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A novel mixed quantum–classical approach to simulating nonadiabatic dynamics of molecules at metal surfaces is presented. The method combines the numerically exact hierarchical equations of motion approach for the quantum electronic degrees of freedom with Langevin dynamics for the classical degrees of freedom, namely, low-frequency vibrational modes within the molecule. The approach extends previous mixed quantum–classical methods based on Langevin equations to models containing strong electron–electron or quantum electronic–vibrational interactions, while maintaining a nonperturbative and non-Markovian treatment of the molecule–metal coupling. To demonstrate the approach, nonequilibrium transport observables are calculated for a molecular nanojunction containing strong interactions. [ABSTRACT FROM AUTHOR]

Protein dynamics have been investigated on a wide range of time scales. Nano‐ and picosecond dynamics have been assigned to local fluctuations, while slower dynamics have been attributed to larger conformational changes. However, it is largely unknown how fast (local) fluctuations can lead to slow global (allosteric) changes. Here, fast molecule‐spanning dynamics on the 100 to 200 ns time scale in the heat shock protein 90 (Hsp90) are shown. Global real‐space movements are assigned to dynamic modes on this time scale, which is possible by a combination of single‐molecule fluorescence, quasi‐elastic neutron scattering and all‐atom molecular dynamics (MD) simulations. The time scale of these dynamic modes depends on the conformational state of the Hsp90 dimer. In addition, the dynamic modes are affected to various degrees by Sba1, a co‐chaperone of Hsp90, depending on the location within Hsp90, which is in very good agreement with MD simulations. Altogether, this data is best described by fast molecule‐spanning dynamics, which precede larger conformational changes in Hsp90 and might be the molecular basis for allostery. This integrative approach provides comprehensive insights into molecule‐spanning dynamics on the nanosecond time scale for a multi‐domain protein. [ABSTRACT FROM AUTHOR]

Principal component analysis (PCA) represents a standard approach to identify collective variables {xi} = x, which can be used to construct the free energy landscape ΔG(x) of a molecular system. While PCA is routinely applied to equilibrium molecular dynamics (MD) simulations, it is less obvious as to how to extend the approach to nonequilibrium simulation techniques. This includes, e.g., the definition of the statistical averages employed in PCA as well as the relation between the equilibrium free energy landscape ΔG(x) and the energy landscapes Δ G (x) obtained from nonequilibrium MD. As an example for a nonequilibrium method, "targeted MD" is considered which employs a moving distance constraint to enforce rare transitions along some biasing coordinate s. The introduced bias can be described by a weighting function P(s), which provides a direct relation between equilibrium and nonequilibrium data, and thus establishes a well-defined way to perform PCA on nonequilibrium data. While the resulting distribution P (x) and energy Δ G ∝ ln P will not reflect the equilibrium state of the system, the nonequilibrium energy landscape Δ G (x) may directly reveal the molecular reaction mechanism. Applied to targeted MD simulations of the unfolding of decaalanine, for example, a PCA performed on backbone dihedral angles is shown to discriminate several unfolding pathways. Although the formulation is in principle exact, its practical use depends critically on the choice of the biasing coordinate s, which should account for a naturally occurring motion between two well-defined end-states of the system. [ABSTRACT FROM AUTHOR]

Image partitioning, or segmentation without semantics, is the task of decomposing an image into distinct segments, or equivalently to detect closed contours. Most prior work either requires seeds, one per segment; or a threshold; or formulates the task as multicut / correlation clustering, an NP-hard problem. Here, we propose an efficient algorithm for graph partitioning, the “Mutex Watershed”. Unlike seeded watershed, the algorithm can accommodate not only attractive but also repulsive cues, allowing it to find a previously unspecified number of segments without the need for explicit seeds or a tunable threshold. We also prove that this simple algorithm solves to global optimality an objective function that is intimately related to the multicut / correlation clustering integer linear programming formulation. The algorithm is deterministic, very simple to implement, and has empirically linearithmic complexity. When presented with short-range attractive and long-range repulsive cues from a deep neural network, the Mutex Watershed gives the best results currently known for the competitive ISBI 2012 EM segmentation benchmark. [ABSTRACT FROM AUTHOR]

