis of compressed modes, finding the minimizer of the variational principle, showing the spatial localization property of compressed modes, and establishing an upper bound on the volume of their support. [ABSTRACT FROM AUTHOR]

Alcohol consumption is widely spread in Switzerlanc Only a small part of the populatior is completely abstinent, approx mately 25C000 persons are addicted tc alcohol. The damage to people's health and the country's economy is sign ficant. Identification and treatment of alcohol use disorders are still a challenge for primary care professionals. The dialogue between doctor ano patient remains the most 'important diagnostic and therapeutic tool, it can be complemented by laboratory testing and questionnaires. The latest development in the field of treatment of alcohol dependency syndrome, which is traditionally subdiv ded into acute and post-acute-treatment, is the acceptance of reduced consumption at least as a temporary treatment goa . Because primary care professionals play a key role in the prevention and dentification of alcohol use disorders, it is important that they are familiar with existing inte'vention options. [ABSTRACT FROM AUTHOR]

Prion diseases are associated with the conversion of the cellular prion protein (PrP) into a pathogenic conformer (PrPSc). A proposed therapeutic approach to avoid the pathogenic transformation is to develop antibodies that bind to PrP and stabilize its structure. POM1 and POM6 are two monoclonal antibodies that bind the globular domain of PrP and have different biological responses, i.e., trigger neurotoxicity mimicking prion infections (POM1) or prevent neurotoxicity (POM6). The crystal structures of PrP in complex with the two antibodies show similar epitopes which seems inconsistent with the opposite phenotypes. Here, we investigate the influence of the POM1 and POM6 antibodies on the flexibility of the mouse PrP by molecular dynamics simulations. The simulations reveal that the POM6/PrP interface is less stable than the POM1/PrP interface, ascribable to localized polar mismatches at the interface, despite the former complex having a larger epitope than the latter. In the presence of any of the two antibodies, the flexibility of the globular domain increases everywhere except for the β 1 - α 1 loop in the POM1/PrP complex which suggests the involvement of this loop in the pathological conversion. The secondary structure of PrP is preserved whereas the polar interactions involving residues Glu146, Arg156 and Arg208 are modified upon antibody binding. • The POM6/prion protein interface is less stable than the POM1/prion protein interface • Antibody binding increases the flexibility of the PrP globular domain, except in the β 1 -α 1 loop which is part of the epitope • The network of intramolecular contacts is perturbed differently upon antibody binding • The binding of the antibodies stabilizes the 3 10 -helix at the C-terminus of α 1 , with POM6 having a more pronounced effect. [ABSTRACT FROM AUTHOR]

BRPF1 plays a scaffolding role in transcription. We report on fragment screening by high-throughput docking to the BRPF1 bromodomain which resulted in six chemotypes with very favorable ligand efficiency (0.45-0.50 kcal/mol per non-hydrogen atom). Twenty crystal structures of BRPF1/ligand complexes show structural conservation in the acetyllysine binding site, common binding motifs, and unusual interactions (e.g., the replacement of a conserved water molecule). The structural information is useful for the design of chemical probes. [ABSTRACT FROM AUTHOR]

This paper describes a kinetic model and a corresponding Monte Carlo simulation method for excitation/deexcitation and ionization/recombination by electron impact in a plasma free of external fields. The atoms and ions in the plasma are represented by continuum densities and the electrons by a particle distribution. A Boltzmann-type equation is formulated and a corresponding H-theorem is formally derived. An efficient Monte Carlo method is developed for an idealized analytic model of the excitation and ionization collision cross sections. To accelerate the simulation, the reduced rejection method and binary search method are used to overcome the singular rate in the recombination process. Numerical results are presented to demonstrate the efficiency of the method on spatially homogeneous problems. The evolution of the electron distribution function and atomic states is studied, revealing the possibility under certain circumstances of system relaxation towards stationary states that are not the equilibrium states, a potential non-ergodic behavior. [ABSTRACT FROM AUTHOR]

In this work we propose a novel negative particle method for the general bilinear collision operators in the spatial homogeneous case and apply it to Coulomb collisions. This new method successfully reduces the growth of particle numbers from the numerical time scale to the physical time scale for Coulomb collisions. We also propose a particle resampling method which reduces the particle number to further improve the efficiency. Various numerical simulations are performed to demonstrate the accuracy and efficiency of the method. [ABSTRACT FROM AUTHOR]

