Epothilones as lead structures for the synthesis-based discovery of new chemotypes for microtubule stabilization

Epothilones are macrocyclic bacterial natural products with potent microtubule-stabilizing and antiproliferative activity. They have served as successful lead structures for the development of several clinical candidates for anticancer therapy. However, the structural diversity of this group of clinical compounds is rather limited, as their structures show little divergence from the original natural product leads. Our own research has explored the question of whether epothilones can serve as a basis for the development of new structural scaffolds, or chemotypes, for microtubule stabilization that might serve as a basis for the discovery of new generations of anticancer drugs. We have elaborated a series of epothilone-derived macrolactones whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of a conformationally constrained side chain, the removal of the C3-hydroxyl group, and the replacement of C12 with nitrogen. So far, this approach has yielded analogs 30 and 40 that are the most advanced, the most rigorously modified, structures, both of which are potent antiproliferative agents with low nanomolar activity against several human cancer cell lines in vitro. The synthesis was achieved through a macrolactone-based strategy or a high-yielding RCM reaction. The 12-aza-epothilone ("azathilone" 40) may be considered a "non-natural" natural product that still retains most of the overall structural characteristics of a true natural product but is structurally unique, because it lies outside of the general scope of Nature's biosynthetic machinery for polyketide synthesis. Like natural epothilones, both 30 and 40 promote tubulin polymerization in vitro and at the cellular level induce cell cycle arrest in mitosis. These facts indicate that cancer cell growth inhibition by these compounds is based on the same mechanistic underpinnings as those for natural epothilones. Interestingly, the 9,10-dehydro analog of 40 is significantly less active than the saturated parent compound, which is contrary to observations for natural epothilones B or D. This may point to differences in the bioactive conformations of N-acyl-12-aza-epothilones like 40 and natural epothilones. In light of their distinct structural features, combined with an epothilone-like (and taxol-like) in vitro biological profile, 30 and 40 can be considered as representative examples of new chemotypes for microtubule stabilization. As such, they may offer the same potential for pharmacological differentiation from the original epothilone leads as various newly discovered microtubule-stabilizing natural products with macrolactone structures, such as laulimalide, peloruside, or dictyostatin.     

Stability of lead(II) complexes of alginate oligomers

The current work reports on the Pb(ll) complexes formed with oligomeric uronic acids (carboxylated saccharide residues) found polymerized in the cell walls and envelopes of algae and bacteria alike. The application of partial acid hydrolysis, size-exclusion chromatography (SEC), 1H NMR, and scanned deposition stripping chronopotentiometry (SSCP) has permitted the determination of stability constants for Pb(II) with both mannuronic (M) and guluronic (G) acid oligomers ranging from the dimer to the pentamer. The determined logarithm of the stability constants range between 4.11 +/- 0.05 and 5.00 +/- 0.04 mol(-1) x dm3 for the eight oligomers studied (pH 6; I = 0.1 mol x dm(-3)). Additional experiments under the same experimental conditions employing galacturonic and glucuronic acid oligomers yielded slightly lower values (2.19 +/- 0.10 to 4.02 +/- 0.07 mol(-1) x dm3) that were expected based on their structure, whereby the monomers which were not included in the alginate oligomer series (unavailable by SEC), yielded the lowest stability constants. This work demonstrates the applicability of the SSCP technique for the determination of stability constants for metal-ligand complexes in which the ligands display relatively low molecular mass. Previous studies on heavy metal interaction with the matrix polysaccharide alginate have largely been restricted to the whole polymer that forms a gel upon binding to network bridging ions such as calcium. The results will be discussed in this context with the emphasis being placed on the relevance of these findings to processes occurring at the biointerface and results from the relevant literature.     

