Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 ± 0.11; Ca(2+) mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs.-Hudson, B. D., Christiansen, E., Tikhonova, I. G., Grundmann, M., Kostenis, E., Adams, D. R., Ulven, T., Milligan, G. Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs.

CoMFA and homology-based models of the glycine binding site of N-methyl-D-aspartate receptor

Homology modeling was used to build 3D models of the N-methyl-D-aspartate (NMDA) receptor glycine binding site on the basis of an X-ray structure of the water-soluble AMPA-sensitive receptor. The docking of agonists and antagonists to these models was used to reveal binding modes of ligands and to explain known structure-activity relationships. Two types of quantitative models, 3D-QSAR/CoMFA and a regression model based on docking energies, were built for antagonists (derivatives of 4-hydroxy-2-quinolone, quinoxaline-2,3-dione, and related compounds). The CoMFA steric and electrostatic maps were superimposed on the homology-based model, and a close correspondence was marked. The derived computational models have permitted the evaluation of the structural features crucial for high glycine binding site affinity and are important for the design of new ligands.

A Physically-Constrained Source Model For FDTD Acoustic Simulation

The Finite Difference Time Domain (FDTD) method is becoming increasingly popular for room acoustics simulation. Yet, the literature on grid excitation methods is relatively sparse, and source functions are traditionally implemented in a hard or additive form
using arbitrarily-shaped functions which do not necessarily obey the physical laws of sound generation. In this paper we formulate
a source function based on a small pulsating sphere model. A physically plausible method to inject a source signal into the grid
is derived from first principles, resulting in a source with a near-flat spectrum that does not scatter incoming waves. In the final
discrete-time formulation, the source signal is the result of passing a Gaussian pulse through a digital filter simulating the dynamics of the pulsating sphere, hence facilitating a physically correct means to design source functions that generate a prescribed sound field.

Application-based workload model for wireless sensor node computing platforms

Wireless sensor node platforms are very diversified and very constrained, particularly in power consumption. When choosing or sizing a platform for a given application, it is necessary to be able to evaluate in an early design stage the impact of those choices. Applied to the computing platform implemented on the sensor node, it requires a good understanding of the workload it must perform. Nevertheless, this workload is highly application-dependent. It depends on the data sampling frequency together with application-specific data processing and management. It is thus necessary to have a model that can represent the workload of applications with various needs and characteristics. In this paper, we propose a workload model for wireless sensor node computing platforms. This model is based on a synthetic application that models the different computational tasks that the computing platform will perform to process sensor data. It allows to model the workload of various different applications by tuning data sampling rate and processing. A case study is performed by modeling different applications and by showing how it can be used for workload characterization. © 2011 IEEE.

School-based counseling using systematic feedback: A cohort study evaluating outcomes and predictors of change

The outcomes of school-based counseling incorporating the Partners for Change Outcome Monitoring System (PCOMS) were evaluated using a cohort design, with multilevel modeling to identify predictors of change. Participants were 288 7-11 year olds experiencing social, emotional or behavioral difficulties. The intervention was associated with significant reductions in psychological distress, with a pre-post effect size (d) of 1.49 on the primary outcome measure and 88.7% clinical improvement. Greater improvements were found for disabled children, older children, and where CBT methods were used. The findings provide support for the use of systematic feedback in therapy with children.

Combining missing-feature theory, speech enhancement, and speaker-dependent/-independent modeling for speech separation

This paper considers the separation and recognition of overlapped speech sentences assuming single-channel observation. A system based on a combination of several different techniques is proposed. The system uses a missing-feature approach for improving crosstalk/noise robustness, a Wiener filter for speech enhancement, hidden Markov models for speech reconstruction, and speaker-dependent/-independent modeling for speaker and speech recognition. We develop the system on the Speech Separation Challenge database, involving a task of separating and recognizing two mixing sentences without assuming advanced knowledge about the identity of the speakers nor about the signal-to-noise ratio. The paper is an extended version of a previous conference paper submitted for the challenge.

Active use of DFIG based Wind Farms for Transient Stability Improvement during Grid Disturbances

The doubly-fed induction generator (DFIG) now represents the dominant technology in wind turbine design. One consequence of this is limited damping and inertial response during transient grid disturbances. A dasiadecoupledpsila strategy is therefore proposed to operate the DFIG grid-side converter (GSC) as a static synchronous compensator (STATCOM) during a fault, supporting the local voltage, while the DFIG operates as a fixed-speed induction generator (FSIG) providing an inertial response. The modeling aspects of the decoupled control strategy, the selection of protection control settings, the significance of the fault location and operation at sub- and super-synchronous speeds are analyzed in detail. In addition, a case study is developed to validate the proposed strategy under different wind penetrations levels. The simulations show that suitable configuration of the decoupled strategy can be deployed to improve system voltage stability and inertial response for a range of scenarios, especially at high wind penetration. The conclusions are placed in context of the practical limitations of the technology employed and the system conditions.

Development and assessment of a robust optimization metric for WAMPAC modeling

A PMU based WAMS is to be placed on a weakly coupled section of distribution grid, with high levels of distributed generation. In anticipation of PMU data a Siemens PSS/E model of the electrical environment has been used to return similar data to that expected from the WAMS. This data is then used to create a metric that reflects optimization, control and protection in the region. System states are iterated through with the most desirable one returning the lowest optimization metric, this state is assessed against the one returned by PSS/E under normal circumstances. This paper investigates the circumstances that trigger SPS in the region, through varying generation between 0 and 110% and compromising the network through line loss under summer minimum and winter maximum conditions. It is found that the optimized state can generally tolerate an additional 2 MW of generation (3% of total) before encroaching the same thresholds and in one instance moves the triggering to 100% of generation output.