In this paper, the valuation problem of a European call option in the presence of both stochastic volatility and transaction costs is considered. In the limit of small transaction costs and fast mean reversion, an asymptotic expression for the option price is obtained. While the dominant term in the expansion is shown to be the classical Black and Scholes solution, the correction terms appear at O(ε1/2) and O(ε). The optimal hedging strategy is then explicitly obtained for Scott's model. [ABSTRACT FROM AUTHOR]

We analyze the chemical space coverage of kinase inhibitors in the public domain from a fragment point of view. A set of 26,668 kinase inhibitors from the ChEMBL database of bioactive molecules were decomposed automatically by fragmentation at rotatable bonds. Remarkably, about half of the resulting 10,302 fragments originate from inaccessible libraries, as they are not present in commercially available compounds. By mapping to the established kinase pharmacophore models, privileged fragments in sub-pockets are identified, for example, the 5681 ring-containing fragments capable of forming bi-dentate hydrogen bonds with the hinge region in the ATP binding site. Surprisingly, hinge-binding fragments in current kinase inhibitors cover only 1% of the potential hinge-binders obtained by decomposing a library of nearly 7.5 million commercially available compounds, which indicates that a large fraction of chemical space is unexplored. [ABSTRACT FROM AUTHOR]

Experimental evidence indicates that the primary structure of the β2-α2 loop region (residues 165-175) in mammalian prion proteins (PrP) influences the conversion from the cellular species (PrPC) to the β-sheet-rich aggregate. Here, we captured the transition of the β2-α2 loop from 310-helical turn to β turn by unbiased molecular dynamics simulations of the single-point mutant Y169G. Multiple conformations along the spontaneous transition of the mutant were then used as starting point for sampling of the free-energy surface of the wild type and other single-point mutants. Using two different methods for the determination of free energy profiles, we found that the barrier for the 310-helical turn to β turn transition of the wild type is higher by about 2.5 kcal/mol than for the Y169G mutant, which is due to favorable stacking of the aromatic rings of Y169 and F175, and a stable hydrogen bond between the side chains of Y169 and D178. The transition of the β2-α2 loop to β turn increases the solvent-exposure of the hydrophobic stretch 169-YSNQNNF-175. The simulations indicate that the strictly conserved Y169 in mammalian prion proteins stabilizes the 310-helical turn in the β2-α2 loop, thus hindering the conversion to an aggregation-prone conformation. [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulations are useful tools for structure-based drug design. We review recent publications in which explicit solvent MD was used at the initial or final stages of high-throughput docking campaigns. In some cases, MD simulations of the protein target have been carried out before docking to generate a conformer of the protein which differs from the available crystal structure(s). Furthermore, MD runs have been performed after docking to assess the predicted binding modes of the top ranking compounds as final filter in silico or to guide chemical synthesis for hit optimization. We present examples of in silico discoveries of tyrosine kinase inhibitors and bromodomain antagonists whose binding mode was predicted by automated docking and further corroborated by MD simulations with final validation by X-ray crystallography. [ABSTRACT FROM AUTHOR]

Experimental protein structures provide spatial information at the atomic level. A further dimension, time, is supplemented by molecular dynamics. Since the pioneering work on the 58-residue inhibitor of bovine pancreatic trypsin in the group of Martin Karplus in the seventies, molecular dynamics simulations have shown that the intrinsic flexibility of proteins is essential for their function. Here, we review simulation studies of bromodomains. These protein modules are involved in the recognition of acetylated lysine side chains, a post-translational modification frequently observed in histone tails. The molecular dynamics simulations have unmasked: (i) the large plasticity of the loops lining the acetyl-lysine binding site (coupled to its self-occlusion), and (ii) multiple binding modes of acetyl-lysine. These simulation results suggest that recognition of histone tails by bromodomains is modulated by their intrinsic flexibility, and further corroborate the utility of molecular dynamics in understanding (macro)molecular recognition. [ABSTRACT FROM AUTHOR]

