Gaussian processes with optimal kernel construction for neuro-degenerative clinical onset prediction

NASA Astrophysics Data System (ADS)

Canas, Liane S.; Yvernault, Benjamin; Cash, David M.; Molteni, Erika; Veale, Tom; Benzinger, Tammie; Ourselin, Sébastien; Mead, Simon; Modat, Marc

2018-02-01

Gaussian Processes (GP) are a powerful tool to capture the complex time-variations of a dataset. In the context of medical imaging analysis, they allow a robust modelling even in case of highly uncertain or incomplete datasets. Predictions from GP are dependent of the covariance kernel function selected to explain the data variance. To overcome this limitation, we propose a framework to identify the optimal covariance kernel function to model the data.The optimal kernel is defined as a composition of base kernel functions used to identify correlation patterns between data points. Our approach includes a modified version of the Compositional Kernel Learning (CKL) algorithm, in which we score the kernel families using a new energy function that depends both the Bayesian Information Criterion (BIC) and the explained variance score. We applied the proposed framework to model the progression of neurodegenerative diseases over time, in particular the progression of autosomal dominantly-inherited Alzheimer's disease, and use it to predict the time to clinical onset of subjects carrying genetic mutation.

Test of the cosmic evolution using Gaussian processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Ming-Jian; Xia, Jun-Qing, E-mail: zhangmj@ihep.ac.cn, E-mail: xiajq@bnu.edu.cn

2016-12-01

Much focus was on the possible slowing down of cosmic acceleration under the dark energy parametrization. In the present paper, we investigate this subject using the Gaussian processes (GP), without resorting to a particular template of dark energy. The reconstruction is carried out by abundant data including luminosity distance from Union2, Union2.1 compilation and gamma-ray burst, and dynamical Hubble parameter. It suggests that slowing down of cosmic acceleration cannot be presented within 95% C.L., in considering the influence of spatial curvature and Hubble constant. In order to reveal the reason of tension between our reconstruction and previous parametrization constraint formore » Union2 data, we compare them and find that slowing down of acceleration in some parametrization is only a ''mirage'. Although these parameterizations fits well with the observational data, their tension can be revealed by high order derivative of distance D. Instead, GP method is able to faithfully model the cosmic expansion history.« less

Squared exponential covariance function for prediction of hydrocarbon in seabed logging application

NASA Astrophysics Data System (ADS)

Mukhtar, Siti Mariam; Daud, Hanita; Dass, Sarat Chandra

2016-11-01

Seabed Logging technology (SBL) has progressively emerged as one of the demanding technologies in Exploration and Production (E&P) industry. Hydrocarbon prediction in deep water areas is crucial task for a driller in any oil and gas company as drilling cost is very expensive. Simulation data generated by Computer Software Technology (CST) is used to predict the presence of hydrocarbon where the models replicate real SBL environment. These models indicate that the hydrocarbon filled reservoirs are more resistive than surrounding water filled sediments. Then, as hydrocarbon depth is increased, it is more challenging to differentiate data with and without hydrocarbon. MATLAB is used for data extractions for curve fitting process using Gaussian process (GP). GP can be classified into regression and classification problems, where this work only focuses on Gaussian process regression (GPR) problem. Most popular choice to supervise GPR is squared exponential (SE), as it provides stability and probabilistic prediction in huge amounts of data. Hence, SE is used to predict the presence or absence of hydrocarbon in the reservoir from the data generated.

Online sparse Gaussian process based human motion intent learning for an electrically actuated lower extremity exoskeleton.

PubMed

Long, Yi; Du, Zhi-Jiang; Chen, Chao-Feng; Dong, Wei; Wang, Wei-Dong

2017-07-01

The most important step for lower extremity exoskeleton is to infer human motion intent (HMI), which contributes to achieve human exoskeleton collaboration. Since the user is in the control loop, the relationship between human robot interaction (HRI) information and HMI is nonlinear and complicated, which is difficult to be modeled by using mathematical approaches. The nonlinear approximation can be learned by using machine learning approaches. Gaussian Process (GP) regression is suitable for high-dimensional and small-sample nonlinear regression problems. GP regression is restrictive for large data sets due to its computation complexity. In this paper, an online sparse GP algorithm is constructed to learn the HMI. The original training dataset is collected when the user wears the exoskeleton system with friction compensation to perform unconstrained movement as far as possible. The dataset has two kinds of data, i.e., (1) physical HRI, which is collected by torque sensors placed at the interaction cuffs for the active joints, i.e., knee joints; (2) joint angular position, which is measured by optical position sensors. To reduce the computation complexity of GP, grey relational analysis (GRA) is utilized to specify the original dataset and provide the final training dataset. Those hyper-parameters are optimized offline by maximizing marginal likelihood and will be applied into online GP regression algorithm. The HMI, i.e., angular position of human joints, will be regarded as the reference trajectory for the mechanical legs. To verify the effectiveness of the proposed algorithm, experiments are performed on a subject at a natural speed. The experimental results show the HMI can be obtained in real time, which can be extended and employed in the similar exoskeleton systems.

Demonstration of emulator-based Bayesian calibration of safety analysis codes: Theory and formulation

DOE PAGES

Yurko, Joseph P.; Buongiorno, Jacopo; Youngblood, Robert

2015-05-28

System codes for simulation of safety performance of nuclear plants may contain parameters whose values are not known very accurately. New information from tests or operating experience is incorporated into safety codes by a process known as calibration, which reduces uncertainty in the output of the code and thereby improves its support for decision-making. The work reported here implements several improvements on classic calibration techniques afforded by modern analysis techniques. The key innovation has come from development of code surrogate model (or code emulator) construction and prediction algorithms. Use of a fast emulator makes the calibration processes used here withmore » Markov Chain Monte Carlo (MCMC) sampling feasible. This study uses Gaussian Process (GP) based emulators, which have been used previously to emulate computer codes in the nuclear field. The present work describes the formulation of an emulator that incorporates GPs into a factor analysis-type or pattern recognition-type model. This “function factorization” Gaussian Process (FFGP) model allows overcoming limitations present in standard GP emulators, thereby improving both accuracy and speed of the emulator-based calibration process. Calibration of a friction-factor example using a Method of Manufactured Solution is performed to illustrate key properties of the FFGP based process.« less

Human motion tracking by temporal-spatial local gaussian process experts.

PubMed

Zhao, Xu; Fu, Yun; Liu, Yuncai

2011-04-01

Human pose estimation via motion tracking systems can be considered as a regression problem within a discriminative framework. It is always a challenging task to model the mapping from observation space to state space because of the high-dimensional characteristic in the multimodal conditional distribution. In order to build the mapping, existing techniques usually involve a large set of training samples in the learning process which are limited in their capability to deal with multimodality. We propose, in this work, a novel online sparse Gaussian Process (GP) regression model to recover 3-D human motion in monocular videos. Particularly, we investigate the fact that for a given test input, its output is mainly determined by the training samples potentially residing in its local neighborhood and defined in the unified input-output space. This leads to a local mixture GP experts system composed of different local GP experts, each of which dominates a mapping behavior with the specific covariance function adapting to a local region. To handle the multimodality, we combine both temporal and spatial information therefore to obtain two categories of local experts. The temporal and spatial experts are integrated into a seamless hybrid system, which is automatically self-initialized and robust for visual tracking of nonlinear human motion. Learning and inference are extremely efficient as all the local experts are defined online within very small neighborhoods. Extensive experiments on two real-world databases, HumanEva and PEAR, demonstrate the effectiveness of our proposed model, which significantly improve the performance of existing models.

Application of Gaussian Process Modeling to Analysis of Functional Unreliability

DOE Office of Scientific and Technical Information (OSTI.GOV)

R. Youngblood

2014-06-01

This paper applies Gaussian Process (GP) modeling to analysis of the functional unreliability of a “passive system.” GPs have been used widely in many ways [1]. The present application uses a GP for emulation of a system simulation code. Such an emulator can be applied in several distinct ways, discussed below. All applications illustrated in this paper have precedents in the literature; the present paper is an application of GP technology to a problem that was originally analyzed [2] using neural networks (NN), and later [3, 4] by a method called “Alternating Conditional Expectations” (ACE). This exercise enables a multifacetedmore » comparison of both the processes and the results. Given knowledge of the range of possible values of key system variables, one could, in principle, quantify functional unreliability by sampling from their joint probability distribution, and performing a system simulation for each sample to determine whether the function succeeded for that particular setting of the variables. Using previously available system simulation codes, such an approach is generally impractical for a plant-scale problem. It has long been recognized, however, that a well-trained code emulator or surrogate could be used in a sampling process to quantify certain performance metrics, even for plant-scale problems. “Response surfaces” were used for this many years ago. But response surfaces are at their best for smoothly varying functions; in regions of parameter space where key system performance metrics may behave in complex ways, or even exhibit discontinuities, response surfaces are not the best available tool. This consideration was one of several that drove the work in [2]. In the present paper, (1) the original quantification of functional unreliability using NN [2], and later ACE [3], is reprised using GP; (2) additional information provided by the GP about uncertainty in the limit surface, generally unavailable in other representations, is discussed; (3) a simple forensic exercise is performed, analogous to the inverse problem of code calibration, but with an accident management spin: given an observation about containment pressure, what can we say about the system variables? References 1. For an introduction to GPs, see (for example) Gaussian Processes for Machine Learning, C. E. Rasmussen and C. K. I. Williams (MIT, 2006). 2. Reliability Quantification of Advanced Reactor Passive Safety Systems, J. J. Vandenkieboom, PhD Thesis (University of Michigan, 1996). 3. Z. Cui, J. C. Lee, J. J. Vandenkieboom, and R. W. Youngblood, “Unreliability Quantification of a Containment Cooling System through ACE and ANN Algorithms,” Trans. Am. Nucl. Soc. 85, 178 (2001). 4. Risk and Safety Analysis of Nuclear Systems, J. C. Lee and N. J. McCormick (Wiley, 2011). See especially §11.2.4.« less

Robust Library Building for Autonomous Classification of Downhole Geophysical Logs Using Gaussian Processes

NASA Astrophysics Data System (ADS)

Silversides, Katherine L.; Melkumyan, Arman

2017-03-01

Machine learning techniques such as Gaussian Processes can be used to identify stratigraphically important features in geophysical logs. The marker shales in the banded iron formation hosted iron ore deposits of the Hamersley Ranges, Western Australia, form distinctive signatures in the natural gamma logs. The identification of these marker shales is important for stratigraphic identification of unit boundaries for the geological modelling of the deposit. Machine learning techniques each have different unique properties that will impact the results. For Gaussian Processes (GPs), the output values are inclined towards the mean value, particularly when there is not sufficient information in the library. The impact that these inclinations have on the classification can vary depending on the parameter values selected by the user. Therefore, when applying machine learning techniques, care must be taken to fit the technique to the problem correctly. This study focuses on optimising the settings and choices for training a GPs system to identify a specific marker shale. We show that the final results converge even when different, but equally valid starting libraries are used for the training. To analyse the impact on feature identification, GP models were trained so that the output was inclined towards a positive, neutral or negative output. For this type of classification, the best results were when the pull was towards a negative output. We also show that the GP output can be adjusted by using a standard deviation coefficient that changes the balance between certainty and accuracy in the results.

An approach for combining airborne LiDAR and high-resolution aerial color imagery using Gaussian processes

NASA Astrophysics Data System (ADS)

Liu, Yansong; Monteiro, Sildomar T.; Saber, Eli

2015-10-01

Changes in vegetation cover, building construction, road network and traffic conditions caused by urban expansion affect the human habitat as well as the natural environment in rapidly developing cities. It is crucial to assess these changes and respond accordingly by identifying man-made and natural structures with accurate classification algorithms. With the increase in use of multi-sensor remote sensing systems, researchers are able to obtain a more complete description of the scene of interest. By utilizing multi-sensor data, the accuracy of classification algorithms can be improved. In this paper, we propose a method for combining 3D LiDAR point clouds and high-resolution color images to classify urban areas using Gaussian processes (GP). GP classification is a powerful non-parametric classification method that yields probabilistic classification results. It makes predictions in a way that addresses the uncertainty of real world. In this paper, we attempt to identify man-made and natural objects in urban areas including buildings, roads, trees, grass, water and vehicles. LiDAR features are derived from the 3D point clouds and the spatial and color features are extracted from RGB images. For classification, we use the Laplacian approximation for GP binary classification on the new combined feature space. The multiclass classification has been implemented by using one-vs-all binary classification strategy. The result of applying support vector machines (SVMs) and logistic regression (LR) classifier is also provided for comparison. Our experiments show a clear improvement of classification results by using the two sensors combined instead of each sensor separately. Also we found the advantage of applying GP approach to handle the uncertainty in classification result without compromising accuracy compared to SVM, which is considered as the state-of-the-art classification method.

Application of a statistical emulator to fire emission modeling

Treesearch

Marwan Katurji; Jovanka Nikolic; Shiyuan Zhong; Scott Pratt; Lejiang Yu; Warren E. Heilman

2015-01-01

We have demonstrated the use of an advanced Gaussian-Process (GP) emulator to estimate wildland fire emissions over a wide range of fuel and atmospheric conditions. The Fire Emission Production Simulator, or FEPS, is used to produce an initial set of emissions data that correspond to some selected values in the domain of the input fuel and atmospheric parameters for...

Penalized gaussian process regression and classification for high-dimensional nonlinear data.

PubMed

Yi, G; Shi, J Q; Choi, T

2011-12-01

The model based on Gaussian process (GP) prior and a kernel covariance function can be used to fit nonlinear data with multidimensional covariates. It has been used as a flexible nonparametric approach for curve fitting, classification, clustering, and other statistical problems, and has been widely applied to deal with complex nonlinear systems in many different areas particularly in machine learning. However, it is a challenging problem when the model is used for the large-scale data sets and high-dimensional data, for example, for the meat data discussed in this article that have 100 highly correlated covariates. For such data, it suffers from large variance of parameter estimation and high predictive errors, and numerically, it suffers from unstable computation. In this article, penalized likelihood framework will be applied to the model based on GPs. Different penalties will be investigated, and their ability in application given to suit the characteristics of GP models will be discussed. The asymptotic properties will also be discussed with the relevant proofs. Several applications to real biomechanical and bioinformatics data sets will be reported. © 2011, The International Biometric Society No claim to original US government works.

Modeling Array Stations in SIG-VISA

NASA Astrophysics Data System (ADS)

Ding, N.; Moore, D.; Russell, S.

2013-12-01

We add support for array stations to SIG-VISA, a system for nuclear monitoring using probabilistic inference on seismic signals. Array stations comprise a large portion of the IMS network; they can provide increased sensitivity and more accurate directional information compared to single-component stations. Our existing model assumed that signals were independent at each station, which is false when lots of stations are close together, as in an array. The new model removes that assumption by jointly modeling signals across array elements. This is done by extending our existing Gaussian process (GP) regression models, also known as kriging, from a 3-dimensional single-component space of events to a 6-dimensional space of station-event pairs. For each array and each event attribute (including coda decay, coda height, amplitude transfer and travel time), we model the joint distribution across array elements using a Gaussian process that learns the correlation lengthscale across the array, thereby incorporating information of array stations into the probabilistic inference framework. To evaluate the effectiveness of our model, we perform ';probabilistic beamforming' on new events using our GP model, i.e., we compute the event azimuth having highest posterior probability under the model, conditioned on the signals at array elements. We compare the results from our probabilistic inference model to the beamforming currently performed by IMS station processing.

Probabilistic safety analysis for urgent situations following the accidental release of a pollutant in the atmosphere

NASA Astrophysics Data System (ADS)

Armand, P.; Brocheton, F.; Poulet, D.; Vendel, F.; Dubourg, V.; Yalamas, T.

2014-10-01

This paper is an original contribution to uncertainty quantification in atmospheric transport & dispersion (AT&D) at the local scale (1-10 km). It is proposed to account for the imprecise knowledge of the meteorological and release conditions in the case of an accidental hazardous atmospheric emission. The aim is to produce probabilistic risk maps instead of a deterministic toxic load map in order to help the stakeholders making their decisions. Due to the urge attached to such situations, the proposed methodology is able to produce such maps in a limited amount of time. It resorts to a Lagrangian particle dispersion model (LPDM) using wind fields interpolated from a pre-established database that collects the results from a computational fluid dynamics (CFD) model. This enables a decoupling of the CFD simulations from the dispersion analysis, thus a considerable saving of computational time. In order to make the Monte-Carlo-sampling-based estimation of the probability field even faster, it is also proposed to recourse to the use of a vector Gaussian process surrogate model together with high performance computing (HPC) resources. The Gaussian process (GP) surrogate modelling technique is coupled with a probabilistic principal component analysis (PCA) for reducing the number of GP predictors to fit, store and predict. The design of experiments (DOE) from which the surrogate model is built, is run over a cluster of PCs for making the total production time as short as possible. The use of GP predictors is validated by comparing the results produced by this technique with those obtained by crude Monte Carlo sampling.

Adaptive Sampling of Time Series During Remote Exploration

NASA Technical Reports Server (NTRS)

Thompson, David R.

2012-01-01

This work deals with the challenge of online adaptive data collection in a time series. A remote sensor or explorer agent adapts its rate of data collection in order to track anomalous events while obeying constraints on time and power. This problem is challenging because the agent has limited visibility (all its datapoints lie in the past) and limited control (it can only decide when to collect its next datapoint). This problem is treated from an information-theoretic perspective, fitting a probabilistic model to collected data and optimizing the future sampling strategy to maximize information gain. The performance characteristics of stationary and nonstationary Gaussian process models are compared. Self-throttling sensors could benefit environmental sensor networks and monitoring as well as robotic exploration. Explorer agents can improve performance by adjusting their data collection rate, preserving scarce power or bandwidth resources during uninteresting times while fully covering anomalous events of interest. For example, a remote earthquake sensor could conserve power by limiting its measurements during normal conditions and increasing its cadence during rare earthquake events. A similar capability could improve sensor platforms traversing a fixed trajectory, such as an exploration rover transect or a deep space flyby. These agents can adapt observation times to improve sample coverage during moments of rapid change. An adaptive sampling approach couples sensor autonomy, instrument interpretation, and sampling. The challenge is addressed as an active learning problem, which already has extensive theoretical treatment in the statistics and machine learning literature. A statistical Gaussian process (GP) model is employed to guide sample decisions that maximize information gain. Nonsta tion - ary (e.g., time-varying) covariance relationships permit the system to represent and track local anomalies, in contrast with current GP approaches. Most common GP models are stationary, e.g., the covariance relationships are time-invariant. In such cases, information gain is independent of previously collected data, and the optimal solution can always be computed in advance. Information-optimal sampling of a stationary GP time series thus reduces to even spacing, and such models are not appropriate for tracking localized anomalies. Additionally, GP model inference can be computationally expensive.

A non-parametric consistency test of the ΛCDM model with Planck CMB data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aghamousa, Amir; Shafieloo, Arman; Hamann, Jan, E-mail: amir@aghamousa.com, E-mail: jan.hamann@unsw.edu.au, E-mail: shafieloo@kasi.re.kr

Non-parametric reconstruction methods, such as Gaussian process (GP) regression, provide a model-independent way of estimating an underlying function and its uncertainty from noisy data. We demonstrate how GP-reconstruction can be used as a consistency test between a given data set and a specific model by looking for structures in the residuals of the data with respect to the model's best-fit. Applying this formalism to the Planck temperature and polarisation power spectrum measurements, we test their global consistency with the predictions of the base ΛCDM model. Our results do not show any serious inconsistencies, lending further support to the interpretation ofmore » the base ΛCDM model as cosmology's gold standard.« less

Fluctuation Dynamics Analysis of gp120 Envelope Protein Reveals a Topologically Based Communication Network

PubMed Central

Shrivastava, Indira; LaLonde, Judith M.

2012-01-01

HIV infection is initiated by binding of the viral glycoprotein gp120, to the cellular receptor CD4. Upon CD4 binding, gp120 undergoes conformational change, permitting binding to the chemokine receptor. Crystal structures of gp120 ternary complex reveal the CD4 bound conformation of gp120. We report here the application of Gaussian Network Model (GNM) to the crystal structures of gp120 bound to CD4 or CD4 mimic and 17b, to study the collective motions of the gp120 core and determine the communication propensities of the residue network. The GNM fluctuation profiles identify residues in the inner domain and outer domain that may facilitate conformational change or stability, respectively. Communication propensities delineate a residue network that is topologically suited for signal propagation from the Phe43 cavity throughout the gp120 outer domain. . These results provide a new context for interpreting gp120 core envelope structure-function relationships. PMID:20718047

Uncertainty-based simulation-optimization using Gaussian process emulation: Application to coastal groundwater management

NASA Astrophysics Data System (ADS)

Rajabi, Mohammad Mahdi; Ketabchi, Hamed

2017-12-01

Combined simulation-optimization (S/O) schemes have long been recognized as a valuable tool in coastal groundwater management (CGM). However, previous applications have mostly relied on deterministic seawater intrusion (SWI) simulations. This is a questionable simplification, knowing that SWI models are inevitably prone to epistemic and aleatory uncertainty, and hence a management strategy obtained through S/O without consideration of uncertainty may result in significantly different real-world outcomes than expected. However, two key issues have hindered the use of uncertainty-based S/O schemes in CGM, which are addressed in this paper. The first issue is how to solve the computational challenges resulting from the need to perform massive numbers of simulations. The second issue is how the management problem is formulated in presence of uncertainty. We propose the use of Gaussian process (GP) emulation as a valuable tool in solving the computational challenges of uncertainty-based S/O in CGM. We apply GP emulation to the case study of Kish Island (located in the Persian Gulf) using an uncertainty-based S/O algorithm which relies on continuous ant colony optimization and Monte Carlo simulation. In doing so, we show that GP emulation can provide an acceptable level of accuracy, with no bias and low statistical dispersion, while tremendously reducing the computational time. Moreover, five new formulations for uncertainty-based S/O are presented based on concepts such as energy distances, prediction intervals and probabilities of SWI occurrence. We analyze the proposed formulations with respect to their resulting optimized solutions, the sensitivity of the solutions to the intended reliability levels, and the variations resulting from repeated optimization runs.

Modeling methods for merging computational and experimental aerodynamic pressure data

NASA Astrophysics Data System (ADS)

Haderlie, Jacob C.

This research describes a process to model surface pressure data sets as a function of wing geometry from computational and wind tunnel sources and then merge them into a single predicted value. The described merging process will enable engineers to integrate these data sets with the goal of utilizing the advantages of each data source while overcoming the limitations of both; this provides a single, combined data set to support analysis and design. The main challenge with this process is accurately representing each data source everywhere on the wing. Additionally, this effort demonstrates methods to model wind tunnel pressure data as a function of angle of attack as an initial step towards a merging process that uses both location on the wing and flow conditions (e.g., angle of attack, flow velocity or Reynold's number) as independent variables. This surrogate model of pressure as a function of angle of attack can be useful for engineers that need to predict the location of zero-order discontinuities, e.g., flow separation or normal shocks. Because, to the author's best knowledge, there is no published, well-established merging method for aerodynamic pressure data (here, the coefficient of pressure Cp), this work identifies promising modeling and merging methods, and then makes a critical comparison of these methods. Surrogate models represent the pressure data for both data sets. Cubic B-spline surrogate models represent the computational simulation results. Machine learning and multi-fidelity surrogate models represent the experimental data. This research compares three surrogates for the experimental data (sequential--a.k.a. online--Gaussian processes, batch Gaussian processes, and multi-fidelity additive corrector) on the merits of accuracy and computational cost. The Gaussian process (GP) methods employ cubic B-spline CFD surrogates as a model basis function to build a surrogate model of the WT data, and this usage of the CFD surrogate in building the WT data could serve as a "merging" because the resulting WT pressure prediction uses information from both sources. In the GP approach, this model basis function concept seems to place more "weight" on the Cp values from the wind tunnel (WT) because the GP surrogate uses the CFD to approximate the WT data values. Conversely, the computationally inexpensive additive corrector method uses the CFD B-spline surrogate to define the shape of the spanwise distribution of the Cp while minimizing prediction error at all spanwise locations for a given arc length position; this, too, combines information from both sources to make a prediction of the 2-D WT-based Cp distribution, but the additive corrector approach gives more weight to the CFD prediction than to the WT data. Three surrogate models of the experimental data as a function of angle of attack are also compared for accuracy and computational cost. These surrogates are a single Gaussian process model (a single "expert"), product of experts, and generalized product of experts. The merging approach provides a single pressure distribution that combines experimental and computational data. The batch Gaussian process method provides a relatively accurate surrogate that is computationally acceptable, and can receive wind tunnel data from port locations that are not necessarily parallel to a variable direction. On the other hand, the sequential Gaussian process and additive corrector methods must receive a sufficient number of data points aligned with one direction, e.g., from pressure port bands (tap rows) aligned with the freestream. The generalized product of experts best represents wind tunnel pressure as a function of angle of attack, but at higher computational cost than the single expert approach. The format of the application data from computational and experimental sources in this work precluded the merging process from including flow condition variables (e.g., angle of attack) in the independent variables, so the merging process is only conducted in the wing geometry variables of arc length and span. The merging process of Cp data allows a more "hands-off" approach to aircraft design and analysis, (i.e., not as many engineers needed to debate the Cp distribution shape) and generates Cp predictions at any location on the wing. However, the cost with these benefits are engineer time (learning how to build surrogates), computational time in constructing the surrogates, and surrogate accuracy (surrogates introduce error into data predictions). This dissertation effort used the Trap Wing / First AIAA CFD High-Lift Prediction Workshop as a relevant transonic wing with a multi-element high-lift system, and this work identified that the batch GP model for the WT data and the B-spline surrogate for the CFD might best be combined using expert belief weights to describe Cp as a function of location on the wing element surface. (Abstract shortened by ProQuest.).

Accurate interatomic force fields via machine learning with covariant kernels

NASA Astrophysics Data System (ADS)

Glielmo, Aldo; Sollich, Peter; De Vita, Alessandro

2017-06-01

We present a novel scheme to accurately predict atomic forces as vector quantities, rather than sets of scalar components, by Gaussian process (GP) regression. This is based on matrix-valued kernel functions, on which we impose the requirements that the predicted force rotates with the target configuration and is independent of any rotations applied to the configuration database entries. We show that such covariant GP kernels can be obtained by integration over the elements of the rotation group SO (d ) for the relevant dimensionality d . Remarkably, in specific cases the integration can be carried out analytically and yields a conservative force field that can be recast into a pair interaction form. Finally, we show that restricting the integration to a summation over the elements of a finite point group relevant to the target system is sufficient to recover an accurate GP. The accuracy of our kernels in predicting quantum-mechanical forces in real materials is investigated by tests on pure and defective Ni, Fe, and Si crystalline systems.

Bayesian soft X-ray tomography using non-stationary Gaussian Processes

NASA Astrophysics Data System (ADS)

Li, Dong; Svensson, J.; Thomsen, H.; Medina, F.; Werner, A.; Wolf, R.

2013-08-01

In this study, a Bayesian based non-stationary Gaussian Process (GP) method for the inference of soft X-ray emissivity distribution along with its associated uncertainties has been developed. For the investigation of equilibrium condition and fast magnetohydrodynamic behaviors in nuclear fusion plasmas, it is of importance to infer, especially in the plasma center, spatially resolved soft X-ray profiles from a limited number of noisy line integral measurements. For this ill-posed inversion problem, Bayesian probability theory can provide a posterior probability distribution over all possible solutions under given model assumptions. Specifically, the use of a non-stationary GP to model the emission allows the model to adapt to the varying length scales of the underlying diffusion process. In contrast to other conventional methods, the prior regularization is realized in a probability form which enhances the capability of uncertainty analysis, in consequence, scientists who concern the reliability of their results will benefit from it. Under the assumption of normally distributed noise, the posterior distribution evaluated at a discrete number of points becomes a multivariate normal distribution whose mean and covariance are analytically available, making inversions and calculation of uncertainty fast. Additionally, the hyper-parameters embedded in the model assumption can be optimized through a Bayesian Occam's Razor formalism and thereby automatically adjust the model complexity. This method is shown to produce convincing reconstructions and good agreements with independently calculated results from the Maximum Entropy and Equilibrium-Based Iterative Tomography Algorithm methods.

Bayesian soft X-ray tomography using non-stationary Gaussian Processes.

PubMed

Li, Dong; Svensson, J; Thomsen, H; Medina, F; Werner, A; Wolf, R

2013-08-01

In this study, a Bayesian based non-stationary Gaussian Process (GP) method for the inference of soft X-ray emissivity distribution along with its associated uncertainties has been developed. For the investigation of equilibrium condition and fast magnetohydrodynamic behaviors in nuclear fusion plasmas, it is of importance to infer, especially in the plasma center, spatially resolved soft X-ray profiles from a limited number of noisy line integral measurements. For this ill-posed inversion problem, Bayesian probability theory can provide a posterior probability distribution over all possible solutions under given model assumptions. Specifically, the use of a non-stationary GP to model the emission allows the model to adapt to the varying length scales of the underlying diffusion process. In contrast to other conventional methods, the prior regularization is realized in a probability form which enhances the capability of uncertainty analysis, in consequence, scientists who concern the reliability of their results will benefit from it. Under the assumption of normally distributed noise, the posterior distribution evaluated at a discrete number of points becomes a multivariate normal distribution whose mean and covariance are analytically available, making inversions and calculation of uncertainty fast. Additionally, the hyper-parameters embedded in the model assumption can be optimized through a Bayesian Occam's Razor formalism and thereby automatically adjust the model complexity. This method is shown to produce convincing reconstructions and good agreements with independently calculated results from the Maximum Entropy and Equilibrium-Based Iterative Tomography Algorithm methods.

Construction of reactive potential energy surfaces with Gaussian process regression: active data selection

NASA Astrophysics Data System (ADS)

Guan, Yafu; Yang, Shuo; Zhang, Dong H.

2018-04-01

Gaussian process regression (GPR) is an efficient non-parametric method for constructing multi-dimensional potential energy surfaces (PESs) for polyatomic molecules. Since not only the posterior mean but also the posterior variance can be easily calculated, GPR provides a well-established model for active learning, through which PESs can be constructed more efficiently and accurately. We propose a strategy of active data selection for the construction of PESs with emphasis on low energy regions. Through three-dimensional (3D) example of H3, the validity of this strategy is verified. The PESs for two prototypically reactive systems, namely, H + H2O ↔ H2 + OH reaction and H + CH4 ↔ H2 + CH3 reaction are reconstructed. Only 920 and 4000 points are assembled to reconstruct these two PESs respectively. The accuracy of the GP PESs is not only tested by energy errors but also validated by quantum scattering calculations.

Image interpolation and denoising for division of focal plane sensors using Gaussian processes.

PubMed

Gilboa, Elad; Cunningham, John P; Nehorai, Arye; Gruev, Viktor

2014-06-16

Image interpolation and denoising are important techniques in image processing. These methods are inherent to digital image acquisition as most digital cameras are composed of a 2D grid of heterogeneous imaging sensors. Current polarization imaging employ four different pixelated polarization filters, commonly referred to as division of focal plane polarization sensors. The sensors capture only partial information of the true scene, leading to a loss of spatial resolution as well as inaccuracy of the captured polarization information. Interpolation is a standard technique to recover the missing information and increase the accuracy of the captured polarization information. Here we focus specifically on Gaussian process regression as a way to perform a statistical image interpolation, where estimates of sensor noise are used to improve the accuracy of the estimated pixel information. We further exploit the inherent grid structure of this data to create a fast exact algorithm that operates in ����(N(3/2)) (vs. the naive ���� (N³)), thus making the Gaussian process method computationally tractable for image data. This modeling advance and the enabling computational advance combine to produce significant improvements over previously published interpolation methods for polarimeters, which is most pronounced in cases of low signal-to-noise ratio (SNR). We provide the comprehensive mathematical model as well as experimental results of the GP interpolation performance for division of focal plane polarimeter.

Bayesian spatio-temporal modeling of particulate matter concentrations in Peninsular Malaysia

NASA Astrophysics Data System (ADS)

Manga, Edna; Awang, Norhashidah

2016-06-01

This article presents an application of a Bayesian spatio-temporal Gaussian process (GP) model on particulate matter concentrations from Peninsular Malaysia. We analyze daily PM10 concentration levels from 35 monitoring sites in June and July 2011. The spatiotemporal model set in a Bayesian hierarchical framework allows for inclusion of informative covariates, meteorological variables and spatiotemporal interactions. Posterior density estimates of the model parameters are obtained by Markov chain Monte Carlo methods. Preliminary data analysis indicate information on PM10 levels at sites classified as industrial locations could explain part of the space time variations. We include the site-type indicator in our modeling efforts. Results of the parameter estimates for the fitted GP model show significant spatio-temporal structure and positive effect of the location-type explanatory variable. We also compute some validation criteria for the out of sample sites that show the adequacy of the model for predicting PM10 at unmonitored sites.

Estimating the expected value of partial perfect information in health economic evaluations using integrated nested Laplace approximation.

PubMed

Heath, Anna; Manolopoulou, Ioanna; Baio, Gianluca

2016-10-15

The Expected Value of Perfect Partial Information (EVPPI) is a decision-theoretic measure of the 'cost' of parametric uncertainty in decision making used principally in health economic decision making. Despite this decision-theoretic grounding, the uptake of EVPPI calculations in practice has been slow. This is in part due to the prohibitive computational time required to estimate the EVPPI via Monte Carlo simulations. However, recent developments have demonstrated that the EVPPI can be estimated by non-parametric regression methods, which have significantly decreased the computation time required to approximate the EVPPI. Under certain circumstances, high-dimensional Gaussian Process (GP) regression is suggested, but this can still be prohibitively expensive. Applying fast computation methods developed in spatial statistics using Integrated Nested Laplace Approximations (INLA) and projecting from a high-dimensional into a low-dimensional input space allows us to decrease the computation time for fitting these high-dimensional GP, often substantially. We demonstrate that the EVPPI calculated using our method for GP regression is in line with the standard GP regression method and that despite the apparent methodological complexity of this new method, R functions are available in the package BCEA to implement it simply and efficiently. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Gaussian Process Regression for Uncertainty Estimation on Ecosystem Data

NASA Astrophysics Data System (ADS)

Menzer, O.; Moffat, A.; Lasslop, G.; Reichstein, M.

2011-12-01

The flow of carbon between terrestrial ecosystems and the atmosphere is mainly driven by nonlinear, complex and time-lagged processes. Understanding the associated ecosystem responses and climatic feedbacks is a key challenge regarding climate change questions such as increasing atmospheric CO2 levels. Usually, the underlying relationships are implemented in models as prescribed functions which interlink numerous meteorological, radiative and gas exchange variables. In contrast, supervised Machine Learning algorithms, such as Artificial Neural Networks or Gaussian Processes, allow for an insight into the relationships directly from a data perspective. Micrometeorological, high resolution measurements at flux towers of the FLUXNET observational network are an essential tool for obtaining quantifications of the ecosystem variables, as they continuously record e.g. CO2 exchange, solar radiation and air temperature. In order to facilitate the investigation of the interactions and feedbacks between these variables, several challenging data properties need to be taken into account: noisy, multidimensional and incomplete (Moffat, Accepted). The task of estimating uncertainties in such micrometeorological measurements can be addressed by Gaussian Processes (GPs), a modern nonparametric method for nonlinear regression. The GP approach has recently been shown to be a powerful modeling tool, regardless of the input dimensionality, the degree of nonlinearity and the noise level (Rasmussen and Williams, 2006). Heteroscedastic Gaussian Processes (HGPs) are a specialized GP method for data with a varying, inhomogeneous noise variance (Goldberg et al., 1998; Kersting et al., 2007), as usually observed in CO2 flux measurements (Richardson et al., 2006). Here, we showed by an evaluation of the HGP performance in several artificial experiments and a comparison to existing nonlinear regression methods, that their outstanding ability is to capture measurement noise levels, concurrently providing reasonable data fits under relatively few assumptions. On the basis of incomplete, half-hourly measured ecosystem data, a HGP was trained to model NEP (Net Ecosystem Production), only with the drivers PPFD (Photosynthetic Photon Flux Density) and Air Temperature. Time information was added to account for the autocorrelation in the flux measurements. Provided with a gap-filled, meteorological time series, NEP and the corresponding random error estimates can then be predicted empirically at high temporal resolution. We report uncertainties in annual sums of CO2 exchange at two flux tower sites in Hainich, Germany and Hesse, France. Similar noise patterns, but different magnitudes between sites were detected, with annual random error estimates of +/- 14.1 gCm^-2yr^-1 and +/- 23.5 gCm^-2yr^-1, respectively, for the year 2001. Existing models calculate uncertainties by evaluating the standard deviation of the model residuals. A comparison to the methods of Reichstein et al. (2005) and Lasslop et al. (2008) showed confidence both in the predictive uncertainties and the annual sums modeled with the HGP approach.

