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Drug-induced liver injury (DILI) is the most common cause of acute liver failure and a frequent reason for withdrawal of candidate drugs during preclinical and clinical testing. An important type of DILI is cholestatic liver injury, caused by buildup of bile salts within hepatocytes; it is frequently associated with inhibition of bile salt transporters, such as the bile salt export pump (BSEP). Reliable in silico models to predict BSEP inhibition directly from chemical structures would significantly reduce costs during drug discovery and could help avoid injury to patients. Unfortunately, models published to date have been insufficiently accurate to encourage wide adoption. We report our development of classification and regression models for BSEP inhibition with substantially improved performance over previously published models. Our model development leveraged the ATOM Modeling PipeLine (AMPL) developed by the ATOM Consortium, which enabled us to train and evaluate thousands of candidate models. In the course of model development, we assessed a variety of schemes for chemical featurization, dataset partitioning and class labeling, and identified those producing models that generalized best to novel chemical entities. Our best performing classification model was a neural network with ROC AUC = 0.88 on our internal test dataset and 0.89 on an independent external compound set. Our best regression model, the first ever reported for predicting BSEP IC50s, yielded a test set $R^2 = 0.56$ and mean absolute error 0.37, corresponding to a mean 2.3-fold error in predicted IC50s, comparable to experimental variation. These models will thus be useful as inputs to mechanistic predictions of DILI and as part of computational pipelines for drug discovery.

Adaptive optics (AO) is a technology that corrects in real time for the blurring effects of atmospheric turbulence, in principle allowing Earth‐bound telescopes to achieve their diffraction limit and to “see” as clearly as if they were in space. The power of AO using natural guide stars has been amply demonstrated in recent years on telescopes up to 3–4 m in diameter. The next breakthrough in astronomical resolution was expected to occur with the implementation of AO on the new generation of large, 8–10 m diameter telescopes. In this paper we report the initial results from the first of these AO systems, now coming on line on the 10 m diameter Keck II Telescope. The results include the highest angular resolution images ever obtained from a single telescope (0 \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland,xspace} \usepackage{amsmath,amsx...

The Image Content Engine (ICE) is being developed to provide cueing assistance to human image analysts faced with increasingly large and intractable amounts of image data. The ICE architecture includes user configurable feature extraction pipelines which produce intermediate feature vector and match surface files which can then be accessed by interactive relational queries. Application of the feature extraction algorithms to large collections of images may be extremely time consuming and is launched as a batch job on a Linux cluster. The query interface accesses only the intermediate files and returns candidate hits nearly instantaneously. Queries may be posed for individual objects or collections. The query interface prompts the user for feedback, and applies relevance feedback algorithms to revise the feature vector weighting and focus on relevant search results. Examples of feature extraction and both model-based and search-by-example queries are presented.

The problem of robust automatic road detection in remotely sensed images is complicated by the fact that the sensor, spatial resolution, acquisition conditions, road width, road orientation and road material composition can all vary. A novel technique for detecting road pixels in multisource remotely sensed images based on the phase (i.e., orientation or directional) information in edge pixels is described. A very dense map of edges extracted from the image is separated into channels, each containing edge pixels whose phases lie within a different range of orientations. The edge map associated with each channel is de-cluttered. A map of road pixels is formed by re-combining the de-cluttered channels into a composite edge image which is itself then separately de-cluttered. Road detection results are provided for DigitalGlobe and TeiraServerUSA images. Road representations suitable for various applications are then discussed

Laboratory and field demonstration results obtained as part of the DARPA-sponsored coherent communications, imaging and targeting (CCIT) program are reviewed. The CCIT concept uses a phase conjugation engine based on a quadrature receiver array, a hologram processor and a spatial light modulator (SLM) for high-speed, digital beam control. Progress on the enabling MEMS SLM, being developed by a consortium consisting of LLNL, academic institutions and small businesses, is presented.