Abstract: The non-receptor tyrosine kinase Syk (spleen tyrosine kinase) is a pharmaceutical relevant target because its over-activation is observed in several autoimmune diseases, allergy, and asthma. Here we report the identification of two novel inhibitors of Syk by high-throughput docking into a rare C-helix-out conformation published recently. Interestingly, both compounds are slightly more active on ZAP70 (Zeta-chain-associated protein kinase 70), which is the kinase closest to Syk in the phylogenetic tree of human kinases. Taken together, the docking pose and experimental results suggest that the higher affinity of the inhibitors for ZAP70 than Syk originates from a more populated C-helix-out conformation in ZAP70. The latter observation is congruent with the 100-fold lower intrinsic activity of ZAP70 than Syk, as the C-helix-out conformation is inactive. The pharmacophore features of DFG-in, C-helix-out compounds are analyzed in relation to DFG-out inhibitors. [Copyright &y& Elsevier]

Summary: The derivation of molecular models from spatial density data generated by X-ray crystallography or electron microscopy is an active field of research. Here, we introduce and evaluate an approach relying on the equilibrium sampling of energy landscapes describing restraints to experimental input data. Our procedure combines density restraints with replica exchange methodologies in the parameter space of the restraints, and we demonstrate its applicability to both flexible polymers and the assembly of protein complexes from rigid components. For the most difficult system studied, we highlight the importance of advanced data analysis techniques in mining poorly converged data further. Successful and unbiased interpretation of input density maps is a prerequisite for using this approach as an auxiliary restraint term in molecular simulations. Because these simulations will also utilize physical interaction potentials, we hope that they will contribute to deriving families of structural models for input data that are ambiguous per se. [ABSTRACT FROM AUTHOR]

Abstract: Very few selective inhibitors of the zeta-chain associated protein kinase 70kDa (ZAP70) have been reported despite its importance in autoimmune diseases. Here, to induce a fit of the so-called gatekeeper residue (Met414) and hydrophobic pocket next to it, a potent Janus kinase 2 (JAK2) inhibitor was first docked into the ATP binding site of ZAP70 by structural alignment of the kinase domains. The resulting model of the complex between ZAP70 and the JAK2 inhibitor was then relaxed by an explicit solvent molecular dynamics simulation with restraints on the backbone atoms. High-throughput docking into the induced-fit conformation of ZAP70 generated by molecular dynamics has revealed 10 low-micromolar inhibitors which correspond to six distinct chemotypes. One of these ZAP70 inhibitors has an IC50 of 110nM for JAK2. [Copyright &y& Elsevier]

A numerical method for investigating singularities in solutions to non-linear evolution equations is presented. The method is based on a complex analytical approach to singularities introduced by Sulem, Sulem and Frisch, which uses analytic continuation of an independent variable and numerical detection of the width of the analyticity strip, defined as the distance δ from the real domain to the nearest complex singularity. Their method, originally formulated for functions of a single variable, is here generalized to problems and functions of several variables. We first analyse the asymptotic behaviour of the multidimensional Fourier transform of an analytic function, and use this to numerically detect the complex singularity surface. The approach allows us to determine the parameters that characterize the singularity surface in a neighbourhood of its closest point to the real domain. [ABSTRACT FROM PUBLISHER]

Atomistic simulations of biological processes offer insights at a high level of spatial and temporal resolution, but accelerated sampling is often required for probing timescales of biologically relevant processes. The resulting data need to be statistically reweighted and condensed in a concise yet faithful manner to facilitate interpretation. Here, we provide evidence that a recently proposed approach for the unsupervised determination of optimized reaction coordinate (RC) can be used for both analysis and reweighting of such data. We first show that for a peptide interconverting between helical and collapsed configurations, the optimal RC permits efficient reconstruction of equilibrium properties from enhanced sampling trajectories. Upon RC-reweighting, kinetic rate constants and free energy profiles are in good agreement with values obtained from equilibrium simulations. In a more challenging test, we apply the method to enhanced sampling simulations of the unbinding of an acetylated lysine-containing tripeptide from the bromodomain of ATAD2. The complexity of this system allows us to investigate the strengths and limitations of these RCs. Overall, the findings presented here underline the potential of the unsupervised determination of reaction coordinates and the synergy with orthogonal analysis methods, such as Markov state models and SAPPHIRE analysis. [ABSTRACT FROM AUTHOR]