Material and morphology parameter sensitivity analysis in particulate composite materials

NASA Astrophysics Data System (ADS)

Zhang, Xiaoyu; Oskay, Caglar

2017-12-01

This manuscript presents a novel parameter sensitivity analysis framework for damage and failure modeling of particulate composite materials subjected to dynamic loading. The proposed framework employs global sensitivity analysis to study the variance in the failure response as a function of model parameters. In view of the computational complexity of performing thousands of detailed microstructural simulations to characterize sensitivities, Gaussian process (GP) surrogate modeling is incorporated into the framework. In order to capture the discontinuity in response surfaces, the GP models are integrated with a support vector machine classification algorithm that identifies the discontinuities within response surfaces. The proposed framework is employed to quantify variability and sensitivities in the failure response of polymer bonded particulate energetic materials under dynamic loads to material properties and morphological parameters that define the material microstructure. Particular emphasis is placed on the identification of sensitivity to interfaces between the polymer binder and the energetic particles. The proposed framework has been demonstrated to identify the most consequential material and morphological parameters under vibrational and impact loads.

A parametric interpretation of Bayesian Nonparametric Inference from Gene Genealogies: Linking ecological, population genetics and evolutionary processes.

PubMed

Ponciano, José Miguel

2017-11-22

Using a nonparametric Bayesian approach Palacios and Minin (2013) dramatically improved the accuracy, precision of Bayesian inference of population size trajectories from gene genealogies. These authors proposed an extension of a Gaussian Process (GP) nonparametric inferential method for the intensity function of non-homogeneous Poisson processes. They found that not only the statistical properties of the estimators were improved with their method, but also, that key aspects of the demographic histories were recovered. The authors' work represents the first Bayesian nonparametric solution to this inferential problem because they specify a convenient prior belief without a particular functional form on the population trajectory. Their approach works so well and provides such a profound understanding of the biological process, that the question arises as to how truly "biology-free" their approach really is. Using well-known concepts of stochastic population dynamics, here I demonstrate that in fact, Palacios and Minin's GP model can be cast as a parametric population growth model with density dependence and environmental stochasticity. Making this link between population genetics and stochastic population dynamics modeling provides novel insights into eliciting biologically meaningful priors for the trajectory of the effective population size. The results presented here also bring novel understanding of GP as models for the evolution of a trait. Thus, the ecological principles foundation of Palacios and Minin (2013)'s prior adds to the conceptual and scientific value of these authors' inferential approach. I conclude this note by listing a series of insights brought about by this connection with Ecology. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

Individualized Gaussian process-based prediction and detection of local and global gray matter abnormalities in elderly subjects.

PubMed

Ziegler, G; Ridgway, G R; Dahnke, R; Gaser, C

2014-08-15

Structural imaging based on MRI is an integral component of the clinical assessment of patients with potential dementia. We here propose an individualized Gaussian process-based inference scheme for clinical decision support in healthy and pathological aging elderly subjects using MRI. The approach aims at quantitative and transparent support for clinicians who aim to detect structural abnormalities in patients at risk of Alzheimer's disease or other types of dementia. Firstly, we introduce a generative model incorporating our knowledge about normative decline of local and global gray matter volume across the brain in elderly. By supposing smooth structural trajectories the models account for the general course of age-related structural decline as well as late-life accelerated loss. Considering healthy subjects' demography and global brain parameters as informative about normal brain aging variability affords individualized predictions in single cases. Using Gaussian process models as a normative reference, we predict new subjects' brain scans and quantify the local gray matter abnormalities in terms of Normative Probability Maps (NPM) and global z-scores. By integrating the observed expectation error and the predictive uncertainty, the local maps and global scores exploit the advantages of Bayesian inference for clinical decisions and provide a valuable extension of diagnostic information about pathological aging. We validate the approach in simulated data and real MRI data. We train the GP framework using 1238 healthy subjects with ages 18-94 years, and predict in 415 independent test subjects diagnosed as healthy controls, Mild Cognitive Impairment and Alzheimer's disease. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Individualized Gaussian process-based prediction and detection of local and global gray matter abnormalities in elderly subjects

PubMed Central

Ziegler, G.; Ridgway, G.R.; Dahnke, R.; Gaser, C.

2014-01-01

Structural imaging based on MRI is an integral component of the clinical assessment of patients with potential dementia. We here propose an individualized Gaussian process-based inference scheme for clinical decision support in healthy and pathological aging elderly subjects using MRI. The approach aims at quantitative and transparent support for clinicians who aim to detect structural abnormalities in patients at risk of Alzheimer's disease or other types of dementia. Firstly, we introduce a generative model incorporating our knowledge about normative decline of local and global gray matter volume across the brain in elderly. By supposing smooth structural trajectories the models account for the general course of age-related structural decline as well as late-life accelerated loss. Considering healthy subjects' demography and global brain parameters as informative about normal brain aging variability affords individualized predictions in single cases. Using Gaussian process models as a normative reference, we predict new subjects' brain scans and quantify the local gray matter abnormalities in terms of Normative Probability Maps (NPM) and global z-scores. By integrating the observed expectation error and the predictive uncertainty, the local maps and global scores exploit the advantages of Bayesian inference for clinical decisions and provide a valuable extension of diagnostic information about pathological aging. We validate the approach in simulated data and real MRI data. We train the GP framework using 1238 healthy subjects with ages 18–94 years, and predict in 415 independent test subjects diagnosed as healthy controls, Mild Cognitive Impairment and Alzheimer's disease. PMID:24742919

Gaussian process regression for forecasting battery state of health

NASA Astrophysics Data System (ADS)

Richardson, Robert R.; Osborne, Michael A.; Howey, David A.

2017-07-01

Accurately predicting the future capacity and remaining useful life of batteries is necessary to ensure reliable system operation and to minimise maintenance costs. The complex nature of battery degradation has meant that mechanistic modelling of capacity fade has thus far remained intractable; however, with the advent of cloud-connected devices, data from cells in various applications is becoming increasingly available, and the feasibility of data-driven methods for battery prognostics is increasing. Here we propose Gaussian process (GP) regression for forecasting battery state of health, and highlight various advantages of GPs over other data-driven and mechanistic approaches. GPs are a type of Bayesian non-parametric method, and hence can model complex systems whilst handling uncertainty in a principled manner. Prior information can be exploited by GPs in a variety of ways: explicit mean functions can be used if the functional form of the underlying degradation model is available, and multiple-output GPs can effectively exploit correlations between data from different cells. We demonstrate the predictive capability of GPs for short-term and long-term (remaining useful life) forecasting on a selection of capacity vs. cycle datasets from lithium-ion cells.

Theoretical study of porous surfaces derived from graphene and boron nitride

NASA Astrophysics Data System (ADS)

Fabris, G. S. L.; Marana, N. L.; Longo, E.; Sambrano, J. R.

2018-02-01

Porous graphene (PG), graphenylene (GP), inorganic graphenylene (IGP-BN), and porous boron nitride (PBN) single-layer have been studied via periodic density functional theory with a modified B3LYP functional and an all-electron Gaussian basis set. The structural, elastic, electronic, vibrational, and topological properties of the surfaces were investigated. The analysis showed that all porous structures had a nonzero band gap, and only PG exhibited a non-planar shape. All porous structures seem to be more susceptible to longitudinal deformation than their pristine counterparts, and GP exhibits a higher strength than graphene in the transversal direction. In addition, the electron densities of GP and IGP-BN are localized closer to the atoms, in contrast with PG and PBN, whose charge density is shifted towards the pore center; this property could find application in various fields, such as gas adsorption.

Voxel-Based Neighborhood for Spatial Shape Pattern Classification of Lidar Point Clouds with Supervised Learning.

PubMed

Plaza-Leiva, Victoria; Gomez-Ruiz, Jose Antonio; Mandow, Anthony; García-Cerezo, Alfonso

2017-03-15

Improving the effectiveness of spatial shape features classification from 3D lidar data is very relevant because it is largely used as a fundamental step towards higher level scene understanding challenges of autonomous vehicles and terrestrial robots. In this sense, computing neighborhood for points in dense scans becomes a costly process for both training and classification. This paper proposes a new general framework for implementing and comparing different supervised learning classifiers with a simple voxel-based neighborhood computation where points in each non-overlapping voxel in a regular grid are assigned to the same class by considering features within a support region defined by the voxel itself. The contribution provides offline training and online classification procedures as well as five alternative feature vector definitions based on principal component analysis for scatter, tubular and planar shapes. Moreover, the feasibility of this approach is evaluated by implementing a neural network (NN) method previously proposed by the authors as well as three other supervised learning classifiers found in scene processing methods: support vector machines (SVM), Gaussian processes (GP), and Gaussian mixture models (GMM). A comparative performance analysis is presented using real point clouds from both natural and urban environments and two different 3D rangefinders (a tilting Hokuyo UTM-30LX and a Riegl). Classification performance metrics and processing time measurements confirm the benefits of the NN classifier and the feasibility of voxel-based neighborhood.

Statistical emulation of landslide-induced tsunamis at the Rockall Bank, NE Atlantic

PubMed Central

Guillas, S.; Georgiopoulou, A.; Dias, F.

2017-01-01

Statistical methods constitute a useful approach to understand and quantify the uncertainty that governs complex tsunami mechanisms. Numerical experiments may often have a high computational cost. This forms a limiting factor for performing uncertainty and sensitivity analyses, where numerous simulations are required. Statistical emulators, as surrogates of these simulators, can provide predictions of the physical process in a much faster and computationally inexpensive way. They can form a prominent solution to explore thousands of scenarios that would be otherwise numerically expensive and difficult to achieve. In this work, we build a statistical emulator of the deterministic codes used to simulate submarine sliding and tsunami generation at the Rockall Bank, NE Atlantic Ocean, in two stages. First we calibrate, against observations of the landslide deposits, the parameters used in the landslide simulations. This calibration is performed under a Bayesian framework using Gaussian Process (GP) emulators to approximate the landslide model, and the discrepancy function between model and observations. Distributions of the calibrated input parameters are obtained as a result of the calibration. In a second step, a GP emulator is built to mimic the coupled landslide-tsunami numerical process. The emulator propagates the uncertainties in the distributions of the calibrated input parameters inferred from the first step to the outputs. As a result, a quantification of the uncertainty of the maximum free surface elevation at specified locations is obtained. PMID:28484339

Statistical emulation of landslide-induced tsunamis at the Rockall Bank, NE Atlantic.

PubMed

Salmanidou, D M; Guillas, S; Georgiopoulou, A; Dias, F

2017-04-01

Statistical methods constitute a useful approach to understand and quantify the uncertainty that governs complex tsunami mechanisms. Numerical experiments may often have a high computational cost. This forms a limiting factor for performing uncertainty and sensitivity analyses, where numerous simulations are required. Statistical emulators, as surrogates of these simulators, can provide predictions of the physical process in a much faster and computationally inexpensive way. They can form a prominent solution to explore thousands of scenarios that would be otherwise numerically expensive and difficult to achieve. In this work, we build a statistical emulator of the deterministic codes used to simulate submarine sliding and tsunami generation at the Rockall Bank, NE Atlantic Ocean, in two stages. First we calibrate, against observations of the landslide deposits, the parameters used in the landslide simulations. This calibration is performed under a Bayesian framework using Gaussian Process (GP) emulators to approximate the landslide model, and the discrepancy function between model and observations. Distributions of the calibrated input parameters are obtained as a result of the calibration. In a second step, a GP emulator is built to mimic the coupled landslide-tsunami numerical process. The emulator propagates the uncertainties in the distributions of the calibrated input parameters inferred from the first step to the outputs. As a result, a quantification of the uncertainty of the maximum free surface elevation at specified locations is obtained.

3D-MICE: integration of cross-sectional and longitudinal imputation for multi-analyte longitudinal clinical data.

PubMed

Luo, Yuan; Szolovits, Peter; Dighe, Anand S; Baron, Jason M

2018-06-01

A key challenge in clinical data mining is that most clinical datasets contain missing data. Since many commonly used machine learning algorithms require complete datasets (no missing data), clinical analytic approaches often entail an imputation procedure to "fill in" missing data. However, although most clinical datasets contain a temporal component, most commonly used imputation methods do not adequately accommodate longitudinal time-based data. We sought to develop a new imputation algorithm, 3-dimensional multiple imputation with chained equations (3D-MICE), that can perform accurate imputation of missing clinical time series data. We extracted clinical laboratory test results for 13 commonly measured analytes (clinical laboratory tests). We imputed missing test results for the 13 analytes using 3 imputation methods: multiple imputation with chained equations (MICE), Gaussian process (GP), and 3D-MICE. 3D-MICE utilizes both MICE and GP imputation to integrate cross-sectional and longitudinal information. To evaluate imputation method performance, we randomly masked selected test results and imputed these masked results alongside results missing from our original data. We compared predicted results to measured results for masked data points. 3D-MICE performed significantly better than MICE and GP-based imputation in a composite of all 13 analytes, predicting missing results with a normalized root-mean-square error of 0.342, compared to 0.373 for MICE alone and 0.358 for GP alone. 3D-MICE offers a novel and practical approach to imputing clinical laboratory time series data. 3D-MICE may provide an additional tool for use as a foundation in clinical predictive analytics and intelligent clinical decision support.

Comparative cellular processing of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp160 by the mammalian subtilisin/kexin-like convertases.

PubMed

Vollenweider, F; Benjannet, S; Decroly, E; Savaria, D; Lazure, C; Thomas, G; Chrétien, M; Seidah, N G

1996-03-01

We present here the pulse and pulse-chase analysis of the biosynthesis of the envelope glycoprotein gp160 and its intracellular processing by the subtilisin/kexin-like convertases furin, PACE4, PC1, PC5 and its isoform PC5/6-B. We demonstrate that furin and to a much lesser extent PACE4, PC5/6-B and PC1 are candidate enzymes capable of processing gp160 intracellularly. Furthermore we show that furin can also process gp160/gp120 into gp77/gp53 products by cleavage at the sequence RIQR/GPGR just preceding the conserved GPGR structure found at the tip of the hypervariable V3 loop. The results show that processing into gp120 could occur at or before the trans-Golgi network (TGN) where sulphation of the oligosaccharide moieties of gp160 was detected. In contrast, the formation of gp77/gp53 by furin is a late event occurring after exit from the TGN. Our data also revealed that the alpha glucosidase I inhibitor N-butyldeoxynojirimycin, although affecting the oligosaccharide composition of gp160, does not impair the processing of either gp160 or gp120 by either furin or PACE4. Finally, the co-expression of the [Arg355, Arg358]-alpha-1-antitrypsin Portland variant was shown to potently inhibit the processing of both gp160 and gp120 by these convertases.

Probabilistic Space Weather Forecasting: a Bayesian Perspective

NASA Astrophysics Data System (ADS)

Camporeale, E.; Chandorkar, M.; Borovsky, J.; Care', A.

2017-12-01

Most of the Space Weather forecasts, both at operational and research level, are not probabilistic in nature. Unfortunately, a prediction that does not provide a confidence level is not very useful in a decision-making scenario. Nowadays, forecast models range from purely data-driven, machine learning algorithms, to physics-based approximation of first-principle equations (and everything that sits in between). Uncertainties pervade all such models, at every level: from the raw data to finite-precision implementation of numerical methods. The most rigorous way of quantifying the propagation of uncertainties is by embracing a Bayesian probabilistic approach. One of the simplest and most robust machine learning technique in the Bayesian framework is Gaussian Process regression and classification. Here, we present the application of Gaussian Processes to the problems of the DST geomagnetic index forecast, the solar wind type classification, and the estimation of diffusion parameters in radiation belt modeling. In each of these very diverse problems, the GP approach rigorously provide forecasts in the form of predictive distributions. In turn, these distributions can be used as input for ensemble simulations in order to quantify the amplification of uncertainties. We show that we have achieved excellent results in all of the standard metrics to evaluate our models, with very modest computational cost.

A flexible cure rate model for spatially correlated survival data based on generalized extreme value distribution and Gaussian process priors.

PubMed

Li, Dan; Wang, Xia; Dey, Dipak K

2016-09-01

Our present work proposes a new survival model in a Bayesian context to analyze right-censored survival data for populations with a surviving fraction, assuming that the log failure time follows a generalized extreme value distribution. Many applications require a more flexible modeling of covariate information than a simple linear or parametric form for all covariate effects. It is also necessary to include the spatial variation in the model, since it is sometimes unexplained by the covariates considered in the analysis. Therefore, the nonlinear covariate effects and the spatial effects are incorporated into the systematic component of our model. Gaussian processes (GPs) provide a natural framework for modeling potentially nonlinear relationship and have recently become extremely powerful in nonlinear regression. Our proposed model adopts a semiparametric Bayesian approach by imposing a GP prior on the nonlinear structure of continuous covariate. With the consideration of data availability and computational complexity, the conditionally autoregressive distribution is placed on the region-specific frailties to handle spatial correlation. The flexibility and gains of our proposed model are illustrated through analyses of simulated data examples as well as a dataset involving a colon cancer clinical trial from the state of Iowa. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Automated recognition of stratigraphic marker shales from geophysical logs in iron ore deposits

NASA Astrophysics Data System (ADS)

Silversides, Katherine; Melkumyan, Arman; Wyman, Derek; Hatherly, Peter

2015-04-01

The mining of stratiform ore deposits requires a means of determining the location of stratigraphic boundaries. A variety of geophysical logs may provide the required data but, in the case of banded iron formation hosted iron ore deposits in the Hamersley Ranges of Western Australia, only one geophysical log type (natural gamma) is collected for this purpose. The information from these logs is currently processed by slow manual interpretation. In this paper we present an alternative method of automatically identifying recurring stratigraphic markers in natural gamma logs from multiple drill holes. Our approach is demonstrated using natural gamma geophysical logs that contain features corresponding to the presence of stratigraphically important marker shales. The host stratigraphic sequence is highly consistent throughout the Hamersley and the marker shales can therefore be used to identify the stratigraphic location of the banded iron formation (BIF) or BIF hosted ore. The marker shales are identified using Gaussian Processes (GP) trained by either manual or active learning methods and the results are compared to the existing geological interpretation. The manual method involves the user selecting the signatures for improving the library, whereas the active learning method uses the measure of uncertainty provided by the GP to select specific examples for the user to consider for addition. The results demonstrate that both GP methods can identify a feature, but the active learning approach has several benefits over the manual method. These benefits include greater accuracy in the identified signatures, faster library building, and an objective approach for selecting signatures that includes the full range of signatures across a deposit in the library. When using the active learning method, it was found that the current manual interpretation could be replaced in 78.4% of the holes with an accuracy of 95.7%.

Hierarchical Bayesian modelling of gene expression time series across irregularly sampled replicates and clusters.

PubMed

Hensman, James; Lawrence, Neil D; Rattray, Magnus

2013-08-20

Time course data from microarrays and high-throughput sequencing experiments require simple, computationally efficient and powerful statistical models to extract meaningful biological signal, and for tasks such as data fusion and clustering. Existing methodologies fail to capture either the temporal or replicated nature of the experiments, and often impose constraints on the data collection process, such as regularly spaced samples, or similar sampling schema across replications. We propose hierarchical Gaussian processes as a general model of gene expression time-series, with application to a variety of problems. In particular, we illustrate the method's capacity for missing data imputation, data fusion and clustering.The method can impute data which is missing both systematically and at random: in a hold-out test on real data, performance is significantly better than commonly used imputation methods. The method's ability to model inter- and intra-cluster variance leads to more biologically meaningful clusters. The approach removes the necessity for evenly spaced samples, an advantage illustrated on a developmental Drosophila dataset with irregular replications. The hierarchical Gaussian process model provides an excellent statistical basis for several gene-expression time-series tasks. It has only a few additional parameters over a regular GP, has negligible additional complexity, is easily implemented and can be integrated into several existing algorithms. Our experiments were implemented in python, and are available from the authors' website: http://staffwww.dcs.shef.ac.uk/people/J.Hensman/.

Efficient nonparametric n -body force fields from machine learning

NASA Astrophysics Data System (ADS)

Glielmo, Aldo; Zeni, Claudio; De Vita, Alessandro

2018-05-01

We provide a definition and explicit expressions for n -body Gaussian process (GP) kernels, which can learn any interatomic interaction occurring in a physical system, up to n -body contributions, for any value of n . The series is complete, as it can be shown that the "universal approximator" squared exponential kernel can be written as a sum of n -body kernels. These recipes enable the choice of optimally efficient force models for each target system, as confirmed by extensive testing on various materials. We furthermore describe how the n -body kernels can be "mapped" on equivalent representations that provide database-size-independent predictions and are thus crucially more efficient. We explicitly carry out this mapping procedure for the first nontrivial (three-body) kernel of the series, and we show that this reproduces the GP-predicted forces with meV /Å accuracy while being orders of magnitude faster. These results pave the way to using novel force models (here named "M-FFs") that are computationally as fast as their corresponding standard parametrized n -body force fields, while retaining the nonparametric character, the ease of training and validation, and the accuracy of the best recently proposed machine-learning potentials.

Voxel-Based Neighborhood for Spatial Shape Pattern Classification of Lidar Point Clouds with Supervised Learning

PubMed Central

Plaza-Leiva, Victoria; Gomez-Ruiz, Jose Antonio; Mandow, Anthony; García-Cerezo, Alfonso

2017-01-01

Improving the effectiveness of spatial shape features classification from 3D lidar data is very relevant because it is largely used as a fundamental step towards higher level scene understanding challenges of autonomous vehicles and terrestrial robots. In this sense, computing neighborhood for points in dense scans becomes a costly process for both training and classification. This paper proposes a new general framework for implementing and comparing different supervised learning classifiers with a simple voxel-based neighborhood computation where points in each non-overlapping voxel in a regular grid are assigned to the same class by considering features within a support region defined by the voxel itself. The contribution provides offline training and online classification procedures as well as five alternative feature vector definitions based on principal component analysis for scatter, tubular and planar shapes. Moreover, the feasibility of this approach is evaluated by implementing a neural network (NN) method previously proposed by the authors as well as three other supervised learning classifiers found in scene processing methods: support vector machines (SVM), Gaussian processes (GP), and Gaussian mixture models (GMM). A comparative performance analysis is presented using real point clouds from both natural and urban environments and two different 3D rangefinders (a tilting Hokuyo UTM-30LX and a Riegl). Classification performance metrics and processing time measurements confirm the benefits of the NN classifier and the feasibility of voxel-based neighborhood. PMID:28294963

Machine learning to design integral membrane channelrhodopsins for efficient eukaryotic expression and plasma membrane localization.

PubMed

Bedbrook, Claire N; Yang, Kevin K; Rice, Austin J; Gradinaru, Viviana; Arnold, Frances H

2017-10-01

There is growing interest in studying and engineering integral membrane proteins (MPs) that play key roles in sensing and regulating cellular response to diverse external signals. A MP must be expressed, correctly inserted and folded in a lipid bilayer, and trafficked to the proper cellular location in order to function. The sequence and structural determinants of these processes are complex and highly constrained. Here we describe a predictive, machine-learning approach that captures this complexity to facilitate successful MP engineering and design. Machine learning on carefully-chosen training sequences made by structure-guided SCHEMA recombination has enabled us to accurately predict the rare sequences in a diverse library of channelrhodopsins (ChRs) that express and localize to the plasma membrane of mammalian cells. These light-gated channel proteins of microbial origin are of interest for neuroscience applications, where expression and localization to the plasma membrane is a prerequisite for function. We trained Gaussian process (GP) classification and regression models with expression and localization data from 218 ChR chimeras chosen from a 118,098-variant library designed by SCHEMA recombination of three parent ChRs. We use these GP models to identify ChRs that express and localize well and show that our models can elucidate sequence and structure elements important for these processes. We also used the predictive models to convert a naturally occurring ChR incapable of mammalian localization into one that localizes well.

Machine learning to design integral membrane channelrhodopsins for efficient eukaryotic expression and plasma membrane localization

PubMed Central

Rice, Austin J.; Gradinaru, Viviana; Arnold, Frances H.

2017-01-01

There is growing interest in studying and engineering integral membrane proteins (MPs) that play key roles in sensing and regulating cellular response to diverse external signals. A MP must be expressed, correctly inserted and folded in a lipid bilayer, and trafficked to the proper cellular location in order to function. The sequence and structural determinants of these processes are complex and highly constrained. Here we describe a predictive, machine-learning approach that captures this complexity to facilitate successful MP engineering and design. Machine learning on carefully-chosen training sequences made by structure-guided SCHEMA recombination has enabled us to accurately predict the rare sequences in a diverse library of channelrhodopsins (ChRs) that express and localize to the plasma membrane of mammalian cells. These light-gated channel proteins of microbial origin are of interest for neuroscience applications, where expression and localization to the plasma membrane is a prerequisite for function. We trained Gaussian process (GP) classification and regression models with expression and localization data from 218 ChR chimeras chosen from a 118,098-variant library designed by SCHEMA recombination of three parent ChRs. We use these GP models to identify ChRs that express and localize well and show that our models can elucidate sequence and structure elements important for these processes. We also used the predictive models to convert a naturally occurring ChR incapable of mammalian localization into one that localizes well. PMID:29059183

Quality-Related Monitoring and Grading of Granulated Products by Weibull-Distribution Modeling of Visual Images with Semi-Supervised Learning.

PubMed

Liu, Jinping; Tang, Zhaohui; Xu, Pengfei; Liu, Wenzhong; Zhang, Jin; Zhu, Jianyong

2016-06-29

The topic of online product quality inspection (OPQI) with smart visual sensors is attracting increasing interest in both the academic and industrial communities on account of the natural connection between the visual appearance of products with their underlying qualities. Visual images captured from granulated products (GPs), e.g., cereal products, fabric textiles, are comprised of a large number of independent particles or stochastically stacking locally homogeneous fragments, whose analysis and understanding remains challenging. A method of image statistical modeling-based OPQI for GP quality grading and monitoring by a Weibull distribution(WD) model with a semi-supervised learning classifier is presented. WD-model parameters (WD-MPs) of GP images' spatial structures, obtained with omnidirectional Gaussian derivative filtering (OGDF), which were demonstrated theoretically to obey a specific WD model of integral form, were extracted as the visual features. Then, a co-training-style semi-supervised classifier algorithm, named COSC-Boosting, was exploited for semi-supervised GP quality grading, by integrating two independent classifiers with complementary nature in the face of scarce labeled samples. Effectiveness of the proposed OPQI method was verified and compared in the field of automated rice quality grading with commonly-used methods and showed superior performance, which lays a foundation for the quality control of GP on assembly lines.

An efficient cardiac mapping strategy for radiofrequency catheter ablation with active learning.

PubMed

Feng, Yingjing; Guo, Ziyan; Dong, Ziyang; Zhou, Xiao-Yun; Kwok, Ka-Wai; Ernst, Sabine; Lee, Su-Lin

2017-07-01

A major challenge in radiofrequency catheter ablation procedures is the voltage and activation mapping of the endocardium, given a limited mapping time. By learning from expert interventional electrophysiologists (operators), while also making use of an active-learning framework, guidance on performing cardiac voltage mapping can be provided to novice operators or even directly to catheter robots. A learning from demonstration (LfD) framework, based upon previous cardiac mapping procedures performed by an expert operator, in conjunction with Gaussian process (GP) model-based active learning, was developed to efficiently perform voltage mapping over right ventricles (RV). The GP model was used to output the next best mapping point, while getting updated towards the underlying voltage data pattern as more mapping points are taken. A regularized particle filter was used to keep track of the kernel hyperparameter used by GP. The travel cost of the catheter tip was incorporated to produce time-efficient mapping sequences. The proposed strategy was validated on a simulated 2D grid mapping task, with leave-one-out experiments on 25 retrospective datasets, in an RV phantom using the Stereotaxis Niobe ® remote magnetic navigation system, and on a tele-operated catheter robot. In comparison with an existing geometry-based method, regression error was reduced and was minimized at a faster rate over retrospective procedure data. A new method of catheter mapping guidance has been proposed based on LfD and active learning. The proposed method provides real-time guidance for the procedure, as well as a live evaluation of mapping sufficiency.

Fast and Scalable Gaussian Process Modeling with Applications to Astronomical Time Series

NASA Astrophysics Data System (ADS)

Foreman-Mackey, Daniel; Agol, Eric; Ambikasaran, Sivaram; Angus, Ruth

2017-12-01

The growing field of large-scale time domain astronomy requires methods for probabilistic data analysis that are computationally tractable, even with large data sets. Gaussian processes (GPs) are a popular class of models used for this purpose, but since the computational cost scales, in general, as the cube of the number of data points, their application has been limited to small data sets. In this paper, we present a novel method for GPs modeling in one dimension where the computational requirements scale linearly with the size of the data set. We demonstrate the method by applying it to simulated and real astronomical time series data sets. These demonstrations are examples of probabilistic inference of stellar rotation periods, asteroseismic oscillation spectra, and transiting planet parameters. The method exploits structure in the problem when the covariance function is expressed as a mixture of complex exponentials, without requiring evenly spaced observations or uniform noise. This form of covariance arises naturally when the process is a mixture of stochastically driven damped harmonic oscillators—providing a physical motivation for and interpretation of this choice—but we also demonstrate that it can be a useful effective model in some other cases. We present a mathematical description of the method and compare it to existing scalable GP methods. The method is fast and interpretable, with a range of potential applications within astronomical data analysis and beyond. We provide well-tested and documented open-source implementations of this method in C++, Python, and Julia.

Raman spectroscopy detection of platelet for Alzheimer’s disease with predictive probabilities

NASA Astrophysics Data System (ADS)

Wang, L. J.; Du, X. Q.; Du, Z. W.; Yang, Y. Y.; Chen, P.; Tian, Q.; Shang, X. L.; Liu, Z. C.; Yao, X. Q.; Wang, J. Z.; Wang, X. H.; Cheng, Y.; Peng, J.; Shen, A. G.; Hu, J. M.

2014-08-01

Alzheimer’s disease (AD) is a common form of dementia. Early and differential diagnosis of AD has always been an arduous task for the medical expert due to the unapparent early symptoms and the currently imperfect imaging examination methods. Therefore, obtaining reliable markers with clinical diagnostic value in easily assembled samples is worthy and significant. Our previous work with laser Raman spectroscopy (LRS), in which we detected platelet samples of different ages of AD transgenic mice and non-transgenic controls, showed great effect in the diagnosis of AD. In addition, a multilayer perception network (MLP) classification method was adopted to discriminate the spectral data. However, there were disturbances, which were induced by noise from the machines and so on, in the data set; thus the MLP method had to be trained with large-scale data. In this paper, we aim to re-establish the classification models of early and advanced AD and the control group with fewer features, and apply some mechanism of noise reduction to improve the accuracy of models. An adaptive classification method based on the Gaussian process (GP) featured, with predictive probabilities, is proposed, which could tell when a data set is related to some kind of disease. Compared with MLP on the same feature set, GP showed much better performance in the experimental results. What is more, since the spectra of platelets are isolated from AD, GP has good expansibility and can be applied in diagnosis of many other similar diseases, such as Parkinson’s disease (PD). Spectral data of 4 month and 12 month AD platelets, as well as control data, were collected. With predictive probabilities, the proposed GP classification method improved the diagnostic sensitivity to nearly 100%. Samples were also collected from PD platelets as classification and comparison to the 12 month AD. The presented approach and our experiments indicate that utilization of GP with predictive probabilities in platelet LRS detection analysis turns out to be more accurate for early and differential diagnosis of AD and has a wide application prospect.

GP Workbench Manual: Technical Manual, User's Guide, and Software Guide

USGS Publications Warehouse

Oden, Charles P.; Moulton, Craig W.

2006-01-01

GP Workbench is an open-source general-purpose geophysical data processing software package written primarily for ground penetrating radar (GPR) data. It also includes support for several USGS prototype electromagnetic instruments such as the VETEM and ALLTEM. The two main programs in the package are GP Workbench and GP Wave Utilities. GP Workbench has routines for filtering, gridding, and migrating GPR data; as well as an inversion routine for characterizing UXO (unexploded ordinance) using ALLTEM data. GP Workbench provides two-dimensional (section view) and three-dimensional (plan view or time slice view) processing for GPR data. GP Workbench can produce high-quality graphics for reports when Surfer 8 or higher (Golden Software) is installed. GP Wave Utilities provides a wide range of processing algorithms for single waveforms, such as filtering, correlation, deconvolution, and calculating GPR waveforms. GP Wave Utilities is used primarily for calibrating radar systems and processing individual traces. Both programs also contain research features related to the calibration of GPR systems and calculating subsurface waveforms. The software is written to run on the Windows operating systems. GP Workbench can import GPR data file formats used by major commercial instrument manufacturers including Sensors and Software, GSSI, and Mala. The GP Workbench native file format is SU (Seismic Unix), and subsequently, files generated by GP Workbench can be read by Seismic Unix as well as many other data processing packages.

The role of proteolytic processing and the stable signal peptide in expression of the Old World arenavirus envelope glycoprotein ectodomain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burri, Dominique J.; Pasquato, Antonella; Ramos da Palma, Joel

2013-02-05

Maturation of the arenavirus GP precursor (GPC) involves proteolytic processing by cellular signal peptidase and the proprotein convertase subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P), yielding a tripartite complex comprised of a stable signal peptide (SSP), the receptor-binding GP1, and the fusion-active transmembrane GP2. Here we investigated the roles of SKI-1/S1P processing and SSP in the biosynthesis of the recombinant GP ectodomains of lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV). When expressed in mammalian cells, the LCMV and LASV GP ectodomains underwent processing by SKI-1/S1P, followed by dissociation of GP1 from GP2. The GP2 ectodomain spontaneously formed trimersmore » as revealed by chemical cross-linking. The endogenous SSP, known to be crucial for maturation and transport of full-length arenavirus GPC was dispensable for processing and secretion of the soluble GP ectodomain, suggesting a specific role of SSP in the stable prefusion conformation and transport of full-length GPC.« less

Laser Raman detection for oral cancer based on a Gaussian process classification method

NASA Astrophysics Data System (ADS)

Du, Zhanwei; Yang, Yongjian; Bai, Yuan; Wang, Lijun; Zhang, Chijun; Chen, He; Luo, Yusheng; Su, Le; Chen, Yong; Li, Xianchang; Zhou, Xiaodong; Jia, Jun; Shen, Aiguo; Hu, Jiming

2013-06-01

Oral squamous cell carcinoma is the most common neoplasm of the oral cavity. The incidence rate accounts for 80% of total oral cancer and shows an upward trend in recent years. It has a high degree of malignancy and is difficult to detect in terms of differential diagnosis, as a consequence of which the timing of treatment is always delayed. In this work, Raman spectroscopy was adopted to differentially diagnose oral squamous cell carcinoma and oral gland carcinoma. In total, 852 entries of raw spectral data which consisted of 631 items from 36 oral squamous cell carcinoma patients, 87 items from four oral gland carcinoma patients and 134 items from five normal people were collected by utilizing an optical method on oral tissues. The probability distribution of the datasets corresponding to the spectral peaks of the oral squamous cell carcinoma tissue was analyzed and the experimental result showed that the data obeyed a normal distribution. Moreover, the distribution characteristic of the noise was also in compliance with a Gaussian distribution. A Gaussian process (GP) classification method was utilized to distinguish the normal people and the oral gland carcinoma patients from the oral squamous cell carcinoma patients. The experimental results showed that all the normal people could be recognized. 83.33% of the oral squamous cell carcinoma patients could be correctly diagnosed and the remaining ones would be diagnosed as having oral gland carcinoma. For the classification process of oral gland carcinoma and oral squamous cell carcinoma, the correct ratio was 66.67% and the erroneously diagnosed percentage was 33.33%. The total sensitivity was 80% and the specificity was 100% with the Matthews correlation coefficient (MCC) set to 0.447 213 595. Considering the numerical results above, the application prospects and clinical value of this technique are significantly impressive.

