Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor

Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G protein-coupled receptors, which are enzymatically cleaved to expose a truncated extracellular N terminus that acts as a tethered activating ligand. PAR-1 is cleaved and activated by the serine protease α-thrombin, is expressed in various tissues (e.g., platelets and vascular cells), and is involved in cellular responses associated with hemostasis, proliferation, and tissue injury. We have discovered a series of potent peptide-mimetic antagonists of PAR-1, exemplified by RWJ-56110. Spatial relationships between important functional groups of the PAR-1 agonist peptide epitope SFLLRN were employed to design and synthesize candidate ligands with appropriate groups attached to a rigid molecular scaffold. Prototype RWJ-53052 was identified and optimized via solid-phase parallel synthesis of chemical libraries. RWJ-56110 emerged as a potent, selective PAR-1 antagonist, devoid of PAR-1 agonist and thrombin inhibitory activity. It binds to PAR-1, interferes with PAR-1 calcium mobilization and cellular function (platelet aggregation; cell proliferation), and has no effect on PAR-2, PAR-3, or PAR-4. By flow cytometry, RWJ-56110 was confirmed as a direct inhibitor of PAR-1 activation and internalization, without affecting N-terminal cleavage. At high concentrations of α-thrombin, RWJ-56110 fully blocked activation responses in human vascular cells, albeit not in human platelets; whereas, at high concentrations of SFLLRN-NH2, RWJ-56110 blocked activation responses in both cell types. Thus, thrombin activates human platelets independently of PAR-1, i.e., through PAR-4, which we confirmed by PCR analysis. Selective PAR-1 antagonists, such as RWJ-56110, should serve as useful tools to study PARs and may have therapeutic potential for treating thrombosis and restenosis.

Impact of Spatial Soil and Climate Input Data Aggregation on Regional Yield Simulations

This work was financially supported by the German Federal Ministry of Food and Agriculture (BMEL) through the Federal Office for Agriculture and Food (BLE), (2851ERA01J). FT and RPR were supported by FACCE MACSUR (3200009600) through the Finnish Ministry of Agriculture and Forestry (MMM). EC, HE and EL were supported by The Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (220-2007-1218) and by the strategic funding ‘Soil-Water-Landscape’ from the faculty of Natural Resources and Agricultural Sciences (Swedish University of Agricultural Sciences) and thank professor P-E Jansson (Royal Institute of Technology, Stockholm) for support. JC, HR and DW thank the INRA ACCAF metaprogramm for funding and Eric Casellas from UR MIAT INRA for support. CB was funded by the Helmholtz project “REKLIM—Regional Climate Change”. CK was funded by the HGF Alliance “Remote Sensing and Earth System Dynamics” (EDA). FH was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) under the Grant FOR1695. FE and SS acknowledge support by the German Science Foundation (project EW 119/5-1). HH, GZ, SS, TG and FE thank Andreas Enders and Gunther Krauss (INRES, University of Bonn) for support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Financial fragility, trade credit and contagion effects during the crisis: a spatial econometric approach to firm-level data

The number of distressed manufacturing firms increased sharply during recessionary phase 2009-13. Financial indebtness traditionally plays a key role in assessing firm solvency but contagion effects that originate from the supply chain are usually neglected in literature. Firm interconnections, captured via the trade credit channel, represent a primary vehicle of individual shocks’ propagation, especially during an economic downturn, when liquidity tensions arise. A representative sample of 11,920 Italian manufacturing firms is considered to model a two-step econometric design, where chain reactions in terms of trade credit accumulation (i.e. default of payments to suppliers) are primarily analyzed by resorting to a spatial autoregressive approach (SAR). Spatial interactions are modeled based on a unique dataset of firm-to-firm transactions registered before the outbreak of the crisis. The second step in instead a binary outcome model where trade credit chains are considered together with data on the bank-firm relationship to assess determinants of distress likelihoods in 2009-13. Results show that outstanding trade debt is affected by the liquidity position of a firm and by positive spatial effects. Trade credit chain reactions are found to exert, in turn, a positive impact on distress likelihoods during the crisis. The latter effect is comparable in magnitude to the one exerted by individual financial rigidity, and stresses the importance to include complex interactions between firms in the analysis of the solvency behavior.

