Approximation of linear conflict-controlled neutral-type systems

We consider a dynamical system described by linear neutral-type functional-differential equations which is controlled under conditions of unknown disturbances. This system is approximated by a system of ordinary differential equations. An aiming procedure between the initial and approximating systems is elaborated. Using such procedure, results of the control theory for ordinary differential systems can be applied to control of the initial system. © 201

Path-Dependent Hamilton–Jacobi Equations: The Minimax Solutions Revised

Motivated by optimal control problems and differential games for functional differential equations of retarded type, the paper deals with a Cauchy problem for a path-dependent Hamilton–Jacobi equation with a right-end boundary condition. Minimax solutions of this problem are studied. The existence and uniqueness result is obtained under assumptions that are weaker than those considered earlier. In contrast to previous works, on the one hand, we do not require any properties concerning positive homogeneity of the Hamiltonian in the impulse variable, and on the other hand, we suppose that the Hamiltonian satisfies a Lipshitz continuity condition with respect to the path variable in the uniform (supremum) norm. The progress is related to the fact that a suitable Lyapunov–Krasovskii functional is built that allows to prove a comparison principle. This functional is in some sense equivalent to the square of the uniform norm of the path variable and, at the same time, it possesses appropriate smoothness properties. In addition, the paper provides non-local and infinitesimal criteria of minimax solutions, their stability with respect to perturbations of the Hamiltonian and the boundary functional, as well as consistency of the approach with the non-path-dependent case. Connection of the problem statement under consideration with some other possible statements (regarding the choice of path spaces and derivatives used) known in the theory of path-dependent Hamilton–Jacobi equations is discussed. Some remarks concerning viscosity solutions of the studied Cauchy problem are given. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature

Rotavirus NSP1 Inhibits NFκB Activation by Inducing Proteasome-Dependent Degradation of β-TrCP: A Novel Mechanism of IFN Antagonism

Mechanisms by which viruses counter innate host defense responses generally involve inhibition of one or more components of the interferon (IFN) system. Multiple steps in the induction and amplification of IFN signaling are targeted for inhibition by viral proteins, and many of the IFN antagonists have direct or indirect effects on activation of latent cytoplasmic transcription factors. Rotavirus nonstructural protein NSP1 blocks transcription of type I IFNα/β by inducing proteasome-dependent degradation of IFN-regulatory factors 3 (IRF3), IRF5, and IRF7. In this study, we show that rotavirus NSP1 also inhibits activation of NFκB and does so by a novel mechanism. Proteasome-mediated degradation of inhibitor of κB (IκBα) is required for NFκB activation. Phosphorylated IκBα is a substrate for polyubiquitination by a multisubunit E3 ubiquitin ligase complex, Skp1/Cul1/F-box, in which the F-box substrate recognition protein is β-transducin repeat containing protein (β-TrCP). The data presented show that phosphorylated IκBα is stable in rotavirus-infected cells because infection induces proteasome-dependent degradation of β-TrCP. NSP1 expressed in isolation in transiently transfected cells is sufficient to induce this effect. Targeted degradation of an F-box protein of an E3 ligase complex with a prominent role in modulation of innate immune signaling and cell proliferation pathways is a unique mechanism of IFN antagonism and defines a second strategy of immune evasion used by rotaviruses

TCRep 3D: An Automated In Silico Approach to Study the Structural Properties of TCR Repertoires

TCRep 3D is an automated systematic approach for TCR-peptide-MHC class I structure prediction, based on homology and ab initio modeling. It has been considerably generalized from former studies to be applicable to large repertoires of TCR. First, the location of the complementary determining regions of the target sequences are automatically identified by a sequence alignment strategy against a database of TCR Vα and Vβ chains. A structure-based alignment ensures automated identification of CDR3 loops. The CDR are then modeled in the environment of the complex, in an ab initio approach based on a simulated annealing protocol. During this step, dihedral restraints are applied to drive the CDR1 and CDR2 loops towards their canonical conformations, described by Al-Lazikani et. al. We developed a new automated algorithm that determines additional restraints to iteratively converge towards TCR conformations making frequent hydrogen bonds with the pMHC. We demonstrated that our approach outperforms popular scoring methods (Anolea, Dope and Modeller) in predicting relevant CDR conformations. Finally, this modeling approach has been successfully applied to experimentally determined sequences of TCR that recognize the NY-ESO-1 cancer testis antigen. This analysis revealed a mechanism of selection of TCR through the presence of a single conserved amino acid in all CDR3β sequences. The important structural modifications predicted in silico and the associated dramatic loss of experimental binding affinity upon mutation of this amino acid show the good correspondence between the predicted structures and their biological activities. To our knowledge, this is the first systematic approach that was developed for large TCR repertoire structural modeling

Finite-dimensional approximations of neutral-type conflict-controlled systems

The paper deals with a dynamical system described by a neutral-type functional differential equation in Hale's form which is controlled under conditions of unknown disturbances. This system is approximated by a controlled system of ordinary differential equations. An aiming procedure between the initial and approximating systems is elaborated. An application of such procedure is given for solving a control problem for linear neutral-type dynamical systems. An illustrative example is considered, simulation results are shown. © 201