Multilayer Joint Gait-Pose Manifolds for Human Gait Motion Modeling.

PubMed

Ding, Meng; Fan, Guolian

2015-11-01

We present new multilayer joint gait-pose manifolds (multilayer JGPMs) for complex human gait motion modeling, where three latent variables are defined jointly in a low-dimensional manifold to represent a variety of body configurations. Specifically, the pose variable (along the pose manifold) denotes a specific stage in a walking cycle; the gait variable (along the gait manifold) represents different walking styles; and the linear scale variable characterizes the maximum stride in a walking cycle. We discuss two kinds of topological priors for coupling the pose and gait manifolds, i.e., cylindrical and toroidal, to examine their effectiveness and suitability for motion modeling. We resort to a topologically-constrained Gaussian process (GP) latent variable model to learn the multilayer JGPMs where two new techniques are introduced to facilitate model learning under limited training data. First is training data diversification that creates a set of simulated motion data with different strides. Second is the topology-aware local learning to speed up model learning by taking advantage of the local topological structure. The experimental results on the Carnegie Mellon University motion capture data demonstrate the advantages of our proposed multilayer models over several existing GP-based motion models in terms of the overall performance of human gait motion modeling.

Probing the cosmic distance duality relation using time delay lenses

NASA Astrophysics Data System (ADS)

Rana, Akshay; Jain, Deepak; Mahajan, Shobhit; Mukherjee, Amitabha; Holanda, R. F. L.

2017-07-01

The construction of the cosmic distance-duality relation (CDDR) has been widely studied. However, its consistency with various new observables remains a topic of interest. We present a new way to constrain the CDDR η(z) using different dynamic and geometric properties of strong gravitational lenses (SGL) along with SNe Ia observations. We use a sample of 102 SGL with the measurement of corresponding velocity dispersion σ0 and Einstein radius θE. In addition, we also use a dataset of 12 two image lensing systems containing the measure of time delay Δ t between source images. Jointly these two datasets give us the angular diameter distance DAol of the lens. Further, for luminosity distance, we use the 740 observations from JLA compilation of SNe Ia. To study the combined behavior of these datasets we use a model independent method, Gaussian Process (GP). We also check the efficiency of GP by applying it on simulated datasets, which are generated in a phenomenological way by using realistic cosmological error bars. Finally, we conclude that the combined bounds from the SGL and SNe Ia observation do not favor any deviation of CDDR and are in concordance with the standard value (η=1) within 2σ confidence region, which further strengthens the theoretical acceptance of CDDR.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rana, Akshay; Mahajan, Shobhit; Mukherjee, Amitabha

The construction of the cosmic distance-duality relation (CDDR) has been widely studied. However, its consistency with various new observables remains a topic of interest. We present a new way to constrain the CDDR η( z ) using different dynamic and geometric properties of strong gravitational lenses (SGL) along with SNe Ia observations. We use a sample of 102 SGL with the measurement of corresponding velocity dispersion σ{sub 0} and Einstein radius θ {sub E} . In addition, we also use a dataset of 12 two image lensing systems containing the measure of time delay Δ t between source images. Jointlymore » these two datasets give us the angular diameter distance D {sub A} {sub ol} of the lens. Further, for luminosity distance, we use the 740 observations from JLA compilation of SNe Ia. To study the combined behavior of these datasets we use a model independent method, Gaussian Process (GP). We also check the efficiency of GP by applying it on simulated datasets, which are generated in a phenomenological way by using realistic cosmological error bars. Finally, we conclude that the combined bounds from the SGL and SNe Ia observation do not favor any deviation of CDDR and are in concordance with the standard value (η=1) within 2σ confidence region, which further strengthens the theoretical acceptance of CDDR.« less

Building machine learning force fields for nanoclusters

NASA Astrophysics Data System (ADS)

Zeni, Claudio; Rossi, Kevin; Glielmo, Aldo; Fekete, Ádám; Gaston, Nicola; Baletto, Francesca; De Vita, Alessandro

2018-06-01

We assess Gaussian process (GP) regression as a technique to model interatomic forces in metal nanoclusters by analyzing the performance of 2-body, 3-body, and many-body kernel functions on a set of 19-atom Ni cluster structures. We find that 2-body GP kernels fail to provide faithful force estimates, despite succeeding in bulk Ni systems. However, both 3- and many-body kernels predict forces within an ˜0.1 eV/Å average error even for small training datasets and achieve high accuracy even on out-of-sample, high temperature structures. While training and testing on the same structure always provide satisfactory accuracy, cross-testing on dissimilar structures leads to higher prediction errors, posing an extrapolation problem. This can be cured using heterogeneous training on databases that contain more than one structure, which results in a good trade-off between versatility and overall accuracy. Starting from a 3-body kernel trained this way, we build an efficient non-parametric 3-body force field that allows accurate prediction of structural properties at finite temperatures, following a newly developed scheme [A. Glielmo et al., Phys. Rev. B 95, 214302 (2017)]. We use this to assess the thermal stability of Ni19 nanoclusters at a fractional cost of full ab initio calculations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akabayov, B.; Akabayov, S; Lee , S

Gene 5 of bacteriophage T7 encodes a DNA polymerase (gp5) responsible for the replication of the phage DNA. Gp5 polymerizes nucleotides with low processivity, dissociating after the incorporation of 1 to 50 nucleotides. Thioredoxin (trx) of Escherichia coli binds tightly (Kd = 5 nM) to a unique segment in the thumb subdomain of gp5 and increases processivity. We have probed the molecular basis for the increase in processivity. A single-molecule experiment reveals differences in rates of enzymatic activity and processivity between gp5 and gp5/trx. Small angle X-ray scattering studies combined with nuclease footprinting reveal two conformations of gp5, one inmore » the free state and one upon binding to trx. Comparative analysis of the DNA binding clefts of DNA polymerases and DNA binding proteins show that the binding surface contains more hydrophobic residues than other DNA binding proteins. The balanced composition between hydrophobic and charged residues of the binding site allows for efficient sliding of gp5/trx on the DNA. We propose a model for trx-induced conformational changes in gp5 that enhance the processivity by increasing the interaction of gp5 with DNA.« less

Biosynthesis and processing of the Autographa californica nuclear polyhedrosis virus gp64 protein.

PubMed

Jarvis, D L; Garcia, A

1994-11-15

gp64 is a major virion envelope glycoprotein of the baculovirus Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV). gp64 plays an important role in AcMNPV infection, probably mediating penetration of one form of the virus into host cells through the endocytic pathway. gp64 also represents an excellent probe for studying the membrane glycoprotein processing capabilities of baculovirus-infected insect cells, which are used widely as a eucaryotic expression system. The goals of this study were to characterize gp64 biosynthesis and processing and determine how N-glycosylation and N-linked oligosaccharide processing influence the fate and function of gp64 in AcMNPV-infected insect cells. We found that gp64 was synthesized in a biphasic fashion, with peaks at 8 and 24 hr postinfection in both the intracellular and extracellular fractions. Interestingly, the first peak preceded detectable budded virus (BV) production, suggesting that gp64 is shed from infected cells early in infection. Transcriptional regulation accounted for the biphasic mode of gp64 protein synthesis, as transcription initiated at a consensus early motif during early times of infection, at a late motif during late times of infection, and there was a lag between the peak of early and the onset of late transcription. In vitro transcription-translation assays showed that the second ATG in the AcMNPV gp64 long open reading frame is used as the translational initiation codon and that downstream sequences encode a functional signal peptide. Pulse-chase analyses, endoglycosidases, and various inhibitors were used to show that some N-linked oligosaccharides on gp64 are processed by glucosidases and alpha-mannosidases in AcMNPV-infected insect cells. These experiments also revealed that at least two differentially processed gp64 glycoforms are produced in these cells and that both can reach the cell surface and assemble into progeny BV. However, N-linked oligosaccharide processing was not required for gp64 cell surface expression, its assembly into infectious BV, or its fusogenic activity. This suggested that any gp64 glycoform produced during infection, regardless of its N-linked carbohydrate structure, can have essentially normal biological properties. By contrast, transport of gp64 to the cell surface, production of infectious BV, and fusogenic activity were reduced in the absence of N-glycosylation, indicating that this modification is necessary for optimal gp64 function.

Quality-Related Monitoring and Grading of Granulated Products by Weibull-Distribution Modeling of Visual Images with Semi-Supervised Learning

PubMed Central

Liu, Jinping; Tang, Zhaohui; Xu, Pengfei; Liu, Wenzhong; Zhang, Jin; Zhu, Jianyong

2016-01-01

The topic of online product quality inspection (OPQI) with smart visual sensors is attracting increasing interest in both the academic and industrial communities on account of the natural connection between the visual appearance of products with their underlying qualities. Visual images captured from granulated products (GPs), e.g., cereal products, fabric textiles, are comprised of a large number of independent particles or stochastically stacking locally homogeneous fragments, whose analysis and understanding remains challenging. A method of image statistical modeling-based OPQI for GP quality grading and monitoring by a Weibull distribution(WD) model with a semi-supervised learning classifier is presented. WD-model parameters (WD-MPs) of GP images’ spatial structures, obtained with omnidirectional Gaussian derivative filtering (OGDF), which were demonstrated theoretically to obey a specific WD model of integral form, were extracted as the visual features. Then, a co-training-style semi-supervised classifier algorithm, named COSC-Boosting, was exploited for semi-supervised GP quality grading, by integrating two independent classifiers with complementary nature in the face of scarce labeled samples. Effectiveness of the proposed OPQI method was verified and compared in the field of automated rice quality grading with commonly-used methods and showed superior performance, which lays a foundation for the quality control of GP on assembly lines. PMID:27367703

Biosynthesis and intracellular movement of the melanosomal membrane glycoprotein gp75, the human b (brown) locus product

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vijayasaradhi, S.; Doskoch, P.M.; Houghton, A.N.

1991-10-01

A 75-kDa melanosomal glycoprotein (gp75) is the product of a gene that maps to the b (brown) locus, a genetic locus that determines coat color in the mouse. The b locus is conserved (88% identity) between mouse and human. The mouse monoclonal antibody TA99 was used to study the biosynthesis and processing of gp75. gp75 was synthesized as a 55-kDa polypeptide, glycosylated by addition and processing of five or more Asn-linked carbohydrate chains through the cis and trans Golgi, and transported to melanosomes as a mature 75-kDa form. Synthesis and processing of gp75 was rapid (T{sub 1/2} < 30 min),more » and early steps in processing were required for efficient export of gp75 was quite stable in the melanosome. Studies with inhibitors of steps in oligosaccharide processing showed that alternative forms of gp75 were generated during trimming reactions by mannosidase IA/IB and that further maturation resulted in the two mature forms of gp75. The authors purpose that the kinetics of biosynthesis and processing reflect events in the biogenesis and maturation of melanosomes.« less

Accurate multimodal probabilistic prediction of conversion to Alzheimer's disease in patients with mild cognitive impairment.

PubMed

Young, Jonathan; Modat, Marc; Cardoso, Manuel J; Mendelson, Alex; Cash, Dave; Ourselin, Sebastien

2013-01-01

Accurately identifying the patients that have mild cognitive impairment (MCI) who will go on to develop Alzheimer's disease (AD) will become essential as new treatments will require identification of AD patients at earlier stages in the disease process. Most previous work in this area has centred around the same automated techniques used to diagnose AD patients from healthy controls, by coupling high dimensional brain image data or other relevant biomarker data to modern machine learning techniques. Such studies can now distinguish between AD patients and controls as accurately as an experienced clinician. Models trained on patients with AD and control subjects can also distinguish between MCI patients that will convert to AD within a given timeframe (MCI-c) and those that remain stable (MCI-s), although differences between these groups are smaller and thus, the corresponding accuracy is lower. The most common type of classifier used in these studies is the support vector machine, which gives categorical class decisions. In this paper, we introduce Gaussian process (GP) classification to the problem. This fully Bayesian method produces naturally probabilistic predictions, which we show correlate well with the actual chances of converting to AD within 3 years in a population of 96 MCI-s and 47 MCI-c subjects. Furthermore, we show that GPs can integrate multimodal data (in this study volumetric MRI, FDG-PET, cerebrospinal fluid, and APOE genotype with the classification process through the use of a mixed kernel). The GP approach aids combination of different data sources by learning parameters automatically from training data via type-II maximum likelihood, which we compare to a more conventional method based on cross validation and an SVM classifier. When the resulting probabilities from the GP are dichotomised to produce a binary classification, the results for predicting MCI conversion based on the combination of all three types of data show a balanced accuracy of 74%. This is a substantially higher accuracy than could be obtained using any individual modality or using a multikernel SVM, and is competitive with the highest accuracy yet achieved for predicting conversion within three years on the widely used ADNI dataset.

Processing of human cytomegalovirus glycoprotein B in recombinant adenovirus-infected cells.

PubMed

Marshall, G S; Fenger, D P; Stout, G G; Knights, M E; Hunt, L A

1996-07-01

Intracellular processing of human cytomegalovirus (HCMV) glycoprotein B (gB; gpUL55) expressed by a recombinant adenovirus (Ad-gB) was studied in human A549 cells as processing events could affect immunogenicity when such viruses are used as live-recombinant vaccines. Cleavage of [35S]methionine-labelled gp13O into gp93 and gp55 reached a maximum after a 3 h chase. Cleavage was completely inhibited by brefeldin A, suggesting that processing normally occurs as a late Golgi or post-Golgi event. Uncleaved gp 130 remained completely sensitive to endo-beta-N-acetylglucosaminidase H (Endo-H) in untreated cells following long chase periods, indicating high-mannose oligosaccharides at all of the 18 N-linked glycosylation sites (Asn-X-Ser/Thr) and retention in the endoplasmic reticulum. Endo-H analysis of gp55 from swainsonine-treated and untreated cells was consistent with glycosylation at all three potential sites, with two oligosaccharides remaining sensitive to Endo-H and one being processed to Endo-H resistance. The heavily glycosylated N-terminal gp93 subunit was not detected by [35S]methionine-labelling but was easily detected along with gp55 after labelling with [3H]mannose. No cleavage of gp 130 was observed in analogous pulse-chase radiolabelling of Ad-gB-infected human fibroblasts, even though these cells are permissive for HCMV replication and can process the native gB molecule. Processing of gB in recombinant adenovirus-infected A549 cells was generally similar to that previously reported for native gB in HCMV-infected fibroblasts.

Differences in signal peptide processing between GP3 glycoproteins of Arteriviridae.

PubMed

Zhang, Minze; Veit, Michael

2018-04-01

We reported previously that carbohydrate attachment to an overlapping glycosylation site adjacent to the signal peptide of GP3 from equine arteritis virus (EAV) prevents cleavage. Here we investigated whether this unusual processing scheme is a feature of GP3s of other Arteriviridae, which all contain a glycosylation site at a similar position. Expression of GP3 from type-1 and type-2 porcine reproductive and respiratory syndrome virus (PRRSV) and from lactate dehydrogenase-elevating virus (LDV) revealed that the first glycosylation site is used, but has no effect on signal peptide cleavage. Comparison of the SDS-PAGE mobility of deglycosylated GP3 from PRRSV and LDV with mutants having or not having a signal peptide showed that GP3´s signal peptide is cleaved. Swapping the signal peptides between GP3 of EAV and PRRSV revealed that the information for co-translational processing is not encoded in the signal peptide, but in the remaining part of GP3. Copyright © 2017 Elsevier Inc. All rights reserved.

Bayesian least squares deconvolution

NASA Astrophysics Data System (ADS)

Asensio Ramos, A.; Petit, P.

2015-11-01

Aims: We develop a fully Bayesian least squares deconvolution (LSD) that can be applied to the reliable detection of magnetic signals in noise-limited stellar spectropolarimetric observations using multiline techniques. Methods: We consider LSD under the Bayesian framework and we introduce a flexible Gaussian process (GP) prior for the LSD profile. This prior allows the result to automatically adapt to the presence of signal. We exploit several linear algebra identities to accelerate the calculations. The final algorithm can deal with thousands of spectral lines in a few seconds. Results: We demonstrate the reliability of the method with synthetic experiments and we apply it to real spectropolarimetric observations of magnetic stars. We are able to recover the magnetic signals using a small number of spectral lines, together with the uncertainty at each velocity bin. This allows the user to consider if the detected signal is reliable. The code to compute the Bayesian LSD profile is freely available.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules.

PubMed

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-12-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules.

PubMed

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules

NASA Astrophysics Data System (ADS)

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-12-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

Estimating the domain of applicability for machine learning QSAR models: a study on aqueous solubility of drug discovery molecules

NASA Astrophysics Data System (ADS)

Schroeter, Timon Sebastian; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

We investigate the use of different Machine Learning methods to construct models for aqueous solubility. Models are based on about 4000 compounds, including an in-house set of 632 drug discovery molecules of Bayer Schering Pharma. For each method, we also consider an appropriate method to obtain error bars, in order to estimate the domain of applicability (DOA) for each model. Here, we investigate error bars from a Bayesian model (Gaussian Process (GP)), an ensemble based approach (Random Forest), and approaches based on the Mahalanobis distance to training data (for Support Vector Machine and Ridge Regression models). We evaluate all approaches in terms of their prediction accuracy (in cross-validation, and on an external validation set of 536 molecules) and in how far the individual error bars can faithfully represent the actual prediction error.

On switching response surface models, with applications to the structural health monitoring of bridges

NASA Astrophysics Data System (ADS)

Worden, K.; Cross, E. J.

2018-01-01

Structural Health Monitoring (SHM) is the engineering discipline of diagnosing damage and estimating safe remaining life for structures and systems. Often, SHM is accomplished by detecting changes in measured quantities from the structure of interest; if there are no competing explanations for the changes, one infers that they are the result of damage. If the structure of interest is subject to changes in its environmental or operational conditions, one must understand the effects of these changes in order that one does not falsely claim that damage has occurred when changes in measured quantities are observed. This problem - the problem of confounding influences - is particularly pressing for civil infrastructure where the given structure is usually openly exposed to the weather and may be subject to strongly varying operational conditions. One approach to understanding confounding influences is to construct a data-based response surface model that can represent measurement variations as a function of environmental and operational variables. The models can then be used to remove environmental and operational variations so that change detection algorithms signal the occurrence of damage alone. The current paper is concerned with such response surface models in the case of SHM of bridges. In particular, classes of response surface models that can switch discontinuously between regimes are discussed. Recently, it has been shown that Gaussian Process (GP) models are an effective means of developing response surface or surrogate models. However, the GP approach runs into difficulties if changes in the latent variables cause the structure of interest to abruptly switch between regimes. A good example here, which is well known in the SHM literature, is given by the Z24 Bridge in Switzerland which completely changed its dynamical behaviour when it cooled below zero degrees Celsius as the asphalt of the deck stiffened. The solution proposed here is to adopt the recently-proposed Treed Gaussian Process (TGP) model as an alternative. The approach is illustrated here on the Z24 bridge and also on data from the Tamar Bridge in the UK which shows marked switching behaviour in certain of its dynamical characteristics when its ambient wind conditions change. It is shown that treed GPs provide an effective approach to response surface modelling and that in the Tamar case, a linear model is in fact sufficient to solve the problem.

Statistical characterization of discrete conservative systems: The web map

NASA Astrophysics Data System (ADS)

Ruiz, Guiomar; Tirnakli, Ugur; Borges, Ernesto P.; Tsallis, Constantino

2017-10-01

We numerically study the two-dimensional, area preserving, web map. When the map is governed by ergodic behavior, it is, as expected, correctly described by Boltzmann-Gibbs statistics, based on the additive entropic functional SB G[p (x ) ] =-k ∫d x p (x ) lnp (x ) . In contrast, possible ergodicity breakdown and transitory sticky dynamical behavior drag the map into the realm of generalized q statistics, based on the nonadditive entropic functional Sq[p (x ) ] =k 1/-∫d x [p(x ) ] q q -1 (q ∈R ;S1=SB G ). We statistically describe the system (probability distribution of the sum of successive iterates, sensitivity to the initial condition, and entropy production per unit time) for typical values of the parameter that controls the ergodicity of the map. For small (large) values of the external parameter K , we observe q -Gaussian distributions with q =1.935 ⋯ (Gaussian distributions), like for the standard map. In contrast, for intermediate values of K , we observe a different scenario, due to the fractal structure of the trajectories embedded in the chaotic sea. Long-standing non-Gaussian distributions are characterized in terms of the kurtosis and the box-counting dimension of chaotic sea.

MHC class II presentation of gp100 epitopes in melanoma cells requires the function of conventional endosomes, and is influenced by melanosomes1

PubMed Central

Robila, Valentina; Ostankovitch, Marina; Altrich-VanLith, Michelle L.; Theos, Alexander C.; Drover, Sheila; Marks, Michael S.; Restifo, Nicholas; Engelhard, Victor H.

2009-01-01

Many human solid tumors express MHC II molecules, and proteins normally localized to melanosomes give rise to MHC II restricted epitopes in melanoma. However, the pathways by which this occurs have not been defined. We analyzed the processing of one such epitope, gp10044-59, derived from gp100/Pmel17. In melanomas that have down-regulated components of the melanosomal pathway, but constitutively express HLA-DR*0401, the majority of gp100 is sorted to LAMP-1hi/MHC II+ late endosomes. Using mutant gp100 molecules with altered intracellular trafficking, we demonstrate that endosomal localization is necessary for gp10044-59 presentation. By depletion of the AP2 adaptor protein using siRNA, we demonstrate that gp100 protein internalized from the plasma membrane to such endosomes is a major source for gp10044-59 epitope production. Gp100 trapped in early endosomes gives rise to epitopes that are indistinguishable from those produced in late endosomes but their production is less sensitive to inhibition of lysosomal proteases. In melanomas containing melanosomes, gp100 is underrepresented in late endosomes, and accumulates in stage II melanosomes devoid of MHC II molecules. Gp10044-59 presentation is dramatically reduced, and processing occurs entirely in early endosomes / stage I melanosomes. This suggests that melanosomes are inefficient antigen processing compartments. Thus, melanoma de-differentiation may be accompanied by increased presentation of MHC II restricted epitopes from gp100 and other melanosome-localized proteins, leading to enhanced immune recognition. PMID:19017974

Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

NASA Astrophysics Data System (ADS)

Saurabh, Suman; Sahoo, Anil Kumar; Maiti, Prabal K.

2016-10-01

Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4.

Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs. abnormal iron content in the brain.

PubMed

Haacke, E Mark; Ayaz, Muhammad; Khan, Asadullah; Manova, Elena S; Krishnamurthy, Bharani; Gollapalli, Lakshman; Ciulla, Carlo; Kim, I; Petersen, Floyd; Kirsch, Wolff

2007-08-01

To establish a baseline of phase differences between tissues in a number of regions of the human brain as a means of detecting iron abnormalities using magnetic resonance imaging (MRI). A fully flow-compensated, three-dimensional (3D), high-resolution, gradient-echo (GRE) susceptibility-weighted imaging (SWI) sequence was used to collect magnitude and phase data at 1.5 T. The phase images were high-pass-filtered and processed region by region with hand-drawn areas. The regions evaluated included the motor cortex (MC), putamen (PUT), globus pallidus (GP), caudate nucleus (CN), substantia nigra (SN), and red nucleus (RN). A total of 75 subjects, ranging in age from 55 to 89 years, were analyzed. The phase was found to have a Gaussian-like distribution with a standard deviation (SD) of 0.046 radians on a pixel-by-pixel basis. Most regions of interest (ROIs) contained at least 100 pixels, giving a standard error of the mean (SEM) of 0.0046 radians or less. In the MC, phase differences were found to be roughly 0.273 radians between CSF and gray matter (GM), and 0.083 radians between CSF and white matter (WM). The difference between CSF and the GP was 0.201 radians, and between CSF and the CN (head) it was 0.213 radians. For CSF and the PUT (the lower outer part) the difference was 0.449 radians, and between CSF and the RN (third slice vascularized region) it was 0.353 radians. Finally, the phase difference between CSF and SN was 0.345 radians. The Gaussian-like distributions in phase make it possible to predict deviations from normal phase behavior for tissues in the brain. Using phase as an iron marker may be useful for studying absorption of iron in diseases such as Parkinson's, Huntington's, neurodegeneration with brain iron accumulation (NBIA), Alzheimer's, and multiple sclerosis (MS), and other iron-related diseases. The phases quoted here will serve as a baseline for future studies that look for changes in iron content. (c) 2007 Wiley-Liss, Inc.

Genetic programming assisted stochastic optimization strategies for optimization of glucose to gluconic acid fermentation.

PubMed

Cheema, Jitender Jit Singh; Sankpal, Narendra V; Tambe, Sanjeev S; Kulkarni, Bhaskar D

2002-01-01

This article presents two hybrid strategies for the modeling and optimization of the glucose to gluconic acid batch bioprocess. In the hybrid approaches, first a novel artificial intelligence formalism, namely, genetic programming (GP), is used to develop a process model solely from the historic process input-output data. In the next step, the input space of the GP-based model, representing process operating conditions, is optimized using two stochastic optimization (SO) formalisms, viz., genetic algorithms (GAs) and simultaneous perturbation stochastic approximation (SPSA). These SO formalisms possess certain unique advantages over the commonly used gradient-based optimization techniques. The principal advantage of the GP-GA and GP-SPSA hybrid techniques is that process modeling and optimization can be performed exclusively from the process input-output data without invoking the detailed knowledge of the process phenomenology. The GP-GA and GP-SPSA techniques have been employed for modeling and optimization of the glucose to gluconic acid bioprocess, and the optimized process operating conditions obtained thereby have been compared with those obtained using two other hybrid modeling-optimization paradigms integrating artificial neural networks (ANNs) and GA/SPSA formalisms. Finally, the overall optimized operating conditions given by the GP-GA method, when verified experimentally resulted in a significant improvement in the gluconic acid yield. The hybrid strategies presented here are generic in nature and can be employed for modeling and optimization of a wide variety of batch and continuous bioprocesses.

Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb.

PubMed

Massberg, Steffen; Schürzinger, Katrin; Lorenz, Michael; Konrad, Ildiko; Schulz, Christian; Plesnila, Nikolaus; Kennerknecht, Elisabeth; Rudelius, Martina; Sauer, Susanne; Braun, Siegmund; Kremmer, Elisabeth; Emambokus, Nikla R; Frampton, Jon; Gawaz, Meinrad

2005-08-23

The platelet glycoprotein (GP) IIb/IIIa integrin binds to fibrinogen and thereby mediates platelet aggregation. Here, we addressed the role of GP IIb for platelet adhesion and determined the relevance of platelet GP IIb for the processes of atherosclerosis and cerebral ischemia-reperfusion (I/R) injury. GP IIb(-/-) mice were generated and bred with ApoE(-/-) animals to create GP IIb(-/-)ApoE(-/-) mice. Platelet adhesion to the mechanically injured or atherosclerotic vessel wall was monitored by in vivo video fluorescence microscopy. In the presence of GP IIb, vascular injury and early atherosclerosis induced platelet adhesion in the carotid artery (CA). In contrast, platelet adhesion was significantly reduced in the absence of GP IIb integrin (P<0.05). To address the contribution of platelet GP IIb to atheroprogression, we determined atherosclerotic lesion formation in the CA and aortic arch (AA) of GP IIb(+/+)ApoE(-/-) or GP IIb(-/-)ApoE(-/-) mice. Interestingly, the absence of GP IIb attenuated lesion formation in CA and AA, indicating that platelets, via GP IIb, contribute substantially to atherosclerosis. Next, we assessed the implication of GP IIb for cerebral I/R injury. We observed that after occlusion of the middle cerebral artery, the cerebral infarct size was drastically reduced in mice lacking GP IIb compared with wild-types. These findings show for the first time in vivo that GP IIb not only mediates platelet aggregation but also triggers platelet adhesion to exposed extracellular matrices and dysfunctional endothelial cells. In a process strictly involving GP IIb, platelets, which are among the first blood cells to arrive at the scene of endothelial dysfunction, contribute essentially to atherosclerosis and cerebral I/R injury.

gp160 of HIV-I synthesized by persistently infected Molt-3 cells is terminally glycosylated: evidence that cleavage of gp160 occurs subsequent to oligosaccharide processing.

PubMed

Merkle, R K; Helland, D E; Welles, J L; Shilatifard, A; Haseltine, W A; Cummings, R D

1991-10-01

The envelope glycoprotein of HIV-I in infected, cultured human T cells is synthesized as a precursor of apparent Mr 160 kDa (gp160) and is cleaved to two glycoproteins, gp120 and gp41, which are the mature envelope glycoproteins in the virus. Neither the temporal and spatial features of glycosylation nor the oligosaccharide processing and proteolytic cleavage of the envelope glycoprotein are well understood. To understand more about these events, we investigated the glycosylation and cleavage of the envelope glycoproteins in the CD4+ human cell line, Molt-3, persistently infected with HIV-I (HTLV IIIB). The carbohydrate analysis of gp160 and gp120 and the behavior of the glycoproteins and glycopeptides derived from them on immobilized lectins demonstrate that both of these glycoproteins contain complex- and high-mannose-type Asn-linked oligosaccharides. In addition, the N-glycanase-resistant oligosaccharides of gp120 were found to contain N-acetyl-galactosamine, a common constituent of Ser/Thr-linked oligosaccharides. Pulse-chase analysis of the conversion of [35S]cysteine-labeled gp160 showed that in Molt-3 cells it takes about 2 h for gp120 to arise with a half-time of conversion of about 5 h. At its earliest detectable occurrence, gp120 was found to contain complex-type Asn-linked oligosaccharides. Taken together, these results indicate that proteolytic cleavage of gp160 to gp120 and gp41 occurs either within the trans-Golgi or in a distal compartment.

Intracellular transport and processing of the Marburg virus surface protein in vertebrate and insect cells.

PubMed

Becker, S; Klenk, H D; Mühlberger, E

1996-11-01

The surface protein (GP) of Marburg virus (MBG) is synthesized as a 90-kDa precursor protein which is cotranslationally modified by the addition of high-mannose sugars (140 kDa). This step is followed by the conversion of the N-linked sugars to endoglycosidase H (endo H)-resistant species and the addition of O-linked oliosaccharides leading to a mature protein of 170-200 kDa approximately 30 min after pulse labelling. The mature form of GP is efficiently transported to the plasma membrane. GP synthesized using the T7 polymerase-driven vaccinia virus expression system was transported with essentially the same kinetics as the authentic GP. However, the protein that is shown to appear 30 min after pulse labeling at the plasma membrane was slighly smaller (160 kDa) than GP incorporated into the virions (170 kDa). Using a recombinant baculovirus, GP was expressed at high levels in insect cells. Three different species could be identified: a 90-kDa unglycosylated GP localized in the cytoplasm and two 140-kDa glycosylated proteins. Characterization of the glycosylated GPs revealed that processing of the oligosaccharides of GP was less efficient in insect cells than in mammalian cells. The majority of GP remained endo H sensitive containing high-mannose type N-linked glycans, whereas only a small fraction became endo H resistant carrying processed N-glycans and O-glycans. Tunicamycin treatment of the GP-expressing cells demonstrated that N-glycosylation is essential for the transport of the MBG surface protein.

A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

NASA Astrophysics Data System (ADS)

Schwörer, Magnus; Wichmann, Christoph; Tavan, Paul

2016-03-01

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). For the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a "first-principles" DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.

A polarizable QM/MM approach to the molecular dynamics of amide groups solvated in water

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwörer, Magnus; Wichmann, Christoph; Tavan, Paul, E-mail: tavan@physik.uni-muenchen.de

2016-03-21

The infrared (IR) spectra of polypeptides are dominated by the so-called amide bands. Because they originate from the strongly polar and polarizable amide groups (AGs) making up the backbone, their spectral positions sensitively depend on the local electric fields. Aiming at accurate computations of these IR spectra by molecular dynamics (MD) simulations, which derive atomic forces from a hybrid quantum and molecular mechanics (QM/MM) Hamiltonian, here we consider the effects of solvation in bulk liquid water on the amide bands of the AG model compound N-methyl-acetamide (NMA). As QM approach to NMA we choose grid-based density functional theory (DFT). Formore » the surrounding MM water, we develop, largely based on computations, a polarizable molecular mechanics (PMM) model potential called GP6P, which features six Gaussian electrostatic sources (one induced dipole, five static partial charge distributions) and, therefore, avoids spurious distortions of the DFT electron density in hybrid DFT/PMM simulations. Bulk liquid GP6P is shown to have favorable properties at the thermodynamic conditions of the parameterization and beyond. Lennard-Jones (LJ) parameters of the DFT fragment NMA are optimized by comparing radial distribution functions in the surrounding GP6P liquid with reference data obtained from a “first-principles” DFT-MD simulation. Finally, IR spectra of NMA in GP6P water are calculated from extended DFT/PMM-MD trajectories, in which the NMA is treated by three different DFT functionals (BP, BLYP, B3LYP). Method-specific frequency scaling factors are derived from DFT-MD simulations of isolated NMA. The DFT/PMM-MD simulations with GP6P and with the optimized LJ parameters then excellently predict the effects of aqueous solvation and deuteration observed in the IR spectra of NMA. As a result, the methods required to accurately compute such spectra by DFT/PMM-MD also for larger peptides in aqueous solution are now at hand.« less

Inhibitors of the entry of HIV into host cells.

PubMed

Meanwell, Nicholas A; Kadow, John F

2003-07-01

The development of mechanistic insight into the process by which HIV enters host cells has revealed a panoply of targets that offer considerable potential as sites for pharmacological intervention. The gp120/gp41 protein complex, expressed on the virion surface, mediates HIV entry by a process initiated by the engagement of the host cell receptor CD4. Subtle conformational changes triggered by this interaction expose elements of gp120 to the seven-transmembrane, G protein-coupled chemokine receptors CCR5 or CXCR4 expressed on host cells, a contact that relieves constraints imposed on gp41 by gp120. This leads to a major conformational rearrangement of gp41, which results in the insertion of the fusion peptide into the host cell membrane and the assembly of the amino terminus heptad repeat into a trimeric form that is subsequently recognized by the carboxy terminal heptad repeat. The latter process leads to juxtaposition of the viral and host cell membranes, a prelude to fusion. The most prominent strategies and targets that are actively being exploited as drug discovery opportunities are inhibition of the attachment of HIV to host cells, blockade of chemokine receptors and interference with the function of gp41. Inhibitors of each of these steps in the HIV entry process with potential clinical relevance are reviewed in the context of their status in the drug development process. The most significant entity to emerge from this area of research to date is enfuvirtide, a 36-amino acid derivative that interferes with the function of gp41. Enfuvirtide is the first HIV entry inhibitor to be granted a license for marketing (it was approved in the US and Europe in March 2003), and its introduction portends the beginning of what promises to be an exciting new era of HIV therapy.

Arenavirus Stable Signal Peptide Is the Keystone Subunit for Glycoprotein Complex Organization

PubMed Central

Bederka, Lydia H.; Bonhomme, Cyrille J.; Ling, Emily L.

