Design and synthesis of an array of selective androgen receptor modulators

We describe the design, using shape comparison and fast docking computer algorithms, and rapid parallel synthesis of a 1300 member array based on GSK7721, a 4-aminobenzonitrile androgen receptor (AR) antagonist identified by focused screening of the GSK compound collection. The array yielded 352 submicromolar and 17 subnanomolar AR agonists as measured by a cell-based reporter gene functional assay. The rapid synthesis of a large number of active compounds provided valuable information in the optimization of AR modulators, which may be useful in treating androgen deficiency in aging males.     

Size and sequence and the volume change of protein folding

The application of hydrostatic pressure generally leads to protein unfolding, implying, in accordance with Le Chatelier's principle, that the unfolded state has a smaller molar volume than the folded state. However, the origin of the volume change upon unfolding, ΔV(u), has yet to be determined. We have examined systematically the effects of protein size and sequence on the value of ΔV(u) using as a model system a series of deletion variants of the ankyrin repeat domain of the Notch receptor. The results provide strong evidence in support of the notion that the major contributing factor to pressure effects on proteins is their imperfect internal packing in the folded state. These packing defects appear to be specifically localized in the 3D structure, in contrast to the uniformly distributed effects of temperature and denaturants that depend upon hydration of exposed surface area upon unfolding. Given its local nature, the extent to which pressure globally affects protein structure can inform on the degree of cooperativity and long-range coupling intrinsic to the folded state. We also show that the energetics of the protein's conformations can significantly modulate their volumetric properties, providing further insight into protein stability.     

Intramolecular "hydroiminiumation and -amidiniumation" of alkenes: a convenient, flexible, and scalable route to cyclic iminium and imidazolinium salts

Addition of a stoichiometric amount of HCl to alkenylaldimines, -formamidines, and -amidines results in the protonation of the sp2-nitrogen atom. The resulting alkenylaldiminium, -formamidinium, and -amidinium salts can be isolated and fully characterized, including single-crystal X-ray diffraction studies. Heating solutions of these salts induces ring closure cleanly and regioselectively via formal "exo" addition of the nitrogen-hydrogen bond to the pendent carbon-carbon double bond, affording the corresponding cyclic aldiminium, dihydroisoquinolinium, and imidazolinium salts. Of special interest, novel 4,4-disubstituted imidazolinium salts are accessible via this synthetic route. Similarly, addition of phosgene to alkenyl ureas and alkenyl amides, followed by gentle heating, cleanly affords C-chloro imidazolinium, and cyclic C-chloro iminium salts, respectively. Treatment of the latter with tetrakis(triphenylphosphine)palladium allows for the preparation of the first transition-metal complex bearing a cyclic arylaminocarbene as ligand. Deuterium labeling experiments suggest that the mechanism of the hydroiminiumation and -amidiniumation reactions involves an intramolecular proton transfer to the double bond in the rate-determining step. This novel synthetic methodology gives access to a variety of N-heterocyclic carbene (NHC) and cyclic alkyl- and arylaminocarbene (CAAC) precursors.     

Crack kinking from an interface crack with initial contact between the crack lips

The authors recently theoretically studied crack kinking and opening from an initially closed crack (without friction) in some homogeneous medium. The same problem, but for an interface crack, is considered here. Comninou has shown that the asymptotic stress field prior to kinking is governed by a single, mode II stress intensity factor (SIF). Using this result, plus a homogeneity property of the problems of elastic fracture mechanics with unilateral contact envisaged, a change of scale, and two reasonable hypotheses, we establish the expression of the SIF at the tip of the small, open crack extension. It is shown that whatever the geometry of the external boundary and the crack and whatever the loading, these SIF depend solely upon the initial (mode II) SIF (in a linear way), the kink angle and Dundurs' parameters α and β. Using this result and Goldstein and Salganik's “principle of local symmetry” to predict the kink angle, one finds that it is independent of the loading but does depend upon Dundurs' parameters α and β. This contrasts with the case of an ordinary (initially closed) crack in some homogeneous medium, for which the kink angle was not only independent of the loading but an absolute constant. However, it is numerically found that the influence of the mismatch of elastic properties upon the kink angle is rather weak.     

Connected functional working spaces: a framework for the teaching and learning of functions at upper secondary level

ZDM – Mathematics Education - This paper aims at contributing to remedy the narrow treatment of functions at upper secondary level. Assuming that students make sense of functions by working...     

Colloid particles in the interaction field of a disclination line in a nematic phase

On the basis of linear hydrodynamics, we analyze the trajectory of particle-hedgehog systems, attracted by a -1/2 disclination (defect line) in a nematic liquid crystal. We show that, as with the interactions between like-particles, the interaction between a particle and a disclination has an electrostatic analogue, the splay replacing the electric field, except for the symmetry properties. The disclination thus attracts the beads along nonradial tracks and in a self-assembling process, or template mechanism, may build a microscopic necklace with them.     

Optimisation of pressurised liquid extraction by experimental design for quantification of pesticides and alkyl phenols in sludge,suspended materials and atmospheric fallout by liquid chromatography–tandem mass spectrometry

The study proposes an analytical method to quantify 10 alkylphenols and 12 pesticides at ultra-trace levels by liquid chromatography in reverse mode coupled to positive electrospray ionisation–tandem mass spectrometry. The extraction procedure from environmental solids was optimised by pressurised liquid extraction using acetonitrile:isopropanol (1:1, v/v). The influence of several extraction experimental factors, temperature, pressure, duration and number of cycles, related to the PLE was investigated by an original and efficient chemometric approach. The optimised extraction method (80 °C, 40 bar, 10 min, 1 cycle) exhibited recoveries between 67 and 127% with RSD mostly under 13%. The whole method was applied to real samples: sludge, suspended materials, atmospheric fallouts and roof deposit. Pollutant levels were between 1 μg kg⁻¹ and 5.9 mg kg⁻¹.     

Improving the adhesion of polymethacrylate thin films onto indium tin oxide electrodes using a silane-based “Molecular Adhesive”

Indium tin oxide (ITO) is the most commonly used transparent conducting substance. It has been used in numerous applications such as light-emitting diodes. In most applications and studies, the ITO surface is further coated with additional layers. The interface between the ITO and the coating is of utmost importance since it affects the physical and chemical properties of the final device. Improving the adhesion between ITO and a coating layer can be achieved by applying a “molecular adhesive” as an inter-phasing molecular layer. In this study, we used 3-(trimethoxysilyl)propyl methacrylate as a “molecule adhesive” for better connection between ITO and a polymethacrylate layer. The samples were studied by electrochemistry, contact angle goniometry, atomic force microscopy, and nano scratch microscopy. These studies clearly show that a simple silanization process formed a thin molecular adhesive layer, which did not influence the physical and chemical properties of the final coated electrode and at the same time increased significantly the adhesion between the ITO and the polymethacrylate coating.