A newanalysis of the 20 μs equilibrium folding/unfoldingmolecular dynamics simulations of the three-stranded antiparallelβ-sheet miniprotein (beta3s) in implicit solvent is presented.The conformation space is reduced in dimensionality by introductionof linear combinations of hydrogen bond distances as the collectivevariables making use of a specially adapted principal component analysis(PCA); i.e., to make structured conformations more pronounced, onlythe formed bonds are included in determining the principal components.It is shown that a three-dimensional (3D) subspace gives a meaningfulrepresentation of the folding behavior. The first component, to whicheight native hydrogen bonds make the major contribution (four in eachbeta hairpin), is found to play the role of the reaction coordinatefor the overall folding process, while the second and third componentsdistinguish the structured conformations. The representative pointsof the trajectory in the 3D space are grouped into conformationalclusters that correspond to locally stable conformations of beta3sidentified in earlier work. A simplified kinetic network based onthe three components is constructed, and it is complemented by a hydrodynamicanalysis. The latter, making use of “passive tracers”in 3D space, indicates that the folding flow is much more complexthan suggested by the kinetic network. A 2D representation of streamlinesshows there are vortices which correspond to repeated local rearrangement,not only around minima of the free energy surface but also in flatregions between minima. The vortices revealed by the hydrodynamicanalysis are apparently not evident in folding pathways generatedby transition-path sampling. Making use of the fact that the valuesof the collective hydrogen bond variables are linearly related tothe Cartesian coordinate space, the RMSD between clusters is determined.Interestingly, the transition rates show an approximate exponentialcorrelation with distance in the hydrogen bond subspace. Comparisonwith the many published studies shows good agreement with the presentanalysis for the parts that can be compared, supporting the robustcharacter of our understanding of this “hydrogen atom”of protein folding. [ABSTRACT FROM AUTHOR]

We investigate the approximate dynamics of several differential equations when the solutions are restricted to a sparse subset of a given basis. The restriction is enforced at every time step by simply applying soft thresholding to the coefficients of the basis approximation. By reducing or compressing the information needed to represent the solution at every step, only the essential dynamics are represented. In many cases, there are natural bases derived from the differential equations, which promote sparsity. We find that our method successfully reduces the dynamics of convection equations, diffusion equations, weak shocks, and vorticity equations with high-frequency source terms. [ABSTRACT FROM AUTHOR]

Aim The aim of this cross-sectional study was to provide normative data (ordinal scores and timed performances) for gross and fine motor tasks in typically developing children between 3 and 5 years of age using the Zurich Neuromotor Assessment (ZNA). Method Typically developing children ( n=101; 48 males, 53 females) between 3 and 5 years of age were enrolled from day-care centres in the greater Zurich area and tested using a modified version of the ZNA; the tests were recorded digitally on video. Intraobserver reliability was assessed on the videos of 20 children by one examiner. Interobserver reliability was assessed by two examiners. Test-retest reliability was performed on an additional 20 children. The modelling approach summarized the data with a linear age effect and an additive term for sex, while incorporating informative missing data in the normative values. Normative data for adaptive motor tasks, pure motor tasks, and static and dynamic balance were calculated with centile curves (for timed performance) and expected ordinal scores (for ordinal scales). Results Interobserver, intraobserver, and test-retest reliability of tasks were moderate to good. Nearly all tasks showed significant age effects, whereas sex was significant only for stringing beads and hopping on one leg. Interpretation These results indicate that timed performance and ordinal scales of neuromotor tasks can be reliably measured in preschool children and are characterized by developmental change and high interindividual variability. [ABSTRACT FROM AUTHOR]

Persistent activity has commonly been considered to be a hallmark of working memory (WM). Recent evidence indicates that neuronal discharges in the medial temporal lobe (MTL) are compatible with WM neural patterns observed in cortical areas. However, the characterization of this activity rarely consists of measurements other than firing rates of single neurons. Moreover, a varied repertoire of firing dynamics has been reported in the MTL regions, which motivate the more detailed examination of the relationships between WM processes and discharge patterns undertaken here. Specifically, we investigate‚ at different resolution levels, firing irregularities in electrode recordings from the hippocampus, amygdala, and the entorhinal cortex of epileptic patients during a WM task. We show that some types of (ir)regularities predict response times of the patients depending on the trial periods under consideration. Prominent burst activity at the population level is observed in the amygdala and entorhinal cortex during memory retrieval. In general, regular and bursty neurons contribute to the decoding of the memory load, yet they display important differences across the three anatomical areas. Our results suggest that nonrandom (non-Poisson) patterns are relevant for WM, which calls for the development and use of statistics complementary to mere spike counts. [ABSTRACT FROM AUTHOR]