2014-01-01

ABSTRACT The rodent arenavirus glycoprotein complex encodes a stable signal peptide (SSP) that is an essential structural component of mature virions. The SSP, GP1, and GP2 subunits of the trimeric glycoprotein complex noncovalently interact to stud the surface of virions and initiate arenavirus infectivity. Nascent glycoprotein production undergoes two proteolytic cleavage events: first within the endoplasmic reticulum (ER) to cleave SSP from the remaining precursor GP1/2 (glycoprotein complex [GPC]) glycoprotein and second within the Golgi stacks by the cellular SKI-1/S1P for GP1/2 processing to yield GP1 and GP2 subunits. Cleaved SSP is not degraded but retained as an essential glycoprotein subunit. Here, we defined functions of the 58-amino-acid lymphocytic choriomeningitis virus (LCMV) SSP in regard to glycoprotein complex processing and maturation. Using molecular biology techniques, confocal microscopy, and flow cytometry, we detected SSP at the plasma membrane of transfected cells. Further, we identified a sorting signal (FLLL) near the carboxyl terminus of SSP that is required for glycoprotein maturation and trafficking. In the absence of SSP, the glycoprotein accumulated within the ER and was unable to undergo processing by SKI-1/S1P. Mutation of this highly conserved FLLL motif showed impaired glycoprotein processing and secretory pathway trafficking, as well as defective surface expression and pH-dependent membrane fusion. Immunoprecipitation of SSP confirmed an interaction between the signal peptide and the GP2 subunit; however, mutations within this FLLL motif disrupted the association of the GP1 subunit with the remaining glycoprotein complex. PMID:25352624

Uncoupling GP1 and GP2 Expression in the Lassa Virus Glycoprotein Complex: Implications for GP1 Ectodomain Shedding

DTIC Science & Technology

2008-12-23

glycoprotein precursor (GPC) signal peptide (SP) or human IgG signal sequences (s.s.). GP2 was secreted from cells only when (1) the transmembrane (TM) domain... peptide (SP) or human IgG signal sequences (s.s.). GP2 was secreted from cells only when (1) the transmembrane (TM) domain was deleted, the...terminal signal peptide (SP), which directs the precursor to the endoplasmic retic- ulum (ER) for further processing [11]. The SP, which has been

Towards a generalized energy prediction model for machine tools

PubMed Central

Bhinge, Raunak; Park, Jinkyoo; Law, Kincho H.; Dornfeld, David A.; Helu, Moneer; Rachuri, Sudarsan

2017-01-01

Energy prediction of machine tools can deliver many advantages to a manufacturing enterprise, ranging from energy-efficient process planning to machine tool monitoring. Physics-based, energy prediction models have been proposed in the past to understand the energy usage pattern of a machine tool. However, uncertainties in both the machine and the operating environment make it difficult to predict the energy consumption of the target machine reliably. Taking advantage of the opportunity to collect extensive, contextual, energy-consumption data, we discuss a data-driven approach to develop an energy prediction model of a machine tool in this paper. First, we present a methodology that can efficiently and effectively collect and process data extracted from a machine tool and its sensors. We then present a data-driven model that can be used to predict the energy consumption of the machine tool for machining a generic part. Specifically, we use Gaussian Process (GP) Regression, a non-parametric machine-learning technique, to develop the prediction model. The energy prediction model is then generalized over multiple process parameters and operations. Finally, we apply this generalized model with a method to assess uncertainty intervals to predict the energy consumed to machine any part using a Mori Seiki NVD1500 machine tool. Furthermore, the same model can be used during process planning to optimize the energy-efficiency of a machining process. PMID:28652687

Towards a generalized energy prediction model for machine tools.

PubMed

Bhinge, Raunak; Park, Jinkyoo; Law, Kincho H; Dornfeld, David A; Helu, Moneer; Rachuri, Sudarsan

2017-04-01

Energy prediction of machine tools can deliver many advantages to a manufacturing enterprise, ranging from energy-efficient process planning to machine tool monitoring. Physics-based, energy prediction models have been proposed in the past to understand the energy usage pattern of a machine tool. However, uncertainties in both the machine and the operating environment make it difficult to predict the energy consumption of the target machine reliably. Taking advantage of the opportunity to collect extensive, contextual, energy-consumption data, we discuss a data-driven approach to develop an energy prediction model of a machine tool in this paper. First, we present a methodology that can efficiently and effectively collect and process data extracted from a machine tool and its sensors. We then present a data-driven model that can be used to predict the energy consumption of the machine tool for machining a generic part. Specifically, we use Gaussian Process (GP) Regression, a non-parametric machine-learning technique, to develop the prediction model. The energy prediction model is then generalized over multiple process parameters and operations. Finally, we apply this generalized model with a method to assess uncertainty intervals to predict the energy consumed to machine any part using a Mori Seiki NVD1500 machine tool. Furthermore, the same model can be used during process planning to optimize the energy-efficiency of a machining process.

Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs

PubMed Central

Jiang, Xiaohong; Dalebout, Tim J.; Bredenbeek, Peter J.; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S.; Lukashevich, Igor S.

2010-01-01

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV GP1 and GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and –GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF and LASV GP proteins in infected cells. YF17D/LASV-GP1&GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1&GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. PMID:21145373

Arbitrage with fractional Gaussian processes

NASA Astrophysics Data System (ADS)

Zhang, Xili; Xiao, Weilin

2017-04-01

While the arbitrage opportunity in the Black-Scholes model driven by fractional Brownian motion has a long history, the arbitrage strategy in the Black-Scholes model driven by general fractional Gaussian processes is in its infancy. The development of stochastic calculus with respect to fractional Gaussian processes allowed us to study such models. In this paper, following the idea of Shiryaev (1998), an arbitrage strategy is constructed for the Black-Scholes model driven by fractional Gaussian processes, when the stochastic integral is interpreted in the Riemann-Stieltjes sense. Arbitrage opportunities in some fractional Gaussian processes, including fractional Brownian motion, sub-fractional Brownian motion, bi-fractional Brownian motion, weighted-fractional Brownian motion and tempered fractional Brownian motion, are also investigated.

Yellow fever 17D-vectored vaccines expressing Lassa virus GP1 and GP2 glycoproteins provide protection against fatal disease in guinea pigs.

PubMed

Jiang, Xiaohong; Dalebout, Tim J; Bredenbeek, Peter J; Carrion, Ricardo; Brasky, Kathleen; Patterson, Jean; Goicochea, Marco; Bryant, Joseph; Salvato, Maria S; Lukashevich, Igor S

2011-02-01

Yellow Fever (YF) and Lassa Fever (LF) are two prevalent hemorrhagic fevers co-circulating in West Africa and responsible for thousands of deaths annually. The YF vaccine 17D has been used as a vector for the Lassa virus glycoprotein precursor (LASV-GPC) or their subunits, GP1 (attachment glycoprotein) and GP2 (fusion glycoprotein). Cloning shorter inserts, LASV-GP1 and -GP2, between YF17D E and NS1 genes enhanced genetic stability of recombinant viruses, YF17D/LASV-GP1 and -GP2, in comparison with YF17D/LASV-GPC recombinant. The recombinant viruses were replication competent and properly processed YF proteins and LASV GP antigens in infected cells. YF17D/LASV-GP1 and -GP2 induced specific CD8+ T cell responses in mice and protected strain 13 guinea pigs against fatal LF. Unlike immunization with live attenuated reassortant vaccine ML29, immunization with YF17D/LASV-GP1 and -GP2 did not provide sterilizing immunity. This study demonstrates the feasibility of YF17D-based vaccine to control LF in West Africa. Copyright © 2010 Elsevier Ltd. All rights reserved.

Different oligosaccharide processing of the membrane-integrated and the secretory form of gp 80 in rat liver.

PubMed

Tauber, R; Schenck, I; Josić, D; Gross, V; Heinrich, P C; Gerok, W; Reutter, W

1986-09-01

Rat liver synthesizes a glycoprotein with Mr of 80.000 (gp 80) which is partly inserted into the plasma membrane and partly secreted into the serum. The membrane-integrated and the secretory form of this glycoprotein have an identical peptide pattern, but different N-linked glycans. Whereas gp 80 from the serum is glycosylated with complex-type oligosaccharides, gp 80 from the plasma membrane has high mannose glycans. Phase separation with Triton X-114 showed that membrane-integrated gp 80 contains hydrophobic portions, whereas secretory gp 80 has hydrophilic properties. Intracellular transport and oligosaccharide processing of gp 80 were studied in vivo in the endoplasmic reticulum, the Golgi apparatus and plasma membranes of rat liver and in serum using pulse-chase labeling with L-[35S]methionine and immunoprecipitation. Peak labeling of gp 80 was reached in the endoplasmic reticulum 10 min after the pulse, in the Golgi apparatus 20 min later, and in the plasma membrane after 2 h; in the serum the specific radioactivity was steadily increasing during the experiment. Gp 80 of the endoplasmic reticulum was completely sensitive to endo-beta-N-glucosaminidase H (endo H), but simultaneously occurred in the Golgi apparatus in an endo H-sensitive and endo H-resistant form. The endo H-sensitive form was transported to the plasma membrane, the endo H-resistant species secreted into the serum. Conversion from the endo H-sensitive to the endo H-resistant form was completed within 10 min after transfer of gp 80 to the Golgi apparatus.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the Protective Efficacy of DNA and Baculovirus-Derived Protein Vaccines for EBOLA Virus in Guinea Pigs

DTIC Science & Technology

2003-01-01

polyclonal antibody (data not shown). Because the GP1 proteins of the two recombinants should be processed identically, we expect that they will have the...monoclonal antibodies to EBOV GP. J.L. Mellquist-Riemenschneider et al. / Virus Research 92 (2003) 187/193 189 known to have limited capability to process ...and oligosaccharides containing sialic acid, respectively. The ZEBOV virion GP did not react with Galantus nivalis agglutinin (GNA), indicating the

Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Costantini, Lindsey M.; Irvin, Susan C.; Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461

The HIV-1 envelope glycoprotein, gp120, binds the host cell receptor, CD4, in the initial step of HIV viral entry and infection. This process is an appealing target for the development of inhibitory drugs and neutralizing antibodies. To study gp120 binding and intracellular trafficking, we engineered a fluorescent fusion of the humanized gp120 JRFL HIV-1 variant and GFP. Gp120-sfGFP is glycosylated with human sugars, robustly expressed, and secreted from cultured human cells. Protein dynamics, quality control, and trafficking can be visualized in live cells. The fusion protein can be readily modified with different gp120 variants or fluorescent proteins. Finally, secreted gp120-sfGFPmore » enables a sensitive and easy binding assay that can quantitatively screen potential inhibitors of gp120-CD4 binding on live cells via fluorescence imaging or laser scanning cytometry. This adaptable research tool should aid in studies of gp120 cell biology and the development of novel anti-HIV drugs. - Highlights: • Development of fluorescent protein labeled HIV-1 envelope gp120. • Imaging of gp120 dynamics and trafficking in live cells. • Quantitative visual assay of antibody-mediated inhibition of gp120 binding to CD4 on live cells.« less

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol.

PubMed

Hacke, Moritz; Björkholm, Patrik; Hellwig, Andrea; Himmels, Patricia; Ruiz de Almodóvar, Carmen; Brügger, Britta; Wieland, Felix; Ernst, Andreas M

2015-07-09

The high pathogenicity of the Ebola virus reflects multiple concurrent processes on infection. Among other important determinants, Ebola fusogenic glycoprotein (GP) has been associated with the detachment of infected cells and eventually leads to vascular leakage and haemorrhagic fever. Here we report that the membrane-anchored GP is sufficient to induce the detachment of adherent cells. The results show that the detachment induced through either full-length GP1,2 or the subunit GP2 depends on cholesterol and the structure of the transmembrane domain. These data reveal a novel molecular mechanism in which GP regulates Ebola virus assembly and suggest that cholesterol-reducing agents could be useful as therapeutics to counteract GP-mediated cell detachment.

A Novel Approach for Determining Source–Receptor Relationships in Model Simulations: A Case Study of Black Carbon Transport in Northern Hemisphere Winter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Po-Lun; Gattiker, J. R.; Liu, Xiaohong

2013-06-27

A Gaussian process (GP) emulator is applied to quantify the contribution of local and remote emissions of black carbon (BC) on the BC concentrations in different regions using a Latin Hypercube sampling strategy for emission perturbations in the offline version of the Community Atmosphere Model Version 5.1 (CAM5) simulations. The source-receptor relationships are computed based on simulations constrained by a standard free-running CAM5 simulation and the ERA-Interim reanalysis product. The analysis demonstrates that the emulator is capable of retrieving the source-receptor relationships based on a small number of CAM5 simulations. Most regions are found susceptible to their local emissions. Themore » emulator also finds that the source-receptor relationships retrieved from the model-driven and the reanalysis-driven simulations are very similar, suggesting that the simulated circulation in CAM5 resembles the assimilated meteorology in ERA-Interim. The robustness of the results provides confidence for applying the emulator to detect dose-response signals in the climate system.« less

Degradation of Green Polyethylene by Pleurotus ostreatus.

PubMed

da Luz, José Maria Rodrigues; Paes, Sirlaine Albino; Ribeiro, Karla Veloso Gonçalves; Mendes, Igor Rodrigues; Kasuya, Maria Catarina Megumi

2015-01-01

We studied the biodegradation of green polyethylene (GP) by Pleurotus ostreatus. The GP was developed from renewable raw materials to help to reduce the emissions of greenhouse gases. However, little information regarding the biodegradation of GP discarded in the environment is available. P. ostreatus is a lignocellulolytic fungus that has been used in bioremediation processes for agroindustrial residues, pollutants, and recalcitrant compounds. Recently, we showed the potential of this fungus to degrade oxo-biodegradable polyethylene. GP plastic bags were exposed to sunlight for up to 120 days to induce the initial photodegradation of the polymers. After this period, no cracks, pits, or new functional groups in the structure of GP were observed. Fragments of these bags were used as the substrate for the growth of P. ostreatus. After 30 d of incubation, physical and chemical alterations in the structure of GP were observed. We conclude that the exposure of GP to sunlight and its subsequent incubation in the presence of P. ostreatus can decrease the half-life of GP and facilitate the mineralization of these polymers.

Stable Lévy motion with inverse Gaussian subordinator

NASA Astrophysics Data System (ADS)

Kumar, A.; Wyłomańska, A.; Gajda, J.

2017-09-01

In this paper we study the stable Lévy motion subordinated by the so-called inverse Gaussian process. This process extends the well known normal inverse Gaussian (NIG) process introduced by Barndorff-Nielsen, which arises by subordinating ordinary Brownian motion (with drift) with inverse Gaussian process. The NIG process found many interesting applications, especially in financial data description. We discuss here the main features of the introduced subordinated process, such as distributional properties, existence of fractional order moments and asymptotic tail behavior. We show the connection of the process with continuous time random walk. Further, the governing fractional partial differential equations for the probability density function is also obtained. Moreover, we discuss the asymptotic distribution of sample mean square displacement, the main tool in detection of anomalous diffusion phenomena (Metzler et al., 2014). In order to apply the stable Lévy motion time-changed by inverse Gaussian subordinator we propose a step-by-step procedure of parameters estimation. At the end, we show how the examined process can be useful to model financial time series.

Classification as clustering: a Pareto cooperative-competitive GP approach.

PubMed

McIntyre, Andrew R; Heywood, Malcolm I

2011-01-01

Intuitively population based algorithms such as genetic programming provide a natural environment for supporting solutions that learn to decompose the overall task between multiple individuals, or a team. This work presents a framework for evolving teams without recourse to prespecifying the number of cooperating individuals. To do so, each individual evolves a mapping to a distribution of outcomes that, following clustering, establishes the parameterization of a (Gaussian) local membership function. This gives individuals the opportunity to represent subsets of tasks, where the overall task is that of classification under the supervised learning domain. Thus, rather than each team member representing an entire class, individuals are free to identify unique subsets of the overall classification task. The framework is supported by techniques from evolutionary multiobjective optimization (EMO) and Pareto competitive coevolution. EMO establishes the basis for encouraging individuals to provide accurate yet nonoverlaping behaviors; whereas competitive coevolution provides the mechanism for scaling to potentially large unbalanced datasets. Benchmarking is performed against recent examples of nonlinear SVM classifiers over 12 UCI datasets with between 150 and 200,000 training instances. Solutions from the proposed coevolutionary multiobjective GP framework appear to provide a good balance between classification performance and model complexity, especially as the dataset instance count increases.

The application and limitations of mathematical modelling in the prediction of permeability across mammalian skin and polydimethylsiloxane membranes.

PubMed

Moss, Gary P; Sun, Yi; Wilkinson, Simon C; Davey, Neil; Adams, Rod; Martin, Gary P; Prapopopolou, M; Brown, Marc B

2011-11-01

Predicting the rate of percutaneous absorption of a drug is an important issue with the increasing use of the skin as a means of moderating and controlling drug delivery. One key feature of this problem domain is that human skin permeability (as K(p)) has been shown to be inherently non-linear when mathematically related to the physicochemical parameters of penetrants. As such, the aims of this study were to apply and evaluate Gaussian process (GP) regression methods to datasets for membranes other than human skin, and to explore how the nature of the dataset may influence its analysis. Permeability data for absorption across rodent and pig skin, and artificial membranes (polydimethylsiloxane, PDMS, i.e. Silastic) membranes was collected from the literature. Two quantitative structure-permeability relationship (QSPR) models were used to compare with the GP models. Further performance metrics were computed in terms of all predictions, and a range of covariance functions were examined: the squared exponential (SE), neural network (NNone) and rational quadratic (QR) covariance functions, along with two simple cases of Matern covariance function (Matern3 and Matern5) where the polynomial order is set to 1 and 2, respectively. As measures of performance, the correlation coefficient (CORR), negative log estimated predictive density (NLL, or negative log loss) and mean squared error (MSE) were employed. The results demonstrated that GP models with different covariance functions outperform QSPR models for human, pig and rodent datasets. For the artificial membranes, GPs perform better in one instance, and give similar results in other experiments (where different covariance parameters produce similar results). In some cases, the GP predictions for some of the artificial membrane dataset are poorly correlated, suggesting that the physicochemical parameters employed in this study might not be appropriate for developing models that represent this membrane. While the results of this study indicate that permeation across rodent (mouse and rat) and pig skin is, in a statistical sense, similar, and that the artificial membranes are poor replacements of human or animal skin, the overriding issue raised in this study is the nature of the dataset and how it can influence the results, and subsequent interpretation, of any model produced for particular membranes. The size of the datasets, in both absolute and comparative senses, appears to influence model quality. Ideally, to generate viable cross-comparisons the datasets for different mammalian membranes should, wherever possible, exhibit as much commonality as possible. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

Binding of human immunodeficiency virus type 1 gp120 to CXCR4 induces mitochondrial transmembrane depolarization and cytochrome c-mediated apoptosis independently of Fas signaling.

PubMed

Roggero, R; Robert-Hebmann, V; Harrington, S; Roland, J; Vergne, L; Jaleco, S; Devaux, C; Biard-Piechaczyk, M

2001-08-01

Apoptosis of CD4(+) T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4(+) T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4(+) T-cell depletion in AIDS.

Binding of Human Immunodeficiency Virus Type 1 gp120 to CXCR4 Induces Mitochondrial Transmembrane Depolarization and Cytochrome c-Mediated Apoptosis Independently of Fas Signaling

PubMed Central

Roggero, Rodolphe; Robert-Hebmann, Véronique; Harrington, Steve; Roland, Joachim; Vergne, Laurence; Jaleco, Sara; Devaux, Christian; Biard-Piechaczyk, Martine

2001-01-01

Apoptosis of CD4+ T lymphocytes, induced by contact between human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120) and its receptors, could contribute to the cell depletion observed in HIV-infected individuals. CXCR4 appears to play an important role in gp120-induced cell death, but the mechanisms involved in this apoptotic process remain poorly understood. To get insight into the signal transduction pathways connecting CXCR4 to apoptosis following gp120 binding, we used different cell lines expressing wild-type CXCR4 and a truncated form of CD4 that binds gp120 but lacks the ability to transduce signals. The present study demonstrates that (i) the interaction of cell-associated gp120 with CXCR4-expressing target cells triggers a rapid dissipation of the mitochondrial transmembrane potential resulting in the cytosolic release of cytochrome c from the mitochondria to cytosol, concurrent with activation of caspase-9 and -3; (ii) this apoptotic process is independent of Fas signaling; and (iii) cooperation with a CD4 signal is not required. In addition, following coculture with cells expressing gp120, a Fas-independent apoptosis involving mitochondria and caspase activation is also observed in primary umbilical cord blood CD4+ T lymphocytes expressing high levels of CXCR4. Thus, this gp120-mediated apoptotic pathway may contribute to CD4+ T-cell depletion in AIDS. PMID:11462036

Crystallogenesis of bacteriophage P22 tail accessory factor gp26 at acidic and neutral pH

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cingolani, Gino, E-mail: cingolag@upstate.edu; Andrews, Dewan; Casjens, Sherwood

2006-05-01

The crystallogenesis of bacteriophage P22 tail-fiber gp26 is described. To study possible pH-induced conformational changes in gp26 structure, native trimeric gp26 has been crystallized at acidic pH (4.6) and a chimera of gp26 fused to maltose-binding protein (MBP-gp26) has been crystallized at neutral and alkaline pH (7-10). Gp26 is one of three phage P22-encoded tail accessory factors essential for stabilization of viral DNA within the mature capsid. In solution, gp26 exists as an extended triple-stranded coiled-coil protein which shares profound structural similarities with class I viral membrane-fusion protein. In the cryo-EM reconstruction of P22 tail extracted from mature virions, gp26more » forms an ∼220 Å extended needle structure emanating from the neck of the tail, which is likely to be brought into contact with the cell’s outer membrane when the viral DNA-injection process is initiated. To shed light on the potential role of gp26 in cell-wall penetration and DNA injection, gp26 has been crystallized at acidic, neutral and alkaline pH. Crystals of native gp26 grown at pH 4.6 diffract X-rays to 2.0 Å resolution and belong to space group P2{sub 1}, with a dimer of trimeric gp26 molecules in the asymmetric unit. To study potential pH-induced conformational changes in the gp26 structure, a chimera of gp26 fused to maltose-binding protein (MBP-gp26) was generated. Hexagonal crystals of MBP-gp26 were obtained at neutral and alkaline pH using the high-throughput crystallization robot at the Hauptman–Woodward Medical Research Institute, Buffalo, NY, USA. These crystals diffract X-rays to beyond 2.0 Å resolution. Structural analysis of gp26 crystallized at acidic, neutral and alkaline pH is in progress.« less

In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of dibenzoylhydrazines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyata, Ken-ichi, E-mail: Miyata.Kenichi@otsuka.jp; Otsuka Pharmaceutical Co., Ltd., Tokushima 771-0182; Nakagawa, Yoshiaki

2016-05-01

P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells to protect humans from xenobiotics. Thus, determining whether chemicals are substrates and/or inhibitors of P-gp is important in risk assessments of pharmacokinetic interactions among chemicals because P-gp-mediated transport processes play a significant role in their absorption and disposition. We previously reported that dibenzoylhydrazines (DBHs) such as tebufenozide and methoxyfenozide (agrochemicals) stimulated P-gp ATPase activity. However, it currently remains unclear whether these derivatives are transport substrates of P-gp and inhibit transport of other chemicals by P-gp. In the presentmore » study, in order to evaluate the interactions of DBHs with other chemicals in humans, we determined whether DBHs are P-gp transport substrates using both the in vitro bidirectional transport assay and the in vivo study of rats. In the in vivo study, we investigated the influence of P-gp inhibitors on the brain to plasma ratio of methoxyfenozide in rats. We also examined the inhibitory effects of DBHs on quinidine (a P-gp substrate) transport by P-gp in order to ascertain whether these derivatives are inhibitors of P-gp. Based on the results, DBHs were concluded to be weak P-gp transport substrates and moderate P-gp inhibitors. However, the risk of DBHs caused by interaction with other chemicals including drugs was considered to be low by considering the DBHs' potential as the substrates and inhibitors of P-gp as well as their plasma concentrations as long as DBHs are properly used. - Highlights: • Transport of DBHs by P-gp was not detected in in vitro bidirectional transport assay. • DBHs were weak P-gp transport substrates based on in vivo studies in rats. • The in vivo studies are useful methods for evaluating P-gp transport substrates. • DBHs inhibit quinidine transport by P-gp in in vitro bidirectional transport assay.« less

Illumination system development using design and analysis of computer experiments

NASA Astrophysics Data System (ADS)

Keresztes, Janos C.; De Ketelaere, Bart; Audenaert, Jan; Koshel, R. J.; Saeys, Wouter

2015-09-01

Computer assisted optimal illumination design is crucial when developing cost-effective machine vision systems. Standard local optimization methods, such as downhill simplex optimization (DHSO), often result in an optimal solution that is influenced by the starting point by converging to a local minimum, especially when dealing with high dimensional illumination designs or nonlinear merit spaces. This work presents a novel nonlinear optimization approach, based on design and analysis of computer experiments (DACE). The methodology is first illustrated with a 2D case study of four light sources symmetrically positioned along a fixed arc in order to obtain optimal irradiance uniformity on a flat Lambertian reflecting target at the arc center. The first step consists of choosing angular positions with no overlap between sources using a fast, flexible space filling design. Ray-tracing simulations are then performed at the design points and a merit function is used for each configuration to quantify the homogeneity of the irradiance at the target. The obtained homogeneities at the design points are further used as input to a Gaussian Process (GP), which develops a preliminary distribution for the expected merit space. Global optimization is then performed on the GP more likely providing optimal parameters. Next, the light positioning case study is further investigated by varying the radius of the arc, and by adding two spots symmetrically positioned along an arc diametrically opposed to the first one. The added value of using DACE with regard to the performance in convergence is 6 times faster than the standard simplex method for equal uniformity of 97%. The obtained results were successfully validated experimentally using a short-wavelength infrared (SWIR) hyperspectral imager monitoring a Spectralon panel illuminated by tungsten halogen sources with 10% of relative error.

The Laplace method for probability measures in Banach spaces

NASA Astrophysics Data System (ADS)

Piterbarg, V. I.; Fatalov, V. R.

1995-12-01

Contents §1. Introduction Chapter I. Asymptotic analysis of continual integrals in Banach space, depending on a large parameter §2. The large deviation principle and logarithmic asymptotics of continual integrals §3. Exact asymptotics of Gaussian integrals in Banach spaces: the Laplace method 3.1. The Laplace method for Gaussian integrals taken over the whole Hilbert space: isolated minimum points ([167], I) 3.2. The Laplace method for Gaussian integrals in Hilbert space: the manifold of minimum points ([167], II) 3.3. The Laplace method for Gaussian integrals in Banach space ([90], [174], [176]) 3.4. Exact asymptotics of large deviations of Gaussian norms §4. The Laplace method for distributions of sums of independent random elements with values in Banach space 4.1. The case of a non-degenerate minimum point ([137], I) 4.2. A degenerate isolated minimum point and the manifold of minimum points ([137], II) §5. Further examples 5.1. The Laplace method for the local time functional of a Markov symmetric process ([217]) 5.2. The Laplace method for diffusion processes, a finite number of non-degenerate minimum points ([116]) 5.3. Asymptotics of large deviations for Brownian motion in the Hölder norm 5.4. Non-asymptotic expansion of a strong stable law in Hilbert space ([41]) Chapter II. The double sum method - a version of the Laplace method in the space of continuous functions §6. Pickands' method of double sums 6.1. General situations 6.2. Asymptotics of the distribution of the maximum of a Gaussian stationary process 6.3. Asymptotics of the probability of a large excursion of a Gaussian non-stationary process §7. Probabilities of large deviations of trajectories of Gaussian fields 7.1. Homogeneous fields and fields with constant dispersion 7.2. Finitely many maximum points of dispersion 7.3. Manifold of maximum points of dispersion 7.4. Asymptotics of distributions of maxima of Wiener fields §8. Exact asymptotics of large deviations of the norm of Gaussian vectors and processes with values in the spaces L_k^p and l^2. Gaussian fields with the set of parameters in Hilbert space 8.1 Exact asymptotics of the distribution of the l_k^p-norm of a Gaussian finite-dimensional vector with dependent coordinates, p > 1 8.2. Exact asymptotics of probabilities of high excursions of trajectories of processes of type \\chi^2 8.3. Asymptotics of the probabilities of large deviations of Gaussian processes with a set of parameters in Hilbert space [74] 8.4. Asymptotics of distributions of maxima of the norms of l^2-valued Gaussian processes 8.5. Exact asymptotics of large deviations for the l^2-valued Ornstein-Uhlenbeck process Bibliography

Continuous-variable quantum Gaussian process regression and quantum singular value decomposition of nonsparse low-rank matrices

NASA Astrophysics Data System (ADS)

Das, Siddhartha; Siopsis, George; Weedbrook, Christian

2018-02-01

With the significant advancement in quantum computation during the past couple of decades, the exploration of machine-learning subroutines using quantum strategies has become increasingly popular. Gaussian process regression is a widely used technique in supervised classical machine learning. Here we introduce an algorithm for Gaussian process regression using continuous-variable quantum systems that can be realized with technology based on photonic quantum computers under certain assumptions regarding distribution of data and availability of efficient quantum access. Our algorithm shows that by using a continuous-variable quantum computer a dramatic speedup in computing Gaussian process regression can be achieved, i.e., the possibility of exponentially reducing the time to compute. Furthermore, our results also include a continuous-variable quantum-assisted singular value decomposition method of nonsparse low rank matrices and forms an important subroutine in our Gaussian process regression algorithm.

MSEE: Stochastic Cognitive Linguistic Behavior Models for Semantic Sensing

DTIC Science & Technology

2013-09-01

recognition, a Gaussian Process Dynamic Model with Social Network Analysis (GPDM-SNA) for a small human group action recognition, an extended GPDM-SNA...44  3.2. Small Human Group Activity Modeling Based on Gaussian Process Dynamic Model and Social Network Analysis (SN-GPDM...51  Approved for public release; distribution unlimited. 3 3.2.3. Gaussian Process Dynamical Model and

Data from fitting Gaussian process models to various data sets using eight Gaussian process software packages.

PubMed

Erickson, Collin B; Ankenman, Bruce E; Sanchez, Susan M

2018-06-01

This data article provides the summary data from tests comparing various Gaussian process software packages. Each spreadsheet represents a single function or type of function using a particular input sample size. In each spreadsheet, a row gives the results for a particular replication using a single package. Within each spreadsheet there are the results from eight Gaussian process model-fitting packages on five replicates of the surface. There is also one spreadsheet comparing the results from two packages performing stochastic kriging. These data enable comparisons between the packages to determine which package will give users the best results.

Degradation of Green Polyethylene by Pleurotus ostreatus

PubMed Central

da Luz, José Maria Rodrigues; Paes, Sirlaine Albino; Ribeiro, Karla Veloso Gonçalves; Mendes, Igor Rodrigues; Kasuya, Maria Catarina Megumi

2015-01-01

We studied the biodegradation of green polyethylene (GP) by Pleurotus ostreatus. The GP was developed from renewable raw materials to help to reduce the emissions of greenhouse gases. However, little information regarding the biodegradation of GP discarded in the environment is available. P. ostreatus is a lignocellulolytic fungus that has been used in bioremediation processes for agroindustrial residues, pollutants, and recalcitrant compounds. Recently, we showed the potential of this fungus to degrade oxo-biodegradable polyethylene. GP plastic bags were exposed to sunlight for up to 120 days to induce the initial photodegradation of the polymers. After this period, no cracks, pits, or new functional groups in the structure of GP were observed. Fragments of these bags were used as the substrate for the growth of P. ostreatus. After 30 d of incubation, physical and chemical alterations in the structure of GP were observed. We conclude that the exposure of GP to sunlight and its subsequent incubation in the presence of P. ostreatus can decrease the half-life of GP and facilitate the mineralization of these polymers. PMID:26076188

Priming Interpretations: Contextual Impact on the Processing of Garden Path Jokes

ERIC Educational Resources Information Center

Mayerhofer, Bastian; Maier, Katja; Schacht, Annekathrin

2016-01-01

In garden path (GP) jokes, a first dominant interpretation is detected as incoherent and subsequently substituted by a hidden joke interpretation. Two important factors for the processing of GP jokes are salience of the initial interpretation and accessibility of the hidden interpretation. Both factors are assumed to be affected by contextual…

Spatio-Temporal Data Analysis at Scale Using Models Based on Gaussian Processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stein, Michael

Gaussian processes are the most commonly used statistical model for spatial and spatio-temporal processes that vary continuously. They are broadly applicable in the physical sciences and engineering and are also frequently used to approximate the output of complex computer models, deterministic or stochastic. We undertook research related to theory, computation, and applications of Gaussian processes as well as some work on estimating extremes of distributions for which a Gaussian process assumption might be inappropriate. Our theoretical contributions include the development of new classes of spatial-temporal covariance functions with desirable properties and new results showing that certain covariance models lead tomore » predictions with undesirable properties. To understand how Gaussian process models behave when applied to deterministic computer models, we derived what we believe to be the first significant results on the large sample properties of estimators of parameters of Gaussian processes when the actual process is a simple deterministic function. Finally, we investigated some theoretical issues related to maxima of observations with varying upper bounds and found that, depending on the circumstances, standard large sample results for maxima may or may not hold. Our computational innovations include methods for analyzing large spatial datasets when observations fall on a partially observed grid and methods for estimating parameters of a Gaussian process model from observations taken by a polar-orbiting satellite. In our application of Gaussian process models to deterministic computer experiments, we carried out some matrix computations that would have been infeasible using even extended precision arithmetic by focusing on special cases in which all elements of the matrices under study are rational and using exact arithmetic. The applications we studied include total column ozone as measured from a polar-orbiting satellite, sea surface temperatures over the Pacific Ocean, and annual temperature extremes at a site in New York City. In each of these applications, our theoretical and computational innovations were directly motivated by the challenges posed by analyzing these and similar types of data.« less

Targeting HIV-1 gp41-induced fusion and pathogenesis for anti-viral therapy.

PubMed

Garg, Himanshu; Viard, Mathias; Jacobs, Amy; Blumenthal, Robert

2011-12-01

HIV gp41 is a metastable protein whose native conformation is maintained in the form of a heterodimer with gp120. The non-covalently associated gp41/gp120 complex forms a trimer on the virus surface. As gp120 engages with HIV's receptor, CD4, and coreceptor, CXCR4 or CCR5, gp41 undergoes several conformational changes resulting in fusion between the viral and cellular membranes. Several lipophilic and amphiphilic domains have been shown to be critical in that process. While the obvious function of gp41 in viral entry is well-established its role in cellular membrane fusion and the link with pathogenesis are only now beginning to appear. Recent targeting of gp41 via fusion inhibitors has revealed an important role of this protein not only in viral entry but also in bystander apoptosis and HIV pathogenesis. Studies by our group and others have shown that the phenomenon of gp41-mediated hemifusion initiates apoptosis in bystander cells and correlates with virus pathogenesis. More interestingly, recent clinical evidence suggests that gp41 mutants arising after Enfuvirtide therapy are associated with CD4 cell increase and immunological benefits. This has in turn been correlated to a decrease in bystander apoptosis in our in vitro as well as in vivo assays. Although a great deal of work has been done to unravel HIV-1 gp41-mediated fusion mechanisms, the factors that regulate gp41-mediated fusion versus hemifusion and the mechanism by which hemifusion initiates bystander apoptosis are not fully understood. Further insight into these issues will open new avenues for drug development making gp41 a critical anti-HIV target both for neutralization and virus attenuation.

Control of Bacteriophage T4 Tail Lysozyme Activity During the Infection Process

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kanamaru, Shuji; Ishiwata, Yasutaka; Suzuki, Toshiharu

2010-07-19

Bacteriophage T4 has an efficient mechanism for injecting the host Escherichia coli cell with genomic DNA. Its gene product 5 (gp5) has a needle-like structure attached to the end of a tube through which the DNA passes on its way out of the head and into the host. The gp5 needle punctures the outer cell membrane and then digests the peptidoglycan cell wall in the periplasmic space. gp5 is normally post-translationally cleaved between residues 351 and 352. The function of this process in controlling the lysozyme activity of gp5 has now been investigated. When gp5 is over-expressed in E. coli,more » two mutants (S351H and S351A) showed a reduction of cleavage products and five other mutants (S351L, S351K, S351Y, S351Q, and S351T) showed no cleavage. Furthermore, in a complementation assay at 20 C, the mutants that had no cleavage of gp5 produced a reduced number of plaques compared to wild-type T4. The crystal structure of the non-cleavage phenotype mutant of gp5, S351L, complexed with gene product 27, showed that the 18 residues in the vicinity of the potential cleavage site (disordered in the wild-type structure) had visible electron density. The polypeptide around the potential cleavage site is exposed, thus allowing access for an E. coli protease. The lysozyme activity is inhibited in the wild-type structure by a loop from the adjacent gp5 monomer that binds into the substrate-binding site. The same inhibition is apparent in the mutant structure, showing that the lysozyme is inhibited before gp5 is cleaved and, presumably, the lysozyme is activated only after gp5 has penetrated the outer membrane.« less

Differential role of gp130-dependent STAT and Ras signalling for haematopoiesis following bone-marrow transplantation.

