Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner-Wadsworth-Emmons-based approach

Integrin inhibitors based on the tripeptide sequence Arg-Gly-Asp (RGD) are potential therapeutics for the treatment of idiopathic pulmonary fibrosis (IPF). Herein, we describe an expeditious three-step synthetic sequence of Horner-Wadsworth-Emmons olefination, diimide reduction, and global deprotection to synthesise cores for these compounds in high yields (63-83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps

Tuning and controlling gene expression noise in synthetic gene networks

Synthetic gene networks can be used to control gene expression and cellular phenotypes in a variety of applications. In many instances, however, such networks can behave unreliably due to gene expression noise. Accordingly, there is a need to develop systematic means to tune gene expression noise, so that it can be suppressed in some cases and harnessed in others, e.g. in cellular differentiation to create population-wide heterogeneity. Here, we present a method for controlling noise in synthetic eukaryotic gene expression systems, utilizing reduction of noise levels by TATA box mutations and noise propagation in transcriptional cascades. Specifically, we introduce TATA box mutations into promoters driving TetR expression and show that these mutations can be used to effectively tune the noise of a target gene while decoupling it from the mean, with negligible effects on the dynamic range and basal expression. We apply mathematical and computational modeling to explain the experimentally observed effects of TATA box mutations. This work, which highlights some important aspects of noise propagation in gene regulatory cascades, has practical implications for implementing gene expression control in synthetic gene networks

Tetra-porphyrin molecular tweezers: two binding sites linked via a polycyclic scaffold and rotating phenyl diimide core

Open Access Article. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.The synthesis of a tetra-porphyrin molecular tweezer with two binding sites is described. The bis-porphyrin binding sites are aligned by a polycyclic scaffold and linked via a freely rotating phenyl diimide core. Synthesis was achieved using a divergent approach employing a novel coupling method for linking two polycyclic units to construct the core, with a copper(II)-mediated phenyl boronic acid coupling found to extend to our polycyclic imide derivative. We expect this chemistry to be a powerful tool in accessing functional polycyclic supramolecular architectures in applications where north/south reactivity and/or directional interactions between modules are important. Porphyrin receptor functionalisation was undertaken last, by a four-fold ACE coupling reaction on the tetra-epoxide derivative of the core

TR-2008005: Weakly Random Additive Preconditioning for Matrix Computations

Our weakly random additive preconditioners facilitate the solution of linear systems of equa-tions and other fundamental matrix computations. Compared to the popular SVD-based multiplicative preconditioners, these preconditioners are generated more readily and for a much wider class of input matrices. Furthermore they better preserve matrix structure and sparseness and have a wider range of applications, in particular to linear systems with rectangular coefficient matrices. We study the generation of such preconditioners and their impact on conditioning of the input matrix. Our analysis and experiments show the power of our approach even where w

TR-2008003: Unified Nearly Optimal Algorithms for Structured Integer Matrices and Polynomials

We seek the solution of banded, Toeplitz, Hankel, Vandermonde, Cauchy and other structured linear systems of equations with integer coefficients. By combining Hensel’s symbolic lifting with either divide-and-conquer algorithms or numerical iterative refinement, we unify the solution for all these structures. We yield the solution in nearly optimal randomized Boolean time, which covers both solution and its correctness verification. Our algorithms and nearly optimal time bounds are extended to the computation of the determinant of a structured integer matrix, its rank and a basis for its null space as well as to some fundamental computations with univariate polynomials that have integer coefficients. Furthermore, we allow to perform lifting modulo a properly bounded power of two t