Are hormones from the neuropeptide Y family recognized by their receptors from the membrane-bound state?

Hormones and many other neurotransmitters, growth factors, odorant molecules, and light all present stimuli for a class of membrane-anchored receptors called G protein-coupled receptors (GPCRs). The GPCRs are the largest family of cell-surface receptors involved in signal transduction. About 1% of all known genes of Drosophila and more than 5% of the genes of Caenorhabditis elegans encode GPCRs. In addition, more than 50% of current therapeutic agents on the market target these receptors. When the enormous biological and pharmaceutical importance of these receptors is considered, it is surprising how little is known about the mechanism with which these receptors recognize their natural ligands. In this review we present a structural approach, utilizing techniques of high-resolution NMR spectroscopy, to address the question of whether peptides from the neuropeptide Y family of neurohormones are recognized directly from solution or from the membrane-bound state. In our studies we discovered that the structures of the membrane-bound species are better correlated to the pharmacological properties of these peptides than the solution structures are. These findings are supported by the observation that many biophysical properties of these peptides seem to be optimized for membrane binding. We finally present a scenario of possible events during receptor recognition.     

Molecular structures and conformational studies of triarylcyclopropyl and related nonsteroidal antiestrogens

Molecular structures and conformational characteristics of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), which were reported previously to be distinctly antiestrogenic and inhibitors of the estrogen-receptor-positive MCF-7 human breast cancer cells in culture, are reported. In addition, structural and conformational features of the DTACs were compared to the first-known nonsteroidal antiestrogen, MER25, and the clinically useful antiestrogen Tamoxifen. The molecular structures of four DTAC compounds were determined by X-ray diffraction. Crystallographic structures show that the DTAC molecules have nearly the same relative conformation for the three aryl rings which is designated as a "nonpropeller" conformation in contrast to the observed "propeller" conformation for the three rings in all known triarylethylenes. Systematic conformational searches were performed to find the conformational preferences of DTACs, MER25, and Tamoxifen using idealized model compounds built from their respective crystal structure. Energy-minimization and conformational-search studies demonstrated that all DTAC molecules have a common, single global minimum energy conformer for their central core containing the dichlorotriarylcyclopropyl system, which is similar to that found in their crystal structures. Conformational search of MER25 showed that the molecule can assume a number of low-energy conformers of which two, one anti (A1) and one gauche (G1A), have about the same energy. The anti conformation is similar to the one observed in its crystal structure and resembles the estrogenic E-isomer of Tamoxifen, while the lowest energy gauche conformer of MER25 resembles more closely the antiestrogenic Z-isomer of Tamoxifen. NMR spectroscopic analysis of MER25 showed that the molecule exists predominantly in the anti conformation in solution. A comparative review of the structural features and bioactivities of Tamoxifen, DTACs, and MER25 provides a possible explanation for their low estrogen receptor binding affinity which is common to these compounds together with their antiestrogenic activity.     

Reflection-transmission photoellipsometry: theory and experiments

We propose a method that uses reflection and transmission photoellipsometry to analyze samples consisting of thin films combined with semitransparent thick layers or substrates in the form of multilayer structures. Athick film or substrate is defined as a layer for which no interference effects can be observed for a given wavelength resolution, and contributions from multiple reflections in the substrate are taken into account in the theoretical treatment. An automatic reflection-transmission spectroscopic ellipsometer was built to test the theory, and satisfactory results have been obtained. Examples corresponding to a strongly absorbing film deposited on a glass substrate and a highly transmitting film also deposited on glass are shown. In both cases a good fit between theory and experiment is found. The photoellipsometric method presented is particularly suited to the analysis of actual samples of energy-efficient coatings for windows.     

Parallel algorithms for image enhancement and segmentation by region growing, with an experimental study

This paper presents efficient and portable implementations of a powerful image enhancement process, the Symmetric Neighborhood Filter (SNF), and an image segmentation technique that makes use of the SNF and a variant of the conventional connected components algorithm which we call -Connected Components. We use efficient techniques for distributing and coalescing data as well as efficient combinations of task and data parallelism. The image segmentation algorithm makes use of an efficient connected components algorithm based on a novel approach for parallel merging. The algorithms have been coded in Split-C and run on a variety of platforms, including the Thinking Machines CM-5, IBM SP-1 and SP-2, Cray Research T3D, Meiko Scientific CS-2, Intel Paragon, and workstation clusters. Our experimental results are consistent with the theoretical analysis (and provide the best known execution times for segmentation, even when compared with machine-specific implementations). Our test data include difficult images from the Landsat Thematic Mapper (TM) satellite data.Also affiliated with the Department of Electrical Engineering.Also affiliated with the Department of Computer Science and the Center for Automation Research.     

Congestion prevention in broadband wireless access systems: An economic approach

While the demand for mobile broadband wireless services continues to increase, radio resources remain scarce. Even with the substantial increase in the supported bandwidth in the next generation broadband wireless access systems (BWASs), it is expected that these systems will severely suffer from congestion, due to the rapid increase in demand of bandwidth-intensive multimedia services. Without efficient bandwidth management and congestion control schemes, network operators may not be able to meet the increasing demand of users for multimedia services, and hence they may suffer an immense revenue loss. In this paper, we propose an admission-level bandwidth management scheme consisting of call admission control (CAC) and dynamic pricing. The main aim of our proposed scheme is to provide monetary incentives to users to use the wireless resources efficiently and rationally, hence, allowing efficient bandwidth management at the admission level. By dynamically determining the prices of units of bandwidth, the proposed scheme can guarantee that the number of connection requests to the system are less than or equal to certain optimal values computed dynamically, hence, ensuring a congestion-free system. The proposed scheme is general and can accommodate different objective functions for the admission control as well as different pricing functions. Comprehensive simulation results with accurate and inaccurate demand modeling are provided to show the effectiveness and strengths of our proposed approach.     