3D teaching: the ideal complement for professionals in design and construction

Today, the requirement of professional skills to university students is constantly increasing in our society. In our opinion, the content offered in official degrees need to be nourished with different variables, enriching their global professional knowledge in a parallel way; that is why, in recent years, there is a great multiplicity of complementary courses at university. One of the most socially demanded technical requirements within the architectural, design or engineering field is the management of 3D drawing software, becoming an indispensable reality in these sectors. Thus, this specific training becomes essential over two-dimension traditional design, because the inclusion of great possibilities of spatial development that go beyond conventional orthographic projections (plans, sections or elevations), allowing modelling and rotation of the selected items from multiple angles and perspectives. Therefore, this paper analyzes the teaching methodology of a complementary course for those technicians in the construction industry interested in computer-aided design, using modelling (SketchupMake) and rendering programs (Kerkythea). The course is developed from the technician point of view, by learning computer management and its application to professional development from a more general to a more specific view through practical examples. The proposed methodology is based on the development of real examples in different professional environments such as rehabilitation, new constructions, opening projects or architectural design. This multidisciplinary contribution improves criticism of students in different areas, encouraging new learning strategies and the independent development of three-dimensional solutions. Thus, the practical implementation of new situations, even suggested by the students themselves, ensures active participation, saving time during the design process and the increase of effectiveness when generating elements which may be represented, moved or virtually tested. In conclusion, this teaching-learning methodology improves the skills and competencies of students to face the growing professional demands of society. After finishing the course, technicians not only improved their expertise in the field of drawing but they also enhanced their capacity for spatial vision; both essential qualities in these sectors that can be applied to their professional development with great success.

Urban Design Guidelines for Human Wellbeing in Martian Settlements

Thesis (Master's)--University of Washington, 2016-06

Efficiency, costs and trade-offs in marine reserve system design

With marine biodiversity conservation the primary goal for reserve planning initiatives, a site's conservation potential is typically evaluated on the basis of the biological and physical features it contains. By comparison, socio-economic information is seldom a formal consideration of the reserve system design problem and generally limited to an assessment of threats, vulnerability or compatibility with surrounding uses. This is perhaps surprising given broad recognition that the success of reserve establishment is highly dependent on widespread stakeholder and community support. Using information on the spatial distribution and intensity of commercial rock lobster catch in South Australia, we demonstrate the capacity of mathematical reserve selection procedures to integrate socio-economic and biophysical information for marine reserve system design. Analyses of trade-offs highlight the opportunities to design representative, efficient and practical marine reserve systems that minimise potential loss to commercial users. We found that the objective of minimising the areal extent of the reserve system was barely compromised by incorporating economic design constraints. With a small increase in area (< 3%) and boundary length (< 10%), the economic impact of marine reserves on the commercial rock lobster fishery was reduced by more than a third. We considered also how a reserve planner might prioritise conservation areas using information on a planning units selection frequency. We found that selection frequencies alone were not a reliable guide for the selection of marine reserve systems, but could be used with approaches such as summed irreplaceability to direct conservation effort for efficient marine reserve design.

Summarizing level-two topological relations in large spatial datasets

Summarizing topological relations is fundamental to many spatial applications including spatial query optimization. In this article, we present several novel techniques to effectively construct cell density based spatial histograms for range (window) summarizations restricted to the four most important level-two topological relations: contains, contained, overlap, and disjoint. We first present a novel framework to construct a multiscale Euler histogram in 2D space with the guarantee of the exact summarization results for aligned windows in constant time. To minimize the storage space in such a multiscale Euler histogram, an approximate algorithm with the approximate ratio 19/12 is presented, while the problem is shown NP-hard generally. To conform to a limited storage space where a multiscale histogram may be allowed to have only k Euler histograms, an effective algorithm is presented to construct multiscale histograms to achieve high accuracy in approximately summarizing aligned windows. Then, we present a new approximate algorithm to query an Euler histogram that cannot guarantee the exact answers; it runs in constant time. We also investigate the problem of nonaligned windows and the problem of effectively partitioning the data space to support nonaligned window queries. Finally, we extend our techniques to 3D space. Our extensive experiments against both synthetic and real world datasets demonstrate that the approximate multiscale histogram techniques may improve the accuracy of the existing techniques by several orders of magnitude while retaining the cost efficiency, and the exact multiscale histogram technique requires only a storage space linearly proportional to the number of cells for many popular real datasets.