Generalized Laplacian Eigenmaps for Modeling and Tracking Human Motions

This paper presents generalized Laplacian eigenmaps, a novel dimensionality reduction approach designed to address stylistic variations in time series. It generates compact and coherent continuous spaces whose geometry is data-driven. This paper also introduces graph-based particle filter, a novel methodology conceived for efficient tracking in low dimensional space derived from a spectral dimensionality reduction method. Its strengths are a propagation scheme, which facilitates the prediction in time and style, and a noise model coherent with the manifold, which prevents divergence, and increases robustness. Experiments show that a combination of both techniques achieves state-of-the-art performance for human pose tracking in underconstrained scenarios.

Physical and numerical constraints in source modeling for finite difference simulation of room acoustics

In finite difference time domain simulation of room acoustics, source functions are subject to various constraints. These depend on the way sources are injected into the grid and on the chosen parameters of the numerical scheme being used. This paper addresses the issue of selecting and designing sources for finite difference simulation, by first reviewing associated aims and constraints, and evaluating existing source models against these criteria. The process of exciting a model is generalized by introducing a system of three cascaded filters, respectively, characterizing the driving pulse, the source mechanics, and the injection of the resulting source function into the grid. It is shown that hard, soft, and transparent sources can be seen as special cases within this unified approach. Starting from the mechanics of a small pulsating sphere, a parametric source model is formulated by specifying suitable filters. This physically constrained source model is numerically consistent, does not scatter incoming waves, and is free from zero- and low-frequency artifacts. Simulation results are employed for comparison with existing source formulations in terms of meeting the spectral and temporal requirements on the outward propagating wave.

Air-Sea Exchange of Legacy POPs in the North Sea Based on Results of Fate and Transport, and Shelf-Sea Hydrodynamic Ocean Models

The air-sea exchange of two legacy persistent organic pollutants (POPs), γ-HCH and PCB 153, in the North Sea, is presented and discussed using results of regional fate and transport and shelf-sea hydrodynamic ocean models for the period 1996–2005. Air-sea exchange occurs through gas exchange (deposition and volatilization), wet deposition and dry deposition. Atmospheric concentrations are interpolated into the model domain from results of the EMEP MSC-East multi-compartmental model (Gusev et al, 2009). The North Sea is net depositional for γ-HCH, and is dominated by gas deposition with notable seasonal variability and a downward trend over the 10 year period. Volatilization rates of γ-HCH are generally a factor of 2–3 less than gas deposition in winter, spring and summer but greater in autumn when the North Sea is net volatilizational. A downward trend in fugacity ratios is found, since gas deposition is decreasing faster than volatilization. The North Sea is net volatilizational for PCB 153, with highest rates of volatilization to deposition found in the areas surrounding polluted British and continental river sources. Large quantities of PCB 153 entering through rivers lead to very high local rates of volatilization.

The progenitor mass of the Type IIP supernova SN 2004et from late-time spectral modeling

SN 2004et is one of the nearest and best-observed Type IIP supernovae, with a progenitor detection as well as good photometric and spectroscopic observational coverage well into the nebular phase. Based on nucleosynthesis from stellar evolution/explosion models we apply spectral modeling to analyze its 140-700 day evolution from ultraviolet to mid-infrared. We find a M_ZAMS= 15 Msun progenitor star (with an oxygen mass of 0.8 Msun) to satisfactorily reproduce [O I] 6300, 6364 {\AA} and other emission lines of carbon, sodium, magnesium, and silicon, while 12 Msun and 19 Msun models under- and overproduce most of these lines, respectively. This result is in fair agreement with the mass derived from the progenitor detection, but in disagreement with hydrodynamical modeling of the early-time light curve. From modeling of the mid-infrared iron-group emission lines, we determine the density of the "Ni-bubble" to rho(t) = 7E-14*(t/100d)^-3 g cm^-3, corresponding to a filling factor of f = 0.15 in the metal core region (V = 1800 km/s). We also confirm that silicate dust, CO, and SiO emission are all present in the spectra.

Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe.

Kinetostatic-model-based Stiffness Analysis of Exechon PKM

As a comparative newly-invented PKM with over-constraints in kinematic chains, the Exechon has attracted extensive attention from the research society. Different from the well-recognized kinematics analysis, the research on the stiffness characteristics of the Exechon still remains as a challenge due to the structural complexity. In order to achieve a thorough understanding of the stiffness characteristics of the Exechon PKM, this paper proposed an analytical kinetostatic model by using the substructure synthesis technique. The whole PKM system is decomposed into a moving platform subsystem, three limb subsystems and a fixed base subsystem, which are connected to each other sequentially through corresponding joints. Each limb body is modeled as a spatial beam with a uniform cross-section constrained by two sets of lumped springs. The equilibrium equation of each individual limb assemblage is derived through finite element formulation and combined with that of the moving platform derived with Newtonian method to construct the governing kinetostatic equations of the system after introducing the deformation compatibility conditions between the moving platform and the limbs. By extracting the 6 x 6 block matrix from the inversion of the governing compliance matrix, the stiffness of the moving platform is formulated. The computation for the stiffness of the Exechon PKM at a typical configuration as well as throughout the workspace is carried out in a quick manner with a piece-by-piece partition algorithm. The numerical simulations reveal a strong position-dependency of the PKM's stiffness in that it is symmetric relative to a work plane due to structural features. At the last stage, the effects of some design variables such as structural, dimensional and stiffness parameters on system rigidity are investigated with the purpose of providing useful information for the structural optimization and performance enhancement of the Exechon PKM. It is worthy mentioning that the proposed methodology of stiffness modeling in this paper can also be applied to other overconstrained PKMs and can evaluate the global rigidity over workplace efficiently with minor revisions.