Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation

The force-dependent interaction between talin and vinculin plays a crucial role in the initiation and growth of focal adhesions. Here we use magnetic tweezers to characterise the mechano-sensitive compact N-terminal region of the talin rod, and show that the three helical bundles R1-R3 in this region unfold in three distinct steps consistent with the domains unfolding independently. Mechanical stretching of talin R1-R3 enhances its binding to vinculin and vinculin binding inhibits talin refolding after force is released. Mutations that stabilize R3 identify it as the initial mechano-sensing domain in talin, unfolding at ~5 pN, suggesting that 5 pN is the force threshold for vinculin binding and adhesion progression

Beyond time-homogeneity for continuous-time multistate Markov models

Multistate Markov models are a canonical parametric approach for data modeling of observed or latent stochastic processes supported on a finite state space. Continuous-time Markov processes describe data that are observed irregularly over time, as is often the case in longitudinal medical and biological data sets, for example. Assuming that a continuous-time Markov process is time-homogeneous, a closed-form likelihood function can be derived from the Kolmogorov forward equations -- a system of differential equations with a well-known matrix-exponential solution. Unfortunately, however, the forward equations do not admit an analytical solution for continuous-time, time-inhomogeneous Markov processes, and so researchers and practitioners often make the simplifying assumption that the process is piecewise time-homogeneous. In this paper, we provide intuitions and illustrations of the potential biases for parameter estimation that may ensue in the more realistic scenario that the piecewise-homogeneous assumption is violated, and we advocate for a solution for likelihood computation in a truly time-inhomogeneous fashion. Particular focus is afforded to the context of multistate Markov models that allow for state label misclassifications, which applies more broadly to hidden Markov models (HMMs), and Bayesian computations bypass the necessity for computationally demanding numerical gradient approximations for obtaining maximum likelihood estimates (MLEs)

THEORETICAL STUDIES OF BILIPROTEIN CHROMOPHORES AND RELATED BILE PIGMENTS BY MOLECULAR ORBITAL AND RAMACHANDRAN TYPE CALCULATIONS

Ramachandran calculations have been used to gain insight into steric hindrance in bile pigments related to biliprotein chromophores. The high optical activity of denatured phycocyanin, as compared to phycoerythrin, has been related to the asymmetric substitution at ring A, which shifts the equilibrium towards the P-helical form of the chromophore. Geometric effects on the electronic structures and transitions have then been studied by molecular orbital calculations for several conjugation systems including the chromophores of phycocyanin. phytochrome P,, cations, cation radicals and tautomeric forms. For these different chromophores some general trends can be deduced. For instance, for a given change in the gross shape (e.g. either unfolding of the molecule from a cyclic-helical to a fully extended geometry, or upon out-of-plane twists of the pyrrole ring A) of the molecules under study, the predicted absorption spectra all change in a simikar way. Nonetheless, there are characteristic distinctions between the different n-systems, both in the transition energies and the charge distribution, which can be related to their known differences in spectroscopic properties and their reactivity

Capturing Fleeting Intermediates in a Catalytic C-H Amination Reaction Cycle

We have applied an ambient ionization technique, desorption electrospray ionization MS, to identify transient reactive species of an archetypal C–H amination reaction catalyzed by a dirhodium tetracarboxylate complex. Using this analytical method, we have detected previously proposed short-lived reaction intermediates, including two nitrenoid complexes that differ in oxidation state. Our findings suggest that an Rh-nitrene oxidant can react with hydrocarbon substrates through a hydrogen atom abstraction pathway and raise the intriguing possibility that two catalytic C–H amination pathways may be operative in a typical bulk solution reaction. As highlighted by these results, desorption electrospray ionization MS should have broad applicability for the mechanistic study of catalytic processes

Differential Forms on Log Canonical Spaces

The present paper is concerned with differential forms on log canonical varieties. It is shown that any p-form defined on the smooth locus of a variety with canonical or klt singularities extends regularly to any resolution of singularities. In fact, a much more general theorem for log canonical pairs is established. The proof relies on vanishing theorems for log canonical varieties and on methods of the minimal model program. In addition, a theory of differential forms on dlt pairs is developed. It is shown that many of the fundamental theorems and techniques known for sheaves of logarithmic differentials on smooth varieties also hold in the dlt setting. Immediate applications include the existence of a pull-back map for reflexive differentials, generalisations of Bogomolov-Sommese type vanishing results, and a positive answer to the Lipman-Zariski conjecture for klt spaces.Comment: 72 pages, 6 figures. A shortened version of this paper has appeared in Publications math\'ematiques de l'IH\'ES. The final publication is available at http://www.springerlink.co