The transposition median problem is NP-complete

During recent years, the genomes of more and more species have been sequenced, providing data for phylogenetic reconstruction based on genome rearrangement measures, where the most important distance measures are the reversal distance and the transposition distance. The two main tasks in all phylogenetic reconstruction algorithms are to calculate pairwise distances and to solve the median of three problem. While the reversal distance problem can be solved in linear time, the reversal median problem has been proven to be NP-complete. The status of the transposition distance problem is still open, but it is conjectured to be more difficult than the reversal problem. This, in turn, also suggests that the transposition median problem is NP-complete. However, this conjecture could not yet be proven. We have now succeeded in giving a non-trivial proof for the NP-completeness of the transposition median problem.     

The synthesis of elastin, collagen, and glycosaminoglycans by high density primary cultures of neonatal rat aortic smooth muscle. An ultrastructural and biochemical study

Primary cultures of neonatal rat aortic smooth muscle cells inoculated at high densities (1 X 10(6) cells/25 cm2 Falcon flask) with adequate nutrient media and pH control grow rapidly and form multilayers of cells with typical "hill and valley" organization. After 10 days growth insoluble elastin formation could be visualized by phase contrast microscopy as small particles which grew rapidly to become larger irregular refractile aggregates and later coalesced to form larger aggregates and small fibres. With light and electronmicroscopy, elastin was the predominant matrix protein formed, with the "hill regions" of cultures containing abundant elastin aggregates and some collagen. In 2-week-old cultures differentiation could be observed within the cell multilayer. The older deeper cells contained more protein synthesis organelles and myofilaments and were in close association with large often coalescing elastin aggregates; compared to younger more superficial cells which contained more free polyribosomes less myofilaments, and were associated with fewer and small elastin aggregates. In older cultures this differentiation was not apparent; the cells contained many myofilaments, dense bodies, and lysosomes. Elastin aggregates and newly formed elastic fibres were abundant in the matrix. Quantitative analysis of insoluble elastin formation in the cell layer during the 4-week culture period indicated continuous biosynthesis and deposition which paralleled that of desmosine formation. Amino-acid analysis of a hot alkali insoluble residue (regarded as elastin) from 30-day-old cultures gave a profile identical with neonatal rat aortic elastin in vivo. Insoluble collagen formation in the cell layer tended to plateau after the log phase of growth was completed (10 days). Proteoglycans were found predominantly in the supernatant media. Glycosaminoglycan analysis revealed a profile of dermatan sulphate (32%), chondroitin 4-sulphate (43%), keratan and heparan sulphate (30%), with only a trace of hyaluronic acid. This study indicates that primary cultures of neonatal rat aortic smooth muscle cells remain differentiated in culture and have the unique capacity to continue to synthesize and deposit large amounts (mg) of insoluble elastin which aggregate and from elastic fibres in vitro.     

Energetic ion loss detector on the Alcator C-Mod tokamak

A scintillator-based energetic ion loss detector has been successfully commissioned on the Alcator C-Mod tokamak. This probe is located just below the outer midplane, where it captures ions of energies up to 2 MeV resulting from ion cyclotron resonance heating. After passing through a collimating aperture, ions impact different regions of the scintillator according to their gyroradius (energy) and pitch angle. The probe geometry and installation location are determined based on modeling of expected lost ions. The resulting probe is compact and resembles a standard plasma facing tile. Four separate fiber optic cables view different regions of the scintillator to provide phase space resolution. Evolving loss levels are measured during ion cyclotron resonance heating, including variation dependent upon individual antennae.     

High performance computing algorithms for land cover dynamics using remote sensing data

Global and regional land cover studies need to apply complex models on selected subsets of large volumes of multi-sensor and multi-temporal data sets that have been derived from raw instrument measurements using widely accepted pre-processing algorithms. The computational and storage requirements of most of these studies far exceed what is possible on a single workstation environment. We have been pursuing a new approach that couples scalable and open distributed heterogeneous hardware with the development of high performance software for processing, indexing and organizing remotely sensed data. Hierarchical data management tools are used to ingest raw data, create metadata and organize the archived data so as to automatically achieve computational load balancing among the available nodes and minimize input/output overheads. We illustrate our approach with four specific examples. The first is the development of the first fast operational scheme for the atmospheric correction of Landsat Thematic Mapper scenes, while the second example focuses on image segmentation using a novel hierarchical connected components algorithm. Retrieval of the global Bidirectional Reflectance Distribution Function in the red and near-infrared wavelengths using four years (1983 to 1986) of Pathfinder Advanced Very High Resolution Radiometer (AVHRR) Land data is the focus of our third example. The fourth example is the development of a hierarchical data organization scheme that allows on-demand processing and retrieval of regional and global AVHRR data sets. Our results show that substantial reductions in computational times can be achieved by the high performance computing technology.