Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N‐terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC‐helix and charged residues upstream of the NtA motif. Additionally, we show that the R‐spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure‐based mechanism for the auto‐transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization‐related drug resistance.     

Measurement of the production cross section for charmed baryons in proton–nucleus interactions at 70 GeV

The results of an analysis of data from the SERP-Е-184 experiment devoted to studying mechanisms of the production of charmed particles in proton–nucleus interactions at 70 GeV and their decays are presented. The data in question were obtained upon irradiating the SVD-2 active target consisting of carbon, silicon, and lead plates with a beam of 70-GeV protons. A detailed simulation on the basis of the FRITIOF7.02 and GEANT3.21 code packages made it possible to optimize event-selection criteria and to calculate the detection efficiency for Λ_c⁺ baryons. After selecting a signal from the threebody decay of a Λ_c⁺ baryon, the inclusive cross section for its production at near-threshold energies, its lifetime, and the parameter of the A dependence of the cross section were found. The Λ_c⁺ -baryon yields are tabulated along with data from other experiments and theoretical predictions.     

Potts model,Dirac propagator,and conformational statistics of semiflexible polymers

A new discretized version of the Dirac propagator ind space and one time dimensions is obtained with the help of the 2d-state, one-dimensional Potts model. The Euclidean version of this propagator describes all conformational properties of semiflexible polymers. It also describes all properties of fully directed self-avoiding walks. The case of semiflexible copolymers composed of a random sequence of fully flexible and semirigid monomer units is also considered. As a by-product, some new results for disordered one-dimensional Ising and Potts models are obtained. In the case of the Potts model the nontrivial extension of the results to higher dimensions is discussed briefly.     

Towards physically motivated proofs of the Poincaré and geometrization conjectures

Although the Poincaré and the geometrization conjectures were recently proved by Perelman, the proof relies heavily on properties of the Ricci flow previously investigated in great detail by Hamilton. Physical realization of such a flow can be found, for instance, in the work by Friedan [D. Friedan, Nonlinear models in 2+ε$2+\epsilon$ dimensions, Ann. Phys. 163 (1985) 318–419]. In his work the renormalization group flow for a nonlinear sigma model in 2+ε$2+\epsilon$ dimensions was obtained and studied. For ε=0$\epsilon =0$, by approximating the β$\beta$-function for such a flow by the lowest order terms in the sigma model coupling constant, the equations for Ricci flow are obtained. In view of such an approximation, the existence of this type of flow in Nature is questionable. In this work, we find totally independent justification for the existence of Ricci flows in Nature. This is achieved by developing a new formalism extending the results of two-dimensional conformal field theories (CFT’s) to three and higher dimensions. Equations describing critical dynamics of these CFT’s are examples of the Yamabe and Ricci flows realizable in Nature. Although in the original works by Perelman some physically motivated arguments can be found, their role in his proof remain rather obscure. In this paper, steps are made toward making these arguments more explicit, thus creating an opportunity for developing alternative, more physically motivated, proofs of the Poincaré and geometrization conjectures.     

Ligand substitution in a transition metal complex: a new type of photocatalytic reaction in a semiconductor

We show that a semiconductor can serve as a photocatalyst for the ligand substitution reaction in coordination compounds of chromium(III). The mechanism of the process includes stages of generation of an electron-hole pair upon action of light quanta with energy equal to (or greater than) the width of the forbidden gap in the semiconductor, capture of the electron from the conduction band by the chromium(III) complex, fast ligand substitution in the chromium(II) complex formed by a solvent molecule, and oxidation of the chromium(II) complex by the hole from the valence band. The reaction of aquation of the complex ions [CrCl₂(H₂O)₄]⁺ proceeds when using the semiconductors (CdS, GaAs), whose conduction band is located in the more negative potential region compared with the standard oxidation-reduction potential of the Cr(III)/Cr(II) pair. We show that the reaction rate is slowed down when electron acceptors (oxygen) and hole acceptors (ethanol) are introduced, which confirms the proposed mechanism.Translated from Teoreticheskaya i Éksperimental'naya Khimiya, Vol. 26, No. 1, pp. 89–92, January–February, 1990.     

Multistrip Western blotting to increase quantitative data output

The qualitative and quantitative measurements of protein abundance and protein modification states are essential in understanding their role in diverse cellular processes. Traditional Western blotting technique, though sensitive, is prone to produce substantial errors and is not readily adapted to high-throughput technologies. We propose a modified immunoblotting procedure, which is based on simultaneous transfer of proteins from multiple gel-strips onto the same membrane, and is compatible with any conventional gel electrophoresis system. As a result, the data output per single blotting cycle can readily be increased up to ten-fold. In contrast to the traditional "one protein detection per electrophoresis cycle", this procedure allows simultaneous monitoring of up to nine different proteins. In addition to maintaining the ability to detect picogram quantities of protein, the modified system substantially improves data accuracy by reducing signal errors by two-fold. Multistrip Western blotting procedure allows making statistically reliable side-by-side comparisons of different or repeated sets of data. Compared to the traditional methods, this approach provides a more economical, reproducible, and effective procedure, facilitating the generation of large amounts of high-quality quantifiable data.     

Reptation theory: geometrical and topological aspects

This paper discusses topological and geometrical aspects of reptation theory which are common to all versions of reptation theory. These are: the postulated existence of the tube, the functional relationship between the tube diameter a and the polymer/monomer density p, the crossover from the Rouse to reptation regime. Statistical mechanics of the geometrically confined polymer chain is reanalyzed by careful separation of the diffusive motion of the chain into the longitudinal and transversal parts. Connection between old results and the new formalism is established. It is shown that the longitudinal motion resembles that known for directed polymers. This provides a source of the effective rigidification of the reptating chain's backbone thus facilitating the viscosity exponent to be larger than 3. The transversal motion is also reanalyzed. It is shown that the diffusion on the Bethe lattice used before to describe the transversal (planar) motion (conformational statistics) of the trapped chain is actually the diffusion on the universal covering of the corresponding Riemannian surface. This fact allows to reanalyze the tube stability using topological arguments. Detailed numerical comparison of the obtained new theoretical results with available experimental and Monte Carlo data is provided. Very good agreement between theory and experiment is found. It is also shown that the emerging physical picture of the tube destruction is isomorphic to that which was developed earlier with the help of the quantum Hall effect analogy (J. Phys. I 4 , 843 (1994)). Remarkable connections between the reptation theory and the theory of quantum chaotic/mesoscopic systems are established thus making the reptation theory part of the more general theory of quantum chaotic systems.     

Search for Scalar Resonance in the ωϕ System in the Pion-Nuclear Interaction at Momentum of 29 GeV/c

Physics of Atomic Nuclei - The charge-exchange reaction $${{\pi }^{ - }}p \to n\omega (783)\phi (1020)$$ , $$\omega \to {{\pi }^{ + }}{{\pi }^{ - }}{{\pi }^{0}}$$ , $$\phi \to {{K}^{ + }}{{K}^{ -...