Visualizing, tracking and reconstructing cell lineages in developing embryos has been an ongoing effort for well over a century. Recent advances in light microscopy, labelling strategies and computational methods to analyse complex image datasets have enabled detailed investigations into the fates of cells. Combined with powerful new advances in genomics and single-cell transcriptomics, the field of developmental biology is able to describe the formation of the embryo like never before. In this Review, we discuss some of the different strategies and applications to lineage tracing in live-imaging data and outline software methodologies that can be applied to various cell-tracking challenges. [ABSTRACT FROM AUTHOR]

Proton conduction along protein-bound "water wires" is an essential feature in membrane proteins. Here, we analyze in detail a transient water wire, which conducts protons via a hydrophobic barrier within a membrane protein to create a proton gradient. It is formed only for a millisecond out of three water molecules distributed at inactive positions in a polar environment in the ground state. The movement into a hydrophobic environment causes characteristic shifts of the water bands reflecting their different chemical properties. These band shifts are identified by time-resolved Fourier Transform Infrared difference spectroscopy and analyzed by biomolecular Quantum Mechanical/Molecular Mechanical simulations. A non-hydrogen bonded ("dangling") O-H stretching vibration band and a broad continuum absorbance caused by a combined vibration along the water wire are identified as characteristic marker bands of such water wires in a hydrophobic environment. The results provide a basic understanding of water wires in hydrophobic environments. [ABSTRACT FROM AUTHOR]

Vibrational energy transfer (VET) is essential for protein function. It is responsible for efficient energy dissipation in reaction sites, and has been linked to pathways of allosteric communication. While it is understood that VET occurs via backbone as well as via non-covalent contacts, little is known about the competition of these two transport channels, which determines the VET pathways. To tackle this problem, we equipped the β-hairpin fold of a tryptophan zipper with pairs of non-canonical amino acids, one serving as a VET injector and one as a VET sensor in a femtosecond pump probe experiment. Accompanying extensive non-equilibrium molecular dynamics simulations combined with a master equation analysis unravel the VET pathways. Our joint experimental/computational endeavor reveals the efficiency of backbone vs. contact transport, showing that even if cutting short backbone stretches of only 3 to 4 amino acids in a protein, hydrogen bonds are the dominant VET pathway. Vibrational energy transfer (VET) is essential for protein function as it is responsible for efficient energy dissipation in reaction sites and is linked to pathways of allosteric communication. Here authors equipped a tryptophan zipper with a VET injector and a VET sensor for femtosecond pump probe experiments to map the VET. [ABSTRACT FROM AUTHOR]

When developing coarse‐grained models of complex processes out of equilibrium, one encounters the non‐stationary generalized Langevin equation. The most important feature of this equation is the presence of a non‐stationary memory kernel. Here, a method is presented to infer this memory kernel from MD simulation data in non‐equilibrium processes. The method provides an improvement of a previously published numerical scheme, the applicability of which is limited by a truncation problem. As an illustration, the method is applied to ion dissociation of NaCl in water, for which non‐trivial dampened oscillations are observed in the memory kernel. [ABSTRACT FROM AUTHOR]

Emergence of the novel pathogenic coronavirus SARS‐CoV‐2 and its rapid pandemic spread presents challenges that demand immediate attention. Here, we describe the development of a semi‐quantitative high‐content microscopy‐based assay for detection of three major classes (IgG, IgA, and IgM) of SARS‐CoV‐2 specific antibodies in human samples. The possibility to detect antibodies against the entire viral proteome together with a robust semi‐automated image analysis workflow resulted in specific, sensitive and unbiased assay that complements the portfolio of SARS‐CoV‐2 serological assays. Sensitive, specific and quantitative serological assays are urgently needed for a better understanding of humoral immune response against the virus as a basis for developing public health strategies to control viral spread. The procedure described here has been used for clinical studies and provides a general framework for the application of quantitative high‐throughput microscopy to rapidly develop serological assays for emerging virus infections. [ABSTRACT FROM AUTHOR]