Formal verification of analog and mixed signal designs: A survey

Analog and mixed signal (AMS) designs are an important part of embedded systems that link digital designs to the analog world. Due to challenges associated with its verification process, AMS designs require a considerable portion of the total design cycle time. In contrast to digital designs, the verification of AMS systems is a challenging task that requires lots of expertise and deep understanding of their behavior. Researchers started lately studying the applicability of formal methods for the verification of AMS systems as a way to tackle the limitations of conventional verification methods like simulation. This paper surveys research activities in the formal verification of AMS designs as well as compares the different proposed approaches

Integrating Abstraction Techniques for Formal Verification of Analog Designs

The verification of analog designs is a challenging and exhaustive task that requires deep understanding of physical behaviours. In this paper, we propose a qualitative based predicate abstraction method for the verification of a class of non-linear analog circuits. In the proposed method, system equations are automatically extracted from a circuit diagram by means of a bond graph. Verification is applied based on combining techniques from constraint solving and computer algebra along with symbolic model checking. Our methodology has the advantage of avoiding exhaustive simulation normally encountered in the verification of analog designs. To this end, we have used Dymola, Hsolver, SMV and Mathematica to implement the verification flow. We illustrate the methodology on several analog examples including Colpitts and tunnel diode oscillators

The ATLAS3D project - XXV: Two-dimensional kinematic analysis of simulated galaxies and the cosmological origin of fast and slow rotators

We present a detailed two-dimensional stellar dynamical analysis of as ample of 44 cosmological hydrodynamical simulations of individual central galaxies with stellar masses of 2 x 1010Msun ∼≤ Mstar ∼≤ 6x 1011Msun. Kinematic maps of the stellar line-of-sight velocity, velocity dispersion, and higher-order Gauss-Hermite moments h3 and h4 are constructed for each central galaxy and for the most massive satellites. The amount of rotation is quantified using the λR-parameter. The velocity, velocity dispersion, h3, and h4 fields of the simulated galaxies show a diversity similar to observed kinematic maps of early-type galaxies in the ATLAS3D survey. This includes fast (regular), slow, and misaligned rotation, hot spheroids with embedded cold disk components as well as galaxies with counter-rotating cores or central depressions in the velocity dispersion. We link the present-day kinematic properties to the individual cosmological formation histories of the galaxies. In general, major galaxy mergers have a significant influence on the rotation properties resulting in both a spin-down as well as a spin-up of the merger remnant. Lower mass galaxies with significant in-situ formation of stars, or with additional gas-rich major mergers - resulting in a spin-up - in their formation history, form elongated fast rotators with a clear anti-correlation of h3 and v/σ. An additional formation path for fast rotators includes gas-poor major mergers leading to a spin-up of the remnants. This formation path does not result in anti-correlated h3 and v/σ. The galaxies most consistent with the rare class of non-rotating round early-type galaxies grow by gas-poor minor mergers alone. In general, more massive galaxies have less in-situ star formation since z ∼ 2, rotate slower and have older stellar populations. (shortened)PostprintPeer reviewe

Femorodistal venous bypass evaluated with intravascular ultrasound

Objective:To evaluate the feasibility of intravascular ultrasound imaging during femorodistal venous bypass procedures to assess qualitative and quantitative parameters of the greater saphenous vein and to detect potential causes for (re)stenosis and/or occlusion.Methods:Intravascular ultrasound data obtained from 15 patients were reviewed and compared with angiographic data.Results:Intravascular ultrasound enabled differentiation between normal and thickened vein wall. Venous side-branches could be located. Intact valves could be differentiated from valves disrupted by valve cutting. Patent anastomoses could be distinguished from anastomoses with some degree of obstruction. Intravascular ultrasound imaging of the inflow and outflow tracts revealed obstructive lesions, not evidenced angiographically. Quantitative analysis revealed that the median normal vein wall thickness (tunica intima and tunica media) was 0.25 mm (range 0.17–0.40 mm). The distinct vein wall thickening encountered in three patients measured 0.82, 0.95 and 1.06 mm, respectively, and was associated with narrowing in two patients. In five of 15 patients intravascular ultrasound findings altered surgical management.Conclusion:Intravascular ultrasound is able to assess qualitative and quantitative parameters of the venous bypass and has the potential to influence surgical management based on morphologic and quantitative data