Design and synthesis of non-peptide mimetics mapping the immunodominant myelin basic protein (MBP83–96) Epitope to function as T-cell receptor antagonists

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83–96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83–96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83–99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS

An introduction to Graph Data Management

A graph database is a database where the data structures for the schema and/or instances are modeled as a (labeled)(directed) graph or generalizations of it, and where querying is expressed by graph-oriented operations and type constructors. In this article we present the basic notions of graph databases, give an historical overview of its main development, and study the main current systems that implement them

Testing deterministic implementations from nondeterministic FSM specifications

In this paper, conformance testing of protocols specified as nondeterministic finite state machines is considered. Protocol implementations are assumed to be deterministic. In this testing scenario, the conformance relation becomes a preorder, so-called reduction relation between FSMs. The reduction relation requires that an implementation machine produces a (sub)set of output sequences that can be produced by its specification machine in response to every input sequence. A method for deriving tests with respect to the reduction relation with full fault coverage for deterministic implementations is proposed based on certain properties of the product of specification and implementation machines. Keywords Conformance testing, test derivation, fault detection, I/O nondeterministic FSMs, equivalence and reduction relations 1 INTRODUCTION Conformance testing of protocol implementations is often formalized as the FSM equivalence problem (Moore, 1956) and (Hennie, 1964). In particular, we ..