While allostery is of paramount importance for protein regulation, the underlying dynamical process of ligand (un)binding at one site, resulting time evolution of the protein structure, and change of the binding affinity at a remote site are not well understood. Here the ligand-induced conformational transition in a widely studied model system of allostery, the PDZ2 domain, is investigated by transient infrared spectroscopy accompanied by molecular dynamics simulations. To this end, an azobenzene derived photoswitch is linked to a peptide ligand in a way that its binding affinity to the PDZ2 domain changes upon switching, thus initiating an allosteric transition in the PDZ2 domain protein. The subsequent response of the protein, covering four decades of time, ranging from ∼1 ns to ∼10 µs, can be rationalized by a remodeling of its rugged free-energy landscape, with very subtle shifts in the populations of a small number of structurally well-defined states. It is proposed that structurally and dynamically driven allostery, often discussed as limiting scenarios of allosteric communication, actually go hand-in-hand, allowing the protein to adapt its free-energy landscape to incoming signals. [ABSTRACT FROM AUTHOR]

Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of molecular processes under consideration. Subsequently, we use these fields to perform temperature-boosted Langevin simulations which account for the desired kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride, trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we reproduce rates from molecular dynamics simulation and experiments within a factor of 2–20, and dissociation constants within a factor of 1–4. Analysis of friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems. Protein-ligand unbinding processes are out of reach for atomistic simulations due to time-scale involved. Here the authors demonstrate an approach relying on dissipation-corrected targeted molecular dynamics that enables to provide binding and unbinding rates with a speed-up of several orders of magnitude. [ABSTRACT FROM AUTHOR]

We performed an analysis of possible mechanisms of ligand recognition in the human nose. The analysis is based on in vivo odor threshold determination and in vitro Ca2+ imaging assays with a C/Si/Ge/Sn switch strategy applied to the compounds Lilial and Bourgeonal, to differentiate between different molecular mechanisms of odorant detection. Our results suggest that odorant detection under threshold conditions is mainly based on the molecular shape, i.e. the van der Waals surface, and electrostatics of the odorants. Furthermore, we show that a single olfactory receptor type is responsible for odor detection of Bourgeonal at the threshold level in humans in vivo. Carrying out a QM analysis of vibrational energies contained in the odorants, there is no evidence for a vibration-based recognition. [ABSTRACT FROM AUTHOR]

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A high-alloy austenitic CrMnNi steel was deformed at temperatures between 213 K and 473 K (−60 °C and 200 °C) and the resulting microstructures were investigated. At low temperatures, the deformation was mainly accompanied by the direct martensitic transformation of γ-austenite to α′-martensite (fcc → bcc), whereas at ambient temperatures, the transformation via ε-martensite (fcc → hcp → bcc) was observed in deformation bands. Deformation twinning of the austenite became the dominant deformation mechanism at 373 K (100 °C), whereas the conventional dislocation glide represented the prevailing deformation mode at 473 K (200 °C). The change of the deformation mechanisms was attributed to the temperature dependence of both the driving force of the martensitic γ → α′ transformation and the stacking fault energy of the austenite. The continuous transition between the ε-martensite formation and the twinning could be explained by different stacking fault arrangements on every second and on each successive {111} austenite lattice plane, respectively, when the stacking fault energy increased. A continuous transition between the transformation-induced plasticity effect and the twinning-induced plasticity effect was observed with increasing deformation temperature. Whereas the formation of α′-martensite was mainly responsible for increased work hardening, the stacking fault configurations forming ε-martensite and twins induced additional elongation during tensile testing. [ABSTRACT FROM AUTHOR]

