High-throughput method for the production and analysis of large natural product libraries for drug discovery

High-throughput methods were applied to the production, analysis, and characterization of libraries of natural products in order to accelerate the drug discovery process for high-throughput screening in the pharmaceutical and biotechnology industries. Library production integrates automated flash chromatography, solid-phase extraction, filtration, and high-throughput parallel four-channel preparative high-performance liquid chromatography to obtain the libraries in 96- or 384-well plates. Libraries consist of purified fractions with approximately one to five compounds per well. Libraries are analyzed prior to biological screening by a high-throughput parallel eight-channel liquid chromatography-evaporative light scattering detection-mass spectrometry system to determine the molecular weight, number, and quantity of compounds in a fraction. After biological screening, active fractions are rapidly purified at the microgram level and individual compounds are rescreened for confirmation of activity. Structures of active compounds are elucidated by NMR spectroscopy and mass spectrometry. Utilization of a novel microcoil probe allows NMR data to be gathered on 50 microg. As a demonstration, a library was made from the stem bark of Taxus brevifolia. Biological screening in the National Cancer Institute's in vitro panel of three cancer cell lines demonstrates that the process enables the discovery of active anticancer compounds not detected in the flash fractions from which the library originates.     

Prolonged rewarding stimulation of the rat medial forebrain bundle: Neurochemical and behavioral consequences.

Extracellular dopamine levels were measured in the rat nucleus accumbens by means of in vivo microdialysis. Delivery of rewarding medial forebrain bundle stimulation at a low rate (5 trains/min) produced a sustained elevation of dopamine levels, regardless of whether train onset was predictable. When the rate of train delivery was increased to 40 trains/min, dopamine levels rose rapidly during the first 40 min but then declined toward the baseline range. The rewarding impact of the stimulation was reduced following prior delivery of stimulation at the high, but not the low, rate. These results support the idea that dopamine tone plays an enabling role in brain stimulation reward and is elevated similarly by predictable and unpredictable stimulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adaptive diagnosis in distributed systems

Real-time problem diagnosis in large distributed computer systems and networks is a challenging task that requires fast and accurate inferences from potentially huge data volumes. In this paper, we propose a cost-efficient, adaptive diagnostic technique called active probing . Probes are end-to-end test transactions that collect information about the performance of a distributed system. Active probing uses probabilistic reasoning techniques combined with information-theoretic approach, and allows a fast online inference about the current system state via active selection of only a small number of most-informative tests. We demonstrate empirically that the active probing scheme greatly reduces both the number of probes (from 60% to 75% in most of our real-life applications), and the time needed for localizing the problem when compared with nonadaptive (preplanned) probing schemes. We also provide some theoretical results on the complexity of probe selection, and the effect of "noisy" probes on the accuracy of diagnosis. Finally, we discuss how to model the system's dynamics using dynamic Bayesian networks (DBNs), and an efficient approximate approach called sequential multifault; empirical results demonstrate clear advantage of such approaches over "static" techniques that do not handle system's changes.     

Negotiating the hybrid: art, theory and genetic technologies

Over the past decade artists have increasingly turned to science in order to investigate technology’s effect. The move from hardware-based technologies to live organisms as media, raises ethical issues that the broader art community is addressing. This paper tracks the history of instrumental disengagement to determine when and how the gradual codification of life contributed to the eventual use of live organisms in art practice.     

On the sixty-four polynomials of Djaferis to stabilize an intervalplant

This paper shows that 32 of the 64 polynomials developed by Djaferis to stabilize an interval plant with a controller are superfluous. Thus it is sufficient to stabilize 32 polynomials simultaneously. Moreover the construction developed in this note allows the implementation of these polynomials in a simple way     

Optimal control law for classical and multiconjugate adaptive optics

Classical adaptive optics (AO) is now a widespread technique for high-resolution imaging with astronomical ground-based telescopes. It generally uses simple and efficient control algorithms. Multiconjugate adaptive optics (MCAO) is a more recent and very promising technique that should extend the corrected field of view. This technique has not yet been experimentally validated, but simulations already show its high potential. The importance for MCAO of an optimal reconstruction using turbulence spatial statistics has already been demonstrated through open-loop simulations. We propose an optimal closed-loop control law that accounts for both spatial and temporal statistics. The prior information on the turbulence, as well as on the wave-front sensing noise, is expressed in a state-space model. The optimal phase estimation is then given by a Kalman filter. The equations describing the system are given and the underlying assumptions explained. The control law is then derived. The gain brought by this approach is demonstrated through MCAO numerical simulations representative of astronomical observation on a 8-m-class telescope in the near infrared. We also discuss the application of this control approach to classical AO. Even in classical AO, the technique could be relevant especially for future extreme AO systems.     

Observations and simulations of the low velocity-to-hypervelocity impact crater transition for a range of penetrator densities into thick aluminum targets

Projectile/target impact crater systems involving soda-lime glass/1100 aluminum, ferritic stainless steel/1100 aluminum, and tungsten carbide/1100 aluminum (corresponding to projectile densities of 2.2, 7.89, and 17 Mg (m³) at impact velocities ranging from 0.56 to 3.99 km/s were examined by light metallography, SEM, and TEM. Plots of crater depth/crater diameter ratio (p/D _c) versus impact velocity exhibited anomalous humps with p/D _c ranging from 0.8 to 5.5 between 1 and 2 km/s, with hypervelocity threshold or steady-state values of p/D _c (>5 km/s) ranging from 0.4 to 1.0; with the p/D _c values increasing with increasing projectile density in each case. This hump-shaped regime, with exaggerated target penetration depths, appears to occur because projectiles remain relatively intact and unfragmented. The crater geometry begins to change when the projectile fragmentation onset velocity (>2 km/s) is exceeded and fragmentation increases with increasing impact velocity. Computer simulations and validation of these simulations were developed which fairly accurately represented residual crater shapes/geometries and correlated experimentally measured microhardness maps with simulated residual yield stress contour maps. Validated computer simulations allowed representative extrapolations of impact craters well beyond the laboratory where melting and solidification occurred at the crater wall, especially for hypervelocity impact (>5 km/s).     

The Emotional Wardrobe

Since the industrial revolution, fashion and technology have been linked through the textile and manufacturing industries, a relationship that has propelled technical innovation and aesthetic and social change. Today, a new alliance is emerging through the integration of electronic technology and smart materials on the body. This study addresses the integration of technology with clothing from a fashion perspective, and examines its expressive and interactive potential. It proposes the concept of The Emotional Wardrobe: clothing that represents and stimulates emotional response through the interface of technology. It asks if fashion can offer a more personal and provocative definition of self, which actively involves the wearer in a mutable aesthetic identity. A multi-disciplinary framework combines fashion, material science and the real-time, affective computing platform, called AffectiveWare. By merging technology and fashion, The Emotional Wardrobe becomes a poetic interface, shifting emphasis from human–computer interaction to computer-aided, human–human communication.