This study examined gross motor performance of 101 typically developing children between 3 and 5 years of age (48 boys, 53 girls, M age = 3.9 yr., SD = 0.5). All children performed 7 different gross motor tasks which were rated on a 5-point scale. Age and sex were assessed by an ordinal-logistic model, and odds ratios were calculated for each task using age and sex as covariates. For standing on one leg, walking on a beam, hopping on one leg, running, and taking stairs, statistically significant age differences were found, while for rising and jumping down, none were apparent. Mean motor performance did not differ between boys and girls on the tasks. The older the children were, the better they performed on the tasks. [ABSTRACT FROM AUTHOR]

This article presents a new formulation of the solution for fully nonlinear and unsteady planar flow of an electron beam in a diode. Using characteristic variables (i.e., variables that follow particle paths) the solution is expressed through an exact analytic, but implicit, formula for any choice of incoming velocity &ngr;0, electric field E0, and current J0. For steady solutions, this approach clarifies the origin of the maximal current 7max, derived by Child and Langmuir for &ngr;0 = 0 and by Jaffe for &ngr;0 > 0. The implicit formulation is used to find (1) unsteady solutions having constant incoming flux J0 > 7max, which leads to formation of a virtual cathode, and (2) time-periodic solutions whose average flux exceeds the adiabatic average of Jmax. [ABSTRACT FROM AUTHOR]

Aims: To determine the motor and cognitive outcome in a regional cohort of survivors of surgically corrected congenital diaphragmatic hernia. Methods: Thirty-three children (85% of survivors) were examined at a mean age of 8.6 years (3.3-15.7 years), seven had a genetic comorbidity. Outcome was assessed with the Wechsler Preschool and Primary Scale of Intelligence 3rd version and the Wechsler Intelligence Scale 4th version. Motor performance was tested with the Movement Assessment Battery for Children 2nd edition in children younger than 5 years and thereafter with the Zurich Neuromotor Assessment. Results: Children without a genetic comorbidity had a normal cognitive outcome (median IQ 103, 70-121), but fine motor (p = 0.008) and gross motor outcome (p = 0.001) were poorer than the norm. Medical variables were not predictive of adverse outcome, whereas genetic comorbidity was the strongest predictor of low IQ (p < 0.001) and of poor motor performance (p = 0.04). Conclusions: In the absence of a genetic comorbidity, children with congenital diaphragmatic hernia have a favourable cognitive outcome, but motor outcome may be affected. This needs to be taken into account for parental counselling. Further, long-term neurodevelopmental assessment in children with congenital diaphragmatic hernia is important to provide early therapeutic interventions. [ABSTRACT FROM AUTHOR]

Abstract: There is strong experimental evidence of the influence of surfactants (e.g., fatty acids) on the kinetics of amyloid fibril formation. However, the structures of mixed assemblies and interactions between surfactants and fibril-forming peptides are still not clear. Here, coarse-grained simulations are employed to study the aggregation kinetics of amyloidogenic peptides in the presence of amphiphilic lipids. The simulations show that the lower the fibril formation propensity of the peptides, the higher the influence of the surfactants on the peptide self-assembly kinetics. In particular, the lag phase of weakly aggregating peptides increases because of the formation of mixed oligomers, which are promoted by hydrophobic interactions and favorable entropy of mixing. A transient peak in the number of surfactants attached to the growing fibril is observed before reaching the mature fibril in some of the simulations. This peak originates from transient fibrillar defects consisting of exposed hydrophobic patches on the fibril surface, which provide a possible explanation for the temporary maximum of fluorescence observed sometimes in kinetic traces of the binding of small-molecule dyes to amyloid fibrils. [Copyright &y& Elsevier]