In this study, the formation of deformation bands during plastic deformation in austenite is analysed. The movement of (partial) dislocations on neighboring lattice planes formed pronounced deformation bands, which were identified as ϵ-martensite if the stacking faults are predominantly aligned on every second {111} lattice plane. In these deformation bands, α′-martensite nuclei are formed, severely fragmenting the mean free path of dislocations. The strain hardening is found to depend directly on the nucleation rate of α′-martensite. The α′-martensite nuclei represented effective barriers for (partial) dislocation movement in the deformation bands. On the basis of three different grain sizes, the strain-hardening capability of the martensitic γ → ϵ → α′ phase transformation is analysed. Although the triggering stress for nucleation of α′-martensite is influenced by grain size, the absolute value of the strain hardening due to α′-martensite formation is the same. This is related to the fact that the continuous fragmentation of the dislocation mean free path is in the same order of magnitude for all grain sizes. Using a basic approach that treated the continuous reduction of the dislocation mean free path as a Hall-Petch-like effect, comparable with strain hardening in TWIP steels, the contribution of the effect to the increasing strength in austenitic TRIP steels is estimated. [ABSTRACT FROM AUTHOR]

Histamine is a neurotransmitter involved in a number of physiological and neuronal functions. In mammals, such as humans, and rodents, the histaminergic neurons found in the tuberomamillary nucleus project widely throughout the central nervous system. Histamine acts as positive modulator of GABAA receptors (GABAARs) and, in high concentrations (10 mM), as negative modulator of the strychnine-sensitive glycine receptor. However, the exact molecular mechanisms by which histamine acts on GABAARs are unknown. In our study, we aimed to identify amino acids potentially involved in the modulatory effect of histamine on GABAARs. We expressed GABAARs with 12 different point mutations in Xenopus laevis oocytes and characterized the effect of histamine on GABA-induced currents using the two-electrode voltage clamp technique. Our data demonstrate that the amino acid residues β2(N265) and β2(M286), which are important for modulation by propofol, are not involved in the action of histamine. However, we found that histamine modulation is dependent on the amino acid residues α1(R120), β2(Y157), β2(D163), β3(V175), and β3(Q185). We showed that the amino acid residues β2(Y157) and β3(Q185) mediate the positive modulatory effect of histamine on GABA-induced currents, whereas α1(R120) and β2(D163) form a potential histamine interaction site in GABAARs. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) form the largest family of membrane receptors in the human genome. Advances in membrane protein crystallization so far resulted in the determination of 24 receptors available as high-resolution atomic structures. We performed the first phylogenetic analysis of GPCRs based on the available set of GPCR structures. We present a new phylogenetic tree of known human rhodopsin-like GPCR sequences based on this structure set. We can distinguish the three separate classes of small-ligand binding GPCRs, peptide binding GPCRs, and olfactory receptors. Analyzing different structural subdomains, we found that small molecule binding receptors most likely have evolved from peptide receptor precursors, with a rhodopsin/S1PR1 ancestor, most likely an ancestral opsin, forming the link between both classes. A light-activated receptor therefore seems to be the origin of the small molecule hormone receptors of the central nervous system. We find hints for a common evolutionary path of both ligand binding site and central sodium/water binding site. Surprisingly, opioid receptors exhibit both a binding cavity and a central sodium/water binding site similar to the one of biogenic amine receptors instead of peptide receptors, making them seemingly prone to bind small molecule ligands, e.g. opiates. Our results give new insights into the relationship and the pharmacological properties of rhodopsin-like GPCRs. [ABSTRACT FROM AUTHOR]