PubMed

Kroy, Daniela C; Hebing, Lisa; Sander, Leif E; Gassler, Nikolaus; Erschfeld, Stephanie; Sackett, Sara; Galm, Oliver; Trautwein, Christian; Streetz, Konrad L

2012-01-01

Bone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment. In contrast, the exact signalling events that control IL-6/gp130-driven haematopoietic stem cell development during BMT remain unresolved. Conditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(ΔMx)), or to selectively disrupt gp130-dependent Ras (gp130(ΔMxRas)) or STAT signalling (gp130(ΔMxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry. BM derived from gp130 deficient donor mice (gp130(ΔMx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(ΔMxRas) and gp130(ΔMxSTAT) donor BM. BMT of gp130(ΔMxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(ΔMxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function. Our data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages.

The applications of Complexity Theory and Tsallis Non-extensive Statistics at Solar Plasma Dynamics

NASA Astrophysics Data System (ADS)

Pavlos, George

2015-04-01

As the solar plasma lives far from equilibrium it is an excellent laboratory for testing complexity theory and non-equilibrium statistical mechanics. In this study, we present the highlights of complexity theory and Tsallis non extensive statistical mechanics as concerns their applications at solar plasma dynamics, especially at sunspot, solar flare and solar wind phenomena. Generally, when a physical system is driven far from equilibrium states some novel characteristics can be observed related to the nonlinear character of dynamics. Generally, the nonlinearity in space plasma dynamics can generate intermittent turbulence with the typical characteristics of the anomalous diffusion process and strange topologies of stochastic space plasma fields (velocity and magnetic fields) caused by the strange dynamics and strange kinetics (Zaslavsky, 2002). In addition, according to Zelenyi and Milovanov (2004) the complex character of the space plasma system includes the existence of non-equilibrium (quasi)-stationary states (NESS) having the topology of a percolating fractal set. The stabilization of a system near the NESS is perceived as a transition into a turbulent state determined by self-organization processes. The long-range correlation effects manifest themselves as a strange non-Gaussian behavior of kinetic processes near the NESS plasma state. The complex character of space plasma can also be described by the non-extensive statistical thermodynamics pioneered by Tsallis, which offers a consistent and effective theoretical framework, based on a generalization of Boltzmann - Gibbs (BG) entropy, to describe far from equilibrium nonlinear complex dynamics (Tsallis, 2009). In a series of recent papers, the hypothesis of Tsallis non-extensive statistics in magnetosphere, sunspot dynamics, solar flares, solar wind and space plasma in general, was tested and verified (Karakatsanis et al., 2013; Pavlos et al., 2014; 2015). Our study includes the analysis of solar plasma time series at three cases: sunspot index, solar flare and solar wind data. The non-linear analysis of the sunspot index is embedded in the non-extensive statistical theory of Tsallis (1988; 2004; 2009). The q-triplet of Tsallis, as well as the correlation dimension and the Lyapunov exponent spectrum were estimated for the SVD components of the sunspot index timeseries. Also the multifractal scaling exponent spectrum f(a), the generalized Renyi dimension spectrum D(q) and the spectrum J(p) of the structure function exponents were estimated experimentally and theoretically by using the q-entropy principle included in Tsallis non-extensive statistical theory, following Arimitsu and Arimitsu (2000, 2001). Our analysis showed clearly the following: (a) a phase transition process in the solar dynamics from high dimensional non-Gaussian SOC state to a low dimensional non-Gaussian chaotic state, (b) strong intermittent solar turbulence and anomalous (multifractal) diffusion solar process, which is strengthened as the solar dynamics makes a phase transition to low dimensional chaos in accordance to Ruzmaikin, Zelenyi and Milovanov's studies (Zelenyi and Milovanov, 1991; Milovanov and Zelenyi, 1993; Ruzmakin et al., 1996), (c) faithful agreement of Tsallis non-equilibrium statistical theory with the experimental estimations of: (i) non-Gaussian probability distribution function P(x), (ii) multifractal scaling exponent spectrum f(a) and generalized Renyi dimension spectrum Dq, (iii) exponent spectrum J(p) of the structure functions estimated for the sunspot index and its underlying non equilibrium solar dynamics. Also, the q-triplet of Tsallis as well as the correlation dimension and the Lyapunov exponent spectrum were estimated for the singular value decomposition (SVD) components of the solar flares timeseries. Also the multifractal scaling exponent spectrum f(a), the generalized Renyi dimension spectrum D(q) and the spectrum J(p) of the structure function exponents were estimated experimentally and theoretically by using the q-entropy principle included in Tsallis non-extensive statistical theory, following Arimitsu and Arimitsu (2000). Our analysis showed clearly the following: (a) a phase transition process in the solar flare dynamics from a high dimensional non-Gaussian self-organized critical (SOC) state to a low dimensional also non-Gaussian chaotic state, (b) strong intermittent solar corona turbulence and an anomalous (multifractal) diffusion solar corona process, which is strengthened as the solar corona dynamics makes a phase transition to low dimensional chaos, (c) faithful agreement of Tsallis non-equilibrium statistical theory with the experimental estimations of the functions: (i) non-Gaussian probability distribution function P(x), (ii) f(a) and D(q), and (iii) J(p) for the solar flares timeseries and its underlying non-equilibrium solar dynamics, and (d) the solar flare dynamical profile is revealed similar to the dynamical profile of the solar corona zone as far as the phase transition process from self-organized criticality (SOC) to chaos state. However the solar low corona (solar flare) dynamical characteristics can be clearly discriminated from the dynamical characteristics of the solar convection zone. At last we present novel results revealing non-equilibrium phase transition processes in the solar wind plasma during a strong shock event, which can take place in Solar wind plasma system. The solar wind plasma as well as the entire solar plasma system is a typical case of stochastic spatiotemporal distribution of physical state variables such as force fields ( ) and matter fields (particle and current densities or bulk plasma distributions). This study shows clearly the non-extensive and non-Gaussian character of the solar wind plasma and the existence of multi-scale strong correlations from the microscopic to the macroscopic level. It also underlines the inefficiency of classical magneto-hydro-dynamic (MHD) or plasma statistical theories, based on the classical central limit theorem (CLT), to explain the complexity of the solar wind dynamics, since these theories include smooth and differentiable spatial-temporal functions (MHD theory) or Gaussian statistics (Boltzmann-Maxwell statistical mechanics). On the contrary, the results of this study indicate the presence of non-Gaussian non-extensive statistics with heavy tails probability distribution functions, which are related to the q-extension of CLT. Finally, the results of this study can be understood in the framework of modern theoretical concepts such as non-extensive statistical mechanics (Tsallis, 2009), fractal topology (Zelenyi and Milovanov, 2004), turbulence theory (Frisch, 1996), strange dynamics (Zaslavsky, 2002), percolation theory (Milovanov, 1997), anomalous diffusion theory and anomalous transport theory (Milovanov, 2001), fractional dynamics (Tarasov, 2013) and non-equilibrium phase transition theory (Chang, 1992). References 1. T. Arimitsu, N. Arimitsu, Tsallis statistics and fully developed turbulence, J. Phys. A: Math. Gen. 33 (2000) L235. 2. T. Arimitsu, N. Arimitsu, Analysis of turbulence by statistics based on generalized entropies, Physica A 295 (2001) 177-194. 3. T. Chang, Low-dimensional behavior and symmetry braking of stochastic systems near criticality can these effects be observed in space and in the laboratory, IEEE 20 (6) (1992) 691-694. 4. U. Frisch, Turbulence, Cambridge University Press, Cambridge, UK, 1996, p. 310. 5. L.P. Karakatsanis, G.P. Pavlos, M.N. Xenakis, Tsallis non-extensive statistics, intermittent turbulence, SOC and chaos in the solar plasma. Part two: Solar flares dynamics, Physica A 392 (2013) 3920-3944. 6. A.V. Milovanov, Topological proof for the Alexander-Orbach conjecture, Phys. Rev. E 56 (3) (1997) 2437-2446. 7. A.V. Milovanov, L.M. Zelenyi, Fracton excitations as a driving mechanism for the self-organized dynamical structuring in the solar wind, Astrophys. Space Sci. 264 (1-4) (1999) 317-345. 8. A.V. Milovanov, Stochastic dynamics from the fractional Fokker-Planck-Kolmogorov equation: large-scale behavior of the turbulent transport coefficient, Phys. Rev. E 63 (2001) 047301. 9. G.P. Pavlos, et al., Universality of non-extensive Tsallis statistics and time series analysis: Theory and applications, Physica A 395 (2014) 58-95. 10. G.P. Pavlos, et al., Tsallis non-extensive statistics and solar wind plasma complexity, Physica A 422 (2015) 113-135. 11. A.A. Ruzmaikin, et al., Spectral properties of solar convection and diffusion, ApJ 471 (1996) 1022. 12. V.E. Tarasov, Review of some promising fractional physical models, Internat. J. Modern Phys. B 27 (9) (2013) 1330005. 13. C. Tsallis, Possible generalization of BG statistics, J. Stat. Phys. J 52 (1-2) (1988) 479-487. 14. C. Tsallis, Nonextensive statistical mechanics: construction and physical interpretation, in: G.M. Murray, C. Tsallis (Eds.), Nonextensive Entropy-Interdisciplinary Applications, Oxford Univ. Press, 2004, pp. 1-53. 15. C. Tsallis, Introduction to Non-Extensive Statistical Mechanics, Springer, 2009. 16. G.M. Zaslavsky, Chaos, fractional kinetics, and anomalous transport, Physics Reports 371 (2002) 461-580. 17. L.M. Zelenyi, A.V. Milovanov, Fractal properties of sunspots, Sov. Astron. Lett. 17 (6) (1991) 425. 18. L.M. Zelenyi, A.V. Milovanov, Fractal topology and strange kinetics: from percolation theory to problems in cosmic electrodynamics, Phys.-Usp. 47 (8), (2004) 749-788.

Implementing portfolio in postgraduate general practice training. Benefits and recommendations.

PubMed

Alotaibi, Fawaz S

2012-10-01

This paper presents a review to explore the literature focusing on portfolio in postgraduate general practice (GP) training, and to examine the impact of implementation of portfolio on learning process, as well as proposing recommendations for its implementation in postgraduate GP training. An electronic search was carried out on several databases for studies addressing portfolio in postgraduate GP training. Six articles were included to address specifically the effectiveness of portfolio in postgraduate GP training. Five of them described successful experiences of portfolio-based learning implementation. Only one article addressed portfolio-based assessment in postgraduate GP training. The existing evidence provides various benefits of professional portfolio-based learning. It does appear to have advantages of stimulating reflective learning, promoting proactive learning, and bridging the hospital experiences of the learners to GP. Moreover, the challenges to implementation of portfolio-based learning are often based on orientation and training of stakeholders.

Participation of the 39-kDa glycoprotein (gp39) of the vitelline envelope of Bufo arenarum eggs in sperm-egg interaction.

PubMed

Barrera, Daniel; Llanos, Ricardo J; Miceli, Dora C

2012-05-01

The acquisition of egg fertilizability in Bufo arenarum takes place during the oviductal transit and during this process the extracellular coelomic envelope (CE) of the eggs is converted into the vitelline envelope (VE). It has been stated that one of the necessary events leading to a fertilizable state is the proteolytic cleavage of CE glycoproteins in the oviductal pars recta by oviductin, a serine protease. Consequently, there is a marked increase in the relative quantity of glycoproteins with 39 (gp39) and 42 kDa (gp42) in the VE. In the present study, sperm-VE binding assays using heat-solubilized biotin-conjugated VE glycoproteins revealed that both gp39 and gp42 have sperm binding capacity. According to this result, our study was focused on gp39, a glycoprotein that we have previously reported as a homologue of mammalian ZPC. For this purpose, rabbit polyclonal antibodies against gp39 were generated at our laboratory. The specificity of the antibodies was confirmed with western blot of VE glycoproteins separated on SDS-PAGE. Immunohistochemical and immunoelectron studies showed gp39 distributed throughout the width of the VE. In addition, immunofluorescence assays probed that gp39 bound to the sperm head. Finally, as an approach to elucidate the possible involvement of gp39 in fertilization, inhibition assays showed that pretreatment of eggs with antibodies against gp39 generated a significant decrease in the fertilization rate. Therefore, our findings suggest that gp39, which is modified by oviductal action, participates as a VE glycoprotein ligand for sperm in Bufo arenarum fertilization.

The process behind the expression of mdr-1/P-gp and mrp/MRP in human leukemia/lymphoma.

PubMed

Hirose, Masao

2009-04-01

There is a controversy over the link between phenotypes of multidrug resistance (MDR) and clinical outcome in leukemia/lymphoma patients. This may be because the process behind the induction and loss of expression of genotypes and phenotypes by which MDR develops and the role of MDR in fresh cells of human leukemia/lymphoma are not clearly defined. P-glycoprotein (P-gp) increased and decreased along with mdr-1 expression in three cell lines out of five vincristine (VCR)-resistant cell lines. MRP appeared with increased mrp expression in the other two cell lines. After the drug was removed from the culture system, mdr-1/P-gp changed in parallel with the level of VCR resistance, although mrp and MRP did not. It was concluded that P-gp is directly derived from mdr-1 and that mdr-1/P-gp supports the VCR-resistance but mrp/MRP is not directly linked to the VCR-resistance. These results should contribute to a better understanding of MDR phenomenon in cancer.

Quantum key distillation from Gaussian states by Gaussian operations.

PubMed

Navascués, M; Bae, J; Cirac, J I; Lewestein, M; Sanpera, A; Acín, A

2005-01-14

We study the secrecy properties of Gaussian states under Gaussian operations. Although such operations are useless for quantum distillation, we prove that it is possible to distill a secret key secure against any attack from sufficiently entangled Gaussian states with nonpositive partial transposition. Moreover, all such states allow for key distillation, when Eve is assumed to perform finite-size coherent attacks before the reconciliation process.

Gaussian Process Interpolation for Uncertainty Estimation in Image Registration

PubMed Central

Wachinger, Christian; Golland, Polina; Reuter, Martin; Wells, William

2014-01-01

Intensity-based image registration requires resampling images on a common grid to evaluate the similarity function. The uncertainty of interpolation varies across the image, depending on the location of resampled points relative to the base grid. We propose to perform Bayesian inference with Gaussian processes, where the covariance matrix of the Gaussian process posterior distribution estimates the uncertainty in interpolation. The Gaussian process replaces a single image with a distribution over images that we integrate into a generative model for registration. Marginalization over resampled images leads to a new similarity measure that includes the uncertainty of the interpolation. We demonstrate that our approach increases the registration accuracy and propose an efficient approximation scheme that enables seamless integration with existing registration methods. PMID:25333127

Resource theory of non-Gaussian operations

NASA Astrophysics Data System (ADS)

Zhuang, Quntao; Shor, Peter W.; Shapiro, Jeffrey H.

2018-05-01

Non-Gaussian states and operations are crucial for various continuous-variable quantum information processing tasks. To quantitatively understand non-Gaussianity beyond states, we establish a resource theory for non-Gaussian operations. In our framework, we consider Gaussian operations as free operations, and non-Gaussian operations as resources. We define entanglement-assisted non-Gaussianity generating power and show that it is a monotone that is nonincreasing under the set of free superoperations, i.e., concatenation and tensoring with Gaussian channels. For conditional unitary maps, this monotone can be analytically calculated. As examples, we show that the non-Gaussianity of ideal photon-number subtraction and photon-number addition equal the non-Gaussianity of the single-photon Fock state. Based on our non-Gaussianity monotone, we divide non-Gaussian operations into two classes: (i) the finite non-Gaussianity class, e.g., photon-number subtraction, photon-number addition, and all Gaussian-dilatable non-Gaussian channels; and (ii) the diverging non-Gaussianity class, e.g., the binary phase-shift channel and the Kerr nonlinearity. This classification also implies that not all non-Gaussian channels are exactly Gaussian dilatable. Our resource theory enables a quantitative characterization and a first classification of non-Gaussian operations, paving the way towards the full understanding of non-Gaussianity.

Variations in understanding the drug-prescribing process: a qualitative study among Swedish GPs.

PubMed

Rahmner, Pia Bastholm; Gustafsson, Lars L; Larsson, Jan; Rosenqvist, Urban; Tomson, Göran; Holmström, Inger

2009-04-01

A majority of doctor-patient meetings result in the patient getting a prescription. This underlines the need for a high-quality prescription process. While studies have been made on single therapeutic drug groups, a complete study of the physicians' general thought process that comprises the prescription of all drugs still remains to be made. To identify variations in ways of understanding drug prescribing among GPs. A descriptive qualitative study was conducted with 20 Swedish physicians. Informants were recruited purposively and their understandings about prescribing were studied in semi-structured interviews. Data were analysed using a phenomenographic approach. Five categories were identified as follows: (A) GP prescribed safe, reliable and well-documented drugs for obvious complaints; (B) GP sought to convince the patient of the most effective drug treatment; (C) GP chose the best drug treatment taking into consideration the patient's entire life situation; (D) GP used clinical judgement and close follow-up to minimize unnecessary drug prescribing and (E) GP prescribed drugs which are cheap for society and environmentally friendly. The categories are interrelated, but have different foci: the biomedical, the patient and the society. Each GP had more than one view but none included all five. The findings also indicate that complexity increases when a drug is prescribed for primary or secondary prevention. GPs understand prescribing differently despite similar external circumstances. The most significant factor to influence prescribing behaviour was the physician's patient relation approach. GPs may need to reflect on difficulties they face while prescribing to enhance their understandings.

Coexistence of domains with distinct order and polarity in fluid bacterial membranes.

PubMed

Vanounou, Sharon; Pines, Dina; Pines, Ehud; Parola, Abraham H; Fishov, Itzhak

2002-07-01

In this study we sought the detection and characterization of bacterial membrane domains. Fluorescence generalized polarization (GP) spectra of laurdan-labeled Escherichia coli and temperature dependencies of both laurdan's GP and fluorescence anisotropy of 1,3-diphenyl-1,3,5-hexatriene (DPH) (rDPH) affirmed that at physiological temperatures, the E. coli membrane is in a liquid-crystalline phase. However, the strong excitation wavelength dependence of rlaurdan at 37 degrees C reflects membrane heterogeneity. Time-resolved fluorescence emission spectra, which display distinct biphasic redshift kinetics, verified the coexistence of two subpopulations of laurdan. In the initial phase, <50 ps, the redshift in the spectral mass center is much faster for laurdan excited at the blue edge (350 nm), whereas at longer time intervals, similar kinetics is observed upon excitation at either blue or red edge (400 nm). Excitation in the blue region selects laurdan molecules presumably located in a lipid domain in which fast intramolecular relaxation and low anisotropy characterize laurdan's emission. In the proteo-lipid domain, laurdan motion and conformation are restricted as exhibited by a slower relaxation rate, higher anisotropy and a lower GP value. Triple-Gaussian decomposition of laurdan emission spectra showed a sharp phase transition in the temperature dependence of individual components when excited in the blue but not in the red region. At least two kinds of domains of distinct polarity and order are suggested to coexist in the liquid-crystalline bacterial membrane: a lipid-enriched and a proteolipid domain. In bacteria with chloramphenicol (Cam)-inhibited protein synthesis, laurdan showed reduced polarity and restoration of an isoemissive point in the temperature-dependent spectra. These results suggest a decrease in membrane heterogeneity caused by Cam-induced domain dissipation.

An alternative to the breeder's and Lande's equations.

PubMed

Houchmandzadeh, Bahram

2014-01-10

The breeder's equation is a cornerstone of quantitative genetics, widely used in evolutionary modeling. Noting the mean phenotype in parental, selected parents, and the progeny by E(Z0), E(ZW), and E(Z1), this equation relates response to selection R = E(Z1) - E(Z0) to the selection differential S = E(ZW) - E(Z0) through a simple proportionality relation R = h(2)S, where the heritability coefficient h(2) is a simple function of genotype and environment factors variance. The validity of this relation relies strongly on the normal (Gaussian) distribution of the parent genotype, which is an unobservable quantity and cannot be ascertained. In contrast, we show here that if the fitness (or selection) function is Gaussian with mean μ, an alternative, exact linear equation of the form R' = j(2)S' can be derived, regardless of the parental genotype distribution. Here R' = E(Z1) - μ and S' = E(ZW) - μ stand for the mean phenotypic lag with respect to the mean of the fitness function in the offspring and selected populations. The proportionality coefficient j(2) is a simple function of selection function and environment factors variance, but does not contain the genotype variance. To demonstrate this, we derive the exact functional relation between the mean phenotype in the selected and the offspring population and deduce all cases that lead to a linear relation between them. These results generalize naturally to the concept of G matrix and the multivariate Lande's equation Δ(z) = GP(-1)S. The linearity coefficient of the alternative equation are not changed by Gaussian selection.

Intra-manufacture Diameter Variability of Rotary Files and Their Corresponding Gutta-Percha Cones Using Laser Scan Micrometre.

PubMed

Mirmohammadi, Hesam; Sitarz, Monika; Shemesh, Hagay

2018-01-01

Manufacturers offer gutta-percha (GP) cones matched with different sizes of endodontic files as an attempt to simplify the obturation process and create a tight seal in the canal. The purpose of this study was to evaluate whether intra-manufacture GP diameters matched the diameters of their corresponding files at different levels using laser micrometre. Twenty files and corresponding GP master cones of Reciproc R40 (40/0.06) (VDW, Munich, Germany), WaveOne Large(40/0.08)(Dentsply Maillefer, Ballaigues, Switzerland), ProTaper F3 (30/0.09) (Dentsply Maillefer, Ballaigues, Switzerland), and Mtwo 40/0.06 (VDW, Munich, Germany) were examined using laser micrometre (LSM 6000 by Mitutoyo, Japan) with accuracy of 1 nm to establish their actual diameter at D 0 , D 1 , D 3 and D 6 . The data was analysed using the independent t -test. The differences were considered at 0.05. The diameter of GP master cones was significantly larger than that of the corresponding files at all levels in all brands. ProTaper GP diameter was closest to the file diameter at D1 (GP=0.35, File=0.35 mm), and D3 (GP=0.48, File=0.49). Within the same manufacturer, GP cone diameters do not match the diameters of their corresponding files. Clinicians are advised to use a GP gauge to cut the tip so as to appropriate the diameter from a smaller sized GP cone.

The effect of linear velocity and flux on performance of ceramic graded permeability membranes when processing skim milk at 50°C.

PubMed

Zulewska, Justyna; Barbano, David M

2014-05-01

Raw milk (about 500 kg) was cold (4°C) separated and then the skim milk was pasteurized at 72°C and a holding time of 16s. The milk was cooled to 4°C and stored at ≤ 4°C until processing. The skim milk was microfiltered using a pilot-scale ceramic graded permeability (GP) microfilter system equipped with 0.1-µm nominal pore diameter ceramic Membralox membranes. First, about 155 kg of pasteurized skim milk was flushed through the system to push the water out of the system. Then, additional pasteurized skim milk (about 320 kg) was microfiltered (stage 1) in a continuous feed-and-bleed 3× process using the same membranes. The retentate from stage 1 was diluted with pasteurized reverse osmosis water in a 1:2 ratio and microfiltered (stage 2) with a GP system. This was repeated 3 times, with total of 3 stages in the process (stage 1 = microfiltration; stages 2 and 3 = diafiltration). The results from first 3 stages of the experiment were compared with previous data when processing skim milk at 50°C using ceramic uniform transmembrane pressure (UTP) membranes. Microfiltration of skim milk using ceramic UTP and GP membranes resulted in similar final retentate in terms of serum proteins (SP) removed. The SP removal rate (expressed by kilogram of SP removed per meter-squared of membrane area) was higher for GP membranes for each stage compared with UTP membranes. A higher passage of SP and SP removal rate for GP than UTP membranes was achieved by using a higher cross-flow velocity when processing skim milk. Increasing flux in subsequent stages did not affect membrane permeability and fouling. We operated under conditions that produced partial membrane fouling, due to using a flux that was less than limiting flux but higher than critical flux. Because the critical flux is a function of the cross-flow velocity, the difference in critical flux between UTP and GP membranes resulted only from operating under different cross-flow velocities (6.6 vs 7.12 for UTP and GP membranes, respectively). Conditions that allow microfiltration operation at higher flux will reduce the membrane surface area required to process the same amount of milk in the same length of time. Less membrane surface area reduces investment costs and uses less energy, water, and chemicals to clean the microfiltration system. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Gaussian processes: a method for automatic QSAR modeling of ADME properties.

PubMed

Obrezanova, Olga; Csanyi, Gabor; Gola, Joelle M R; Segall, Matthew D

2007-01-01

In this article, we discuss the application of the Gaussian Process method for the prediction of absorption, distribution, metabolism, and excretion (ADME) properties. On the basis of a Bayesian probabilistic approach, the method is widely used in the field of machine learning but has rarely been applied in quantitative structure-activity relationship and ADME modeling. The method is suitable for modeling nonlinear relationships, does not require subjective determination of the model parameters, works for a large number of descriptors, and is inherently resistant to overtraining. The performance of Gaussian Processes compares well with and often exceeds that of artificial neural networks. Due to these features, the Gaussian Processes technique is eminently suitable for automatic model generation-one of the demands of modern drug discovery. Here, we describe the basic concept of the method in the context of regression problems and illustrate its application to the modeling of several ADME properties: blood-brain barrier, hERG inhibition, and aqueous solubility at pH 7.4. We also compare Gaussian Processes with other modeling techniques.

Constraining cosmic curvature by using age of galaxies and gravitational lenses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rana, Akshay; Mahajan, Shobhit; Mukherjee, Amitabha

We use two model-independent methods to constrain the curvature of the universe. In the first method, we study the evolution of the curvature parameter (Ω {sub k} {sup 0}) with redshift by using the observations of the Hubble parameter and transverse comoving distances obtained from the age of galaxies. Secondly, we also use an indirect method based on the mean image separation statistics of gravitationally lensed quasars. The basis of this methodology is that the average image separation of lensed images will show a positive, negative or zero correlation with the source redshift in a closed, open or flat universemore » respectively. In order to smoothen the datasets used in both the methods, we use a non-parametric method namely, Gaussian Process (GP). Finally from first method we obtain Ω {sub k} {sup 0} = 0.025±0.57 for a presumed flat universe while the cosmic curvature remains constant throughout the redshift region 0 < z < 1.37 which indicates that the universe may be homogeneous. Moreover, the combined result from both the methods suggests that the universe is marginally closed. However, a flat universe can be incorporated at 3σ level.« less

Incorporating approximation error in surrogate based Bayesian inversion

NASA Astrophysics Data System (ADS)

Zhang, J.; Zeng, L.; Li, W.; Wu, L.

2015-12-01

There are increasing interests in applying surrogates for inverse Bayesian modeling to reduce repetitive evaluations of original model. In this way, the computational cost is expected to be saved. However, the approximation error of surrogate model is usually overlooked. This is partly because that it is difficult to evaluate the approximation error for many surrogates. Previous studies have shown that, the direct combination of surrogates and Bayesian methods (e.g., Markov Chain Monte Carlo, MCMC) may lead to biased estimations when the surrogate cannot emulate the highly nonlinear original system. This problem can be alleviated by implementing MCMC in a two-stage manner. However, the computational cost is still high since a relatively large number of original model simulations are required. In this study, we illustrate the importance of incorporating approximation error in inverse Bayesian modeling. Gaussian process (GP) is chosen to construct the surrogate for its convenience in approximation error evaluation. Numerical cases of Bayesian experimental design and parameter estimation for contaminant source identification are used to illustrate this idea. It is shown that, once the surrogate approximation error is well incorporated into Bayesian framework, promising results can be obtained even when the surrogate is directly used, and no further original model simulations are required.

Some error bounds for K-iterated Gaussian recursive filters

NASA Astrophysics Data System (ADS)

Cuomo, Salvatore; Galletti, Ardelio; Giunta, Giulio; Marcellino, Livia

2016-10-01

Recursive filters (RFs) have achieved a central role in several research fields over the last few years. For example, they are used in image processing, in data assimilation and in electrocardiogram denoising. More in particular, among RFs, the Gaussian RFs are an efficient computational tool for approximating Gaussian-based convolutions and are suitable for digital image processing and applications of the scale-space theory. As is a common knowledge, the Gaussian RFs, applied to signals with support in a finite domain, generate distortions and artifacts, mostly localized at the boundaries. Heuristic and theoretical improvements have been proposed in literature to deal with this issue (namely boundary conditions). They include the case in which a Gaussian RF is applied more than once, i.e. the so called K-iterated Gaussian RFs. In this paper, starting from a summary of the comprehensive mathematical background, we consider the case of the K-iterated first-order Gaussian RF and provide the study of its numerical stability and some component-wise theoretical error bounds.

Lessons learnt from incidents reported by postgraduate trainees in Dutch general practice. A prospective cohort study.

PubMed

Zwart, Dorien L M; Heddema, Wendelien S; Vermeulen, Margit I; van Rensen, Elizabeth L J; Verheij, Theo J M; Kalkman, Cor J

2011-10-01

There is an inherent tension between allowing trainees in general practice (GP) to feel comfortable to report and learn from errors in a blame-free environment while still assuring high-quality and safe patient care. Unfortunately, little is known about the types and potential severity of incidents that may confront GP trainees. Furthermore, incident reporting by resident trainees is hindered by their concern that such transparency might result in more negative performance evaluations. To explore the number and nature of incidents that were reported by GP trainees and to determine whether there were differences between the reporters and non-reporters based on their performance evaluations. Prospective cohort study. Confidential and voluntary incident reporting was implemented in GP vocational training of the University Medical Center Utrecht, the Netherlands. Seventy-nine GP trainees were asked to report incidents over 6 months. Mixed methods were used to analyse the data. 24 trainees reported a total of 44 incidents. 23 incidents concerned the work process and 17 concerned problems with diagnosis or therapy. Three-quarters (34/44) of incidents were determined to be not specifically related to the inexperience of the GP trainees. While actual patient harm was determined to be minimal or absent in two-thirds of incidents (29/44), the potential for moderate, major, or catastrophic harm was 89% (39/44). Trainees performing best on their performance assessment in the domain of clinical expertise reported incidents more often (43% vs 18%, p<0.03) than those who performed at a lower level. GP trainees rated highly by their faculty voluntarily reported incidents in the delivery of clinical care when given a safe, blame-free, and confidential reporting process. Most incidents were not found to be directly related to the inexperience of the trainee, but were caused by failing organisational processes in the healthcare delivery system. Moreover, the trainees who tended to report these incidents were those whose performance was highly evaluated in the domain of clinical expertise.

[Method of correcting sensitivity nonuniformity using gaussian distribution on 3.0 Tesla abdominal MRI].

PubMed

Hayashi, Norio; Miyati, Tosiaki; Takanaga, Masako; Ohno, Naoki; Hamaguchi, Takashi; Kozaka, Kazuto; Sanada, Shigeru; Yamamoto, Tomoyuki; Matsui, Osamu

2011-01-01

In the direction where the phased array coil used in parallel magnetic resonance imaging (MRI) is perpendicular to the arrangement, sensitivity falls significantly. Moreover, in a 3.0 tesla (3T) abdominal MRI, the quality of the image is reduced by changes in the relaxation time, reinforcement of the magnetic susceptibility effect, etc. In a 3T MRI, which has a high resonant frequency, the signal of the depths (central part) is reduced in the trunk part. SCIC, which is sensitivity correction processing, has inadequate correction processing, such as that edges are emphasized and the central part is corrected. Therefore, we used 3T with a Gaussian distribution. The uneven compensation processing for sensitivity of an abdomen MR image was considered. The correction processing consisted of the following methods. 1) The center of gravity of the domain of the human body in an abdomen MR image was calculated. 2) The correction coefficient map was created from the center of gravity using the Gaussian distribution. 3) The sensitivity correction image was created from the correction coefficient map and the original picture image. Using the Gaussian correction to process the image, the uniformity calculated using the NEMA method was improved significantly compared to the original image of a phantom. In a visual evaluation by radiologists, the uniformity was improved significantly using the Gaussian correction processing. Because of the homogeneous improvement of the abdomen image taken using 3T MRI, the Gaussian correction processing is considered to be a very useful technique.

Visualization of the entire differentiation process of murine M cells: suppression of their maturation in cecal patches.

PubMed

Kimura, S; Yamakami-Kimura, M; Obata, Y; Hase, K; Kitamura, H; Ohno, H; Iwanaga, T

2015-05-01

The microfold (M) cell residing in the follicle-associated epithelium is a specialized epithelial cell that initiates mucosal immune responses by sampling luminal antigens. The differentiation process of M cells remains unclear due to limitations of analytical methods. Here we found that M cells were classified into two functionally different subtypes based on the expression of Glycoprotein 2 (GP2) by newly developed image cytometric analysis. GP2-high M cells actively took up luminal microbeads, whereas GP2-negative or low cells scarcely ingested them, even though both subsets equally expressed the other M-cell signature genes, suggesting that GP2-high M cells represent functionally mature M cells. Further, the GP2-high mature M cells were abundant in Peyer's patch but sparse in the cecal patch: this was most likely due to a decrease in the nuclear translocation of RelB, a downstream transcription factor for the receptor activator of nuclear factor-κB signaling. Given that murine cecum contains a protrusion of beneficial commensals, the restriction of M-cell activity might contribute to preventing the onset of any excessive immune response to the commensals through decelerating the M-cell-dependent uptake of microorganisms.

The Elementary Mass Action Rate Constants of P-gp Transport for a Confluent Monolayer of MDCKII-hMDR1 Cells

PubMed Central

Tran, Thuy Thanh; Mittal, Aditya; Aldinger, Tanya; Polli, Joseph W.; Ayrton, Andrew; Ellens, Harma; Bentz, Joe

2005-01-01

The human multi-drug resistance membrane transporter, P-glycoprotein, or P-gp, has been extensively studied due to its importance to human health and disease. Thus far, the kinetic analysis of P-gp transport has been limited to steady-state Michaelis-Menten approaches or to compartmental models, neither of which can prove molecular mechanisms. Determination of the elementary kinetic rate constants of transport will be essential to understanding how P-gp works. The experimental system we use is a confluent monolayer of MDCKII-hMDR1 cells that overexpress P-gp. It is a physiologically relevant model system, and transport is measured without biochemical manipulations of P-gp. The Michaelis-Menten mass action reaction is used to model P-gp transport. Without imposing the steady-state assumptions, this reaction depends upon several parameters that must be simultaneously fitted. An exhaustive fitting of transport data to find all possible parameter vectors that best fit the data was accomplished with a reasonable computation time using a hierarchical algorithm. For three P-gp substrates (amprenavir, loperamide, and quinidine), we have successfully fitted the elementary rate constants, i.e., drug association to P-gp from the apical membrane inner monolayer, drug dissociation back into the apical membrane inner monolayer, and drug efflux from P-gp into the apical chamber, as well as the density of efflux active P-gp. All three drugs had overlapping ranges for the efflux active P-gp, which was a benchmark for the validity of the fitting process. One novel finding was that the association to P-gp appears to be rate-limited solely by drug lateral diffusion within the inner monolayer of the plasma membrane for all three drugs. This would be expected if P-gp structure were open to the lipids of the apical membrane inner monolayer, as has been suggested by recent structural studies. The fitted kinetic parameters show how P-gp efflux of a wide range of xenobiotics has been maximized. PMID:15501934

Galectin-8 regulates targeting of Gp135/podocalyxin and lumen formation at the apical surface of renal epithelial cells.