High-resolution surveillance imaging with apertures greater than a few inches over horizontal or slant paths at optical or infrared wavelengths will typically be limited by atmospheric aberrations. With static targets and static platforms, we have previously demonstrated near-diffraction limited imaging of various targets including personnel and vehicles over horizontal and slant paths ranging from less than a kilometer to many tens of kilometers using adaptations to bispectral speckle imaging techniques. Nominally, these image processing methods require the target to be static with respect to its background during the data acquisition since multiple frames are required. To obtain a sufficient number of frames and also to allow the atmosphere to decorrelate between frames, data acquisition times on the order of one second are needed. Modifications to the original imaging algorithm will be needed to deal with situations where there is relative target to background motion. In this paper, we present an extension of these imaging techniques to accommodate mobile platforms and moving targets.

The Solid-State, Heat-Capacity Laser (SSHCL), under development at Lawrence Livermore National Laboratory is a large aperture (100 cm{sup 2}), confocal, unstable resonator requiring near-diffraction-limited beam quality. There are two primary sources of the aberrations in the system: residual, static aberrations from the fabrication of the optical components and predictable, time-dependent, thermally-induced index gradients within the gain medium. A deformable mirror placed within the cavity is used to correct the aberrations that are sensed externally with a Shack-Hartmann wavefront sensor. Although it is more challenging than external correction, intracavity correction enables control of the mode growth within the resonator, resulting in the ability to correct a more aberrated system longer. The overall system design, measurement techniques and correction algorithms are discussed. Experimental results from initial correction of the static aberrations and dynamic correction of the time-dependent aberrations are presented.

The Imaging and Detection Program (IDP) within Laser Programs at Lawrence Livermore National Laboratory (LLNL) in cooperation with the Hughes Aircraft Company has developed a versatile, high performance, airborne experimental test-bed (AETB) capability. The test-bed has been developed for a wide range of research and development experimental applications including radar and radiometry plus, with additional aircraft modifications, optical systems. The airborne test-bed capability has been developed within a Douglas EA-3B Skywarrior jet aircraft provided and flown by the Hughes Aircraft Company. The current test-bed payload consists of an X-band radar system, a navigation system, a high-speed data acquisition, and a real-time processing capability. The medium power radar system is configured to operate in a high resolution, synthetic aperture radar (SAR) mode and is highly configurable in terms of waveforms, PRF, bandwidth, etc. Antennas are mounted on a 2-axis gimbal in the belly radome of the aircraft which provides pointing and stabilization. Aircraft position and antenna attitude are derived from a dedicated navigational system and provided to the real-time SAR image processor for instant image reconstruction and analysis. This paper presents a further description of the test-bed and payload subsystems plus preliminary results of SAR imagery.

We introduce a wave-optics based simulation code written to model a complete free space laser communications link, including a detailed model of an adaptive optics compensation system. We present the results obtained by this model, where the phase of a communications laser beam is corrected, after it propagates through a turbulent atmosphere. The phase of the received laser beam is measured using a Shack-Hartmann wavefront sensor, and the correction method utilizes a MEMS mirror. Strehl improvement and amount of power coupled to the receiving fiber results for both 1 km horizontal and 28 km slant paths will be presented.

Direct detection of photons emitted or reflected by an extrasolar planet is an extremely difficult but extremely exciting application of adaptive optics. Typical contrast levels for an extrasolar planet would be 109 - Jupiter is a billion times fainter than the sun. Current adaptive optics systems can only achieve contrast levels of 106, but so-called extreme adaptive optics systems with 104 -105 degrees of freedom could potentially detect extrasolar planets. We explore the scaling laws defining the performance of these systems, first set out by Angel (1994), and derive a different definition of an optimal system. Our sensitivity predictions are somewhat more pessimistic than the original paper, due largely to slow decorrelation timescales for some noise sources, though choosing to site an ExAO system at a location with exceptional r0 (e.g. Mauna Kea) can offset this. We also explore the effects of segment aberrations in a Keck-like telescope on ExAO; although the effects are significant, they can be mitigated through Lyot coronagraphy.© (2002) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Horizontal path laser communications are beginning to provide attractive alternatives for high-speed optical communications. In particular, companies are beginning to sell fiberless alternatives for intranet and sporting event video. These applications are primarily aimed at short distance applications (on the order of 1 km pathlength). There exists a potential need to extend this pathlength to distances much greater than a 1km. For cases of long distance optical propagation, atmospheric turbulence will ultimately limit the maximum achievable data rate. In this paper, we propose a method of improved signal quality through the use of adaptive optics. In particular, we show work in progress toward a high-speed, small footprint Adaptive Optics system for horizontal path laser communications. Such a system relies heavily on recent progress in Micro-Electro-Mechanical Systems (MEMS) deformable mirrors as well as improved communication and computational components. In this paper we detail two Adaptive Optics approaches for improved through-put, the first is the compensated receiver (the traditional Adaptive Optics approach), the second is the compensated transmitter/receiver. The second approach allows for correction of the optical wavefront before transmission from the transmitter and prior to detection at the receiver.