The aspartic protease β-secretase (BACE) catalyzes the hydrolysis of the amyloid precursor protein (APP) which leads to amyloid-β aggregation and, ultimately, the perilous Alzheimer's disease. The conformational dynamics and free energy surfaces of BACE at three steps of the catalytic cycle are studied here by explicit solvent molecular dynamics simulations (multiple runs for a total of 2.2 μs). The overall plasticity of BACE is essentially identical for the three states of the substrate: the octapeptide reactant, gem-diol intermediate, and cleavage products. In contrast, the network of hydrogen bonds in the active site is more stable in the complex of BACE with the gem-diol intermediate than the other two states of the substrate. The spontaneous release of the C-terminal (P1'-P4') fragment of the product follows a single-exponential time dependence with a time constant of 50 ns and does not require the opening of the flap. The fast dissociation of the C-terminal fragment is consistent with the transmembrane location and orientation of APP and its further processing by γ-secretase. On the other hand, the N-terminal (P4-P1) fragment of the product does not exit the BACE active site within the simulation time scale of 80 ns. A unified network analysis of the complexes of BACE with the three states of the substrate provides an estimation of the activation free energy associated with the structural rearrangements that involve only noncovalent interactions. The estimated rearrangement barriers are not negligible (up to 3 kcal/mol) but are significantly smaller than the barrier of the peptide bond hydrolysis reaction. [ABSTRACT FROM AUTHOR]

Multiple independent molecular dynamics (MD) simulations are often carried out starting from a single protein structure or a set of conformations that do not correspond to a thermodynamic ensemble. Therefore, a significant statistical bias is usually present in the Markov state model generated by simply combining the whole MD sampling into a network whose nodes and links are clusters of snapshots and transitions between them, respectively. Here, we introduce a depth-first search algorithm to extract from the whole conformation space network the largest ergodic component, i.e., the subset of nodes of the network whose transition matrix corresponds to an ergodic Markov chain. For multiple short MD simulations of a globular protein (as in distributed computing), the steady state, i.e., stationary distribution determined using the largest ergodic component, yields more accurate free energy profiles and mean first passage times than the original network or the ergodic network obtained by imposing detailed balance by means of symmetrization of the transition counts. [ABSTRACT FROM AUTHOR]

In this paper nonlocal boundary conditions for the Navier-Stokes equations are derived, starting from the Boltzmann equation in the limit for the Knudsen number being vanishingly small. In the same spirit of (Lombardo et al. in J. Stat. Phys. 130:69-82, ) where a nonlocal Poisson scattering kernel was introduced, a gaussian scattering kernel which models nonlocal interactions between the gas molecules and the wall boundary is proposed. It is proved to satisfy the global mass conservation and a generalized reciprocity relation. The asymptotic expansion of the boundary-value problem for the Boltzmann equation, provides, in the continuum limit, the Navier-Stokes equations associated with a class of nonlocal boundary conditions of the type used in turbulence modeling. [ABSTRACT FROM AUTHOR]

The spontaneous dissociation of six small ligands from the active site of FKBP (the FK506 binding protein) is investigated by explicit water molecular dynamics simulations and network analysis. The ligands have between four (dimethylsulphoxide) and eleven (5-diethylamino-2-pentanone) non-hydrogen atoms, and an affinity for FKBP ranging from 20 to 0.2 mM. The conformations of the FKBP/ligand complex saved along multiple trajectories (50 runs at 310 K for each ligand) are grouped according to a set of intermolecular distances into nodes of a network, and the direct transitions between them are the links. The network analysis reveals that the bound state consists of several subbasins, i.e., binding modes characterized by distinct intermolecular hydrogen bonds and hydrophobic contacts. The dissociation kinetics show a simple (i.e., singleexponential) time dependence because the unbinding barrier is much higher than the barriers between subbasins in the bound state. The unbinding transition state is made up of heterogeneous positions and orientations of the ligand in the FKBP active site, which correspond to multiple pathways of dissociation. For the six small ligands of FKBP, the weaker the binding affinity the closer to the bound state (along the intermolecular distance) are the transition state structures, which is a new manifestation of Hammond behavior. Experimental approaches to the study of fragment binding to proteins have limitations in temporal and spatial resolution. Our network analysis of the unbinding simulations of small inhibitors from an enzyme paints a clear picture of the free energy landscape (both thermodynamics and kinetics) of ligand unbinding. [ABSTRACT FROM AUTHOR]

