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.     

Monolithically-integrated BiVO4/p+-n GaAs1-xPx tandem photoanodes capable of unassisted solar water splitting

Monolithically-integrated tandem photoanodes were fabricated on substrates consisting of epitaxial n-GaAs_1-xP_x (x ? 0.32) grown on n⁺-GaAs wafers. A p⁺-n junction photovoltaic (PV) cell was first formed by zinc diffusion into the n-GaAs_0.68P_0.32 from a deposited ZnO coating. After diffusion the ZnO serves as a transparent electrical contact to the resulting p⁺-GaAs_0.68P_0.32 surface layer. Transparent, conducting SnO₂:F provides chemical and mechanical protection for the ZnO and the underlying PV cell, and it electrically connects this cell to a top BiVO₄ photocatalyst layer. In some photoanodes, a WO₃ thin film was interposed between the SnO₂:F and BiVO₄. All oxide coatings were produced by ultrasonic spray pyrolysis except WO₃, which was spin coated. Unassisted (unbiased) solar water splitting was achieved, with a solar-to-hydrogen efficiency approaching 2%, without addition of any co-catalyst to the BiVO₄ surface. This work can provide insights to other researchers regarding scalable, low cost approaches for the planar monolithic integration of oxide photoanode materials with PV cells to create new tandem devices.     

Kinetic,thermodynamic parameters and in vitro digestion of tannase from Aspergillus tamarii URM 7115

Tannase is an enzyme used in various industries and produced by a large number of microorganisms. The aim of this study was to evaluate tannase production to determine the biochemical, kinetic, and thermodynamic properties and to simulate tannase in vitro digestion. The tannase-producing fungal strain was isolated from “jamun” leaves and identified as Aspergillus tamarii. Temperature at 26°C for 67?h was the best combination for maximum tannase activity (6.35-fold; initial activity in Plackett–Burman design—15.53?U/mL and average final activity in Doehlert design—98.68?U/mL). The crude extract of tannase was optimally active at 40°C, pH 5.5 and 6.5. Moreover, tannase was stimulated by Na⁺, Ca²⁺, Mg²⁺, and Mn²⁺. The half-life at 40°C lasted 247.55?min. The free energy of Gibbs, enthalpy, and entropy, at 40°C, was 81.47, 16.85, and ?0.21?kJ/mol?·?K, respectively. After total digestion, 123.95% of the original activity was retained. Results suggested that tannase from A. tamarii URM 7115 is an enzyme of interest for industrial applications, such as gallic acid production, additive for feed industry, and for beverage manufacturing, due to its catalytic and thermodynamic properties.     

Niobium-containing catalysts—the state of the art

This review article is devoted to the materials containing niobium, which have been discovered or developed in the past few years and exhibit the potential application in heterogeneous catalysis. Niobium oxides and mixed oxides as well as sulfides, nitrides (oxynitrides), carbides (oxycarbides), and phosphates are considered. Among the catalytic processes in which Nb-containing materials were tested, liquid and gas phase oxidation is described in details, and the role of niobium in the prevention of the catalyst from SO₂ poisoning is mentioned.     

Design Methodology and Area Sensitivity Analysis of Horizontal Subsurface Flow Constructed Wetlands

An approach is presented to satisfy the demand for simple criteria, guidelines and models for the preliminary sizing of horizontal subsurface flow (SF) constructed wetland systems. This approach eliminates time-consuming calculations and iterations by providing graphical solutions for wetland system sizing. Therefore, it can be used for the preliminary assessment of new or performance evaluation of existing subsurface flow constructed wetland systems. The validity of this methodology is checked with data from existing systems and is found to be quite satisfactory. This methodology is combined with simple equations predicting the maximum wetland capacity in summer, so as to assist designers in sizing installations in tourist areas with increased summer populations. Furthermore, based on this methodology, a sensitivity analysis is performed of the area requirements for wastewaters of various strengths and various design conditions and performance criteria. The results provide a useful overview to engineers and further simplify the design methodology of new subsurface flow constructed wetland systems.     

Interaction of triton X-100 on silica: A relationship between surface characteristics and adsorption isotherms

Adsorption of Triton X-100 on various silica substrates has been investigated. A number of solids, including a natural quartz, this quartz washed with HCl acid and subsequently heated at 1273 K; two aerosils and one Kieselgel silicas were studied. These solids exhibit surface areas in the range of 5 to 430 m² g^?1. All the Triton adsorption isotherms display an S-shape at the adsorption temperatures studied (298 and 308 K). It has been found that the pretreatments of natural quartz (by water washing, impurities removed by acid and/or high temperature calcination) affect considerably the amounts of TX-100 adsorbed. Measurements of surface composition have been made by X-ray photoelectron spectroscopy (XPS) with particular emphasis on the presence of impurities and on the number of OH groups at the surface of the samples. The nature of the surface hydroxyl has also been studied by infrared spectroscopy. Furthermore, the specific number of hydroxyl groups on the surface of the silica samples has been determined by thermogravimetric analysis. Finally an attempt to correlate solid surface characteristics with adsorption isotherms has been developed.     

An algorithm for architecture partitioning in high-speed networks with bursty traffic

This paper analyzes the performance of a switching architecture. The performance measures include the elapsed time of packet transfer and the waiting time to begin transfer. The architecture is partitioned depending on the type of network used and the expected traffic in the network. Every partition has a switch with a buffer that can absorb surges of bursty traffic within the network partition. The buffer size depends on the type of the network and incoming traffic. The partition size depends on the network bandwidth, network traffic, packet size and buffer size. Examples of different networks are used to show the applications of the model. The results show that the elapsed time of packet switch transfer depends exponentially on the number of partitions in the network.     

Performance of acrylate-poly(ethylene oxide) polymer electrolytes in lithium batteries

Results for the performance of lithium/Mn0₂ batteries containing solid polymer electrolytes based on poly(ethylene oxide) blends with some acrylic derivatives are presented. The ionic conductivities of the electrolytes are promising for battery application. It was found, however, that interfacial phenomena impair the battery efficiency. Impedance spectroscopy shows resistive limitations at the anode interface of the batteries, caused either by formation of an electrically distinguishable resistive layer or by chemical interaction between the polymer and lithium, influencing, most probably, the kinetics of the lithium oxidation reaction.