PubMed

Lim, HooiCheng; Yu, Chun-Ying; Jou, Tzuu-Shuh

2017-11-01

Establishment of apical-basal polarity, through correct targeting of polarity determinants to distinct domains of the plasma membrane, is a fundamental process for the development of functioning epithelial tubules. Here we report that galectin (Gal)-8 regulates apical-basal polarity of Madin-Darby canine kidney (MDCK) cells via apical targeting of 135-kDa glycoprotein (Gp135). Gal-8 interacts with newly synthesized Gp135 in a glycan-dependent manner. Gal-8 knockdown induces aberrant lumens at the lateral domain and mistargeting of Gp135 to this structure, thus disrupting the kidney epithelial polarity of MDCK cells, which organize lumens at the apical surface. The O -glycosylation deletion mutant of Gp135 phenocopies the effect of Gal-8 knockdown, which suggests that Gal-8 is the decoding machinery for the apical sorting signals of Gp135 residing at its O -glycosylation-rich region. Collectively, our results reveal a new role of Gal-8 in the development of luminal organs by regulating targeting of apical polarity protein Gp135.-Lim, H., Yu, C.-Y., Jou, T.-S. Galectin-8 regulates targeting of Gp135/podocalyxin and lumen formation at the apical surface of renal epithelial cells. © FASEB.

Exposure of LS-180 Cells to Drugs of Diverse Physicochemical and Therapeutic Properties Up-regulates P-glycoprotein Expression and Activity

PubMed Central

Abuznait, Alaa H.; Patrick, Shawn G.; Kaddoumi, Amal

2011-01-01

Purpose Drug transporters are increasingly recognized as important determinants of variability in drug disposition and therapeutic response, both in pre-clinical and clinical stages of drug development process. The role P-glycoprotein (P-gp) plays in drug interactions via its inhibition is well established. However, much less knowledge is available about drugs effect on P-gp up-regulation. The objective of this work was to in vitro investigate and rank commonly used drugs according to their potencies to up-regulate P-gp activity utilizing the same experimental conditions. Methods The in vitro potencies of several drugs of diverse physicochemical and therapeutic properties including rifampicin, dexamethasone, caffeine, verapamil, pentylenetetrazole, hyperforin, and β-estradiol over broad concentration range to up-regulate P-gp expression and activity were examined. For dose-response studies, LS-180 cells were treated with different concentrations of the selected drugs followed by P-gp protein and gene expressions analyses. P-gp functionality was determined by uptake studies with rhodamine 123 as a P-gp substrate, followed by Emax/EC50 evaluation. Results The results demonstrated a dose-dependent increase in P-gp expression and activity following treatments. At 50 μM concentration (hyperforin, 0.1 μM), examined drugs increased P-gp protein and gene expressions by up to 5.5 and 6.2-fold, respectively, while enhanced P-gp activity by 1.8–4-fold. The rank order of these drugs potencies to up-regulate P-gp activity was as following: hyperforin ⋙ dexamethasone ≈ β-estradiol > caffeine > rifampicin ≈ pentylenetetrazole > verapamil. Conclusions These drugs have the potential to be involved in drug interactions when administered with other drugs that are P-gp substrates. Further studies are needed to in vivo evaluate these drugs and verify the consequences of such induction on P-gp activity for in vitro-in vivo correlation purposes. PMID:21733412

An empirical analysis of the distribution of overshoots in a stationary Gaussian stochastic process

NASA Technical Reports Server (NTRS)

Carter, M. C.; Madison, M. W.

1973-01-01

The frequency distribution of overshoots in a stationary Gaussian stochastic process is analyzed. The primary processes involved in this analysis are computer simulation and statistical estimation. Computer simulation is used to simulate stationary Gaussian stochastic processes that have selected autocorrelation functions. An analysis of the simulation results reveals a frequency distribution for overshoots with a functional dependence on the mean and variance of the process. Statistical estimation is then used to estimate the mean and variance of a process. It is shown that for an autocorrelation function, the mean and the variance for the number of overshoots, a frequency distribution for overshoots can be estimated.

Orthogonal Gaussian process models

DOE PAGES

Plumlee, Matthew; Joseph, V. Roshan

2017-01-01

Gaussian processes models are widely adopted for nonparameteric/semi-parametric modeling. Identifiability issues occur when the mean model contains polynomials with unknown coefficients. Though resulting prediction is unaffected, this leads to poor estimation of the coefficients in the mean model, and thus the estimated mean model loses interpretability. This paper introduces a new Gaussian process model whose stochastic part is orthogonal to the mean part to address this issue. As a result, this paper also discusses applications to multi-fidelity simulations using data examples.

Orthogonal Gaussian process models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plumlee, Matthew; Joseph, V. Roshan

Gaussian processes models are widely adopted for nonparameteric/semi-parametric modeling. Identifiability issues occur when the mean model contains polynomials with unknown coefficients. Though resulting prediction is unaffected, this leads to poor estimation of the coefficients in the mean model, and thus the estimated mean model loses interpretability. This paper introduces a new Gaussian process model whose stochastic part is orthogonal to the mean part to address this issue. As a result, this paper also discusses applications to multi-fidelity simulations using data examples.

Separation of components from a scale mixture of Gaussian white noises

NASA Astrophysics Data System (ADS)

Vamoş, Călin; Crăciun, Maria

2010-05-01

The time evolution of a physical quantity associated with a thermodynamic system whose equilibrium fluctuations are modulated in amplitude by a slowly varying phenomenon can be modeled as the product of a Gaussian white noise {Zt} and a stochastic process with strictly positive values {Vt} referred to as volatility. The probability density function (pdf) of the process Xt=VtZt is a scale mixture of Gaussian white noises expressed as a time average of Gaussian distributions weighted by the pdf of the volatility. The separation of the two components of {Xt} can be achieved by imposing the condition that the absolute values of the estimated white noise be uncorrelated. We apply this method to the time series of the returns of the daily S&P500 index, which has also been analyzed by means of the superstatistics method that imposes the condition that the estimated white noise be Gaussian. The advantage of our method is that this financial time series is processed without partitioning or removal of the extreme events and the estimated white noise becomes almost Gaussian only as result of the uncorrelation condition.

Poly-Gaussian model of randomly rough surface in rarefied gas flow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aksenova, Olga A.; Khalidov, Iskander A.

2014-12-09

Surface roughness is simulated by the model of non-Gaussian random process. Our results for the scattering of rarefied gas atoms from a rough surface using modified approach to the DSMC calculation of rarefied gas flow near a rough surface are developed and generalized applying the poly-Gaussian model representing probability density as the mixture of Gaussian densities. The transformation of the scattering function due to the roughness is characterized by the roughness operator. Simulating rough surface of the walls by the poly-Gaussian random field expressed as integrated Wiener process, we derive a representation of the roughness operator that can be appliedmore » in numerical DSMC methods as well as in analytical investigations.« less

Expression of HIV gp120 protein increases sensitivity to the rewarding properties of methamphetamine in mice

PubMed Central

Kesby, James P.; Hubbard, David T.; Markou, Athina; Semenova, Svetlana

2012-01-01

Methamphetamine abuse and human immunodeficiency virus (HIV) infection induce neuropathological changes in corticolimbic brain areas involved in reward and cognitive function. Little is known about the combined effects of methamphetamine and HIV infection on cognitive and reward processes. The HIV/gp120 protein induces neurodegeneration in mice, similar to HIV-induced pathology in humans. We investigated the effects of gp120 expression on associative learning, preference for methamphetamine and non-drug reinforcers, and sensitivity to the conditioned rewarding properties of methamphetamine in transgenic (tg) mice expressing HIV/gp120 protein (gp120-tg). gp120-tg mice learned the operant response for food at the same rate as non-tg mice. In the two-bottle choice procedure with restricted access to drugs, gp120-tg mice exhibited greater preference for methamphetamine and saccharin than non-tg mice, whereas preference for quinine was similar between genotypes. Under conditions of unrestricted access to methamphetamine, the mice exhibited a decreased preference for increasing methamphetamine concentrations. However, male gp120-tg mice showed a decreased preference for methamphetamine at lower concentrations than non-tg male mice. gp120-tg mice developed methamphetamine-induced conditioned place preference at lower methamphetamine doses compared with non-tg mice. No differences in methamphetamine pharmacokinetics were found between genotypes. These results indicate that gp120-tg mice exhibit no deficits in associative learning or reward/motivational function for a natural reinforcer. Interestingly, gp120 expression resulted in increased preference for methamphetamine and a highly palatable non-drug reinforcer (saccharin) and increased sensitivity to methamphetamine-induced conditioned reward. These data suggest that HIV-positive individuals may have increased sensitivity to methamphetamine, leading to high methamphetamine abuse potential in this population. PMID:23252824

Specificity of interactions among the DNA-packaging machine components of T4-related bacteriophages.

PubMed

Gao, Song; Rao, Venigalla B

2011-02-04

Tailed bacteriophages use powerful molecular motors to package the viral genome into a preformed capsid. Packaging at a rate of up to ∼2000 bp/s and generating a power density twice that of an automobile engine, the phage T4 motor is the fastest and most powerful reported to date. Central to DNA packaging are dynamic interactions among the packaging components, capsid (gp23), portal (gp20), motor (gp17, large "terminase"), and regulator (gp16, small terminase), leading to precise orchestration of the packaging process, but the mechanisms are poorly understood. Here we analyzed the interactions between small and large terminases of T4-related phages. Our results show that the gp17 packaging ATPase is maximally stimulated by homologous, but not heterologous, gp16. Multiple interaction sites are identified in both gp16 and gp17. The specificity determinants in gp16 are clustered in the diverged N- and C-terminal domains (regions I-III). Swapping of diverged region(s), such as replacing C-terminal RB49 region III with that of T4, switched ATPase stimulation specificity. Two specificity regions, amino acids 37-52 and 290-315, are identified in or near the gp17-ATPase "transmission" subdomain II. gp16 binding at these sites might cause a conformational change positioning the ATPase-coupling residues into the catalytic pocket, triggering ATP hydrolysis. These results lead to a model in which multiple weak interactions between motor and regulator allow dynamic assembly and disassembly of various packaging complexes, depending on the functional state of the packaging machine. This might be a general mechanism for regulation of the phage packaging machine and other complex molecular machines.

Blockade of P-Glycoprotein Decreased the Disposition of Phenformin and Increased Plasma Lactate Level.

PubMed

Choi, Min-Koo; Song, Im-Sook

2016-03-01

This study aimed to investigate the in vivo relevance of P-glycoprotein (P-gp) in the pharmacokinetics and adverse effect of phenformin. To investigate the involvement of P-gp in the transport of phenformin, a bi-directional transport of phenformin was carried out in LLC-PK1 cells overexpressing P-gp, LLC-PK1-Pgp. Basal to apical transport of phenformin was 3.9-fold greater than apical to basal transport and became saturated with increasing phenformin concentration (2-75 μM) in LLC-PK1-Pgp, suggesting the involvement of P-gp in phenformin transport. Intrinsic clearance mediated by P-gp was 1.9 μL/min while passive diffusion clearance was 0.31 μL/min. Thus, P-gp contributed more to phenformin transport than passive diffusion. To investigate the contribution of P-gp on the pharmacokinetics and adverse effect of phenformin, the effects of verapamil, a P-gp inhibitor, on the pharmacokinetics of phenformin were also examined in rats. The plasma concentrations of phenformin were increased following oral administration of phenformin and intravenous verapamil infusion compared with those administerd phenformin alone. Pharmacokinetic parameters such as Cmax and AUC of phenformin increased and CL/F and Vss/F decreased as a consequence of verapamil treatment. These results suggested that P-gp blockade by verapamil may decrease the phenformin disposition and increase plasma phenformin concentrations. P-gp inhibition by verapamil treatment also increased plasma lactate concentration, which is a crucial adverse event of phenformin. In conclusion, P-gp may play an important role in phenformin transport process and, therefore, contribute to the modulation of pharmacokinetics of phenformin and onset of plasma lactate level.

Blockade of P-Glycoprotein Decreased the Disposition of Phenformin and Increased Plasma Lactate Level

PubMed Central

Choi, Min-Koo; Song, Im-Sook

2016-01-01

This study aimed to investigate the in vivo relevance of P-glycoprotein (P-gp) in the pharmacokinetics and adverse effect of phenformin. To investigate the involvement of P-gp in the transport of phenformin, a bi-directional transport of phenformin was carried out in LLC-PK1 cells overexpressing P-gp, LLC-PK1-Pgp. Basal to apical transport of phenformin was 3.9-fold greater than apical to basal transport and became saturated with increasing phenformin concentration (2–75 μM) in LLC-PK1-Pgp, suggesting the involvement of P-gp in phenformin transport. Intrinsic clearance mediated by P-gp was 1.9 μL/min while passive diffusion clearance was 0.31 μL/min. Thus, P-gp contributed more to phenformin transport than passive diffusion. To investigate the contribution of P-gp on the pharmacokinetics and adverse effect of phenformin, the effects of verapamil, a P-gp inhibitor, on the pharmacokinetics of phenformin were also examined in rats. The plasma concentrations of phenformin were increased following oral administration of phenformin and intravenous verapamil infusion compared with those administerd phenformin alone. Pharmacokinetic parameters such as Cmax and AUC of phenformin increased and CL/F and Vss/F decreased as a consequence of verapamil treatment. These results suggested that P-gp blockade by verapamil may decrease the phenformin disposition and increase plasma phenformin concentrations. P-gp inhibition by verapamil treatment also increased plasma lactate concentration, which is a crucial adverse event of phenformin. In conclusion, P-gp may play an important role in phenformin transport process and, therefore, contribute to the modulation of pharmacokinetics of phenformin and onset of plasma lactate level. PMID:26797108

Exploring movement and energy in human P-glycoprotein conformational rearrangement.

PubMed

Zhang, Yue; Gong, Weikang; Wang, Yan; Liu, Yang; Li, Chunhua

2018-04-24

Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is one of the main reasons for the multidrug resistance (MDR) of tumor cells. It has been confirmed that during the substrate transport process, P-gp experiences a large-scale structural rearrangement from the inward- to outward-facing states. However, the mechanism of how the nucleotide-binding domains (NBDs) control the transmembrane domains (TMDs) to open towards the periplasm in the outward-facing state has not yet been fully characterized. Herein, targeted molecular dynamics simulations were performed to explore the conformational rearrangement of human P-gp. The results show that the allosteric process proceeds in a coupled way, and first the transition is driven by the NBDs, and then transmitted to the cytoplasmic parts of TMDs, finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement, which mainly occurs in xy plane and ensures the formation of the correct ATP-binding pockets. The analyses on the interaction energies between the six structure segments (cICLs) from the TMDs and NBDs reveal that their subtle energy differences play an important role in causing the periplasmic parts of the transmembrane helices to separate from each other in the established directions and in appropriate amplitudes. This conclusion can explain the two experimental phenomena about human P-gp in some extent. These studies have provided a detailed exploration into human P-gp rearrangement process and given an energy insight into the TMD reorientation during P-gp transition.

Recurrence plots of discrete-time Gaussian stochastic processes

NASA Astrophysics Data System (ADS)

Ramdani, Sofiane; Bouchara, Frédéric; Lagarde, Julien; Lesne, Annick

2016-09-01

We investigate the statistical properties of recurrence plots (RPs) of data generated by discrete-time stationary Gaussian random processes. We analytically derive the theoretical values of the probabilities of occurrence of recurrence points and consecutive recurrence points forming diagonals in the RP, with an embedding dimension equal to 1. These results allow us to obtain theoretical values of three measures: (i) the recurrence rate (REC) (ii) the percent determinism (DET) and (iii) RP-based estimation of the ε-entropy κ(ε) in the sense of correlation entropy. We apply these results to two Gaussian processes, namely first order autoregressive processes and fractional Gaussian noise. For these processes, we simulate a number of realizations and compare the RP-based estimations of the three selected measures to their theoretical values. These comparisons provide useful information on the quality of the estimations, such as the minimum required data length and threshold radius used to construct the RP.

Rheological study of physical cross-linked quaternized cellulose hydrogels induced by β-glycerophosphate.

PubMed

You, Jun; Zhou, Jinping; Li, Qian; Zhang, Lina

2012-03-20

As a weak base, β-glycerophosphate (β-GP) was used to spontaneously initiate gelation of quaternized cellulose (QC) solutions at body temperature. The QC/β-GP solutions are flowable below or at room temperature but gel rapidly under physiological conditions. In order to clarify the sol-gel transition process of the QC/β-GP systems, the complex was investigated by dynamic viscoelastic measurements. The shear storage modulus (G') and loss modulus (G″) as a function of (1) concentration of β-GP (c(β-GP)), (2) concentration of QC (c(QC)), (3) degree of substitution (DS; i.e., the average number of substituted hydroxyl groups in the anhydroglucose unit) of QC, (4) viscosity-average molecular weight (M(η)) of QC, and (5) solvent medium were studied by the oscillatory rheology. The sol-gel transition temperature of QC/β-GP solutions decreased with an increase of c(QC) and c(β-GP), the M(η) of QC, and a decrease of the DS of QC and pH of the solvent. The sol-gel transition temperature and time could be easily controlled by adjusting the concentrations of QC and β-GP, M(η) and DS of QC, and the solvent medium. Gels formed after heating were irreversible; i.e., after cooling to lower temperature they could not be dissolved to become liquid again. The aggregation and entanglement of QC chains, electrostatic interaction, and hydrogen bonding between QC and β-GP were the main factors responsible for the irreversible sol-gel transition behavior of QC/β-GP systems.

Patients’ experiences of referral for colorectal cancer

PubMed Central

2013-01-01

Background Outcomes for colorectal cancer patients vary significantly. Compared to other countries, Australia has a good record with patient outcomes, yet there is little information available on the referral pathway. This paper explores the views of Australian patients and their experiences of referral for colorectal cancer treatment following diagnosis; the aim was to improve our understanding of the referral pathway and guide the development of future interventions. Methods A purposive sampling strategy was used, recruiting 29 patients representing urban and rural areas from 3 Australian states who participated in 4 focus groups. Seven patients provided individual interviews to supplement the data. Recordings were transcribed verbatim, data was coded with NVivo software and analysed thematically before deductive analysis. Results Four aspects of the referral process were identified by patients, namely detection/diagnosis, referral for initial treatment/specialist care, the roles of the GP/specialist, and the patient’s perceived involvement in the process. The referral process was characterised by a lack of patient involvement, with few examples of shared decision-making and few examples of limited choice. However, patients did not always feel they had the knowledge to make informed decisions. Information exchange was highly valued by patients when it occurred, and it increased their satisfaction with the process. Other factors mediating care included the use of the public versus private health system, the quality of information exchange (GP to specialist and GP to patient), continuity of care between GP and specialist, and the extent of information provision when patients moved between specialist and GP care. Conclusions Patients described poor GP continuity, ad hoc organisational systems and limited information exchange, at both interpersonal and inter-organisational levels, all leading to sub-optimal care. Implementation of a system of information feedback to GPs and engagement with them might improve information exchange for patients, enabling them to be more involved in improved referral outcomes. PMID:23972115

Characterization of the receptors for mycobacterial cord factor in Guinea pig.

PubMed

Toyonaga, Kenji; Miyake, Yasunobu; Yamasaki, Sho

2014-01-01

Guinea pig is a widely used animal for research and development of tuberculosis vaccines, since its pathological disease process is similar to that present in humans. We have previously reported that two C-type lectin receptors, Mincle (macrophage inducible C-type lectin, also called Clec4e) and MCL (macrophage C-type lectin, also called Clec4d), recognize the mycobacterial cord factor, trehalose-6,6'-dimycolate (TDM). Here, we characterized the function of the guinea pig homologue of Mincle (gpMincle) and MCL (gpMCL). gpMincle directly bound to TDM and transduced an activating signal through ITAM-bearing adaptor molecule, FcRγ. Whereas, gpMCL lacked C-terminus and failed to bind to TDM. mRNA expression of gpMincle was detected in the spleen, lymph nodes and peritoneal macrophages and it was strongly up-regulated upon stimulation of zymosan and TDM. The surface expression of gpMincle was detected on activated macrophages by a newly established monoclonal antibody that also possesses a blocking activity. This antibody potently suppressed TNF production in BCG-infected macrophages. Collectively, gpMincle is the TDM receptor in the guinea pig and TDM-Mincle axis is involved in host immune responses against mycobacteria.

Hairpin Folding of HIV gp41 Abrogates Lipid Mixing Function at Physiologic pH and Inhibits Lipid Mixing by Exposed gp41 Constructs†

PubMed Central

Sackett, Kelly; Nethercott, Matthew J.; Shai, Yechiel; Weliky, David P.

2009-01-01

Conformational changes in the HIV gp41 protein are directly correlated with fusion between the HIV and target cell plasma membranes which is the initial step of infection. Key gp41 fusion conformations include an early extended conformation termed pre-hairpin which contains exposed regions and a final low energy conformation termed hairpin which has compact six-helix bundle structure. Current fusion models debate the roles of hairpin and pre-hairpin conformations in the process of membrane merger. In the present work, gp41 constructs have been engineered which correspond to fusion relevant parts of both pre-hairpin and hairpin conformations, and have been analyzed for their ability to induce lipid mixing between membrane vesicles. The data correlate membrane fusion function with the pre-hairpin conformation and suggest that one of the roles of the final hairpin conformation is sequestration of membrane perturbing gp41 regions with consequent loss of the membrane disruption induced earlier by the pre-hairpin structure. To our knowledge, this is the first biophysical study to delineate the membrane fusion potential of gp41 constructs modeling key fusion conformations. PMID:19222185

Crystallographic Insights into the Autocatalytic Assembly Mechanism of a Bacteriophage Tail Spike

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiang, Ye; Leiman, Petr G.; Li, Long

2010-02-03

The tailed bacteriophage phi29 has 12 'appendages' (gene product 12, gp12) attached to its neck region that participate in host cell recognition and entry. In the cell, monomeric gp12 undergoes proteolytic processing that releases the C-terminal domain during assembly into trimers. We report here crystal structures of the protein before and after catalytic processing and show that the C-terminal domain of gp12 is an 'autochaperone' that aids trimerization. We also show that autocleavage of the C-terminal domain is a posttrimerization event that is followed by a unique ATP-dependent release. The posttranslationally modified N-terminal part has three domains that function tomore » attach the appendages to the phage, digest the cell wall teichoic acids, and bind irreversibly to the host, respectively. Structural and sequence comparisons suggest that some eukaryotic and bacterial viruses as well as bacterial adhesins might have a similar maturation mechanism as is performed by phi29 gp12 for Bacillus subtilis.« less

Single molecular dynamic interactions between glycophorin A and lectin as probed by atomic force microscopy.

PubMed

Yan, Chao; Yersin, Alexandre; Afrin, Rehana; Sekiguchi, Hiroshi; Ikai, Atsushi

2009-09-01

Glycophorin A (GpA) is one of the most abundant transmembrane proteins in human erythrocytes and its interaction with lectins has been studied as model systems for erythrocyte related biological processes. We performed a force measurement study using the force mode of atomic force microscopy (AFM) to investigate the single molecular level biophysical mechanisms involved in GpA-lectin interactions. GpA was mounted on a mica surface or natively presented on the erythrocyte membrane and probed with an AFM tip coated with the monomeric but multivalent Psathyrella velutina lectin (PVL) through covalent crosslinkers. A dynamic force spectroscopy study revealed similar interaction properties in both cases, with the unbinding force centering around 60 pN with a weak loading rate dependence. Hence we identified the presence of one energy barrier in the unbinding process. Force profile analysis showed that more than 70% of GpAs are free of cytoskeletal associations in agreement with previous reports.

[Computer usage among primary health care physicians in the Vukovar-Srijem County].

PubMed

Iveković, Hrvoje

2002-01-01

A survey was carried out, aiming at identification of the current usage of computers among primary health care physicians of the Vukovar-Srijem County. The results indicated poor knowledge and practice concerning the computer usage among examinees: 58% of the responders are not aware of the possibilities of computer usage in a GP office and 82% have not had an opportunity to see the software specialised for usage at GP offices. The results obtained from this survey indicate that none of the examinees use computer during daily routine work at the GP office. Only 26% of the examinees have got a computer, and use it at home, mostly for text processing. The Internet is used actively by 8% of examinees. Lack of education and equipment have been identified as main obstacles in the process of introducing computers to GP offices. Positive attitude towards computer usage has been identified, representing an important stimulus towards a more active role of the health centres management in solving this problem.

The Tetherin Antagonism of the Ebola Virus Glycoprotein Requires an Intact Receptor-Binding Domain and Can Be Blocked by GP1-Specific Antibodies.

PubMed

Brinkmann, Constantin; Nehlmeier, Inga; Walendy-Gnirß, Kerstin; Nehls, Julia; González Hernández, Mariana; Hoffmann, Markus; Qiu, Xiangguo; Takada, Ayato; Schindler, Michael; Pöhlmann, Stefan

2016-12-15

The glycoprotein of Ebola virus (EBOV GP), a member of the family Filoviridae, facilitates viral entry into target cells. In addition, EBOV GP antagonizes the antiviral activity of the host cell protein tetherin, which may otherwise restrict EBOV release from infected cells. However, it is unclear how EBOV GP antagonizes tetherin, and it is unknown whether the GP of Lloviu virus (LLOV), a filovirus found in dead bats in Northern Spain, also counteracts tetherin. Here, we show that LLOV GP antagonizes tetherin, indicating that tetherin may not impede LLOV spread in human cells. Moreover, we demonstrate that appropriate processing of N-glycans in tetherin/GP-coexpressing cells is required for tetherin counteraction by EBOV GP. Furthermore, we show that an intact receptor-binding domain (RBD) in the GP1 subunit of EBOV GP is a prerequisite for tetherin counteraction. In contrast, blockade of Niemann-Pick disease type C1 (NPC1), a cellular binding partner of the RBD, did not interfere with tetherin antagonism. Finally, we provide evidence that an antibody directed against GP1, which protects mice from a lethal EBOV challenge, may block GP-dependent tetherin antagonism. Our data, in conjunction with previous reports, indicate that tetherin antagonism is conserved among the GPs of all known filoviruses and demonstrate that the GP1 subunit of EBOV GP plays a central role in tetherin antagonism. Filoviruses are reemerging pathogens that constitute a public health threat. Understanding how Ebola virus (EBOV), a highly pathogenic filovirus responsible for the 2013-2016 Ebola virus disease epidemic in western Africa, counteracts antiviral effectors of the innate immune system might help to define novel targets for antiviral intervention. Similarly, determining whether Lloviu virus (LLOV), a filovirus detected in bats in northern Spain, is inhibited by innate antiviral effectors in human cells might help to determine whether the virus constitutes a threat to humans. The present study shows that LLOV, like EBOV, counteracts the antiviral effector protein tetherin via its glycoprotein (GP), suggesting that tetherin does not pose a defense against LLOV spread in humans. Moreover, our work identifies the GP1 subunit of EBOV GP, in particular an intact receptor-binding domain, as critical for tetherin counteraction and provides evidence that antibodies directed against GP1 can interfere with tetherin counteraction. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Efficiency of serum protein removal from skim milk with ceramic and polymeric membranes at 50 degrees C.

PubMed

Zulewska, J; Newbold, M; Barbano, D M

2009-04-01

Raw milk (2,710 kg) was separated at 4 degrees C, the skim milk was pasteurized (72 degrees C, 16 s), split into 3 batches, and microfiltered using pilot-scale ceramic uniform transmembrane pressure (UTP; Membralox model EP1940GL0.1microA, 0.1 microm alumina, Pall Corp., East Hills, NY), ceramic graded permeability (GP; Membralox model EP1940GL0.1microAGP1020, 0.1 microm alumina, Pall Corp.), and polymeric spiral-wound (SW; model FG7838-OS0x-S, 0.3 microm polyvinylidene fluoride, Parker-Hannifin, Process Advanced Filtration Division, Tell City, IN) membranes. There were differences in flux among ceramic UTP, ceramic GP, and polymeric SW microfiltration membranes (54.08, 71.79, and 16.21 kg/m2 per hour, respectively) when processing skim milk at 50 degrees C in a continuous bleed-and-feed 3x process. These differences in flux among the membranes would influence the amount of membrane surface area required to process a given volume of milk in a given time. Further work is needed to determine if these differences in flux are maintained over longer processing times. The true protein contents of the microfiltration permeates from UTP and GP membranes were higher than from SW membranes (0.57, 0.56, and 0.38%, respectively). Sodium-dodecyl-sulfate-PAGE gels for permeates revealed a higher casein proportion in GP and SW permeate than in UTP permeate, with the highest passage of casein through the GP membrane under the operational conditions used in this study. The slight cloudiness of the permeates produced using the GP and SW systems may have been due to the presence of a small amount of casein, which may present an obstacle in their use in applications when clarity is an important functional characteristic. More beta-lactoglobulin passed through the ceramic membranes than through the polymeric membrane. The efficiency of removal of serum proteins in a continuous bleed-and-feed 3x process at 50 degrees C was 64.40% for UTP, 61.04% for GP, and 38.62% for SW microfiltration membranes. The SW polymeric membranes had a much higher rejection of serum proteins than did the ceramic membranes, consistent with the sodium-dodecyl-sulfate PAGE data. Multiple stages and diafiltration would be required to produce a 60 to 65% serum protein reduced micellar casein concentrate with SW membranes, whereas only one stage would be needed for the ceramic membranes used in this study.

A sea lamprey glycoprotein hormone receptor similar with gnathostome thyrotropin hormone receptor.

PubMed

Freamat, Mihael; Sower, Stacia A

2008-10-01

The specificity of the vertebrate hypothalamic-pituitary-gonadal and hypothalamic-pituitary-thyroid axes is explained by the evolutionary refinement of the specificity of expression and selectivity of interaction between the glycoprotein hormones GpH (FSH, LH, and TSH) and their cognate receptors GpH-R (FSH-R, LH-R, and TSH-R). These two finely tuned signaling pathways evolved by gene duplication and functional divergence from an ancestral GpH/GpH-R pair. Comparative analysis of the protochordate and gnathostome endocrine systems suggests that this process took place prior or concomitantly with the emergence of the gnathostome lineage. Here, we report identification and characterization of a novel glycoprotein hormone receptor (lGpH-R II) in the Agnathan sea lamprey. This 781 residue protein was found approximately 43% identical with mammalian TSH-R and FSH-R representative sequences, and similarly with these two classes of mammalian receptors it is assembled from ten exons. A synthetic ligand containing the lamprey glycoprotein hormone beta-chain tethered upstream of a mammalian alpha-chain activated the lGpH-R II expressed in COS-7 cells but in a lesser extent than lGpH-R I. Molecular phylogenetic analysis of vertebrate GpH-R protein sequences suggests a closer relationship between lGpH-R II and gnathostome thyrotropin receptors. Overall, the presence and characteristics of the lamprey glycoprotein hormone receptors suggest existence of a primitive functionally overlapping glycoprotein hormone/glycoprotein hormone receptor system in this animal.

Ebola virus glycoprotein Fc fusion protein confers protection against lethal challenge in vaccinated mice

PubMed Central

Konduru, Krishnamurthy; Bradfute, Steven B.; Jacques, Jerome; Manangeeswaran, Mohanraj; Nakamura, Siham; Morshed, Sufi; Wood, Steven C.; Bavari, Sina

2011-01-01

Ebola virus is a Filoviridae that causes hemorrhagic fever in humans and induces high morbidity and mortality rates. Filoviruses are classified as "Category A bioterrorism agents", and currently there are no licensed therapeutics or vaccines to treat and prevent infection. The Filovirus glycoprotein (GP) is sufficient to protect individuals against infection, and several vaccines based on GP are under development including recombinant adenovirus, parainfluenza virus, Venezuelan equine encephalitis virus, vesicular stomatitis virus (VSV) and virus-like particles. Here we describe the development of a GP Fc fusion protein as a vaccine candidate. We expressed the extracellular domain of the Zaire Ebola virus (ZEBOV) GP fused to the Fc fragment of human IgG1 (ZEBOVGP-Fc) in mammalian cells and showed that GP undergoes the complex furin cleavage and processing observed in the native membrane-bound GP. Mice immunized with ZEBOVGP-Fc developed T-cell immunity against ZEBOV GP and neutralizing antibodies against replication-competent VSV-G deleted recombinant VSV containing ZEBOV GP. The ZEBOVGP-Fc vaccinated mice were protected against challenge with a lethal dose of ZEBOV. These results show that vaccination with the ZEBOVGP-Fc fusion protein alone without the need of a viral vector or assembly into virus-like particles is sufficient to induce protective immunity against ZEBOV in mice. Our data suggested that Filovirus GP Fc fusion proteins could be developed as a simple, safe, efficacious, and cost effective vaccine against Filovirus infection for human use. PMID:21329775

Verification of directed self-assembly (DSA) guide patterns through machine learning

NASA Astrophysics Data System (ADS)

Shim, Seongbo; Cai, Sibo; Yang, Jaewon; Yang, Seunghune; Choi, Byungil; Shin, Youngsoo

2015-03-01

Verification of full-chip DSA guide patterns (GPs) through simulations is not practical due to long runtime. We develop a decision function (or functions), which receives n geometry parameters of a GP as inputs and predicts whether the GP faithfully produces desired contacts (good) or not (bad). We take a few sample GPs to construct the function; DSA simulations are performed for each GP to decide whether it is good or bad, and the decision is marked in n-dimensional space. The hyper-plane that separates good marks and bad marks in that space is determined through machine learning process, and corresponds to our decision function. We try a single global function that can be applied to any GP types, and a series of functions in which each function is customized for different GP type; they are then compared and assessed in 10nm technology.

Impact of Leishmania Infection on Host Macrophage Nuclear Physiology and Nucleopore Complex Integrity

PubMed Central

Isnard, Amandine; Christian, Jan G.; Kodiha, Mohamed; Stochaj, Ursula; McMaster, W. Robert; Olivier, Martin

2015-01-01

The protease GP63 is an important virulence factor of Leishmania parasites. We previously showed that GP63 reaches the perinuclear area of host macrophages and that it directly modifies nuclear translocation of the transcription factors NF-κB and AP-1. Here we describe for the first time, using molecular biology and in-depth proteomic analyses, that GP63 alters the host macrophage nuclear envelope, and impacts on nuclear processes. Our results suggest that GP63 does not appear to use a classical nuclear localization signal common between Leishmania species for import, but degrades nucleoporins, and is responsible for nuclear transport alterations. In the nucleoplasm, GP63 activity accounts for the degradation and mislocalization of proteins involved amongst others in gene expression and in translation. Collectively, our data indicates that Leishmania infection strongly affects nuclear physiology, suggesting that targeting of nuclear physiology may be a strategy beneficial for virulent Leishmania parasites. PMID:25826301

Quantum entanglement beyond Gaussian criteria

PubMed Central

Gomes, R. M.; Salles, A.; Toscano, F.; Souto Ribeiro, P. H.; Walborn, S. P.

2009-01-01

Most of the attention given to continuous variable systems for quantum information processing has traditionally been focused on Gaussian states. However, non-Gaussianity is an essential requirement for universal quantum computation and entanglement distillation, and can improve the efficiency of other quantum information tasks. Here we report the experimental observation of genuine non-Gaussian entanglement using spatially entangled photon pairs. The quantum correlations are invisible to all second-order tests, which identify only Gaussian entanglement, and are revealed only under application of a higher-order entanglement criterion. Thus, the photons exhibit a variety of entanglement that cannot be reproduced by Gaussian states. PMID:19995963

Quantum entanglement beyond Gaussian criteria.

PubMed

Gomes, R M; Salles, A; Toscano, F; Souto Ribeiro, P H; Walborn, S P

2009-12-22

Most of the attention given to continuous variable systems for quantum information processing has traditionally been focused on Gaussian states. However, non-Gaussianity is an essential requirement for universal quantum computation and entanglement distillation, and can improve the efficiency of other quantum information tasks. Here we report the experimental observation of genuine non-Gaussian entanglement using spatially entangled photon pairs. The quantum correlations are invisible to all second-order tests, which identify only Gaussian entanglement, and are revealed only under application of a higher-order entanglement criterion. Thus, the photons exhibit a variety of entanglement that cannot be reproduced by Gaussian states.