Risk factors associated with colostrum quality in Norwegian dairy cows

The objectives of the present study were to evaluate colostrum quality in Norwegian dairy cows based on IgG content, and to identify associations between possible risk factors and low colostral IgG. A longitudinal cross-sectional survey on calf health in Norway was performed between June 2004 and December 2006. The participating dairy herds were randomly selected among herds registered in the Norwegian Dairy Herd Recording System as having at least 15 cow years. The participating farmers were requested to sample 10 mL of colostrum from the first milking after calving from 12 cows that had calved during the defined project period of 365 d. Colostrum samples from 1,250 cows from 119 herds were collected. The material consisted of 451, 337, 213, and 249 samples collected from cows in their first, second, third, and fourth parity or more, respectively. Analysis was performed on IgG content by using single radial immunodiffusion. Mixed models with herd as a cluster were fit by using grams of IgG per liter of colostrum as the dependent variable for the statistical analyses. The IgG content in the colostrum sampled ranged from 4 to 235 g/L, with a median of 45.0 g of IgG/L, with the 10th, 25th, 75th, and 90th percentiles being 23.1, 31.4, 63.6, and 91.6 g of IgG/L, respectively. Altogether, 57.8% of the samples contained less than the desired 50 g of IgG/L of colostrum. Cows in their fourth parity or more were found to have significantly higher levels of IgG per liter of colostrum than cows in their first or second parity. Colostrum from cows in their second parity had the lowest level of IgG. Cows calving during the winter months (December, January, and February) produced colostrum with a significantly lower IgG content compared with cows calving in any other season of the year. Somatic cell count, measured after calving, was significantly higher in cows producing colostrum of inferior quality compared with those producing high-quality colostrum. Of the total variation in colostrum quality, 13.7% could be explained by cluster effects within herd. The variation in IgG content in colostrum produced by Norwegian dairy cows indicates a need for improved colostrum quality control and subsequent adjustment of the colostrum feeding regimen to ensure a protective immunological status for newborn calves.     

Comparative analysis of RF LDMOS capacitance reliability under accelerated ageing tests

This paper presents the results of comparative reliability study of C–V characteristics through three accelerated ageing tests for stress applied to an RF LDMOS: Thermal shock tests (TST, air–air test), thermal cycling tests (TCT, air–air test) and high temperature storage life (HTSL). The two first tests are carried out with a drain current flowing through the device during stress. The investigation findings of electrical parameter degradations after various ageing tests are discussed. Feedback capacitance (Crs) is reduced by 16% and gate–drain capacitance (Cgd) by 42%. This means that the tracking of these parameters enables to consider the hot carrier injection as the dominant degradation phenomenon. A physical simulation software has been used to confirm qualitatively degradation phenomena.     

Investigation of Enhancement Band Using Double Screen Frequency Selective Surfaces with Koch Fractal Geometry at Millimeter Wave Range

Numerical and theoretical investigations are presented for a double screen frequency selective surface (DSFSS) with perfectly conducting Koch fractal patch elements. The work was developed in two steps, in the first step two Koch fractal FSS screens were designed using the commercial software Ansoft Designer^TM. In the second these FSS were cascaded and separated by an air gap layer, forming the so-called DSFSS, to improve the bandwidth behavior. Thereafter, a numerical cascading technique is used to analyze the effect of the air gap on the DSFSS. The results were compared and a good agreement was observed.     

Cracking cone fracture after cold compaction of argillaceous particles

Cold uniaxial pressing of powder into a green body is a common forming process used in ceramic and pharmaceutical industries. Argillaceous particles are used as a model system to investigate granule failure during compaction. Indeed, the volume enclosed between the die and punches is reduced and the powder consolidates until a final height is obtained or a prescribed compacting pressure is reached. Desired properties of the green body are high strength, uniform density, no defects and fracture. In this work an experimental investigation has been focused on the ‘cracking cone’ fracture in powder compacts. This includes studies of crack propagation and determination of operating conditions to avoid the green body fracture. The numerical modelling is implemented using a finite element method based on the Von Mises criterion. A case of simulation is presented to demonstrate the ability of the model to compute the distribution of the relative stresses.     