The silicon/germanium/tin analogues of the lily-of-the-valley odorants lilial (rac-1a), compounds rac-1b, rac-1c, and rac-1d, and bourgeonal (2a), compounds 2b, 2c, and 2d, were synthesized and characterized for their olfactory properties, including GC-olfactometry studies. Compounds rac-1a-c and 2a-c possess a typical lily-of-the-valley odor, whereas the stanna-analogues rac-1d and 2d, despite some floral aspects, clearly no longer belong to the lily-of-the-valley family. In both series of the carbon/silicon/germanium/tin analogues studied, the lily-of-the-valley odor decreases in the order of carbon2+ imaging. Bourgeonal (2a) showed the highest activation potency, whereas lilial (rac-1a) and sila-bourgeonal (2b) exhibited lower activation potencies. Sila-lilial (rac-1b), germa-lilial (rac-1c), and stanna-lilial (rac-1d), as well as germabourgeonal (2c) and stanna-bourgeonal (2d), did not activate heterologously expressed hOR17-4 at the concentrations tested. The carbon/silicon/germanium/tin switch strategy thus showed that the stanna-derivatives clearly exceeded the molecular dimensions of the odorant receptor(s) responsible for the recognition of lily-of-the-valley odorants, although the receptor affinity was already affected with the sila- and germaanalogues. These data could later be used in the qualitative and quantitative evaluation of computational receptor models. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (NPs) embedded in lithium niobate were fabricated via ion beam synthesis and are suitable for various plasmonic applications, e.g. enhancement of optical nonlinear effects. After room temperature silver implantation, annealing in the temperature range of 400–600 °C was performed in order to recrystallize the damaged lithium niobate surface layer. The shape of the silver NPs, their optical properties as well as the structural properties of their surrounding matrix have been analyzed for various annealing steps. TEM investigations show that annealing at 400 °C does not lead to recrystallization of the damaged lithium niobate. A recrystallization occurs upon increasing the annealing temperature to 500 or 600 °C, but simultaneously a second phase consisting of lithium triniobate forms. This is additionally supported by XRD measurements. By utilizing dynamic annealing, i.e. implanting silver at elevated temperatures of 400 °C, it is shown that the LiNbO3 matrix stays single crystalline during ion implantation and no LiNb3O8 is formed. This is additionally verified by comparing the positions of the surface plasmon resonances with calculations based on Mie’s scattering theory. [ABSTRACT FROM AUTHOR]

In the present work the influence of phosphor on the flowability, the effect on the infiltration of ZrO2 open foam ceramics and the martensite formation as well as the resulting mechanical properties of high alloyed CrMnNi as-cast steels is studied. Additionally, the effect of phosphor on surface tension is investigated. The study is performed using thermodynamic calculations, static tensile tests, notch-bar impact tests, optical light microscopy, scanning electron microscopy, energy dispersive X-ray analysis, electron backscatter diffraction, and the magnetic scale for the detection of ferromagnetic phase fractions. Maximum bubble pressure method is used to measure the surface tension of the liquid steel. The martensite phase fraction is not significantly influenced with increasing phosphor content. The flowability and the quality of the infiltration of open foam ceramics are improved with increasing phosphor contents. The investigated specimens show an increasing yield and an ultimate tensile strength with higher phosphor contents. The uniform and the fracture elongation as well as the notch impact resistance remain at high values. Moreover, an increase in phosphor content did not significantly change the surface tension of the investigated CrMnNi alloys. [ABSTRACT FROM AUTHOR]

The effect of the manganese content (0-11%) on the transformation temperatures, the mechanical properties and microstructure development of five highly alloyed 14Cr- XMn-6Ni cast stainless steels with 0.1% nitrogen was studied. The examinations reveal that the Ms, As, and Af temperatures decrease with increasing manganese contents. As a result of low austenite stability, room temperature austenitic-martensitic as-cast microstructure was formed at manganese contents between 0 and 3%. At manganese levels of 6% and higher a fully austenitic as-cast microstructure was observed. The temperature dependence of tensile properties in alloys was explained on the basis of varying contributions to the strength and ductility of deformation-induced martensite and twin formation mechanisms. All investigated cast steel alloys achieved yield strengths above 200 MPa at room temperature. The increased proof stress is caused by solid solution strengthening due to the addition of nitrogen and manganese as well as phase hardening by as-quenched martensite. [ABSTRACT FROM AUTHOR]

Microstructure defects control the TRIP effect and/or the TWIP effect and contribute significantly to the absorption of deformation energy in plastically deformed austenitic CrMnNi steels. In this study, the propagation and interaction of dislocations, stacking faults and twins connected with the formation of Lomer-Cottrell locks, stacking fault tetrahedra, dislocation clusters, deformation bands, microtwins with high-energy incoherent twin boundaries and the nucleation of α′- martensite in the areas of the high local lattice strain due to the fluctuation of the stacking fault density and the lattice shearing, were analysed in the CrMnNi TRIP steel after different deformation extents via transmission electron microscope with high resolution and via scanning electron microscope. [ABSTRACT FROM AUTHOR]