Gaussian processes with built-in dimensionality reduction: Applications to high-dimensional uncertainty propagation

NASA Astrophysics Data System (ADS)

Tripathy, Rohit; Bilionis, Ilias; Gonzalez, Marcial

2016-09-01

Uncertainty quantification (UQ) tasks, such as model calibration, uncertainty propagation, and optimization under uncertainty, typically require several thousand evaluations of the underlying computer codes. To cope with the cost of simulations, one replaces the real response surface with a cheap surrogate based, e.g., on polynomial chaos expansions, neural networks, support vector machines, or Gaussian processes (GP). However, the number of simulations required to learn a generic multivariate response grows exponentially as the input dimension increases. This curse of dimensionality can only be addressed, if the response exhibits some special structure that can be discovered and exploited. A wide range of physical responses exhibit a special structure known as an active subspace (AS). An AS is a linear manifold of the stochastic space characterized by maximal response variation. The idea is that one should first identify this low dimensional manifold, project the high-dimensional input onto it, and then link the projection to the output. If the dimensionality of the AS is low enough, then learning the link function is a much easier problem than the original problem of learning a high-dimensional function. The classic approach to discovering the AS requires gradient information, a fact that severely limits its applicability. Furthermore, and partly because of its reliance to gradients, it is not able to handle noisy observations. The latter is an essential trait if one wants to be able to propagate uncertainty through stochastic simulators, e.g., through molecular dynamics codes. In this work, we develop a probabilistic version of AS which is gradient-free and robust to observational noise. Our approach relies on a novel Gaussian process regression with built-in dimensionality reduction. In particular, the AS is represented as an orthogonal projection matrix that serves as yet another covariance function hyper-parameter to be estimated from the data. To train the model, we design a two-step maximum likelihood optimization procedure that ensures the orthogonality of the projection matrix by exploiting recent results on the Stiefel manifold, i.e., the manifold of matrices with orthogonal columns. The additional benefit of our probabilistic formulation, is that it allows us to select the dimensionality of the AS via the Bayesian information criterion. We validate our approach by showing that it can discover the right AS in synthetic examples without gradient information using both noiseless and noisy observations. We demonstrate that our method is able to discover the same AS as the classical approach in a challenging one-hundred-dimensional problem involving an elliptic stochastic partial differential equation with random conductivity. Finally, we use our approach to study the effect of geometric and material uncertainties in the propagation of solitary waves in a one dimensional granular system.

Gaussian processes with built-in dimensionality reduction: Applications to high-dimensional uncertainty propagation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tripathy, Rohit, E-mail: rtripath@purdue.edu; Bilionis, Ilias, E-mail: ibilion@purdue.edu; Gonzalez, Marcial, E-mail: marcial-gonzalez@purdue.edu

2016-09-15

Uncertainty quantification (UQ) tasks, such as model calibration, uncertainty propagation, and optimization under uncertainty, typically require several thousand evaluations of the underlying computer codes. To cope with the cost of simulations, one replaces the real response surface with a cheap surrogate based, e.g., on polynomial chaos expansions, neural networks, support vector machines, or Gaussian processes (GP). However, the number of simulations required to learn a generic multivariate response grows exponentially as the input dimension increases. This curse of dimensionality can only be addressed, if the response exhibits some special structure that can be discovered and exploited. A wide range ofmore » physical responses exhibit a special structure known as an active subspace (AS). An AS is a linear manifold of the stochastic space characterized by maximal response variation. The idea is that one should first identify this low dimensional manifold, project the high-dimensional input onto it, and then link the projection to the output. If the dimensionality of the AS is low enough, then learning the link function is a much easier problem than the original problem of learning a high-dimensional function. The classic approach to discovering the AS requires gradient information, a fact that severely limits its applicability. Furthermore, and partly because of its reliance to gradients, it is not able to handle noisy observations. The latter is an essential trait if one wants to be able to propagate uncertainty through stochastic simulators, e.g., through molecular dynamics codes. In this work, we develop a probabilistic version of AS which is gradient-free and robust to observational noise. Our approach relies on a novel Gaussian process regression with built-in dimensionality reduction. In particular, the AS is represented as an orthogonal projection matrix that serves as yet another covariance function hyper-parameter to be estimated from the data. To train the model, we design a two-step maximum likelihood optimization procedure that ensures the orthogonality of the projection matrix by exploiting recent results on the Stiefel manifold, i.e., the manifold of matrices with orthogonal columns. The additional benefit of our probabilistic formulation, is that it allows us to select the dimensionality of the AS via the Bayesian information criterion. We validate our approach by showing that it can discover the right AS in synthetic examples without gradient information using both noiseless and noisy observations. We demonstrate that our method is able to discover the same AS as the classical approach in a challenging one-hundred-dimensional problem involving an elliptic stochastic partial differential equation with random conductivity. Finally, we use our approach to study the effect of geometric and material uncertainties in the propagation of solitary waves in a one dimensional granular system.« less

What is a good general practitioner (GP)? The development and evaluation of a multi-source feedback instrument for GP appraisal.

PubMed

Shepherd, Annabel; Lough, Murray

2010-05-01

Although multi-source feedback (MSF) has been used in primary healthcare, the development of an MSF instrument specific to this setting in the UK has not been previously described. The aims of this study were to develop and evaluate an MSF instrument for GPs in Scotland taking part in appraisal. The members of ten primary healthcare teams in the west of Scotland were asked to provide comments in answer to the question, 'What is a good GP?'. The data were reduced and coded by two researchers and questions were devised. Following content validity testing the MSF process was evaluated with volunteers using face-to-face interviews and a postal survey. Thirty-seven statements covering the six domains of communication skills, professional values, clinical care, working with colleagues, personality issues and duties and responsibilities were accepted as relevant by ten primary healthcare teams using a standard of 80 percent agreement. The evaluation found the MSF process to be feasible and acceptable and participants provided some evidence of educational impact. An MSF instrument for GPs has been developed based on the concept of 'the good GP' as described by the primary healthcare team. The evaluation of the resultant MSF process illustrates the potential of MSF, when delivered in the supportive environment of GP appraisal, to provide feedback which has the possibility of improving working relationships between GPs and their colleagues.

Structural and Functional Studies on the Marburg Virus GP2 Fusion Loop.

PubMed

Liu, Nina; Tao, Yisong; Brenowitz, Michael D; Girvin, Mark E; Lai, Jonathan R

2015-10-01

Marburg virus (MARV) and the ebolaviruses belong to the family Filoviridae (the members of which are filoviruses) that cause severe hemorrhagic fever. Infection requires fusion of the host and viral membranes, a process that occurs in the host cell endosomal compartment and is facilitated by the envelope glycoprotein fusion subunit, GP2. The N-terminal fusion loop (FL) of GP2 is a hydrophobic disulfide-bonded loop that is postulated to insert and disrupt the host endosomal membrane during fusion. Here, we describe the first structural and functional studies of a protein corresponding to the MARV GP2 FL. We found that this protein undergoes a pH-dependent conformational change, as monitored by circular dichroism and nuclear magnetic resonance. Furthermore, we report that, under low pH conditions, the MARV GP2 FL can induce content leakage from liposomes. The general aspects of this pH-dependent structure and lipid-perturbing behavior are consistent with previous reports on Ebola virus GP2 FL. However, nuclear magnetic resonance studies in lipid bicelles and mutational analysis indicate differences in structure exist between MARV and Ebola virus GP2 FL. These results provide new insight into the mechanism of MARV GP2-mediated cell entry. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Gp63-like molecules in Phytomonas serpens: possible role in the insect interaction.

PubMed

d'Avila-Levy, Claudia M; Santos, Lívia O; Marinho, Fernanda A; Dias, Felipe A; Lopes, Angela H; Santos, André L S; Branquinha, Marta H

2006-06-01

In this study, we demonstrated that metallopeptidase inhibitors (EDTA, EGTA, and 1,10-phenanthroline) were able to arrest Phytomonas serpens growth in distinct patterns. This parasite released exclusively metallopeptidases to the extracellular environment, whereas in cellular extracts only cysteine peptidases were detected. In addition, an extracellular polypeptide of 60 kDa reacted in Western blotting probed with polyclonal antibody raised against gp63 of Leishmania amazonensis. In the cellular parasite extract, this antibody recognized bands migrating at 63 and 52 kDa, which partitioned on both aqueous and membrane-rich fractions. Flow cytometry and fluorescence microscopy analyses showed that the gp63-like molecules have a surface location. Moreover, phospholipase C (PLC)-treated parasites reduced the number of gp63-positive cells. The anti-cross-reacting determinant (CRD) and anti-gp63 antibodies recognized the 60-kDa band in the supernatant from PLC-treated cells, suggesting that this protein is glycosylphosphatidylinositol-anchored to the plasma membrane. This is the first report on the presence of gp63-like molecules in members of the Phytomonas genus. The pretreatment of the parasites with anti-gp63 antibody significantly diminished their adhesion index to explanted salivary glands of the phytophagous insect Oncopeltus fasciatus, suggesting a potential involvement of the gp63-like molecules in the adhesive process of this plant trypanosomatid.

HIV-1 infection: functional competition between gp41 and interleukin-2.

PubMed

Sanhadji, Kamel; Tardy, Jean-Claude; Touraine, Jean-Louis

2010-08-01

To determine whether the gp41 of HIV-1 could adhere to the interleukin (IL)-2 receptor at the surface of target cells in vitro, we analysed in vitro the possible functional competition between various forms of the HIV-1 gp41 molecule (i.e. peptides, trimeric or primary structures) and IL-2. This competition has been analysed in a test involving the proliferation of an IL-2-dependent cell line (CTLL2). The putative interaction between the IL-2 molecule and HIV-1 has also been assayed on MT4 cells (CD4(+) T lymphocytes) in culture. The gp41 trimeric molecule and an HIV-1 gp41 peptide (578-590 aminoacid sequence) dramatically inhibited CTLL2 cell proliferation, despite the presence of IL-2. The addition of serum, containing anti-gp41 antibodies, from HIV-1 patients resulted in a significant abolition of this inhibition. The concomitant incubation of IL-2 and HIV-1 with MT4 cells resulted in a strong decrease (70%) in HIV-1 p24 release. These data suggest that the gp41 of HIV-1 can use the IL-2 receptor during the process of HIV-1 infection and that there is some functional mimesis between gp41 and IL-2. Copyright 2010 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Hyperoxia, unlike phorbol ester, induces glutathione peroxidase through a protein kinase C-independent mechanism.

PubMed Central

Jornot, L; Junod, A F

1997-01-01

Human selenium-dependent glutathione peroxidase (GP) is implicated as a mechanism of resistance against oxygen free radicals. The 5' flanking sequence upstream from the coding region of GP contained an oxygen-responsive element termed ORE1 that is responsive to hypoxia, as well as several copies of the activator protein-1 (AP-1)- and AP-1-like-binding sites. In this study, we sought to define the molecular events that lead to GP gene transcription in response to hyperoxia in human umbilical-vein endothelial cells, and asked whether such induction is mimicked and sustained by activation of protein kinase C (PKC) by phorbol esters. Treatment of cells with 100 nM phorbol 12,13-dibutyrate (PdBu) induced a delayed (24-48 h) but significant (2-fold) increase in steady-state GP mRNA levels. Steady-state GP mRNA levels also rose after exposure to 95% O2, again after considerable delay (48-72 h). For both PdBu and oxygen, induction was transcriptionally regulated, as demonstrated by nuclear run-on experiments. The simulations by PdBu and oxygen were additive. In contrast with PdBu, hyperoxia did not stimulate translocation of PKC from the cytosol to the particulate fraction, although the specific activity of both cytosolic and particulate-associated PKC was increased 2-fold in cells exposed to 95% O2 for 5 days. In addition, gel mobility-shift assays using double-stranded tumour-promoting-agent-responsive element (TRE) and nuclear extracts derived from phorbol- and oxygen-treated cells revealed that PdBu, but not hyperoxia, increased AP-1 DNA-binding activity. On the other hand, the up-regulation of GP expression by oxygen could not be accounted for by the ORE1 core sequence, since no specific protein-DNA binding activity could be detected using nuclear extracts from hyperoxic cells and ORE1. Taken together, these results suggest that there may be different molecular mechanisms controlling GP expression. After exposure to PdBu, GP undergoes transcriptional activation via a process that can be readily explained by a classic AP-1 interaction with the TRE sites in the GP promoter. During hyperoxia, GP also undergoes transcriptional activity, but via a process that appears to involve neither TRE nor ORE1. PMID:9337858

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Jiansen; Xue, Hailing; Ma, Jing

HIV CRF07 B′/C is a strain circulating mainly in northwest region of China. The gp41 region of CRF07 is derived from a clade C virus. In order to compare the difference of CRF07 gp41 with that of typical clade B virus, we solved the crystal structure of the core region of CRF07 gp41. Compared with clade B gp41, CRF07 gp41 evolved more basic and hydrophilic residues on its helix bundle surface. Based on sequence alignment, a hyper-mutant cluster located in the middle of HR2 heptads repeat was identified. The mutational study of these residues revealed that this site is importantmore » in HIV mediated cell–cell fusion and plays critical roles in conformational changes during viral invasion. - Highlights: • We solved the crystal structure of HIV CRF07 gp41 core region. • A hyper-mutant cluster in the middle of HR2 heptads repeat was identified. • The hyper-mutant site is important in HIV-cell fusion. • The model will help to understand the HIV fusion process.« less

The predictive validity of a situational judgement test, a clinical problem solving test and the core medical training selection methods for performance in specialty training .

PubMed

Patterson, Fiona; Lopes, Safiatu; Harding, Stephen; Vaux, Emma; Berkin, Liz; Black, David

2017-02-01

The aim of this study was to follow up a sample of physicians who began core medical training (CMT) in 2009. This paper examines the long-term validity of CMT and GP selection methods in predicting performance in the Membership of Royal College of Physicians (MRCP(UK)) examinations. We performed a longitudinal study, examining the extent to which the GP and CMT selection methods (T1) predict performance in the MRCP(UK) examinations (T2). A total of 2,569 applicants from 2008-09 who completed CMT and GP selection methods were included in the study. Looking at MRCP(UK) part 1, part 2 written and PACES scores, both CMT and GP selection methods show evidence of predictive validity for the outcome variables, and hierarchical regressions show the GP methods add significant value to the CMT selection process. CMT selection methods predict performance in important outcomes and have good evidence of validity; the GP methods may have an additional role alongside the CMT selection methods. © Royal College of Physicians 2017. All rights reserved.

Kinect Posture Reconstruction Based on a Local Mixture of Gaussian Process Models.

PubMed

Liu, Zhiguang; Zhou, Liuyang; Leung, Howard; Shum, Hubert P H

2016-11-01

Depth sensor based 3D human motion estimation hardware such as Kinect has made interactive applications more popular recently. However, it is still challenging to accurately recognize postures from a single depth camera due to the inherently noisy data derived from depth images and self-occluding action performed by the user. In this paper, we propose a new real-time probabilistic framework to enhance the accuracy of live captured postures that belong to one of the action classes in the database. We adopt the Gaussian Process model as a prior to leverage the position data obtained from Kinect and marker-based motion capture system. We also incorporate a temporal consistency term into the optimization framework to constrain the velocity variations between successive frames. To ensure that the reconstructed posture resembles the accurate parts of the observed posture, we embed a set of joint reliability measurements into the optimization framework. A major drawback of Gaussian Process is its cubic learning complexity when dealing with a large database due to the inverse of a covariance matrix. To solve the problem, we propose a new method based on a local mixture of Gaussian Processes, in which Gaussian Processes are defined in local regions of the state space. Due to the significantly decreased sample size in each local Gaussian Process, the learning time is greatly reduced. At the same time, the prediction speed is enhanced as the weighted mean prediction for a given sample is determined by the nearby local models only. Our system also allows incrementally updating a specific local Gaussian Process in real time, which enhances the likelihood of adapting to run-time postures that are different from those in the database. Experimental results demonstrate that our system can generate high quality postures even under severe self-occlusion situations, which is beneficial for real-time applications such as motion-based gaming and sport training.

Semisupervised Gaussian Process for Automated Enzyme Search.

PubMed

Mellor, Joseph; Grigoras, Ioana; Carbonell, Pablo; Faulon, Jean-Loup

2016-06-17

Synthetic biology is today harnessing the design of novel and greener biosynthesis routes for the production of added-value chemicals and natural products. The design of novel pathways often requires a detailed selection of enzyme sequences to import into the chassis at each of the reaction steps. To address such design requirements in an automated way, we present here a tool for exploring the space of enzymatic reactions. Given a reaction and an enzyme the tool provides a probability estimate that the enzyme catalyzes the reaction. Our tool first considers the similarity of a reaction to known biochemical reactions with respect to signatures around their reaction centers. Signatures are defined based on chemical transformation rules by using extended connectivity fingerprint descriptors. A semisupervised Gaussian process model associated with the similar known reactions then provides the probability estimate. The Gaussian process model uses information about both the reaction and the enzyme in providing the estimate. These estimates were validated experimentally by the application of the Gaussian process model to a newly identified metabolite in Escherichia coli in order to search for the enzymes catalyzing its associated reactions. Furthermore, we show with several pathway design examples how such ability to assign probability estimates to enzymatic reactions provides the potential to assist in bioengineering applications, providing experimental validation to our proposed approach. To the best of our knowledge, the proposed approach is the first application of Gaussian processes dealing with biological sequences and chemicals, the use of a semisupervised Gaussian process framework is also novel in the context of machine learning applied to bioinformatics. However, the ability of an enzyme to catalyze a reaction depends on the affinity between the substrates of the reaction and the enzyme. This affinity is generally quantified by the Michaelis constant KM. Therefore, we also demonstrate using Gaussian process regression to predict KM given a substrate-enzyme pair.

Nonparametric estimation of stochastic differential equations with sparse Gaussian processes.

PubMed

García, Constantino A; Otero, Abraham; Félix, Paulo; Presedo, Jesús; Márquez, David G

2017-08-01

The application of stochastic differential equations (SDEs) to the analysis of temporal data has attracted increasing attention, due to their ability to describe complex dynamics with physically interpretable equations. In this paper, we introduce a nonparametric method for estimating the drift and diffusion terms of SDEs from a densely observed discrete time series. The use of Gaussian processes as priors permits working directly in a function-space view and thus the inference takes place directly in this space. To cope with the computational complexity that requires the use of Gaussian processes, a sparse Gaussian process approximation is provided. This approximation permits the efficient computation of predictions for the drift and diffusion terms by using a distribution over a small subset of pseudosamples. The proposed method has been validated using both simulated data and real data from economy and paleoclimatology. The application of the method to real data demonstrates its ability to capture the behavior of complex systems.

Behavioral and neurophysiological evidence for the enhancement of cognitive control under dorsal pallidal deep brain stimulation in Huntington's disease.

PubMed

Beste, Christian; Mückschel, Moritz; Elben, Saskia; J Hartmann, Christian; McIntyre, Cameron C; Saft, Carsten; Vesper, Jan; Schnitzler, Alfons; Wojtecki, Lars

2015-07-01

Deep brain stimulation of the dorsal pallidum (globus pallidus, GP) is increasingly considered as a surgical therapeutic option in Huntington's disease (HD), but there is need to identify outcome measures useful for clinical trials. Computational models consider the GP to be part of a basal ganglia network involved in cognitive processes related to the control of actions. We examined behavioural and event-related potential (ERP) correlates of action control (i.e., error monitoring) and evaluated the effects of deep brain stimulation (DBS). We did this using a standard flanker paradigm and evaluated error-related ERPs. Patients were recruited from a prospective pilot trial for pallidal DBS in HD (trial number NCT00902889). From the initial four patients with Huntington's chorea, two patients with chronic external dorsal pallidum stimulation were available for follow-up and able to perform the task. The results suggest that the external GP constitutes an important basal ganglia element not only for error processing and behavioural adaptation but for general response monitoring processes as well. Response monitoring functions were fully controllable by switching pallidal DBS stimulation on and off. When stimulation was switched off, no neurophysiological and behavioural signs of error and general performance monitoring, as reflected by the error-related negativity and post-error slowing in reaction times were evident. The modulation of response monitoring processes by GP-DBS reflects a side effect of efforts to alleviate motor symptoms in HD. From a clinical neurological perspective, the results suggest that DBS in the external GP segment can be regarded as a potentially beneficial treatment with respect to cognitive functions.

The frantic play of the concealed HIV envelope cytoplasmic tail

PubMed Central

2013-01-01

Lentiviruses have unusually long envelope (Env) cytoplasmic tails, longer than those of other retroviruses. Whereas the Env ectodomain has received much attention, the gp41 cytoplasmic tail (gp41-CT) is one of the least studied parts of the virus. It displays relatively high conservation compared to the rest of Env. It has been long established that the gp41-CT interacts with the Gag precursor protein to ensure Env incorporation into the virion. The gp41-CT contains distinct motifs and domains that mediate both intensive Env intracellular trafficking and interactions with numerous cellular and viral proteins, optimizing viral infectivity. Although they are not fully understood, a multiplicity of interactions between the gp41-CT and cellular factors have been described over the last decade; these interactions illustrate how Env expression and incorporation into virions is a finely tuned process that has evolved to best exploit the host system with minimized genetic information. This review addresses the structure and topology of the gp41-CT of lentiviruses (mainly HIV and SIV), their domains and believed functions. It also considers the cellular and viral proteins that have been described to interact with the gp41-CT, with a particular focus on subtype-related polymorphisms. PMID:23705972

Multidrug-resistance gene 1-type p-glycoprotein (MDR1 p-gp) inhibition by tariquidar impacts on neuroendocrine and behavioral processing of stress.

PubMed

Thoeringer, Christoph K; Wultsch, Thomas; Shahbazian, Anaid; Painsipp, Evelin; Holzer, Peter

2007-01-01

The multidrug-resistance gene 1-type p-glycoprotein (MDR1 p-gp) is a major gate-keeper at the blood-brain barrier (BBB), protecting the central nervous system from accumulation of toxic xenobiotics and drugs. In addition, MDR1 p-gp has been found to control the intracerebral access of glucocorticoid hormones and thus to modulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) system. In view of the implication of glucocorticoids in the control of behavior, we examined how acute pharmacological inhibition of MDR1 p-gp at the BBB by tariquidar (XR9576; 12 mg/kg, PO) impacts the neuroendocrine and behavioral processing of stress in C57BL/6JIcoHim inbred mice. Inhibition of MDR1 p-gp at the BBB did not alter emotional behavior at baseline. However, mice that were sensitized by water-avoidance stress, a mild psychological stressor, displayed significantly reduced anxiety-related behavior in the elevated plus-maze test when treated with tariquidar. Tariquidar, however, had no effect on stress-coping performance assessed in the forced swim test. Investigating the impact of acute MDR1 p-gp inhibition on the glucocorticoid system, we observed a significant attenuation of the mild stress-induced increase of plasma corticosterone after tariquidar administration. In order to examine whether the anti-anxiety effect of tariquidar in sensitized animals is mediated by glucocorticoids, the animals were treated with corticosterone (1mg/kg, SC) immediately after exposure to water-avoidance stress. Corticosterone caused a significant anxiolytic-like effect in this stress-related anxiety protocol, whereas tariquidar could not further enhance corticosterone's anti-anxiety effects. The current data show for the first time that pharmacological inhibition of MDR1 p-gp at the murine BBB by tariquidar alters emotional behavior and HPA axis activity. By facilitating the entry of corticosterone into the brain, tariquidar enhances feedback inhibition of the HPA system and in this way improves anxiety-related stress processing. These findings highlight a novel approach to the treatment of stress-related affective disorders in humans.

Drift-Free Indoor Navigation Using Simultaneous Localization and Mapping of the Ambient Heterogeneous Magnetic Field

NASA Astrophysics Data System (ADS)

Chow, J. C. K.

2017-09-01

In the absence of external reference position information (e.g. surveyed targets or Global Navigation Satellite Systems) Simultaneous Localization and Mapping (SLAM) has proven to be an effective method for indoor navigation. The positioning drift can be reduced with regular loop-closures and global relaxation as the backend, thus achieving a good balance between exploration and exploitation. Although vision-based systems like laser scanners are typically deployed for SLAM, these sensors are heavy, energy inefficient, and expensive, making them unattractive for wearables or smartphone applications. However, the concept of SLAM can be extended to non-optical systems such as magnetometers. Instead of matching features such as walls and furniture using some variation of the Iterative Closest Point algorithm, the local magnetic field can be matched to provide loop-closure and global trajectory updates in a Gaussian Process (GP) SLAM framework. With a MEMS-based inertial measurement unit providing a continuous trajectory, and the matching of locally distinct magnetic field maps, experimental results in this paper show that a drift-free navigation solution in an indoor environment with millimetre-level accuracy can be achieved. The GP-SLAM approach presented can be formulated as a maximum a posteriori estimation problem and it can naturally perform loop-detection, feature-to-feature distance minimization, global trajectory optimization, and magnetic field map estimation simultaneously. Spatially continuous features (i.e. smooth magnetic field signatures) are used instead of discrete feature correspondences (e.g. point-to-point) as in conventional vision-based SLAM. These position updates from the ambient magnetic field also provide enough information for calibrating the accelerometer bias and gyroscope bias in-use. The only restriction for this method is the need for magnetic disturbances (which is typically not an issue for indoor environments); however, no assumptions are required for the general motion of the sensor (e.g. static periods).

Toward Effective HIV Vaccination INDUCTION OF BINARY EPITOPE REACTIVE ANTIBODIES WITH BROAD HIV NEUTRALIZING ACTIVITY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishiyama, Yasuhiro; Planque, Stephanie; Mitsuda, Yukie

2009-11-23

We describe murine monoclonal antibodies (mAbs) raised by immunization with an electrophilic gp120 analog (E-gp120) expressing the rare ability to neutralize genetically heterologous human immunodeficiency virus (HIV) strains. Unlike gp120, E-gp120 formed covalent oligomers. The reactivity of gp120 and E-gp120 with mAbs to reference neutralizing epitopes was markedly different, indicating their divergent structures. Epitope mapping with synthetic peptides and electrophilic peptide analogs indicated binary recognition of two distinct gp120 regions by anti-E-gp120 mAbs, the 421-433 and 288-306 peptide regions. Univalent Fab and single chain Fv fragments expressed the ability to recognize both peptides. X-ray crystallography of an anti-E-gp120 Fab fragmentmore » revealed two neighboring cavities, the typical antigen-binding cavity formed by the complementarity determining regions (CDRs) and another cavity dominated by antibody heavy chain variable (VH) domain framework (FR) residues. Substitution of the FR cavity VH Lys-19 residue by an Ala residue resulted in attenuated binding of the 421-433 region peptide probe. The CDRs and VH FR replacement/silent mutation ratios exceeded the ratio for a random mutation process, suggesting adaptive development of both putative binding sites. All mAbs studied were derived from VH1 family genes, suggesting biased recruitment of the V gene germ line repertoire by E-gp120. The conserved 421-433 region of gp120 is essential for HIV binding to host CD4 receptors. This region is recognized weakly by the FR of antibodies produced without exposure to HIV, but it usually fails to induce adaptive synthesis of neutralizing antibodies. We present models accounting for improved CD4-binding site recognition and broad HIV neutralizing activity of the mAbs, long sought goals in HIV vaccine development.« less

The role of culture in the general practice consultation process.

PubMed

Ali, Nasreen; Atkin, Karl; Neal, Richard

2006-11-01

In this paper, we will examine the importance of culture and ethnicity in the general practice consultation process. Good communication is associated with positive health outcomes. We will, by presenting qualitative material from an empirical study, examine the way in which communication within the context of a general practitioner (GP) consultation may be affected by ethnicity and cultural factors. The aim of the study was to provide a detailed understanding of the ways in which white and South Asian patients communicate with white GPs and to explore any similarities and differences in communication. This paper reports on South Asian and white patients' explanations of recent videotaped consultations with their GP. We specifically focus on the ways in which issues of ethnic identity impacted upon the GP consultation process, by exploring how our sample of predominantly white GPs interacted with their South Asian patients and the extent to which the GP listened to the patients' needs, gave patients information, engaged in social conversation and showed friendliness. We then go on to examine patients' suggestions on improvements (if any) to the consultation. We conclude, by showing how a non-essentialist understanding of culture helps to comprehend the consultation process when the patients are from Great Britain's ethnicised communities. Our findings, however, raise generic issues of relevance to all multi-racial and multi-ethnic societies.

Practice nurse appraisal: evaluation report.

PubMed

Murie, Jill; Wilson, Anne; Cerinus, Marie

2009-07-01

As general practice nurses (GPNs) now perform many activities formerly undertaken by general practitioners (GPs), the paperwork and process of the Scottish GP appraisal scheme may be usefully replicated for GPN appraisal. Eight GPNs adapted paperwork. Ten GP appraisers in NHS Lanarkshire were invited to interview their GPN(s) using the adapted paperwork. Both groups evaluated the project from 'descriptive' (participation and process) and 'reflective' or qualitative perspectives. Eight GPs appraised 11 GPNs using a ten-page document. GPNs reported that the documentation was helpful in preparing for and participating in the interview, as well as the planning of future objectives and development. GPs reported that the appraisal interview incorporated GPNs' views, the content was relevant, and their approach nonjudgemental and developmental. Some expressed concern that their participation had not helped them identify ways of addressing GPN learning needs. There was clear indication from GPNs that trained colleagues rather than GP employers are preferred appraisers. Improvements in the paperwork would be required. There is potential to replicate the paperwork and processes used in GP appraisal to GPNs, subject to refinement of the paperwork and engagement of trained nurse colleagues in the process. This may reduce the effect of collusion, inhibition or conflict of interest. However, GPN personal development still must be reconciled with practice priorities and development. The results of this pilot indicate a positive response in terms of participation and process. Further research should examine GPN appraisal using an external nurse appraiser, training issues and resource implications.

Simulation of time series by distorted Gaussian processes

NASA Technical Reports Server (NTRS)

Greenhall, C. A.

1977-01-01

Distorted stationary Gaussian process can be used to provide computer-generated imitations of experimental time series. A method of analyzing a source time series and synthesizing an imitation is shown, and an example using X-band radiometer data is given.

Nonturbulent dispersion processes in complex terrain

Treesearch

Michael A. Fosberg; Douglas G. Fox; E.A. Howard; Jack D. Cohen

1976-01-01

Mass divergence influences on plume dispersion modify classic Gaussian calculations by as much as a factor of two in complex terrain. The Gaussian plume was derived in flux form to include this process.Authors' response to comments and criticism received following this publication:

Multi-pose facial correction based on Gaussian process with combined kernel function

NASA Astrophysics Data System (ADS)

Shi, Shuyan; Ji, Ruirui; Zhang, Fan

2018-04-01

In order to improve the recognition rate of various postures, this paper proposes a method of facial correction based on Gaussian Process which build a nonlinear regression model between the front and the side face with combined kernel function. The face images with horizontal angle from -45° to +45° can be properly corrected to front faces. Finally, Support Vector Machine is employed for face recognition. Experiments on CAS PEAL R1 face database show that Gaussian process can weaken the influence of pose changes and improve the accuracy of face recognition to certain extent.

Occupancy mapping and surface reconstruction using local Gaussian processes with Kinect sensors.

PubMed

Kim, Soohwan; Kim, Jonghyuk

2013-10-01

Although RGB-D sensors have been successfully applied to visual SLAM and surface reconstruction, most of the applications aim at visualization. In this paper, we propose a noble method of building continuous occupancy maps and reconstructing surfaces in a single framework for both navigation and visualization. Particularly, we apply a Bayesian nonparametric approach, Gaussian process classification, to occupancy mapping. However, it suffers from high-computational complexity of O(n(3))+O(n(2)m), where n and m are the numbers of training and test data, respectively, limiting its use for large-scale mapping with huge training data, which is common with high-resolution RGB-D sensors. Therefore, we partition both training and test data with a coarse-to-fine clustering method and apply Gaussian processes to each local clusters. In addition, we consider Gaussian processes as implicit functions, and thus extract iso-surfaces from the scalar fields, continuous occupancy maps, using marching cubes. By doing that, we are able to build two types of map representations within a single framework of Gaussian processes. Experimental results with 2-D simulated data show that the accuracy of our approximated method is comparable to previous work, while the computational time is dramatically reduced. We also demonstrate our method with 3-D real data to show its feasibility in large-scale environments.

How Do Gut Feelings Feature in Tutorial Dialogues on Diagnostic Reasoning in GP Traineeship?

ERIC Educational Resources Information Center

Stolper, C. F.; Van de Wiel, M. W. J.; Hendriks, R. H. M.; Van Royen, P.; Van Bokhoven, M. A.; Van der Weijden, T.; Dinant, G. J.

2015-01-01

Diagnostic reasoning is considered to be based on the interaction between analytical and non-analytical cognitive processes. Gut feelings, a specific form of non-analytical reasoning, play a substantial role in diagnostic reasoning by general practitioners (GPs) and may activate analytical reasoning. In GP traineeships in the Netherlands, trainees…

Single-molecule FRET studies of the cooperative and non-cooperative binding kinetics of the bacteriophage T4 single-stranded DNA binding protein (gp32) to ssDNA lattices at replication fork junctions

PubMed Central

Lee, Wonbae; Gillies, John P.; Jose, Davis; Israels, Brett A.; von Hippel, Peter H.; Marcus, Andrew H.

2016-01-01

Gene 32 protein (gp32) is the single-stranded (ss) DNA binding protein of the bacteriophage T4. It binds transiently and cooperatively to ssDNA sequences exposed during the DNA replication process and regulates the interactions of the other sub-assemblies of the replication complex during the replication cycle. We here use single-molecule FRET techniques to build on previous thermodynamic studies of gp32 binding to initiate studies of the dynamics of the isolated and cooperative binding of gp32 molecules within the replication complex. DNA primer/template (p/t) constructs are used as models to determine the effects of ssDNA lattice length, gp32 concentration, salt concentration, binding cooperativity and binding polarity at p/t junctions. Hidden Markov models (HMMs) and transition density plots (TDPs) are used to characterize the dynamics of the multi-step assembly pathway of gp32 at p/t junctions of differing polarity, and show that isolated gp32 molecules bind to their ssDNA targets weakly and dissociate quickly, while cooperatively bound dimeric or trimeric clusters of gp32 bind much more tightly, can ‘slide’ on ssDNA sequences, and exhibit binding dynamics that depend on p/t junction polarities. The potential relationships of these binding dynamics to interactions with other components of the T4 DNA replication complex are discussed. PMID:27694621

Which positive factors determine the GP satisfaction in clinical practice? A systematic literature review.

PubMed

Le Floch, B; Bastiaens, H; Le Reste, J Y; Lingner, H; Hoffman, R D; Czachowski, S; Assenova, R; Koskela, T H; Klemenc-Ketis, Z; Nabbe, P; Sowinska, A; Montier, T; Peremans, L

2016-09-13

Looking at what makes General Practitioners (GPs) happy in their profession, may be important in increasing the GP workforce in the future. The European General Practice Research Network (EGPRN) created a research team (eight national groups) in order to clarify the factors involved in GP job satisfaction throughout Europe. The first step of this study was a literature review to explore how the satisfaction of GPs had been studied before. The research question was "Which factors are related to GP satisfaction in Clinical Practice?" Systematic literature review according to the PRISMA statement. The databases searched were Pubmed, Embase and Cochrane. All articles were identified, screened and included by two separate research teams, according to inclusion or exclusion criteria. Then, a qualitative appraisal was undertaken. Next, a thematic analysis process was undertaken to capture any issue relevant to the research question. The number of records screened was 458. One hundred four were eligible. Finally, 17 articles were included. The data revealed 13 subthemes, which were grouped into three major themes for GP satisfaction. First there were general profession-related themes, applicable to many professions. A second group of issues related specifically to a GP setting. Finally, a third group was related to professional life and personal issues. A number of factors leading to GP job satisfaction, exist in literature They should be used by policy makers within Europe to increase the GP workforce. The research team needs to undertake qualitative studies to confirm or enhance those results.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berrada, K., E-mail: kberrada@ictp.it; The Abdus Salam International Centre for Theoretical Physics, Strada Costiera 11, Miramare-Trieste; Ooi, C. H. Raymond

Robustness of the geometric phase (GP) with respect to different noise effects is a basic condition for an effective quantum computation. Here, we propose a useful quantum system with real physical parameters by studying the GP of a pair of Stokes and anti-Stokes photons, involving Raman emission processes with and without photonic band gap (PBG) effect. We show that the properties of GP are very sensitive to the change of the Rabi frequency and time, exhibiting collapse phenomenon as the time becomes significantly large. The system allows us to obtain a state which remains with zero GP for longer times.more » This result plays a significant role to enhance the stabilization and control of the system dynamics. Finally, we investigate the nonlocal correlation (entanglement) between the pair photons by taking into account the effect of different parameters. An interesting correlation between the GP and entanglement is observed showing that the PBG stabilizes the fluctuations in the system and makes the entanglement more robust against the change of time and frequency.« less

Improved model reduction and tuning of fractional-order PI(λ)D(μ) controllers for analytical rule extraction with genetic programming.

