A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

High-level expression of functional rat neuronal nitric oxide synthase in Escherichia coli.

The neuronal nitric oxide synthase (nNOS) has been successfully overexpressed in Escherichia coli, with average yields of 125-150 nmol (20-24 mg) of enzyme per liter of cells. The cDNA for nNOS was subcloned into the pCW vector under the control of the tac promotor and was coexpressed with the chaperonins groEL and groES in the protease-deficient BL21 strain of E. coli. The enzyme produced is replete with heme and flavins and, after overnight incubation with tetrahydrobiopterin, contains 0.7 pmol of tetrahydrobiopterin per pmol of nNOS. nNOS is isolated as a predominantly high-spin heme protein and demonstrates spectral properties that are identical to those of nNOS isolated from stably transfected human kidney 293 cells. It binds N omega-nitroarginine dependent on the presence of bound tetrahydrobiopterin and exhibits a Kd of 45 nM. The enzyme is completely functional; the specific activity is 450 nmol/min per mg. This overexpression system will be extremely useful for rapid, inexpensive preparation of large amounts of active nNOS for use in mechanistic and structure/function studies, as well as for drug design and development.

New framework for score segmentation and analysis in OpenMusic

We present new tools for the segmentation and analysis of musical scores in the OpenMusic computer-aided composition environment. A modular object-oriented framework enables the creation of segmentations on score objects and the implementation of automatic or semi-automatic analysis processes. The analyses can be performed and displayed thanks to customizable classes and callbacks. Concrete examples are given, in particular with the implementation of a semi-automatic harmonic analysis system and a framework for rhythmic transcription.

Efficient tool path computation using multi-core GPUs

Tool path generation is one of the most complex problems in Computer Aided Manufacturing. Although some efficient strategies have been developed, most of them are only useful for standard machining. However, the algorithms used for tool path computation demand a higher computation performance, which makes the implementation on many existing systems very slow or even impractical. Hardware acceleration is an incremental solution that can be cleanly added to these systems while keeping everything else intact. It is completely transparent to the user. The cost is much lower and the development time is much shorter than replacing the computers by faster ones. This paper presents an optimisation that uses a specific graphic hardware approach using the power of multi-core Graphic Processing Units (GPUs) in order to improve the tool path computation. This improvement is applied on a highly accurate and robust tool path generation algorithm. The paper presents, as a case of study, a fully implemented algorithm used for turning lathe machining of shoe lasts. A comparative study will show the gain achieved in terms of total computing time. The execution time is almost two orders of magnitude faster than modern PCs.

imaxin|software: PLN aplicada a la mejora de la comunicación multilingüe de empresas e instituciones

imaxin|software es una empresa creada en 1997 por cuatro titulados en ingeniería informática cuyo objetivo ha sido el de desarrollar videojuegos multimedia educativos y procesamiento del lenguaje natural multilingüe. 17 años más tarde, hemos desarrollado recursos, herramientas y aplicaciones multilingües de referencia para diferentes lenguas: Portugués (Galicia, Portugal, Brasil, etc.), Español (España, Argentina, México, etc.), Inglés, Catalán y Francés. En este artículo haremos una descripción de aquellos principales hitos en relación a la incorporación de estas tecnologías PLN al sector industrial e institucional.

Isobutane Alkylation Process Synthesis by means of Hybrid Simulation-Multiobjective Optimization

Multiobjective Generalized Disjunctive Programming (MO-GDP) optimization has been used for the synthesis of an important industrial process, isobutane alkylation. The two objective functions to be simultaneously optimized are the environmental impact, determined by means of LCA (Life Cycle Assessment), and the economic potential of the process. The main reason for including the minimization of the environmental impact in the optimization process is the widespread environmental concern by the general public. For the resolution of the problem we employed a hybrid simulation- optimization methodology, i.e., the superstructure of the process was developed directly in a chemical process simulator connected to a state of the art optimizer. The model was formulated as a GDP and solved using a logic algorithm that avoids the reformulation as MINLP -Mixed Integer Non Linear Programming-. Our research gave us Pareto curves compounded by three different configurations where the LCA has been assessed by two different parameters: global warming potential and ecoindicator-99.

Computers in aeronautics and space research at the Lewis Research Center /

"Sep 90"--P. [12].

The use of computers in literature searching and related reference activities in libraries : papers presented at the 1975 Clinic on Library Applications of Data Processing, April 27-30, 1975 /

Includes bibliographical references.

