Preferential exclusion of sucrose from recombinant interleukin-1 receptor antagonist: role in restricted conformational mobility and compaction of native state

Understanding the mechanism for sucrose-induced protein stabilization is important in many diverse fields, ranging from biochemistry and environmental physiology to pharmaceutical science. Timasheff and Lee [Lee, J. C. & Timasheff, S. N. (1981) J. Biol. Chem. 256, 7193-7201] have established that thermodynamic stabilization of proteins by sucrose is due to preferential exclusion of the sugar from the protein's surface, which increases protein chemical potential. The current study measures the preferential exclusion of 1 M sucrose from a protein drug, recombinant interleukin 1 receptor antagonist (rhIL-1ra). It is proposed that the degree of preferential exclusion and increase in chemical potential are directly proportional to the protein surface area and that, hence, the system will favor the protein state with the smallest surface area. This mechanism explains the observed sucrose-induced restriction of rhIL-1ra conformational fluctuations, which were studied by hydrogen-deuterium exchange and cysteine reactivity measurements. Furthermore, infrared spectroscopy of rhlL-1ra suggested that a more ordered native conformation is induced by sucrose. Electron paramagnetic resonance spectroscopy demonstrated that in the presence of sucrose, spin-labeled cysteine 116 becomes more buried in the protein's interior and that the hydrodynamic diameter of the protein is reduced. The preferential exclusion of sucrose from the protein and the resulting shift in the equilibrium between protein states toward the most compact conformation account for sucrose-induced effects on rhIL-1ra.     

A new approach to rheumatoid arthritis

Slow-acting antirheumatic drugs (SAARDs) are usually prescribed in rheumatoid arthritis only when non-steroid anti-inflammatory drugs can no longer suppress the inflammation or when articular damage is radiologically apparent. It was established recently that articular damage occurs in an early phase of RA. This damage is linked to subsequent disability; to prevent it is the purpose of SAARDs. In view of the short-term reduction of arthritis activity and improvement of function as well as the meanwhile established fact that the side effects of SAARDs are not different from those of other antirheumatic agents, SAARDs should be prescribed in an early phase of RA.     

Situating natural language understanding within experience-based design

Building useful systems with an ability to understand "real" natural language input has long been an elusive goal for Artificial Intelligence. Well-known problems such as ambiguity, indirectness, and incompleteness of natural language inputs have thwarted efforts to build natural language interfaces to intelligent systems. In this article, we report on our work on a model of understanding natural language design specifications of physical devices such as simple electrical circuits. Our system, called KA, solves the classical problems of ambiguity, incompleteness and indirectness by exploiting the knowledge and problem-solving processes in the situation of designing simple physical devices. In addition, KA acquires its knowledge structures (apart from a basic ontology of devices) from the results of its problem-solving processes. Thus, KA can be bootstrapped to understand design specifications and user feedback about new devices using the knowledge structures it acquired from similar devices designed previously.In this paper, we report on three investigations in the KA project. Our first investigation demonstrates that KA can resolve ambiguities in design specifications as well as infer unarticulated requirements using the ontology, the knowledge structures, and the problem-solving processes provided by its design situation. The second investigation shows that KA's problem-solving capabilities help ascertain the relevance of indirect design specifications, and identify unspecified relations between detailed requirements. The third investigation demonstrates the extensibility of KA's theory of natural language understanding by showing that KA can interpret user feedback as well as design requirements. Our results demonstrate that situating language understanding in problem solving, such as device design in KA, provides effective solutions to unresolved problems in natural language processing.     

Power-dependent dispersion in far-off-resonant raman scattering

We investigate the saturation effects of power broadening, Stark shifting, and population transfer on Stokes conversion in stimulated Raman scattering. We do not make the usual rotating wave approximation because the detuning from the next electronic state is assumed to be in the optical regime. Retaining the counter-rotating terms allows an exact determination of the pump and Stokes indexes of refraction. Steady-state solutions for the Stokes intensity and phase are obtained and the effects of making the rotating wave approximation (RWA) are discussed. Finally, we examine the behavior of these solutions for Stokes conversion in hydrogen gas when geometric propagation is appropriate.     

Integrating trust into the CyberCraft Initiative via the Trust Vectors model [Application Notes]

This research supports the hypothesis that the Trust Vector model can be modified to fit the CyberCraft Initiative, and that there are limits to the utility of historical data. This research proposed some modifications and expansions to the Trust Model Vector, and identified areas for future research.     

Probing stress effects in HfO2 gate stacks with time dependent measurements

Effects of constant voltage stress (CVS) on gate stacks consisting of an ALD HfO₂ dielectric with various interfacial layers were studied with time dependent sensing measurements: DC I–V, pulse I–V, and charge pumping (CP) at different frequencies. The process of injected electron trapping/de-trapping on pre-existing defects in the bulk of the high-κ film was found to constitute the major contribution to the time dependence of the threshold voltage (V_t) shift during stress. The trap generation observed with the low frequency CP measurements is suggested to occur within the interfacial oxide layer or the interfacial layer/high-κ interface, with only a minor effect on V_t.