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.     

Are max-specified infant facial expressions during face-to-face interaction consistent with differential emotions theory?

Differential emotions theory (DET) proposes that infant facial expressions of emotions are differentiated. To test this hypothesis, the authors examined infant facial expressions longitudinally at 2, 4, and 6 mo of age during face-to-face play and a "still-face" interaction with their mothers. Infant expressions were coded using the Maximally Discriminative Facial Movement Coding System (Max). Consistent with DET, discrete positive expressions occurred more of the time and were of longer duration than blended expressions of positive affect. Contrary to DET, at no age did the proportions or durations of discrete and blended negative expressions differ, and they showed different patterns of developmental change. One is led to either reject or revise DET or else question the adequacy of the Max system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Downhole Upgrading of Extra-heavy Crude Oil Using Hydrogen Donors and Methane Under Steam Injection Conditions

An extra-heavy crude oil underground upgrading process is described which involves the downhole addition of a hydrogen donor additive under steam injection conditions (280-315°C and residence times of at least 24-h). Laboratory experiments showed a 4° increase in the API gravity (from 9 to 12°) of the upgraded product, a two-fold reduction in the viscosity and, an approximately 8% decrease in the asphaltene content with respect to the original crude. Further increases on the temperature led to products with improved properties reaching 15°API at 315°C. It was found that the presence of the natural formation (catalysts) and methane (natural gas) is necessary to enhance the properties of the upgraded crude oil. From GC and GC-MS results a reaction pathway is proposed that involves hydrogen transfers from tetralin to the extra-heavy crude oil resulting in the formation of 1,2-dihydronaphthalene. This compound is then transformed into naphthalene, further upgrading of crude oil through hydrogen donation. The results of the experiments carried out in the presence and absence of the mineral formation and with an inert solid (SiC) strongly indicate that the former acts as a catalyst and not as a heat transfer matrix. Isotopic labeling studies (CD₄ and ¹³CH₄) give evidences that, most probably, methane is involved in the upgrading reactions.     

Gaussian,Lobatto and Radau positive quadrature rules with a prescribed abscissa

For a given $\theta \in (a,b)$ , we investigate the question whether there exists a positive quadrature formula with maximal degree of precision which has the prescribed abscissa $\theta $ plus possibly $a$ and/or $b$ , the endpoints of the interval of integration. This study relies on recent results on the location of roots of quasi-orthogonal polynomials. The above positive quadrature formulae are useful in studying problems in one-sided polynomial $L_1$ approximation.     

Stability independent of delay using rational functions

This paper is concerned with the problem of assessing the stability of linear systems with a single time-delay. Stability analysis of linear systems with time-delays is complicated by the need to locate the roots of a transcendental characteristic equation. In this paper we show that a linear system with a single time-delay is stable independent of delay if and only if a certain rational function parameterized by an integer k and a positive real number T has only stable roots for any finite T≥0 and any k≥2. We then show how this stability result can be further simplified by analyzing the roots of an associated polynomial parameterized by a real number δ in the open interval (0,1). The paper is closed by showing counterexamples where stability of the roots of the rational function when k=1 is not sufficient for stability of the associated linear system with time-delay. We also introduce a variation of an existing frequency-sweeping necessary and sufficient condition for stability independent of delay which resembles the form of a generalized Nyquist criterion. The results are illustrated by numerical examples.     

Implementation and analysis of multigrid schemes with finite elements for elliptic optimal control problems

The detailed implementation and analysis of a finite element multigrid scheme for the solution of elliptic optimal control problems is presented. A particular focus is in the definition of smoothing strategies for the case of constrained control problems. For this setting, convergence of the multigrid scheme is discussed based on the BPX framework. Results of numerical experiments are reported to illustrate and validate the optimal efficiency and robustness of the performance of the present multigrid strategy.     

Bringing Scheme programming to the iPhone—Experience

The iPhone SDK provides a powerful platform for the development of applications that make use of iPhone capabilities, such as sensors, GPS, Wi‐Fi, or Bluetooth connectivity. We observe that so far the development of iPhone applications has mostly been restricted to using Objective‐C. However, developing applications in plain Objective‐C on the iPhone OS suffers from limitations, such as the need for explicit memory management and lack of syntactic extension mechanism. Moreover, when developing distributed applications in Objective‐C, programmers have to manually deal with distribution concerns, such as service discovery, remote communication, and failure handling. In this paper, we discuss our experience in porting the Scheme programming language to the iPhone OS and how it can be used together with Objective‐C to develop iPhone applications. To support the interaction between Scheme programs and the underlying iPhone APIs, we have implemented a language symbiosis layer that enables programmers to access the iPhone SDK libraries from Scheme. In addition, we have designed high‐level distribution constructs to ease the development of distributed iPhone applications in an event‐driven style. We validate and discuss these constructs with a series of examples, including an iPod controller, a maps application, and a distributed multiplayer Scrabble‐like game. We discuss the lessons learned from this experience for other programming language ports to mobile platforms. Copyright © 2011 John Wiley & Sons, Ltd.