Understanding the value of integrated RFID systems: a case study from apparel retail

This contribution is concerned with the business value of Radio Frequency Identification (RFID) technology in retail. We present a case study of an RFID project at Galeria Kaufhof, a subsidiary of Metro Group and one of the largest department store chains in Europe. The project encompasses a variety of RFID applications at the intersection of store logistics and customer service. The contribution that our study makes to the literature is threefold. First, we describe an innovative large-scale trial that goes beyond what was done in earlier projects in several respects. The most fundamental difference from previous trials is the full integration of RFID event data with point-of-sale (POS) and master data, which for the first time offers the retailer the opportunity to directly observe and analyse physical in-store processes. Second, the heterogeneity of RFID applications implemented by Kaufhof allows us to theorise about the effects that RFID may have on business processes from an IT value perspective. We develop a conceptual model to explain the different cause-and-effect chains between RFID investments and their impact on firm performance, the role of complementary and contextual factors, and the difficulty of assessing these impacts using objective performance measures. Third, we compare the case to a prior trial conducted by Kaufhof about 5 years earlier. The differences between the lessons that the company learned in the two projects illustrate the impact of technological advances and standardisation efforts in recent years on managerial perceptions of RFID business value, which allows for the derivation of a number of useful implications for practice.     

Diffraction d’une onde rampante par une ligne de discontinuité du plan tangent

This article is devoted to the study of the problem of diffraction of a creeping wave by a line of discontinuity of the tangent plane forming a salient edge. The author proposes a method based on the usual postulates of the Geometrical Theory of Diffraction. He exposes the principle of the method as well as the steps leading to the expressions of the dyadic diffraction coefficients.     

Low sintering temperature of (Zn0.65Mg0.35)TiO3–xCaTiO3-based dielectric with controlled temperature coefficient

(Zn_0.65Mg_0.35)TiO₃–xCaTiO₃-based dielectric ceramics sintered at low temperature thanks to ZnO–B₂O₃ glass phase addition are investigated. The effects of such additions on the dilatometric curves, the microstructure, the phase composition and the dielectric properties have been carefully examined. It is shown that the sintering temperature is significantly lowered to 930 °C by the addition of 2 wt.% of ZnO–B₂O₃ glass phase. The temperature coefficient of permittivity (τ_?) could be controlled by varying the CaTiO₃ content and lead to near zero τ_? value. As an optimal composition, (Zn_0.65Mg_0.35)TiO₃ + 7%CaTiO₃, co-sinterable with silver electrodes at 930 °C, exhibits at 1 MHz, a relative permittivity of ?_r = 21, a temperature coefficient of the permittivity τ_? of ?4 ppm/°C and low dielectric losses (tan(δ) < 10^?3). These interesting properties make this system promising to manufacture Ag-based electrodes multilayer dielectric devices.     

Separation of particles from hot gases using metallic foams

One of the most complicated tasks in the field of hot gas cleaning is the removal of particles from a complex mixture of degradation products formed during thermal treatment. A robust and completely reliable technology is still to be developed to achieve high efficiencies. In the past few years, significant improvements have been brought to gas cleaning technologies. Nevertheless, none of the existing processes has proved fully successful.The aim of this work is to perform the filtration of particles generated in fluidized bed gasification experiments using metallic foams. The gasified material used is dried sewage sludge. Nickel–chromium metallic foams are likely to have inherent properties that would make them suitable for use in structures where strength, high temperature-resistance and corrosion resistance are required. Moreover, metallic foams are characterized structurally by their cell topology, relative density, high porosity (? = 0.95) and cell size. In hot gas filtration, high temperature-resistance and low pressure drop to specific area ratio are essential characteristics. In the present work, several experimental operating conditions (heating time, temperature, washing method and metallic foam thickness) are investigated. The pressure drops in the metallic foams during filtration are calculated. The experimental results obtained are compared with numerical simulation results and a good agreement is obtained. The metallic foams are simulated from tomography results and a model is created.