The development of high brightness and short pulse width (200 picoseconds) x-ray lasers now offers biologists the possibility of high-resolution imaging of specimens in an aqueous environment without the blurring effects associated with natural motions and chemical erosion. As a step toward developing the capabilities of this type of x-ray microscopy, a tantalum x-ray laser at 44.83 angstrom wavelength was used together with an x-ray zone plate lens to image both unlabeled and selectively gold-labeled dried rat sperm nuclei. The observed images show approximately 500 angstrom features, illustrate the importance of x-ray microscopy in determining chemical composition, and provide information about the uniformity of sperm chromatin organization and the extent of sperm chromatin hydration.

Wavefront reconstruction techniques using the least-squares estimators are computationally quite expensive. We compare wavelet and Fourier transforms techniques in addressing the computation issues of wavefront reconstruction in adaptive optics. It is shown that because the Fourier approach is not simply a numerical approximation technique unlike the wavelet method, the Fourier approach might have advantages in terms of numerical accuracy. To optimize the wavelet method, a statistical study might be necessary to use the best basis functions or 'approximation tree.'

Sustained operation of high average power solid-state lasers currently requires an adaptive resonator to produce the optimal beam quality. We describe the architecture of a real-time adaptive control system for correcting intra-cavity aberrations in a heat capacity laser. Image data collected from a wavefront sensor are processed and used to control phase with a high-spatial-resolution deformable mirror. Our controller takes advantage of recent developments in low-cost, high-performance processor technology. A desktop-based computational engine and object- oriented software architecture replaces the high-cost rack-mount embedded computers of previous systems.

The wavefront controller for the Keck Observatory AO system consists of two separate real-time control loops: a tip-tilt control loop to remove tilt from the incoming wavefront, and a deformable mirror control loop to remove higher-order aberrations. In this paper, we describe these control loops and analyze their performance using diagnostic data acquired during the integration and testing of the AO system on the telescope. Disturbance rejection curves for the controllers are calculated from the experimental data and compared to theory. The residual wavefront errors due to control loop bandwidth are also calculated from the data, and possible improvements to the controller performance are discussed.

Results of experiments with the laser guide star adaptive optics system on the 3-meter Shane telescope at Lick Observatory have demonstrated a factor of 4 performance improvement over previous results. Stellar images recorded at a wavelength of 2 micrometers were corrected to over 40 percent of the theoretical diffraction-limited peak intensity. For the previous two years, this sodium-layer laser guide star system has corrected stellar images at this wavelength to approximately 10 percent of the theoretical peak intensity limit. After a campaign to improve the beam quality of the laser system, and to improve calibration accuracy and stability of the adaptive optics system using new techniques for phase retrieval and phase-shifting diffraction interferometry, the system performance has been substantially increased. The next step will be to use the Lick system for astronomical science observations, and to demonstrate this level of performance with the new system being installed on the 10-meter Keck II telescope.

We have developed and tested a method for minimizing static aberrations in adaptive optics systems. In order to correct the static phase aberrations, we need to measure the aberrations through the entire system. We have employed various phase retrieval algorithms to detect these aberrations. We have performed simulations of our experimental setup demonstrating that phase retrieval can improve the static aberrations to below the 20 nm rms level, with the limiting factor being local turbulence in the A0 system. Experimentally thus far, we have improved the static aberrations down to the 50 nm level, with the limiting factor being the ability to adjust the deformable mirror. This should be improved with better control algorithms now being implemented.

The laser guide star adaptive optics system currently being developed for the Keck 2 telescope consists of several major subsystems: the optical bench, wavefront control, user interface and supervisory control, and the laser system. The paper describes the design and implementation of the wavefront control subsystem that controls a 349 actuator deformable mirror for high order correction and tip-tilt mirrors for stabilizing the image and laser positions.