Some results on the design of field experiments for comparing unreplicated treatments

In early generation variety trials, large numbers of new breeders' lines need to be compared, and usually there is little seed available for each new line. A so-called unreplicated trial has each new line on just one plot at a site, but includes several (often around five) replicated check or control (or standard) varieties. The total proportion of check plots is usually between 10% and 20%. The aim of the trial is to choose some good performing lines (usually around 1/3 of those tested) to go on for further testing, rather than precise estimation of their mean yield. Now that spatial analyses of data from field experiments are becoming more common, there is interest in an efficient layout of an experiment given a proposed spatial analysis. Some possible design criteria are discussed, and efficient layouts under spatial dependence are considered.

Tailoring magnetic field gradient design to magnet cryostat geometry

Eddy currents induced within a magnetic resonance imaging (MRI) cryostat bore during pulsing of gradient coils can be applied constructively together with the gradient currents that generate them, to obtain good quality gradient uniformities within a specified imaging volume over time. This can be achieved by simultaneously optimizing the spatial distribution and temporal pre-emphasis of the gradient coil current, to account for the spatial and temporal variation of the secondary magnetic fields due to the induced eddy currents. This method allows the tailored design of gradient coil/magnet configurations and consequent engineering trade-offs. To compute the transient eddy currents within a realistic cryostat vessel, a low-frequency finite-difference time-domain (FDTD) method using total-field scattered-field (TFSF) scheme has been performed and validated

A flexible, extensible object oriented real-time near photorealistic visualization system:the system framework design

In this paper we describe a novel, extensible visualization system currently under development at Aston University. We introduce modern programming methods, such as the use of data driven programming, design patterns, and the careful definition of interfaces to allow easy extension using plug-ins, to 3D landscape visualization software. We combine this with modern developments in computer graphics, such as vertex and fragment shaders, to create an extremely flexible, extensible real-time near photorealistic visualization system. In this paper we show the design of the system and the main sub-components. We stress the role of modern programming practices and illustrate the benefits these bring to 3D visualization. © 2006 Springer-Verlag Berlin Heidelberg.

The design of environmental test rigs

Product reliability and its environmental performance have become critical elements within a product's specification and design. To obtain a high level of confidence in the reliability of the design it is customary to test the design under realistic conditions in a laboratory. The objective of the work is to examine the feasibility of designing mechanical test rigs which exhibit prescribed dynamical characteristics. The design is then attached to the rig and excitation is applied to the rig, which then transmits representative vibration levels into the product. The philosophical considerations made at the outset of the project are discussed as they form the basis for the resulting design methodologies. It is attempted to directly identify the parameters of a test rig from the spatial model derived during the system identification process. It is shown to be impossible to identify a feasible test rig design using this technique. A finite dimensional optimal design methodology is developed which identifies the parameters of a discrete spring/mass system which is dynamically similar to a point coordinate on a continuous structure. This design methodology is incorporated within another procedure which derives a structure comprising a continuous element and a discrete system. This methodology is used to obtain point coordinate similarity for two planes of motion, which is validated by experimental tests. A limitation of this approach is that it is impossible to achieve multi-coordinate similarity due to an interaction of the discrete system and the continuous element at points away from the coordinate of interest. During the work the importance of the continuous element is highlighted and a design methodology is developed for continuous structures. The design methodology is based upon distributed parameter optimal design techniques and allows an initial poor design estimate to be moved in a feasible direction towards an acceptable design solution. Cumulative damage theory is used to provide a quantitative method of assessing the quality of dynamic similarity. It is shown that the combination of modal analysis techniques and cumulative damage theory provides a feasible design synthesis methodology for representative test rigs.

INTAMAP: the design and implementation of an interoperable automated interpolation web service

INTAMAP is a Web Processing Service for the automatic spatial interpolation of measured point data. Requirements were (i) using open standards for spatial data such as developed in the context of the Open Geospatial Consortium (OGC), (ii) using a suitable environment for statistical modelling and computation, and (iii) producing an integrated, open source solution. The system couples an open-source Web Processing Service (developed by 52°North), accepting data in the form of standardised XML documents (conforming to the OGC Observations and Measurements standard) with a computing back-end realised in the R statistical environment. The probability distribution of interpolation errors is encoded with UncertML, a markup language designed to encode uncertain data. Automatic interpolation needs to be useful for a wide range of applications and the algorithms have been designed to cope with anisotropy, extreme values, and data with known error distributions. Besides a fully automatic mode, the system can be used with different levels of user control over the interpolation process.

Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics

Context - Diffusion tensor imaging (DTI) studies in adults with bipolar disorder (BD) indicate altered white matter (WM) in the orbitomedial prefrontal cortex (OMPFC), potentially underlying abnormal prefrontal corticolimbic connectivity and mood dysregulation in BD. Objective - To use tract-based spatial statistics (TBSS) to examine WM skeleton (ie, the most compact whole-brain WM) in subjects with BD vs healthy control subjects. Design - Cross-sectional, case-control, whole-brain DTI using TBSS. Setting - University research institute. Participants - Fifty-six individuals, 31 having a DSM-IV diagnosis of BD type I (mean age, 35.9 years [age range, 24-52 years]) and 25 controls (mean age, 29.5 years [age range, 19-52 years]). Main Outcome Measures - Fractional anisotropy (FA) longitudinal and radial diffusivities in subjects with BD vs controls (covarying for age) and their relationships with clinical and demographic variables. Results - Subjects with BD vs controls had significantly greater FA (t > 3.0, P = .05 corrected) in the left uncinate fasciculus (reduced radial diffusivity distally and increased longitudinal diffusivity centrally), left optic radiation (increased longitudinal diffusivity), and right anterothalamic radiation (no significant diffusivity change). Subjects with BD vs controls had significantly reduced FA (t > 3.0, P = .05 corrected) in the right uncinate fasciculus (greater radial diffusivity). Among subjects with BD, significant negative correlations (P < .01) were found between age and FA in bilateral uncinate fasciculi and in the right anterothalamic radiation, as well as between medication load and FA in the left optic radiation. Decreased FA (P < .01) was observed in the left optic radiation and in the right anterothalamic radiation among subjects with BD taking vs those not taking mood stabilizers, as well as in the left optic radiation among depressed vs remitted subjects with BD. Subjects having BD with vs without lifetime alcohol or other drug abuse had significantly decreased FA in the left uncinate fasciculus. Conclusions - To our knowledge, this is the first study to use TBSS to examine WM in subjects with BD. Subjects with BD vs controls showed greater WM FA in the left OMPFC that diminished with age and with alcohol or other drug abuse, as well as reduced WM FA in the right OMPFC. Mood stabilizers and depressed episode reduced WM FA in left-sided sensory visual processing regions among subjects with BD. Abnormal right vs left asymmetry in FA in OMPFC WM among subjects with BD, likely reflecting increased proportions of left-sided longitudinally aligned and right-sided obliquely aligned myelinated fibers, may represent a biologic mechanism for mood dysregulation in BD.

A computational model of intonation for yorùbá text-to-speech synthesis:design and analysis

In this paper we present the design and analysis of an intonation model for text-to-speech (TTS) synthesis applications using a combination of Relational Tree (RT) and Fuzzy Logic (FL) technologies. The model is demonstrated using the Standard Yorùbá (SY) language. In the proposed intonation model, phonological information extracted from text is converted into an RT. RT is a sophisticated data structure that represents the peaks and valleys as well as the spatial structure of a waveform symbolically in the form of trees. An initial approximation to the RT, called Skeletal Tree (ST), is first generated algorithmically. The exact numerical values of the peaks and valleys on the ST is then computed using FL. Quantitative analysis of the result gives RMSE of 0.56 and 0.71 for peak and valley respectively. Mean Opinion Scores (MOS) of 9.5 and 6.8, on a scale of 1 - -10, was obtained for intelligibility and naturalness respectively.

Determination of excitation profile and dielectric function spatial nonuniformity in porous silicon by using WKB approach

We develop an analytical model based on the WKB approach to evaluate the experimental results of the femtosecond pump-probe measurements of the transmittance and reflectance obtained on thin membranes of porous silicon. The model allows us to retrieve a pump-induced nonuniform complex dielectric function change along the membrane depth. We show that the model fitting to the experimental data requires a minimal number of fitting parameters while still complying with the restriction imposed by the Kramers-Kronig relation. The developed model has a broad range of applications for experimental data analysis and practical implementation in the design of devices involving a spatially nonuniform dielectric function, such as in biosensing, wave-guiding, solar energy harvesting, photonics and electro-optical devices.