Analogues of capsaicin with agonist activity as novel analgesic agents: structure-activity studies. 4. Potent, orally active analgesics

Structural features of three regions of the capsaicin molecule necessary for agonist properties were delineated by a previously reported modular approach. These in vitro agonist effects were shown to correlate with analgesic potency in rodent models. Combination of optimal structural features from each of these regions of the capsaicin molecule have led to highly potent agonists (eg., 1b). Evaluation in vivo established that 1b had analgesic properties but poor oral activity, short duration of action, and excitatory side effects which precluded further development of this compound. Preliminary metabolism studies had shown that the phenol moiety of 1b was rapidly glucuronidated in vivo, providing a possible explanation for the poor pharmacokinetic profile. Subsequent specific modification of the phenol group led to compounds 2a-j, which retained in vitro potency. The in vivo profiles of two representatives of this series, 2a,h, were much improved over the "parent" phenol series, and they are candidates for development as analgesic agents.     

The mismatch negativity to frequency deviant stimuli during natural sleep

Eight subjects spent a single night in the sleep laboratory. Event-related potentials (ERPs) were recorded during the presentation of two auditory "oddball' stimulus conditions in which tonal frequency was manipulated. In the first condition, 1000 Hz "standard' and 2000 Hz "deviant' tones were presented. In the second condition, the deviant tone was reduced to 1050 Hz. In both conditions, deviant probability was 0.2. Stimuli were presented every 600 ms during wakefulness and stages 2, 4, and REM of sleep. A distinctive N1 wave was visible in both stimulus conditions when the subject was awake. The deviant stimuli elicited a "mismatch negativity' (MMN) that inverted in polarity at the mastoid. In REM sleep, an N1 and a MMN were also elicited in both conditions. In the large deviance condition, the MMN had a slightly attenuated amplitude and was shorter in duration while in the small deviant condition, its peak latency was unusually early. Neither the N1 nor the MMN could be recorded in non-REM sleep.     

Picbreeder: a case study in collaborative evolutionary exploration of design space

For domains in which fitness is subjective or difficult to express formally, interactive evolutionary computation (IEC) is a natural choice. It is possible that a collaborative process combining feedback from multiple users can improve the quality and quantity of generated artifacts. Picbreeder, a large-scale online experiment in collaborative interactive evolution (CIE), explores this potential. Picbreeder is an online community in which users can evolve and share images, and most importantly, continue evolving others' images. Through this process of branching from other images, and through continually increasing image complexity made possible by the underlying neuroevolution of augmenting topologies (NEAT) algorithm, evolved images proliferate unlike in any other current IEC system. This paper discusses not only the strengths of the Picbreeder approach, but its challenges and shortcomings as well, in the hope that lessons learned will inform the design of future CIE systems.     

Map‐aided localization in sparse global positioning system environments using vision and particle filtering

A map‐aided localization approach using vision, inertial sensors when available, and a particle filter is proposed and empirically evaluated. The approach, termed PosteriorPose, uses a Bayesian particle filter to augment global positioning system (GPS) and inertial navigation solutions with vision‐based measurements of nearby lanes and stop lines referenced against a known map of environmental features. These map‐relative measurements are shown to improve the quality of the navigation solution when GPS is available, and they are shown to keep the navigation solution converged in extended GPS blackouts. Measurements are incorporated with careful hypothesis testing and error modeling to account for non‐Gaussian and multimodal errors committed by GPS and vision‐based detection algorithms. Using a set of data collected with Cornell's autonomous car, including a measure of truth via a high‐precision differential corrections service, an experimental investigation of important design elements of the PosteriorPose estimator is conducted. The algorithm is shown to statistically outperform a tightly coupled GPS/inertial navigation solution both in full GPS coverage and in extended GPS blackouts. Statistical performance is also studied as a function of road type, filter likelihood models, bias models, and filter integrity tests. © 2011 Wiley Periodicals, Inc.     

Hard multidimensional multiple choice knapsack problems, an empirical study

Recent advances in algorithms for the multidimensional multiple choice knapsack problems have enabled us to solve rather large problem instances. However, these algorithms are evaluated with very limited benchmark instances. In this study, we propose new methods to systematically generate comprehensive benchmark instances. Some instances with special correlation properties between parameters are found to be several orders of magnitude harder than those currently used for benchmarking the algorithms. Experiments on an existing exact algorithm and two generic solvers show that instances whose weights are uncorrelated with the profits are easier compared with weakly or strongly correlated cases. Instances with classes containing similar set of profits for items and with weights strongly correlated to the profits are the hardest among all instance groups investigated. These hard instances deserve further study and understanding their properties may shed light to better algorithms.     

A three phase serpentine micro electrode array for AC electroosmotic flow pumping

A new three-phase electrode array with a serpentine electrode is designed and prototyped using PolyMUMPs process for micro flow pumping. Numerical model of the micropump has been developed using COMSOL Multiphysics™. Experimental testing is conducted and time-averaged flow velocities from testing and simulation agree well. Peak time-averaged flow velocity of 270 μm/s is achieved at 30 Hz using ethanol.     

VWDC大会见闻

美国时间6月719,Apple公司在位于旧金山的Moscone中心举行了2010年全球开发者大会（WWDC）,本次大会吸引了全球57个国家5200余名开发者的参与。开发者会议议程被分为5个部分：一、应用程序框架;二、核心操作系统;三、Xcode开发工具;四、图像和媒体;五、互联网网络。其中会议的重点是新版iPhone以及iOS4的推介。     

Experimental Evaluation and Formal Analysis of High‐Level Tasks with Dynamic Obstacle Anticipation on a Full‐Sized Autonomous Vehicle

Certifying the behavior of autonomous systems is essential to the development and deployment of systems in safety‐critical applications. This paper presents an approach to using a correct‐by‐construction controller with the probabilistic results of dynamic obstacle anticipation, and validates the approach with experimental data obtained from Cornell's full‐scale autonomous vehicle. The obstacle anticipation (used to calculate the probability of collision with dynamic obstacles around the vehicle) is abstracted to a set of Boolean observations, which are then used by the synthesized controller (a state machine generated from temporal logic task specifications). The obstacle anticipation, sensor abstraction, and synthesized controller are implemented on a full‐scale autonomous vehicle, and experimental data are collected and compared with a formal analysis of the probabilistic behavior of the system. A comparison of the results shows good agreement between the formal analysis and the experimental results.     

Practical considerations for high spatial and temporal resolution dynamic transmission electron microscopy

Although recent years have seen significant advances in the spatial resolution possible in the transmission electron microscope (TEM), the temporal resolution of most microscopes is limited to video rate at best. This lack of temporal resolution means that our understanding of dynamic processes in materials is extremely limited. High temporal resolution in the TEM can be achieved, however, by replacing the normal thermionic or field emission source with a photoemission source. In this case the temporal resolution is limited only by the ability to create a short pulse of photoexcited electrons in the source, and this can be as short as a few femtoseconds. The operation of the photo-emission source and the control of the subsequent pulse of electrons (containing as many as 5 x 10(7) electrons) create significant challenges for a standard microscope column that is designed to operate with a single electron in the column at any one time. In this paper, the generation and control of electron pulses in the TEM to obtain a temporal resolution <10(-6)s will be described and the effect of the pulse duration and current density on the spatial resolution of the instrument will be examined. The potential of these levels of temporal and spatial resolution for the study of dynamic materials processes will also be discussed.