Atmospheric turbulence severely limits the resolution of ground-based telescopes. Adaptive optics can correct for the aberrations caused by the atmosphere, but requires a bright wavefront reference source in close angular proximity to the object being imaged. Since natural reference stars of the necessary brightness are relatively rare, methods of generating artificial reference beacons have been under active investigation for more than a decade. In this paper, we report the first significant image improvement achieved using a sodium-layer laser guide star as a wavefront reference for a high-order adaptive optics system. An artificial beacon was created by resonant scattering from atomic sodium in the mesosphere, at an altitude of 95 km. Using this laser guide star, an adaptive optics system on the 3 m Shane Telescope at Lick Observatory produced a factor of 2.4 increase in peak intensity and a factor of 2 decrease in full width at half maximum of a stellar image, compared with image motion compensation alone. The Strehl ratio when using the laser guide star as the reference was 65% of that obtained with a natural guide star, and the image full widths at half maximum were identical, 0.3 arc sec, using either the laser or the natural guide star. This sodium-layer laser guide star technique holds great promise for the world's largest telescopes.

Our objective in this report is to develop methods to determine the output pupil wavefront using intensity measurements directly from the science detector. This wavefront can then be used to determine a reference wavefront which will precorrect for the non-common-path aberrations and produce the desired wavefront at the science detector. We describe two phase retrieval algorithms that can be used and a set of simulation studies of AO system calibration. We present the initial experimental results of applying this technique in calibration of the Lick Observatory laser guidestar AO system in a later paper.

A sodium-layer laser guide star adaptive optics system has been developed at Lawrence Livermore National Laboratory (LLNL) for use on the 3-meter Shane telescope at Lick Observatory. The system is based on a 127-actuator continuous-surface deformable mirror, a Hartmann wavefront sensor equipped with a fast-framing low-noise CCD camera, and a pulsed solid-state-pumped dye laser tuned to the atomic sodium resonance line at 589 nm. The adaptive optics system has been tested on the Shane telescope using natural reference stars yielding up to a factor of 12 increase in image peak intensity and a factor of 6.5 reduction in image full width at half maximum (FWHM). The results are consistent with theoretical expectations. The laser guide star system has been installed and operated on the Shane telescope yielding a beam with 22 W average power at 589 nm. Based on experimental data, this laser should generate an 8th magnitude guide star at this site, and the integrated laser guide star adaptive optics system should produce images with Strehl ratios of 0.4 at 2.2 {mu}m in median seeing and 0.7 at 2.2 {mu}m in good seeing.

We will describe an adaptive optics system developed for the 1 meter Nickel and 3 meter Shane telescopes at Lick Observatory. Observing wavelengths will be in the visible for the 1 meter telescope and in the near IR on the 3 meter. The adaptive optics system design is based on a 69 actuator continuous surface deformable mirror and a Hartmann wavefront sensor equipped with an intensified CCD framing camera. The system has been tested at the Cassegrain focus of the 1 meter telescope where the subaperture size is 12.5 cm. The wavefront control calculations are performed on a four processor single board computer controlled by a Unix-based system. We will describe the optical system and give details of the wavefront control system design. We will present predictions of the system performance and initial test results.

The architecture and major system components of the sodium-layer laser guide star system at LLNL will be described, and experimental results reported. The subsystems include the laser system, the beam delivery system including a pulse stretcher and beam pointing control, the beam director, and the telescope with its adaptive-optics package.

We present the design and implementation of a very compact adaptive optics system that senses the return light from a sodium guide-star and controls a deformable mirror and a pointing mirror to compensate atmospheric perturbations in the wavefront. The deformable mirror has 19 electrostrictive actuators and triangular subapertures. The wavefront sensor is a Hartmann sensor with lenslets on triangular centers. The high-bandwidth steering mirror assembly incorporates an analog controller that samples the tilt with an avalanche photodiode quad cell. An f/25 imaging leg focuses the light into a science camera that can either obtain long-exposure images or speckle data. In laboratory tests overall Strehl ratios were improved by a factor of 3 when a mylar sheet was used as an aberrator. The crossover frequency at unity gain is 30 Hz.

