Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.     

Case studies on process sequence design in cold forming of engine valve slider and self-locking nuts

Two cases on process sequence design are presented. One describes the procedure for manufacturing an engine valve slider, and the other for self-locking nut manufacturing. They are based on experts' experience. All operations required to produce final products, from raw material are shown, and general considerations and rules for forming sequence design are explained. For engine valve sliders several upsetting processes are used preforming operations and the final product is obtained by combined forward and backward extrusion. In manufacturing of self-locking nuts special features involved in design are shown in turning the workpiece upside down during the process sequence and producing intentionally a minor crack for the final operation of piercing. In addition, both macro structure and micro structure analysis for major deformation processes are shown.     

Broadly tunable deep blue laser based on a star-shaped oligofluorene truxene

We report amplified spontaneous emission (ASE) and optically pumped deep-blue-emitting distributed feedback (DFB) lasers based on a star-shaped oligofluorene truxene molecule. A low ASE threshold of 2.1 kW/cm² at 439 nm was achieved. The material exhibits a high net gain of 38 cm^?1 and also low optical loss coefficient of 3.5 cm^?1. Second-order DFB lasers show tuning of the emission wavelength from 422 to 473 nm, and a minimum threshold density of 515 W/cm². This is the broadest tuning range (51 nm) reported for organic deep-blue/blue lasing materials.     

Structure and composition of CO2/H2 and CO2/H2/C3H8 hydrate in relation to simultaneous CO2 capture and H2 production

Gas hydrates from a (40/60 mol %) CO₂/H₂ mixture, and from a (38.2/59.2/2.6 mol %) CO₂/H₂/C₃H₈ mixture, were synthesized using ice powder. The gas uptake curves were determined from pressure drop measurements and samples were analyzed using spectroscopic techniques to identify the structure and determine the cage occupancies. Powder X‐ray diffraction (PXRD) analysis at ?110°C was used to determine the crystal structure. From the PXRD measurement it was found that the CO₂/H₂ hydrate is structure I and shows a self‐preservation behavior similar to that of CO₂ hydrate. The ternary gas mixture was found to form pure structure II hydrate at 3.8 MPa. We have applied attenuated total reflection infrared spectroscopic analysis to measure the CO₂ distribution over the large and small cavities. ¹H MAS NMR and Raman were used to follow H₂ enclathration in the small cages of structure I, as well as structure II hydrate. © 2009 American Institute of Chemical Engineers AIChE J, 2009     

A comparative study on the electrical and mechanical behaviour of multi‐walled carbon nanotube composites prepared by diluting a masterbatch with various types of polypropylenes

Polypropylene (PP) nanocomposites with multi‐walled carbon nanotubes (CNT) were produced by a small‐scale masterbatch melt dilution technique using five PP differing in melt flow index (MFI) and degree of maleination. PP used in a masterbatch has MFI = 12 (PP₁₂), the others used PP which have MFI = 2 or MFI = 8. The state of CNT dispersion as assessed by melt rheological and morphological investigations indicated a better dispersion when using unmodified PP with MFI = 8 (PP₈) and the masterbatch's PP₁₂. Electrical conductivity results showed nanotube percolation at contents between 1.1 and 2.0 vol %, whereas lower values were obtained for the matrices with the best dispersion, i.e., PP₈ and PP₁₂. The dependencies of the relative Young's modulus on the CNT content showed that the maleinization improved the interfacial interactions between the components, especially in the case of maleated PP with MFI = 8 (PP‐MA₈), but the better dispersion was prevented by the incompatibility between polar groups of PP‐MA and the nonpolar origin masterbatch PP₁₂. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Effect of loading‐unloading cycles on impact‐damaged jute/glass hybrid laminates

The production of glass/plant fiber hybrid laminates is a possibility for obtaining semistructural materials with sufficient impact properties, and a better life cycle analysis (LCA) profile than fiberglass. The simplest and possibly the most effective configuration for the production of these hybrids would involve the use of a plant fiber reinforced laminate as the core between two glass fiber reinforced laminates. A main limitation to the use of composites including plant fibers is that their properties may be significantly affected by the presence of damage, so that even the application of a low stress level can result in laminate failure. In particular, it is suggested that when loading is repeatedly applied and removed, residual properties may vary in an unpredictable way. In this work, E‐glass/jute hybrid reinforced laminates, impacted in a range of energies (10, 12.5, and 15 J), have been subjected to post‐impact cyclic flexural tests with a step loading procedure. This would allow evaluating the effect of damage dissipation offered by the plant fiber reinforced core. The tests have also been monitored by acoustic emission (AE), which has confirmed the existence of severe limitations to the use of this hybrid material when impacted at energies close to penetration. POLYM. COMPOS., 2009. © 2009 Society of Plastics Engineers     

Composite Electrodes for Electrochemical Supercapacitors

Manganese dioxide nanofibers with length ranged from 0.1 to 1 μm and a diameter of about 4–6 nm were prepared by a chemical precipitation method. Composite electrodes for electrochemical supercapacitors were fabricated by impregnation of the manganese dioxide nanofibers and multiwalled carbon nanotubes (MWCNT) into porous Ni plaque current collectors. Obtained composite electrodes, containing 85% of manganese dioxide and 15 mass% of MWCNT, as a conductive additive, with total mass loading of 7–15 mg cm⁻², showed a capacitive behavior in 0.5-M Na₂SO₄ solutions. The decrease in stirring time during precipitation of the nanofibers resulted in reduced agglomeration and higher specific capacitance (SC). The highest SC of 185 F g⁻¹ was obtained at a scan rate of 2 mV s⁻¹ for mass loading of 7 mg cm⁻². The SC decreased with increasing scan rate and increasing electrode mass.     

Formation Routes of Nanocomposite Coatings in Detonation Spraying of Ti3SiC2-Cu Powders

In thermally sprayed coatings, nano-sized features of the microstructure may be either inherited from the nanostructured agglomerates of the feedstock powder or form as a result of rapid cooling of molten particles upon deposition. Applying a process of the computer-controlled detonation spraying (CCDS) to Ti₃SiC₂-Cu composite powders produced by high-energy mechanical milling, we show that both routes are possible depending on the spraying conditions. When the nanostructure of the Ti₃SiC₂-Cu coating is inherited from the feedstock powder—under very mild conditions of detonation spraying, which exclude melting, so is the phase composition of the coating. In higher-temperature conditions of spraying, a significant fraction of the copper matrix melts and the interaction between Ti₃SiC₂ and Cu occurs. The TiC _x -Cu(Si) coatings that form show crystallites of both phases in the nano-range. In this case, rapid solidification of the molten fraction of the particles is responsible for the formation of the coatings with a nanostructured matrix. Due to the flexibility of the CCDS process, conditions of spraying were found such that a composite coating with very fine crystallites of the Cu(Si) matrix (30 nm) and a hardness of 273 HV could be obtained.