Abstract: Aggregation of amyloid-β (Aβ) peptide, a 39- to 43-residue fragment of the amyloid precursor protein, is associated with Alzheimer''s disease, the most common form of dementia in the elderly population. Several experimental studies have tried to characterize the atomic details of amyloid fibrils, which are the final product of Aβ aggregation. Much less is known about species forming during the early stages of aggregation, in particular about the monomeric state of the Aβ peptide that may be viewed as the product of the very first step in the hypothesized amyloid cascade. Here, the equilibrium ensembles of monomeric Aβ alloforms Aβ1–40 and Aβ1–42 are investigated by Monte Carlo simulations using an atomistic force field and implicit solvent model that have been shown previously to correctly reproduce the ensemble properties of other intrinsically disordered polypeptides. Our simulation results indicate that at physiological temperatures, both alloforms of Aβ assume a largely collapsed globular structure. Conformations feature a fluid hydrophobic core formed, on average, by contacts both within and between the two segments comprising residues 12–21 and 24–40/42, respectively. Furthermore, the 11 N-terminal residues are completely unstructured, and all charged side chains, in particular those of Glu22 and Asp23, remain exposed to solvent. Taken together, these observations indicate a micelle-like† [†] The terms “micelle-like architecture” and “micelle-like” used throughout this article refer to the average conformation of an individual polypeptide chain and do not imply the assembly of several molecules, unless otherwise noted. architecture at the monomer level whose implications for oligomerization, as well as fibril formation and elongation, are discussed. We establish quantitatively the intrinsic disorder of Aβ and find the propensity to form regular secondary structure to be low but sequence specific. In the presence of a global and unspecific bias for backbone conformations to populate the β-basin, the β-sheet propensity along the sequence is consistent with the arrangement of the monomer within the fibril, as derived from solid-state NMR data. These observations indicate that the primary sequence partially encodes fibril structure, but that fibril elongation must be thought of as a templated assembly step. [Copyright &y& Elsevier]

We review our computational tools for high-throughput screening by fragment-based docking of large collections of small molecules. Applications to six different enzymes, four proteases, and two protein kinases, are presented. Remarkably, several low-micromolar inhibitors were discovered in each of the high-throughput docking campaigns. Probable reasons for the lack of submicromolar inhibitors are the tiny fraction of chemical space covered by the libraries of available compounds, as well as the approximations in the methods employed for scoring, and the use of a rigid conformation of the target protein. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents numerical computations of complex singular solutions to the 3D incompressible Euler equations. The Euler solutions found here consist of a complex valued velocity field that contains all positive wavenumbers; satisfies the usual Euler equations but with complex initial data. The real valued velocity (where ) is an approximate singular solution to the Euler equations under Moore’s approximation. The method for computing singular solutions is an extension of that in Caflisch (1993)  for axisymmetric flow with swirl, but with several improvements that prevent the extreme magnification of round-off error which affected previous computations. This enables the first clean analysis of the singular surface in three-dimensional complex space. We find singularities in the velocity field of the form for near 3/2 and , where denotes the singularity surface. The logarithmic singular surface is related to the double exponential growth of vorticity observed in recent numerical simulations. [Copyright &y& Elsevier]

It is difficult to investigate folding kinetics by conventional atomistic simulations of proteins. The replica exchange molecular dynamics (REMD) simulation technique enhances conformational sampling at the expenses of reduced kinetic information, which in REMD is directly available only for very short time scales. Here, we propose a procedure for obtaining kinetic data from REMD by making use of the equilibrium transitions network (ETN) sampled at the temperature of interest. This information is supplemented by mean folding times extracted from ETNs at higher REMD temperatures and scaled according to the Arrhenius equation. The procedure is applied to a three-stranded antiparallel β-sheet peptide which has a very heterogeneous denatured state with a broad entropic basin and several enthalpic traps. Despite the complexity of the system and the REMD exchange time of only 0.1 ns, the procedure is able to estimate folding times (ranging from about 0.1 μs at the melting temperature of 330 K to about 8 μs at 286 K) as well as transition times from individual non-native basins to the native state. [ABSTRACT FROM AUTHOR]