For the modeling of the mechanical behavior of a two phase alloy with the rule of mixture (RM), the flow stress of both phases is needed. In order to obtain these information for the α′-martensite in high alloyed TRIP-steels, compression tests at cryogenic temperatures were performed to create a fully deformation-induced martensitic microstructure. This martensitic material condition was subsequently tested under compressive loading at −60, 20, and 100°C and at strain rates of 10−3, 100, and 103 s−1 to determine the mechanical properties. The α′-martensite possesses high strength and surprisingly good ductility up to 60% of compressive strain. Using the flow stress behavior of the α′-martensite and that of the stable austenitic steel AISI 316L, the flow stress behavior of the high alloyed CrMnNi TRIP-steel is modeled successfully using a special RM proposed by Narutani et al. [ABSTRACT FROM AUTHOR]

The mechanical behavior and microstructure evolution during deformation of novel austenitic Cr-Mn-Ni as-cast steels with varied Ni content were investigated at various temperatures using static tensile tests, optical microscopy, and the magnetic scale for the detection of ferromagnetic phase fraction. To summarize all knowledge about the deformation-induced processes, the STT and DTT diagrams were developed for Cr-Mn-Ni steels. The diagrams illustrate the different deformation mechanisms depending on temperature and tension load, and quantify the elongation of the deformation mechanisms. The deformation-induced ε- and α' martensite formation and twinning - the TRIP and TWIP effects - occur in the Cr-Mn-Ni steels depending on the chemical composition and temperature. The differences of deformation-induced processes depend on thermodynamics and are confirmed by thermodynamic calculations. The nucleation threshold of γ → α′ transformation was determined for the investigated Cr-Mn-Ni steels. [ABSTRACT FROM AUTHOR]

Abstract: Most of the currently available G protein-coupled receptor (GPCR) crystal structures represent an inactive receptor state, which has been considered to be suitable only for the discovery of antagonists and inverse agonists in structure-based computational ligand screening. Using the β2-adrenergic receptor (B2AR) as a model system, we show that a dynamic homology model based on an “active” opsin structure without further incorporation of experimental data performs better than the crystal structure of the inactive B2AR in finding agonists over antagonists/inverse agonists. Such “active-like state” dynamic homology models can therefore be used to selectively identify GPCR agonists in in silico ligand libraries. [Copyright &y& Elsevier]

A material model is presented that accounts for strain rate dependent inelastic deformation and strain-induced phase transformation in TRIP-steels. Modifications for the kinetics equations of the strain-induced phase transformation, introduced by Stringfellow, are proposed to overcome a drawback of Stringfellow's model. A parameter identification strategy that relies on Gauss-Markov estimates is used to determine the model parameters from experimental data of a recently developed cast TRIP-steel. Good agreement is observed between experimental results of the compression test and the corresponding finite element simulation employing the proposed model. This forms the basis for future applications of the material model in the design of composites and structures. [ABSTRACT FROM AUTHOR]

High-resolution protein ground-state structures of proton pumps and channels have revealed internal protein-bound water molecules. Their possible active involvement in protein function has recently come into focus. An illustration of the formation of a protonated protein-bound water cluster that is actively involved in proton transfer was described for the membrane protein bacteriorhodopsin (bR) [Garczarek F, Gerwert K (2006) Nature 439:109-112]. Here we show through a combination of time-resolved FTIR spectroscopy and molecular dynamics simulations that three protein-bound water molecules are rearranged by a protein conformational change that resulted in a transient Grotthuss-type proton-transfer chain extending through a hydrophobic protein region of bR. This transient linear water chain facilitates proton transfer at an intermediate conformation only, thereby directing proton transfer within the protein. The rearrangement of protein-bound water molecules that we describe, from inactive positions in the ground state to an active chain in an intermediate state, appears to be energetically favored relative to transient incorporation of water molecules from the bulk. Our discovery provides insight into proton-transfer mechanisms through hydrophobic core regions of ubiquitous membrane spanning proteins such as G-protein coupled receptors or cytochrome C oxidases. [ABSTRACT FROM AUTHOR]