[College of Engineering (University of Michigan) publications].

Also contains brochures, directories, manuals, and programs from various College of Engineering student organizations such as the Society of Women Engineers and Tau Beta Pi.

Trust me, I'm your boss: Trust and power in supervisor-supervisee communication

This study examined employees' perceptions of trust, power and mentoring in manager-employee relationships in a variety of sectors, including health care, education, hospitality and retail. The main theoretical frameworks used were communication accommodation theory and social identity theory, in examining the manager-employee relationships from an in-group/out-group perspective. Computer-aided content analyses revealed a number of emergent communication and relationship themes that impact upon the level of 'in-groupness' and therefore trust in supervisor-supervisee relationships. While it may be illusory to believe that any organization can enjoy complete trust among its workforce, it is clear that certain communication characteristics can result in greater trust in manager-employee relationships, even within the context of organizational constraints. It is argued that the results of the study could be used to inform human resource management academics of key aspects of managerial communication that should be further researched, and also provide insights into the main communication skills that managers should focus upon to improve trust in the workplace.

Application of X-ray microtomography to numerical simulations of agglomerate breakage by distinct element method

Computer-aided tomography has been used for many years to provide significant information about the internal properties of an object, particularly in the medical fraternity. By reconstructing one-dimensional (ID) X-ray images, 2D cross-sections and 3D renders can provide a wealth of information about an object's internal structure. An extension of the methodology is reported here to enable the characterization of a model agglomerate structure. It is demonstrated that methods based on X-ray microtomography offer considerable potential in the validation and utilization of distinct element method simulations also examined.

Discovery, structure and biological activities of the cyclotides

The cyclotides are a family of small disulfide rich proteins that have a cyclic peptide backbone and a cystine knot formed by three conserved disulfide bonds. The combination of these two structural motifs contributes to the exceptional chemical, thermal and enzymatic stability of the cyclotides, which retain bioactivity after boiling. They were initially discovered based on native medicine or screening studies associated with some of their various activities, which include uterotonic action, anti-HIV activity, neurotensin antagonism, and cytotoxicity. They are present in plants from the Rubiaceae, Violaceae and Cucurbitaccae families and their natural function in plants appears to be in host defense: they have potent activity against certain insect pests and they also have antimicrobial activity. There are currently around 50 published sequences of cyclotides and their rate of discovery has been increasing over recent years. Ultimately the family may comprise thousands of members. This article describes the background to the discovery of the cyclotides, their structural characterization, chemical synthesis, genetic origin, biological activities and potential applications in the pharmaceutical and agricultural industries. Their unique topological features make them interesting from a protein folding perspective. Because of their highly stable peptide framework they might make useful templates in drug design programs, and their insecticidal activity opens the possibility of applications in crop protection.

Countering cooperative effects in protease inhibitors using constrained b-strand-mimicking templates in focused combinatorial libraries

A major problem in de novo design of enzyme inhibitors is the unpredictability of the induced fit, with the shape of both ligand and enzyme changing cooperatively and unpredictably in response to subtle structural changes within a ligand. We have investigated the possibility of dampening the induced fit by using a constrained template as a replacement for adjoining segments of a ligand. The template preorganizes the ligand structure, thereby organizing the local enzyme environment. To test this approach, we used templates consisting of constrained cyclic tripeptides, formed through side chain to main chain linkages, as structural mimics of the protease-bound extended beta-strand conformation of three adjoining amino acid residues at the N- or C-terminal sides of the scissile bond of substrates. The macrocyclic templates were derivatized to a range of 30 structurally diverse molecules via focused combinatorial variation of nonpeptidic appendages incorporating a hydroxyethylamine transition-state isostere. Most compounds in the library were potent inhibitors of the test protease (HIV-1 protease). Comparison of crystal structures for five protease-inhibitor complexes containing an N-terminal macrocycle and three protease-inhibitor complexes containing a C-terminal macrocycle establishes that the macrocycles fix their surrounding enzyme environment, thereby permitting independent variation of acyclic inhibitor components with only local disturbances to the protease. In this way, the location in the protease of various acyclic fragments on either side of the macrocyclic template can be accurately predicted. This type of templating strategy minimizes the problem of induced fit, reducing unpredictable cooperative effects in one inhibitor region caused by changes to adjacent enzyme-inhibitor interactions. This idea might be exploited in template-based approaches to inhibitors of other proteases, where a beta-strand mimetic is also required for recognition, and also other protein-binding ligands where different templates may be more appropriate.