Total Syntheses of Amphidinolide H and G

Eureka! The first conquest of the exceptionally potent cytotoxic agent amphidinolide H, which exhibits activity in the picomolar range against human epidermoid cancer cells, was long overdue. The successful route critically hinges upon the scrupulous optimization of the fragment-coupling events (see picture; RCM=ring-closing metathesis) and on the careful adjustment of the peripheral protecting-group pattern

Total Syntheses of Amphidinolides B1, B4, G1, H1 and Structure Revision of Amphidinolide H2

Nature is a pretty unselective “chemist” when it comes to making the highly cytotoxic amphidinolide macrolides of the B/G/H series. To date, 16 different such compounds have been isolated, all of which could now be approached by a highly convergent and largely catalysis-based route (see figure). This notion is exemplified by the total synthesis of five prototype members of this family. Dinoflagellates of the genus Amphidinium produce a “library” of closely related secondary metabolites of mixed polyketide origin, which are extremely scarce but highly promising owing to the exceptional cytotoxicity against various cancer cell lines. Because of the dense array of sensitive functionalities on their largely conserved macrocyclic frame, however, these amphidinolides of the B, D, G and H types elapsed many previous attempts at their synthesis. Described herein is a robust, convergent and hence general blueprint which allowed not only to conquest five prototype members of these series, but also holds the promise of making “non-natural” analogues available by diverted total synthesis. This notion transpires for a synthesis-driven structure revision of amphidinolide H2. The successful route hinges upon a highly productive Stille–Migita cross-coupling reaction at the congested and chemically labile 1,3-diene site present in all such targets, which required the development of a modified chloride- and fluoride-free protocol. The macrocyclic ring could be formed with high efficiency and selectivity by ring-closing metathesis (RCM) engaging a vinyl epoxide unit as one of the reaction partners. Because of the sensitivity of the targets to oxidizing and reducing conditions as well as to pH changes, the proper adjustment of the protecting group pattern for the peripheral -OH functions also constitutes a critical aspect, which has to converge to silyl groups only once the diene is in place. Tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) turned out to be a sufficiently mild fluoride source to allow for the final deprotection without damaging the precious macrolides

The BANCA Database and Evaluation Protocol

In this paper we describe the acquisition and content of a new large, realistic and challenging multi-modal database intended for training and testing multi-modal verification systems. The BANCA database was captured in four European languages in two modalities (face and voice). For recording, both high and low quality microphones and cameras were used. The subjects were recorded in three different scenarios, controlled, degraded and adverse over a period of three months. In total 208 people were captured, half men and half women. In this paper we also describe a protocol for evaluating verification algorithms on the database. The database will be made available to the research community through http://www.ee.surrey.ac.uk/Research/VSSP/banca

Modulation of transforming growth factor beta signalling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: involvement of Sp1 in both early and late response cells to transforming growth factor beta

International audienc

Adiponectin Upregulates Prolyl-4-Hydroxylase α1 Expression in Interleukin 6-Stimulated Human Aortic Smooth Muscle Cells by Regulating ERK 1/2 and Sp1

Adiponectin is an anti-atherogenic adipokine that inhibits the development of plaque by mechanisms that are not completely understood. Extracellular matrix (ECM) may have a role in the pathogenesis of atherosclerosis. We explored the effect and mechanisms of adiponectin on the synthesis of prolyl-4-hydroxylase (P4H) in interleukin 6 (IL-6)-stimulated human aortic smooth muscle cells (HASMCs). P4Hα1 mRNA level was quantified by RT-PCR, the protein levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and P4Hα1 were quantified by western blot analysis, and activation of specific protein 1 (Sp1) was determined by electrophoretic mobility shift assay and subcellular localization of Sp1 by immunofluorescence analysis. Adiponectin significantly increased P4Hα1 mRNA and protein levels in IL-6-stimulated HASMCs in a dose- and time-dependent manner. As well, ERK1/2 and Sp1 played a crucial role in the effect of adiponectin upregulating P4Hα1 expression in IL-6-stimulated HASMCs. Adiponectin abrogated the effects of IL-6 on collagen III level, which may indicate that P4Hα1 is essential for folding the procollagen polypeptide chains into stabilized collagen. Adiponectin attenuates IL-6–inhibited P4Hα1 synthesis and stabilizes collagen formation in HASMCs through a Sp1-ERK1/2-P4Hα1-dependent pathway

Deconvolution and Tracking for Ocean Acoustic Tomography.

Ocean acoustic tomography involves the observation of several versions of a transmitted signal at the receiver side of an underwater acoustic communication system, that are due to multipath propagation in the ocean. The estimation and the tracking of multipath propagation parameters is considered in this contribution. We propose a bayesian approach to this problem in two steps. First, a deconvolution method is performed record by record and yields an initial estimation of the arrival times. Then, the slow evolution of arrival times over several observations enables applying image processing techniques for peak tracking. In addition, the proposed method accounts for possible distortions of the transmitted signal during the propagation, which significantly influences the arrival time estimation performance. The proposed method is tested on real data

Digital Signal Processing Performance analysis of Hurst exponent estimators using surrogate-data and fractional lognormal noise models: Application to breathing signals from preterm infants

The use of the Hurst exponent (H) to quantify the fractal characteristics of biological signals and its potential to detect abnormalities has aroused, recently, the interest of many researchers. Numerous techniques to estimate H are described in the literature, yet the choice of the most performing one is not straightforward. In this paper, we proposed some tests using artificial signals from experimental data and stochastic models to evaluate the robustness of three estimation techniques. Different surrogate-data tests, including a novel method to parametrize the degree of correlation in experimental signals with H (Hurst-adjusted surrogates), were first carried out. Then, simulated signals with prescribed H were obtained from fractional Gaussian noise modified properly to follow the lognormal laws observed in empirical data. The tests were applied to examine detrended fluctuation analysis (DFA), discrete wavelet transform and least squares based on standard deviation (LSSD) methods in the particular case of interbreath interval signals from preterm infants. Simulations showed that none of the estimators were robust for every breathing pattern (regular, erratic and periodic) and should not be applied blindly without performing the preliminary tests proposed here. The LSSD technique was the most precise in general, but DFA was more robust with highly spiked patterns