Accessory β-subunits of the KCNE gene family modulate the function of various cation channel α-subunits by the formation of heteromultimers. Among the most dramatic changes of biophysical properties of a voltage-gated channel by KCNEs are the effects of KCNE1 on KCNQ1 channels. KCNQ1 and KCNE1 are believed to form nativeIKs channels. Here, we characterize molecular determinants of KCNE1 interaction with KCNQ1 channels by scanning mutagenesis, double mutant cycle analysis, and molecular dynamics simulations. Our findings suggest that KCNE1 binds to the outer face of the KCNQ1 channel pore domain, modifies interactions between voltage sensor, S4-S5 linker and the pore domain, leading to structural modifications of the selectivity filter and voltage sensor domain. Molecular dynamics simulations suggest a stable interaction of the KCNE1 transmembrane α-helix with the pore domain S5/S6 and part of the voltage sensor domain S4 of KCNQ1 in a putative pre-open channel state. Formation of this state may induce slow activation gating, the pivotal characteristic of native cardiac IKs channels. This new KCNQ1-KCNE1 model may become useful for dynamic modeling of disease-associated mutant IKs channels. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The temperature dependence of the martensite formation and the mechanical properties of three high alloyed Cr-Mn-Ni as-cast steels with varying Ni contents were studied. The results showed that the M and M temperatures of the steels decrease with increasing nickel contents. Therefore the strain-induced martensite formation, the TRIP effect and the temperature anomaly of the elongations occurs at lower temperatures. The steel alloyed with 3% nickel shows a stress induced formation of martensite and a dynamic strain aging. Depending on the nickel content and the temperature a TWIP effect occurs additionally to the TRIP effect in the investigated steels. The study was performed by using static tensile tests, dilatometer tests, optical microscopy and the magnetic scale for the detection of ferromagnetic phase fractions. [ABSTRACT FROM AUTHOR]

Abstract: A computational approach to predict structures of rhodopsin-like G protein-coupled receptors (GPCRs) is presented and evaluated by comparison to the X-ray structural models. By combining sequence alignment, the rhodopsin crystal structure, and point mutation data on the β2 adrenoreceptor (b2ar), we predict a (−)-epinephrine-bound computational model of the β2 adrenoreceptor. The model is evaluated by molecular dynamics simulations and by comparison with the recent X-ray structures of b2ar. The overall correspondence between the predicted and the X-ray structural model is high. Especially the prediction of the ligand binding site is accurate. This shows that the proposed dynamic homology modelling approach can be used to create reasonable models for the understanding of structure and dynamics of other rhodopsin-like GPCRs. [Copyright &y& Elsevier]

A unique RNA–RNA interaction occurs between uncharged tRNA and the untranslated mRNA leader region of bacterial T box genes. The interaction results in activation of a transcriptional antitermination molecular switch (riboswitch) by stabilizing an antiterminator RNA element and precluding formation of a competing transcriptional terminator RNA element. The stabilization requires the base pairing of cognate tRNA acceptor end nucleotides with the antiterminator. To develop an appropriate model system for detailed structural studies and to screen for small molecule disruption of this important RNA–RNA interaction, steady-state fluorescence measurements of antiterminator model RNAs were used to determine the dissociation constant for model tRNA binding. The antiterminator-binding affinity for the full, minihelix, microhelix, and tetramer tRNA models differed by orders of magnitude. In addition, not all of the tRNA models exhibited functionally relevant binding specificity. The results from these experiments highlight the importance of looking beyond the level of known base pairing interactions when designing functionally relevant models of riboswitch systems. [ABSTRACT FROM AUTHOR]

We report a gastrointestinal infection caused by Mucor indicus in a patient with severe head injuries. Monotherapy with high-dose liposomal amphotericin B successfully eradicated the mucormycosis. Nevertheless, subsequently a hemicolectomy was necessary due to recurrent bleeding from a deep ulcer. Mucor indicus is an uncommon fungal pathogen, typically found in starters used for food fermentation. Reviewing other reports on Mucor indicus infections, primary gastrointestinal manifestations seem to be typical and indicate an oral route of infection. [ABSTRACT FROM AUTHOR]