High‐Throughput Kinetic Analysis for Target‐Directed Covalent Ligand Discovery

Cysteine‐reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high‐quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan‐reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine‐reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2‐selective allosteric (type IV) kinase inhibitor whose novel mode‐of‐action could be exploited therapeutically.     

Isotope Abundance Ratios of Sr In Wine Provenance Determinations,in A Tree-Root Activity Study,and Of Pb in A Pollution Study on Tree-Rings

Abstract

In this contribution, the various and fundamentally different uses and applications of isotope signatures (of both heavy and light elements) are discussed. Examples are given for the successful use of ⁸⁷Sr/⁸⁶Sr in uncovering fraud in wine trade. Also, in an experiment related to “Waldsterben”, ⁸⁷Sr/⁸⁶Sr analyses reveal rather unexpected responses of spruces and maple-trees to mechanical damage of their roots. In another study, from ²⁰⁶Pb/²⁰⁷Pb (and ²⁰⁸Pb/²⁰⁷Pb) analyses of tree growth-rings it is demonstrated that they do not accurately record lead burdens in the environment. This is contrary to current views on the subject of tree-rings as reliable banks of past heavy metal pollutions of the biosphere. Furthermore, new perspectives of applications of isotopes in biological tissues, including those of cosmogenic and nucleogenic origin will be shortly outlined.     

Existence and Homogenisation of Travelling Waves Bifurcating from Resonances of Reaction–Diffusion Equations in Periodic Media

The existence of travelling wave type solutions is studied for a scalar reaction diffusion equation in \(\mathbb {R}^2\) with a nonlinearity which depends periodically on the spatial variable. We treat the coefficient of the linear term as a parameter and we formulate the problem as an infinite spatial dynamical system. Using a centre manifold reduction we obtain a finite dimensional dynamical system on the centre manifold with fully degenerate linear part. By phase space analysis and Conley index methods we find conditions on the parameter and nonlinearity for the existence of travelling wave type solutions with particular wave speeds. The analysis provides an approach to the homogenisation problem as the period of the periodic dependence in the nonlinearity tends to zero.     

Exponential averaging for Hamiltonian evolution equations

We derive estimates on the magnitude of non-adiabatic interaction between a Hamiltonian partial differential equation and a high-frequency nonlinear oscillator. Assuming spatial analyticity of the initial conditions, we show that the dynamics can be transformed to the uncoupled dynamics of an infinite-dimensional Hamiltonian system and an anharmonic oscillator, up to coupling terms which are exponentially small in a certain power of the frequency of the oscillator. The result is derived from an abstract averaging theorem for infinite-dimensional analytic evolution equations in Gevrey spaces. Refining upon a similar result by Neishtadt for analytic ordinary differential equations, the temporal estimate crucially depends on the spatial regularity of the initial condition. The result shows to what extent the strong resonances between rapid forcing and highly oscillatory spatial modes can be suppressed by the choice of sufficiently smooth initial data. An application is provided by a system of nonlinear Schrödinger equations, coupled to a rapidly forcing single mode, representing small-scale oscillations. We provide an example showing that the estimates for partial differential equations we derive here are necessarily different from those in the context of ordinary differential equations.

     

Time course of speech changes in response to unanticipated short-term changes in hearing state

The timing of changes in parameters of speech production was investigated in six cochlear implant users by switching their implant microphones off and on a number of times in a single experimental session. The subjects repeated four short, two-word utterances, /dV1n#SV2d/ (S = /s/ or /S/), in quasi-random order. The changes between hearing and nonhearing states were introduced by a voice-activated switch at V1 onset. "Postural" measures were made of vowel sound pressure level (SPL), duration, F0; contrast measures were made of vowel separation (distance between pair members in the formant plane) and sibilant separation (difference in spectral means). Changes in parameter values were averaged over multiple utterances, lined up with respect to the switch. No matter whether prosthetic hearing was blocked or restored, contrast measures for vowels and sibilants did not change systematically. Some changes in duration, SPL and F0 were observed during the vowel within which hearing state was changed, V1, as well as during V2 and subsequent utterance repetitions. Thus, sound segment contrasts appear to be controlled differently from the postural parameters of speaking rate and average SPL and F0. These findings are interpreted in terms of the function of hypothesized feedback and feedforward mechanisms for speech motor control.     

Maximal growth rate at the Rosensweig instability: theory,experiment, and numerics

We investigate the growth of a pattern of liquid crests emerging in a layer of magnetic liquid when subjected to a magnetic field oriented normally to the fluid surface. After a step like increase of the magnetic field, the temporal evolution of the pattern amplitude is measured by means of a Hall-sensor array. The extracted growth rate is compared with predictions from linear stability analysis by taking into account the nonlinear magnetization curve M (H). The remaining discrepancy can be resolved by numerical calculations via the finite element method. By starting with a finite surface perturbation it can reproduce the temporal evolution of the pattern amplitude and the growth rate. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Fully Coupled Fluid‐Structure Interaction using Weak Coupling

We consider the procedure of computing the response of a coupled fluid‐structure interaction problem. Often we have existing software to solve each subproblem separately, and want to couple both. This setting seems to allow only the so‐called weak coupling, which is not sufficient for some problems. We show how to solve the so‐called strong coupling – a totally implicit formulation – by using only the solvers for the subproblems.     

TacoxDNA: A user-friendly web server for simulations of complex DNA structures,from single strands to origami

Simulations of nucleic acids at different levels of structural details are increasingly used to complement and interpret experiments in different fields, from biophysics to medicine and materials science. However, the various structural models currently available for DNA and RNA and their accompanying suites of computational tools can be very rarely used in a synergistic fashion. The tacoxDNA webserver and standalone software package presented here are a step toward a long-sought interoperability of nucleic acids models. The webserver offers a simple interface for converting various common input formats of DNA structures and setting up molecular dynamics (MD) simulations. Users can, for instance, design DNA rings with different topologies, such as knots, with and without supercoiling, by simply providing an XYZ coordinate file of the DNA centre-line. More complex DNA geometries, as designable in the cadnano, CanDo and Tiamat tools, can also be converted to all-atom or oxDNA representations, which can then be used to run MD simulations. Though the latter are currently geared toward the native and LAMMPS oxDNA representations, the open-source package is designed to be further expandable. TacoxDNA is available at http://tacoxdna.sissa.it . © 2019 Wiley Periodicals, Inc.     

Titanium-catalyzed vinylic and allylic cf bond activation-scope, limitations and mechanistic insight

The hydrodefluorination (HDF) of fluoroalkenes in the presence of a variety of titanium catalysts was studied with respect to scope, selectivity, and mechanism. Optimization revealed that the catalyst requires low steric bulk and high electron density; secondary silanes serve as the preferred hydride source. A broad range of substrates yield partially fluorinated alkenes, such as previously unknown (Z)-1,2-(difluorovinyl)ferrocene. Mechanistic studies indicate a titanium(III) hydride as the active species, which forms a titanium(III) fluoride by H/F exchange with the substrate. The HDF step can follow both an insertion/elimination and a σ-bond metathesis mechanism; the E/Z selectivity is controlled by the substrate. The catalysts' ineffieciency towards fluoroallenes was rationalized by studying their reactivity towards Group?6 hydride complexes.