We discuss issues in optimizing the design of adaptive optics and laser guide star systems for the Keck Telescope. The initial tip-tilt system will use Keck's chopping secondary mirror. We describe design constraints, choice of detector, and expected performance of this tip-tilt system as well as its sky coverage. The adaptive optics system is being optimized for wavelengths of 1 - 2.2 micrometers . We are studying adaptive optics concepts which use a wavefront sensor with varying numbers of subapertures, so as to respond to changing turbulence conditions. The goal is to be able to `gang together' groups of deformable mirror subapertures under software control, when conditions call for larger subapertures. We present performance predictions as a function of sky coverage and the number of deformable mirror degrees of freedom. We analyze the predicted brightness of several candidate laser guide star systems, as a function of laser power and pulse format. These predictions are used to examine the resulting Strehl as a function of observing wavelength. We discuss laser waste heat and thermal management issues, and conclude with an overview of instruments under design to take advantage of the Keck adaptive optics system.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Recent results from the Laser Guide Star Project at Lawrence Livermore National Laboratory are presented. Photometry of the return signal has shown that the photon return is approximately 10 photons/cm2/ms at the pupil of the receiving telescope in agreement with a detailed model of the sodium interaction. Wavefronts of the laser guide star have also been measured with a Shack-Hartmann technique and power spectra have been shown to agree with those of nearby natural stars. Plans for closed loop demonstrations using the laser guide star at LLNL and nearby Lick Observatory are discussed.© (1993) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Tomographic x-ray holography may make possible the imaging of biological objects at high resolution in three dimensions. We performed a demonstration experiment with soft x-rays to explore the feasibility of this technique. Coherent 3.2 nm undulator radiation was used to record Fourier transform holograms of a microfabricated test object from various illumination angles. The holograms were numerically reconstructed according to the principles of diffraction tomography, yielding images of the object that are well resolved in three dimensions.© (1993) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The x-ray holography program at the Lawrence Livermore National Laboratory has two principal goals: the development of x-ray diffraction techniques for DNA sequence analysis and the development of x-ray laser holography for structural analysis of intact biological cells and organelles. DNA sequence analysis will be accomplished via x-ray diffraction techniques to determine the ensemble average of the sequence of labels along the individual elements of crystalline DNA. X-ray laser holographic imaging will be accomplished via 3-D x-ray holography to elucidate the structure of few hundred angstrom objects such as 300 A chromatin fibers, nuclear pores and nucleic acid replication complexes in living cells. Existing laboratory x-ray lasers will be used to produce flash x-ray holograms of the biological structures.

The angular resolution of long-exposure images from ground-based telescopes equipped with laser guide star adaptive optics systems is fundamentally limited by the the accuracy with which the tip-tilt aberrations introduced by the atmosphere can be corrected. Assuming that a natural star is used as the tilt reference, the residual error due to tilt anisoplanatism can significantly degrade the long-exposure resolution even if the tilt reference star is separated from the object being imaged by a small angle. Given the observed distribution of stars in the sky, the need to find a tilt reference star quite close to the object restricts the fraction of the sky over which long-exposure images with diffraction limited resolution can be obtained. In this paper, the authors present a comprehensive performance analysis of tip-tilt compensation systems that use a natural star as a tilt reference, taking into account properties of the atmosphere and of the Galactic stellar populations, and optimizing over the system operating parameters to determine the fundamental limits to the long-exposure resolution. Their results show that for a ten meter telescope on Mauna Kea, if the image of the tilt reference star is uncorrected, about half the sky can be imaged in the Vmore » band with long-exposure resolution less than 60 milli-arc-seconds (mas), while if the image of the tilt reference star is fully corrected, about half the sky can be imaged in the V band with long-exposure resolution less than 16 mas. Furthermore, V band images long-exposure resolution of less than 16 mas may be obtained with a ten meter telescope on Mauna Kea for unresolved objects brighter than magnitude 22 that are fully corrected by a laser guide star adaptive optics system. This level of resolution represents about 70% of the diffraction limit of a ten meter telescope in the V band and is more than a factor of 45 better than the median seeing in the V band on Mauna Kea.« less