PubMed

Das, Saptarshi; Pan, Indranil; Das, Shantanu; Gupta, Amitava

2012-03-01

Genetic algorithm (GA) has been used in this study for a new approach of suboptimal model reduction in the Nyquist plane and optimal time domain tuning of proportional-integral-derivative (PID) and fractional-order (FO) PI(λ)D(μ) controllers. Simulation studies show that the new Nyquist-based model reduction technique outperforms the conventional H(2)-norm-based reduced parameter modeling technique. With the tuned controller parameters and reduced-order model parameter dataset, optimum tuning rules have been developed with a test-bench of higher-order processes via genetic programming (GP). The GP performs a symbolic regression on the reduced process parameters to evolve a tuning rule which provides the best analytical expression to map the data. The tuning rules are developed for a minimum time domain integral performance index described by a weighted sum of error index and controller effort. From the reported Pareto optimal front of the GP-based optimal rule extraction technique, a trade-off can be made between the complexity of the tuning formulae and the control performance. The efficacy of the single-gene and multi-gene GP-based tuning rules has been compared with the original GA-based control performance for the PID and PI(λ)D(μ) controllers, handling four different classes of representative higher-order processes. These rules are very useful for process control engineers, as they inherit the power of the GA-based tuning methodology, but can be easily calculated without the requirement for running the computationally intensive GA every time. Three-dimensional plots of the required variation in PID/fractional-order PID (FOPID) controller parameters with reduced process parameters have been shown as a guideline for the operator. Parametric robustness of the reported GP-based tuning rules has also been shown with credible simulation examples. Copyright © 2011 ISA. Published by Elsevier Ltd. All rights reserved.

Analysis of Select Herpes Simplex Virus 1 (HSV-1) Proteins for Restriction of Human Immunodeficiency Virus Type 1 (HIV-1): HSV-1 gM Protein Potently Restricts HIV-1 by Preventing Intracellular Transport and Processing of Env gp160.

PubMed

Polpitiya Arachchige, Sachith; Henke, Wyatt; Pramanik, Ankita; Kalamvoki, Maria; Stephens, Edward B

2018-01-15

Virus-encoded proteins that impair or shut down specific host cell functions during replication can be used as probes to identify potential proteins/pathways used in the replication of viruses from other families. We screened nine proteins from herpes simplex virus 1 (HSV-1) for the ability to enhance or restrict human immunodeficiency virus type 1 (HIV-1) replication. We show that several HSV-1 proteins (glycoprotein M [gM], US3, and UL24) potently restricted the replication of HIV-1. Unlike UL24 and US3, which reduced viral protein synthesis, we observed that gM restriction of HIV-1 occurred through interference with the processing and transport of gp160, resulting in a significantly reduced level of mature gp120/gp41 released from cells. Finally, we show that an HSV-1 gM mutant lacking the majority of the C-terminal domain (HA-gM[Δ345-473]) restricted neither gp160 processing nor the release of infectious virus. These studies identify proteins from heterologous viruses that can restrict viruses through novel pathways. IMPORTANCE HIV-1 infection of humans results in AIDS, characterized by the loss of CD4 + T cells and increased susceptibility to opportunistic infections. Both HIV-1 and HSV-1 can infect astrocytes and microglia of the central nervous system (CNS). Thus, the identification of HSV-1 proteins that directly restrict HIV-1 or interfere with pathways required for HIV-1 replication could lead to novel antiretroviral strategies. The results of this study show that select viral proteins from HSV-1 can potently restrict HIV-1. Further, our results indicate that the gM protein of HSV-1 restricts HIV-1 through a novel pathway by interfering with the processing of gp160 and its incorporation into virus maturing from the cell. Copyright © 2018 American Society for Microbiology.

Laguerre-Gaussian, Hermite-Gaussian, Bessel-Gaussian, and Finite-Energy Airy Beams Carrying Orbital Angular Momentum in Strongly Nonlocal Nonlinear Media

NASA Astrophysics Data System (ADS)

Wu, Zhenkun; Gu, Yuzong

2016-12-01

The propagation of two-dimensional beams is analytically and numerically investigated in strongly nonlocal nonlinear media (SNNM) based on the ABCD matrix. The two-dimensional beams reported in this paper are described by the product of the superposition of generalized Laguerre-Gaussian (LG), Hermite-Gaussian (HG), Bessel-Gaussian (BG), and circular Airy (CA) beams, carrying an orbital angular momentum (OAM). Owing to OAM and the modulation of SNNM, we find that the propagation of these two-dimensional beams exhibits complete rotation and periodic inversion: the spatial intensity profile first extends and then diminishes, and during the propagation the process repeats to form a breath-like phenomenon.

Analysis of randomly time varying systems by gaussian closure technique

NASA Astrophysics Data System (ADS)

Dash, P. K.; Iyengar, R. N.

1982-07-01

The Gaussian probability closure technique is applied to study the random response of multidegree of freedom stochastically time varying systems under non-Gaussian excitations. Under the assumption that the response, the coefficient and the excitation processes are jointly Gaussian, deterministic equations are derived for the first two response moments. It is further shown that this technique leads to the best Gaussian estimate in a minimum mean square error sense. An example problem is solved which demonstrates the capability of this technique for handling non-linearity, stochastic system parameters and amplitude limited responses in a unified manner. Numerical results obtained through the Gaussian closure technique compare well with the exact solutions.

Flexible pillared graphene-paper electrodes for high-performance electrochemical supercapacitors.

PubMed

Wang, Gongkai; Sun, Xiang; Lu, Fengyuan; Sun, Hongtao; Yu, Mingpeng; Jiang, Weilin; Liu, Changsheng; Lian, Jie

2012-02-06

Flexible graphene paper (GP) pillared by carbon black (CB) nanoparticles using a simple vacuum filtration method is developed as a high-performance electrode material for supercapacitors. Through the introduction of CB nanoparticles as spacers, the self-restacking of graphene sheets during the filtration process is mitigated to a great extent. The pillared GP-based supercapacitors exhibit excellent electrochemical performances and cyclic stabilities compared with GP without the addition of CB nanoparticles. At a scan rate of 10 mV s(-1) , the specific capacitance of the pillared GP is 138 F g(-1) and 83.2 F g(-1) with negligible 3.85% and 4.35% capacitance degradation after 2000 cycles in aqueous and organic electrolytes, respectively. At an extremely fast scan rate of 500 mV s (-1) , the specific capacitance can reach 80 F g(-1) in aqueous electrolyte. No binder is needed for assembling the supercapacitor cells and the pillared GP itself may serve as a current collector due to its intrinsic high electrical conductivity. The pillared GP has great potential in the development of promising flexible and ultralight-weight supercapacitors for electrochemical energy storage. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Flexible Pillared Graphene-Paper Electrodes for High-Performance Electrochemical Supercapacitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Gongkai; Sun, Xiang; Lu, Fengyuan

2011-12-08

Flexible graphene paper (GP) pillared by carbon black (CB) nanoparticles using a simple vacuum filtration method is developed as a high-performance electrode material for supercapacitors. Through the introduction of CB nanoparticles as spacers, the self-restacking of graphene sheets during the filtration process is mitigated to a great extent. The pillared GP-based supercapacitors exhibit excellent electrochemical performances and cyclic stabilities compared with GP without the addition of CB nanoparticles. At a scan rate of 10 mV s -1, the specific capacitance of the pillared GP is 138 F g -1 and 83.2 F g -1 with negligible 3.85% and 4.35% capacitancemore » degradation after 2000 cycles in aqueous and organic electrolytes, respectively. At an extremely fast scan rate of 500 mV s -1, the specific capacitance can reach 80 F g -1 in aqueous electrolyte. No binder is needed for assembling the supercapacitor cells and the pillared GP itself may serve as a current collector due to its intrinsic high electrical conductivity. Finally, the pillared GP has great potential in the development of promising flexible and ultralight-weight supercapacitors for electrochemical energy storage.« less

Individualised training to improve teaching competence of general practitioner trainers: a randomised controlled trial.

PubMed

Schol, Sandrina; Goedhuys, Jo; Notten, Ton; Betz, Wim

2005-10-01

In Flanders an important part of training to become a general practitioner (GP) is undertaken within a general practice. This requires a GP trainer to know how to facilitate learning processes. This paper reports a study focused on the research question: Does short but individualised training of GP trainers contribute to their teaching competence? A total of 47 GP trainers were randomly divided into 2 groups of a pretest/post-test control group design. After a multiple-station teaching assessment test (MSTAT), the experimental group received a short but individualised training to improve teaching competence while the control group were given no specific programme regarding teaching competence. One year later, all participants were invited to sit the post-test. In all, 61 GP trainers participated in the pretest and 51 in the post-test; 44 GP trainers participated in both tests. Despite the large attrition, the internal validity of the experiment was preserved. Beginners gained a median score of 2.04 (on a scale of 0-5) on the first MSTAT. In the post-test, the experimental group (median = 3.12) scored significantly better on the entire test (Mann-Whitney U = 166.5, P < 0.05) compared with the control group (median = 2.84). However, the GP trainers in the control group also appeared to have made progress. General practitioners who start as GP trainers have insufficient teaching competence to guarantee good coaching of students. A personal programme leads to progress in teaching competence; however, it would seem that more time and support are necessary to allow GP trainers to gain full teaching competence. The fact that the control group made progress as well suggests that the test had an important learning effect.

Cognitive deficits associated with combined HIV gp120 expression and chronic methamphetamine exposure in mice.

PubMed

Kesby, James P; Markou, Athina; Semenova, Svetlana

2015-01-01

Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e. similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Cognitive deficits associated with combined HIV gp120 expression and chronic methamphetamine exposure in mice

PubMed Central

Kesby, James P.; Markou, Athina; Semenova, Svetlana

2014-01-01

Methamphetamine abuse is common among individuals infected by human immunodeficiency virus (HIV). Neurocognitive outcomes tend to be worse in methamphetamine users with HIV. However, it is unclear whether discrete cognitive domains are susceptible to impairment after combined HIV infection and methamphetamine abuse. The expression of HIV/gp120 protein induces neuropathology in mice similar to HIV-induced pathology in humans. We investigated the separate and combined effects of methamphetamine exposure and gp120 expression on cognitive function in transgenic (gp120-tg) and control mice. The mice underwent an escalating methamphetamine binge regimen and were tested in novel object/location recognition, object-in-place recognition, and Barnes maze tests. gp120 expression disrupted performance in the object-in-place test (i.e., similar time spent with all objects, regardless of location), indicating deficits in associative recognition memory. gp120 expression also altered reversal learning in the Barnes maze, suggesting impairments in executive function. Methamphetamine exposure impaired spatial strategy in the Barnes maze, indicating deficits in spatial learning. Methamphetamine-exposed gp120-tg mice had the lowest spatial strategy scores in the final acquisition trials in the Barnes maze, suggesting greater deficits in spatial learning than all of the other groups. Although HIV infection involves interactions between multiple proteins and processes, in addition to gp120, our findings in gp120-tg mice suggest that humans with the dual insult of HIV infection and methamphetamine abuse may exhibit a broader spectrum of cognitive deficits than those with either factor alone. Depending on the cognitive domain, the combination of both insults may exacerbate deficits in cognitive performance compared with each individual insult. PMID:25476577

Non-Gaussian Multi-resolution Modeling of Magnetosphere-Ionosphere Coupling Processes

NASA Astrophysics Data System (ADS)

Fan, M.; Paul, D.; Lee, T. C. M.; Matsuo, T.

2016-12-01

The most dynamic coupling between the magnetosphere and ionosphere occurs in the Earth's polar atmosphere. Our objective is to model scale-dependent stochastic characteristics of high-latitude ionospheric electric fields that originate from solar wind magnetosphere-ionosphere interactions. The Earth's high-latitude ionospheric electric field exhibits considerable variability, with increasing non-Gaussian characteristics at decreasing spatio-temporal scales. Accurately representing the underlying stochastic physical process through random field modeling is crucial not only for scientific understanding of the energy, momentum and mass exchanges between the Earth's magnetosphere and ionosphere, but also for modern technological systems including telecommunication, navigation, positioning and satellite tracking. While a lot of efforts have been made to characterize the large-scale variability of the electric field in the context of Gaussian processes, no attempt has been made so far to model the small-scale non-Gaussian stochastic process observed in the high-latitude ionosphere. We construct a novel random field model using spherical needlets as building blocks. The double localization of spherical needlets in both spatial and frequency domains enables the model to capture the non-Gaussian and multi-resolutional characteristics of the small-scale variability. The estimation procedure is computationally feasible due to the utilization of an adaptive Gibbs sampler. We apply the proposed methodology to the computational simulation output from the Lyon-Fedder-Mobarry (LFM) global magnetohydrodynamics (MHD) magnetosphere model. Our non-Gaussian multi-resolution model results in characterizing significantly more energy associated with the small-scale ionospheric electric field variability in comparison to Gaussian models. By accurately representing unaccounted-for additional energy and momentum sources to the Earth's upper atmosphere, our novel random field modeling approach will provide a viable remedy to the current numerical models' systematic biases resulting from the underestimation of high-latitude energy and momentum sources.

Bayesian Analysis of Non-Gaussian Long-Range Dependent Processes

NASA Astrophysics Data System (ADS)

Graves, T.; Franzke, C.; Gramacy, R. B.; Watkins, N. W.

2012-12-01

Recent studies have strongly suggested that surface temperatures exhibit long-range dependence (LRD). The presence of LRD would hamper the identification of deterministic trends and the quantification of their significance. It is well established that LRD processes exhibit stochastic trends over rather long periods of time. Thus, accurate methods for discriminating between physical processes that possess long memory and those that do not are an important adjunct to climate modeling. We have used Markov Chain Monte Carlo algorithms to perform a Bayesian analysis of Auto-Regressive Fractionally-Integrated Moving-Average (ARFIMA) processes, which are capable of modeling LRD. Our principal aim is to obtain inference about the long memory parameter, d,with secondary interest in the scale and location parameters. We have developed a reversible-jump method enabling us to integrate over different model forms for the short memory component. We initially assume Gaussianity, and have tested the method on both synthetic and physical time series such as the Central England Temperature. Many physical processes, for example the Faraday time series from Antarctica, are highly non-Gaussian. We have therefore extended this work by weakening the Gaussianity assumption. Specifically, we assume a symmetric α -stable distribution for the innovations. Such processes provide good, flexible, initial models for non-Gaussian processes with long memory. We will present a study of the dependence of the posterior variance σ d of the memory parameter d on the length of the time series considered. This will be compared with equivalent error diagnostics for other measures of d.

Refolding of soluble leukemia inhibitory factor receptor fusion protein (gp 190 sol DAF) from urea.

PubMed

Liu, H; Moreau, J F; Gualde, N; Fu, J

1997-04-01

The insoluble inclusion bodies of soluble leukemia inhibitory factor receptor fusion protein (gp 190 sol DAF) was solubilized in 8 M urea on the unfolding transitions, and several factors on the aggregate formation were indirectly analyzed for the refolding of gp 190 sol DAF. Results indicate that the refolding yield can be considerably increased at lowering concentration of the unfolding protein, a little soluble protein with the slow refolding appears in the process of the aggregate formation and the concentration of the denaturant must be down to a minimum level for its refolding.

A Bernoulli Gaussian Watermark for Detecting Integrity Attacks in Control Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weerakkody, Sean; Ozel, Omur; Sinopoli, Bruno

We examine the merit of Bernoulli packet drops in actively detecting integrity attacks on control systems. The aim is to detect an adversary who delivers fake sensor measurements to a system operator in order to conceal their effect on the plant. Physical watermarks, or noisy additive Gaussian inputs, have been previously used to detect several classes of integrity attacks in control systems. In this paper, we consider the analysis and design of Gaussian physical watermarks in the presence of packet drops at the control input. On one hand, this enables analysis in a more general network setting. On the othermore » hand, we observe that in certain cases, Bernoulli packet drops can improve detection performance relative to a purely Gaussian watermark. This motivates the joint design of a Bernoulli-Gaussian watermark which incorporates both an additive Gaussian input and a Bernoulli drop process. We characterize the effect of such a watermark on system performance as well as attack detectability in two separate design scenarios. Here, we consider a correlation detector for attack recognition. We then propose efficiently solvable optimization problems to intelligently select parameters of the Gaussian input and the Bernoulli drop process while addressing security and performance trade-offs. Finally, we provide numerical results which illustrate that a watermark with packet drops can indeed outperform a Gaussian watermark.« less

Preserved visual lexicosemantics in global aphasia: a right-hemisphere contribution?

PubMed

Gold, B T; Kertesz, A

2000-12-01

Extensive testing of a patient, GP, who encountered large-scale destruction of left-hemisphere (LH) language regions was undertaken in order to address several issues concerning the ability of nonperisylvian areas to extract meaning from printed words. Testing revealed recognition of superordinate boundaries of animals, tools, vegetables, fruit, clothes, and furniture. GP was able to distinguish proper names from other nouns and from nonwords. GP was also able to differentiate words representing living things from those denoting nonliving things. The extent of LH infarct resulting in a global impairment to phonological and syntactic processing suggests LH specificity for these functions but considerable right-hemisphere (RH) participation in visual lexicosemantic processing. The relative preservation of visual lexicosemantic abilities despite severe impairment to all aspects of phonological coding demonstrates the importance of the direct route to the meaning of single printed words.

Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits

PubMed Central

2014-01-01

Background The trimeric envelope glycoproteins (Env) on the surface of HIV-1 virions are the targets for neutralizing antibodies (NAbs). No candidate HIV-1 immunogen has yet induced potent, broadly active NAbs (bNAbs). Part of the explanation may be that previously tested Env proteins inadequately mimic the functional, native Env complex. Trimerization and the proteolytic processing of Env precursors into gp120 and gp41 profoundly alter antigenicity, but soluble cleaved trimers are too unstable to serve as immunogens. By introducing stabilizing mutations (SOSIP), we constructed soluble, cleaved Env trimers derived from the HIV-1 subtype A isolate BG505 that resemble native Env spikes on virions both structurally and antigenically. Results We used surface plasmon resonance (SPR) to quantify antibody binding to different forms of BG505 Env: the proteolytically cleaved SOSIP.664 trimers, cleaved gp120-gp41ECTO protomers, and gp120 monomers. Non-NAbs to the CD4-binding site bound only marginally to the trimers but equally well to gp120-gp41ECTO protomers and gp120 monomers, whereas the bNAb VRC01, directed to the CD4bs, bound to all three forms. In contrast, bNAbs to V1V2 glycan-dependent epitopes bound preferentially (PG9 and PG16) or exclusively (PGT145) to trimers. We also explored the antigenic consequences of three different features of SOSIP.664 gp140 trimers: the engineered inter-subunit disulfide bond, the trimer-stabilizing I559P change in gp41ECTO, and proteolytic cleavage at the gp120-gp41ECTO junction. Each of these three features incrementally promoted native-like trimer antigenicity. We compared Fab and IgG versions of bNAbs and validated a bivalent model of IgG binding. The NAbs showed widely divergent binding kinetics and degrees of binding to native-like BG505 SOSIP.664. High off-rate constants and low stoichiometric estimates of NAb binding were associated with large amounts of residual infectivity after NAb neutralization of the corresponding BG505.T332N pseudovirus. Conclusions The antigenicity and structural integrity of cleaved BG505 SOSIP.664 trimers render these proteins good mimics of functional Env spikes on virions. In contrast, uncleaved gp140s antigenically resemble individual gp120-gp41ECTO protomers and gp120 monomers, but not native trimers. Although NAb binding to functional trimers may thus be both necessary and sufficient for neutralization, the kinetics and stoichiometry of the interaction influence the neutralizing efficacy of individual NAbs. PMID:24884783

On the application of Rice's exceedance statistics to atmospheric turbulence.

NASA Technical Reports Server (NTRS)

Chen, W. Y.

1972-01-01

Discrepancies produced by the application of Rice's exceedance statistics to atmospheric turbulence are examined. First- and second-order densities from several data sources have been measured for this purpose. Particular care was paid to each selection of turbulence that provides stationary mean and variance over the entire segment. Results show that even for a stationary segment of turbulence, the process is still highly non-Gaussian, in spite of a Gaussian appearance for its first-order distribution. Data also indicate strongly non-Gaussian second-order distributions. It is therefore concluded that even stationary atmospheric turbulence with a normal first-order distribution cannot be considered a Gaussian process, and consequently the application of Rice's exceedance statistics should be approached with caution.

Edge detection - Image-plane versus digital processing

NASA Technical Reports Server (NTRS)

Huck, Friedrich O.; Fales, Carl L.; Park, Stephen K.; Triplett, Judith A.

1987-01-01

To optimize edge detection with the familiar Laplacian-of-Gaussian operator, it has become common to implement this operator with a large digital convolution mask followed by some interpolation of the processed data to determine the zero crossings that locate edges. It is generally recognized that this large mask causes substantial blurring of fine detail. It is shown that the spatial detail can be improved by a factor of about four with either the Wiener-Laplacian-of-Gaussian filter or an image-plane processor. The Wiener-Laplacian-of-Gaussian filter minimizes the image-gathering degradations if the scene statistics are at least approximately known and also serves as an interpolator to determine the desired zero crossings directly. The image-plane processor forms the Laplacian-of-Gaussian response by properly combining the optical design of the image-gathering system with a minimal three-by-three lateral-inhibitory processing mask. This approach, which is suggested by Marr's model of early processing in human vision, also reduces data processing by about two orders of magnitude and data transmission by up to an order of magnitude.

The anti-tumor effect and mechanisms of action of penta-acetyl geniposide.

PubMed

Peng, C H; Huang, C N; Wang, C J

2005-06-01

Gardenia, the fruit of Gardenia jasminoides Ellis, has been widely used to treat liver and gall bladder disorders in Chinese medicine. It has been shown recently that geniposide, the main ingredient of Gardenia Fructus, exhibits the anti-tumor effect. In this review, we discuss the anti-tumor effect and possible mechanisms of a derivative from Gardenia Fructus, penta-acetyl geniposide ((Ac)5GP). It has been demonstrated that (Ac)5GP plays more potent roles than geniposide in chemoprevention. (Ac)5GP decreased DNA damage and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) by activating the phase II enzymes glutathione S-transferase (GST) and GSH peroxidase (GSH-Px). It reduced the growth and development of inoculated C6 glioma cells especially in pre-treated rats. In addition to the preventive effect, (Ac)5GP exerts its actions on apoptosis and growth arrest. Treatment of (Ac)5GP caused DNA fragmentation of glioma cells. (Ac)5GP induced sub- G1 peak through the activation of apoptotic cascades PKCdelta/JNK/Fas/caspase8 and caspase 3. Besides, p53/Bax signaling was suggested to be involved in (Ac)5GP-induced apoptosis, though its downstream cascades needs further clarified. (Ac)5GP has also been shown to inhibit DNA synthesis of tumor cells. It arrested cell cycle at G0/ G1 by inducing the expression of p21, thus suppressing the cyclin D1/cdk4 complex formation and the phosphorylation of E2F. The phosphorylation status of p53 on serine 392 correlated with the process of growth arrest. Evidences from the in vivo experiments showed that (Ac)5GP is not harmful to liver, heart and kidney. In conclusion, (Ac)5GP is highly suggested to be an anti-tumor agent for development in the future.

Practical implementation of good practice in health, environment and safety management in enterprise in the Lodz region.

PubMed

Michalak, Jacek

2002-10-01

Good practice in health, environment and safety management in enterprise (GP HESME) is the process that aims at continuous improvement in health, environment and safety performance, involving all stakeholders within and outside the enterprise. The GP HESME system is intended to function at different levels: international, national, local community, and enterprise. The most important issues at the first stage of GP HESME implementation in the Lodz region are described. Also, the proposals of future activities in Lodz are presented. Practical implementation of GP HESME requires close co-operation among all stakeholders: local authorities, employers, employees, research institutions, and the state inspectorate. The WHO and the Nofer Institute of Occupational Medicine (NIOM) are initiating implementation, delivering professional consultation, education and training of stakeholders in the NIOM School of Public Health. The implementation of GP HESME in the Lodz region started in 1999 from a WHO meeting on criteria and indicators, followed by close collaboration of NIOM with the city's Department of Public Health. 'Directions of Actions for Health of Lodz Citizens' is now the city's official document that includes GP HESME as an important part of public health policy in Lodz. Several conferences were organized by NIOM together with the Professional Managers' Club, Labor Inspection, and the city's Department of Public Health to assess the most important needs of enterprises. The employers and managerial staff, who predominated among the participants, stated the need for tailored sets of indicators and economic appraisal of GP HESME activities. Special attention is paid to GP HESME in supermarkets and community-owned enterprises, e.g., a local transportation company. A special program for small- and medium-size enterprises will be the next step of GP HESME in the Lodz region. The implementation of GP HESME is possible if the efforts of local authorities; research institutions and state inspectorate are combined with the support of employers' organizations.

Microwave absorbing property of silicone rubber composites with added carbonyl iron particles and graphite platelet

NASA Astrophysics Data System (ADS)

Xu, Yonggang; Zhang, Deyuan; Cai, Jun; Yuan, Liming; Zhang, Wenqiang

2013-02-01

Silicone rubber composites filled with carbonyl iron particles (CIPs) and graphite platelet (GP) were prepared using non-coating or coating processes. The complex permittivity and permeability of the composites were measured using a vector network analyzer in the frequency range of 1-18 GHz and dc electric conductivity was measured by the standard four-point contact method. The results showed that CIPs/GP composites fabricated in the coating process had the highest permittivity and permeability due to the particle orientation and interactions between the two absorbents. The coating process resulted in a decreased effective eccentricity of the absorbents, and the dc conductivity increased according to Neelakanta's equations. The reflection loss (RL) value showed that the composites had an excellent absorbing property in the L-band, minimum -11.85 dB at 1.5 mm and -15.02 dB at 2 mm. Thus, GP could be an effective additive in preparing thin absorbing composites in the L-band.

A new method measuring the interaction of radiotracers with the human P-glycoprotein (P-gp) transporter.

PubMed

Vraka, Chrysoula; Dumanic, Monika; Racz, Teresa; Pichler, Florian; Philippe, Cecile; Balber, Theresa; Klebermass, Eva-Maria; Wagner, Karl-Heinz; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus

2018-05-01

In drug development, biomarkers for cerebral applications have a lower success rate compared to cardiovascular drugs or tumor therapeutics. One reason is the missing blood brain barrier penetration, caused by the tracer's interaction with efflux transporters such as the P-gp (MDR1 or ABCB1). Aim of this study was the development of a reliable model to measure the interaction of radiotracers with the human efflux transporter P-gp in parallel to the radiolabeling process. LigandTracer® Technology was used with the wildtype cell line MDCKII and the equivalent cell line overexpressing human P-gp (MDCKII-hMDR1). The method was evaluated based on established PET tracers with known interaction with the human P-gp transporter and in nanomolar concentration (15 nM). [ 11 C]SNAP-7941 and [ 18 F]FE@SNAP were used as P-gp substrates by comparing the real-time model with an uptake assay and μPET images. [ 11 C]DASB [ 11 C]Harmine, [ 18 F]FMeNER,[ 18 F]FE@SUPPY and [ 11 C]Me@HAPTHI were used as tracers without interactions with P-gp in vitro. However, [ 11 C]Me@HAPTHI shows a significant increase in SUV levels after blocking with Tariquidar. The developed real-time kinetic model uses directly PET tracers in a compound concentration, which is reflecting the in vivo situation. This method may be used at an early stage of radiopharmaceutical development to measure interactions to P-gp before conducting animal experiments. Copyright © 2018 Elsevier Inc. All rights reserved.

HIV Glycoprotein Gp120 Impairs Fast Axonal Transport by Activating Tak1 Signaling Pathways

PubMed Central

Berth, Sarah H.; Mesnard-Hoaglin, Nichole; Wang, Bin; Kim, Hajwa; Song, Yuyu; Sapar, Maria; Morfini, Gerardo

2016-01-01

Sensory neuropathies are the most common neurological complication of HIV. Of these, distal sensory polyneuropathy (DSP) is directly caused by HIV infection and characterized by length-dependent axonal degeneration of dorsal root ganglion (DRG) neurons. Mechanisms for axonal degeneration in DSP remain unclear, but recent experiments revealed that the HIV glycoprotein gp120 is internalized and localized within axons of DRG neurons. Based on these findings, we investigated whether intra-axonal gp120 might impair fast axonal transport (FAT), a cellular process critical for appropriate maintenance of the axonal compartment. Significantly, we found that gp120 severely impaired both anterograde and retrograde FAT. Providing a mechanistic basis for these effects, pharmacological experiments revealed an involvement of various phosphotransferases in this toxic effect, including members of mitogen-activated protein kinase pathways (Tak-1, p38, and c-Jun N-terminal Kinase (JNK)), inhibitor of kappa-B-kinase 2 (IKK2), and PP1. Biochemical experiments and axonal outgrowth assays in cell lines and primary cultures extended these findings. Impairments in neurite outgrowth in DRG neurons by gp120 were rescued using a Tak-1 inhibitor, implicating a Tak-1 mitogen-activated protein kinase pathway in gp120 neurotoxicity. Taken together, these observations indicate that kinase-based impairments in FAT represent a novel mechanism underlying gp120 neurotoxicity consistent with the dying-back degeneration seen in DSP. Targeting gp120-based impairments in FAT with specific kinase inhibitors might provide a novel therapeutic strategy to prevent axonal degeneration in DSP. PMID:27872270

Retinoic acid regulates cell-shape and -death of E-FABP (FABP5)-immunoreactive septoclasts in the growth plate cartilage of mice.

PubMed

Bando, Yasuhiko; Yamamoto, Miyuki; Sakiyama, Koji; Sakashita, Hide; Taira, Fuyoko; Miyake, Genki; Iseki, Shoichi; Owada, Yuji; Amano, Osamu

2017-09-01

Septoclasts, which are mononuclear and spindle-shaped cells with many processes, have been considered to resorb the transverse septa of the growth plate (GP) cartilage at the chondro-osseous junction (COJ). We previously reported the expression of epidermal-type fatty acid-binding protein (E-FABP, FABP5) and localization of peroxisome proliferator-activated receptor (PPAR)β/δ, which mediates the cell survival or proliferation, in septoclasts. On the other hand, retinoic acid (RA) can bind to E-FABP and is stored abundantly in the GP cartilage. From these information, it is possible to hypothesize that RA in the GP is incorporated into septoclasts during the cartilage resorption and regulates the growth and/or death of septoclasts. To clarify the mechanism of the cartilage resorption induced by RA, we administered an overdose of RA or its precursor vitamin A (VA)-deficient diet to young mice. In mice of both RA excess and VA deficiency, septoclasts decreased in the number and cell size in association with shorter and lesser processes than those in normal mice, suggesting a substantial suppression of resorption by septoclasts in the GP cartilage. Lack of PPARβ/δ-expression, TUNEL reaction, RA receptor (RAR)β, and cellular retinoic acid-binding protein (CRABP)-II were induced in E-FABP-positive septoclasts under RA excess, suggesting the growth arrest/cell-death of septoclasts, whereas cartilage-derived retinoic acid-sensitive protein (CD-RAP) inducing the cell growth arrest or morphological changes was induced in septoclasts under VA deficiency. These results support and do not conflict with our hypothesis, suggesting that endogenous RA in the GP is possibly incorporated in septoclasts and utilized to regulate the activity of septoclasts resorbing the GP cartilage.

Molecular Dissection of the Homotrimeric Sliding Clamp of T4 Phage: Two Domains of a Subunit Display Asymmetric Characteristics.

PubMed

Singh, Manika Indrajit; Jain, Vikas

2016-01-26

Sliding clamp proteins are circular dimers or trimers that encircle DNA and serve as processivity factors during DNA replication. Their presence in all the three domains of life and in bacteriophages clearly indicates their high level of significance. T4 gp45, besides functioning as the DNA polymerase processivity factor, also moonlights as the late promoter transcription determinant. Here we report a detailed biophysical analysis of gp45. The chemical denaturation of gp45 probed by circular dichroism spectroscopy, tryptophan fluorescence anisotropy, and blue-native polyacrylamide gel electrophoresis suggests that the protein follows a three-state denaturation profile and displays an intermediate molten globule-like state. The three-state transition was found to be the result of the sequential unfolding of the two domains, the N-terminal domain (NTD) and the C-terminal domain (CTD), of gp45. The experiments involving Trp fluorescence quenching by acrylamide demonstrate that the CTD undergoes substantial changes in conformation during formation of the intermediate state. Further biophysical dissection of the individual domain reveals contrasting properties of the two domains. The NTD unfolds at low urea concentrations and is also susceptible to protease cleavage, whereas the CTD resists urea-mediated denaturation and is not amenable to protease digestion even at higher urea concentrations. These experiments allow us to conclude that the two domains of gp45 differ in their dynamics. While the CTD shows stability and rigidity, we find that the NTD is unstable and flexible. We believe that the asymmetric characteristics of the two domains and the interface they form hold significance in gp45 structure and function.

Toxicokinetics and toxicodynamics of chlorpyrifos is altered in embryos of Japanese medaka exposed to oil sands process-affected water: evidence for inhibition of P-glycoprotein.

PubMed

Alharbi, Hattan A; Alcorn, Jane; Al-Mousa, Ahmed; Giesy, John P; Wiseman, Steve B

2017-05-01

Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface mining oil sands industry in Alberta, Canada. Studies were performed in vitro by use of Caco-2 cells, and in vivo with larvae of Japanese medaka (Oryzias latipes) to determine if organic compounds from the aqueous phase of OSPW inhibit ATP binding cassette protein ABCB1 (permeability-glycoprotein, P-gp). Neutral and basic fractions of OSPW inhibited activity of P-gp in Caco-2 cells by 1.9- and 2.0-fold, respectively, while the acidic fraction had the least effect. The organophosphate pesticides chlorpyrifos (a substrate of P-gp) and malathion (not a substrate of P-gp), were used as model chemicals to investigate inhibition of P-gp in larvae. Co-exposure to chlorpyrifos and an extract of OSPW containing basic and neutral compounds reduced survival of larvae to 26.5% compared to survival of larvae exposed only to chlorpyrifos, which was 93.7%. However, co-exposure to malathion and the extract of OSPW did not cause acute lethality compared to exposure only to malathion. Accumulation and bioconcentration of chlorpyrifos, but not malathion, was greater in larvae co-exposed with the extract of OSPW. The terminal elimination half-life of chlorpyrifos in larvae exposed to chlorpyrifos in freshwater was 5 days compared with 11.3 days in larvae exposed to chlorpyrifos in OSPW. Results suggest that in non-acute exposures, basic and neutral organic compounds in the water-soluble fraction of OSPW inhibit activity of P-gp, which suggests that OSPW has the potential to cause adverse effects by chemosensitization. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Revisiting non-Gaussianity from non-attractor inflation models

NASA Astrophysics Data System (ADS)

Cai, Yi-Fu; Chen, Xingang; Namjoo, Mohammad Hossein; Sasaki, Misao; Wang, Dong-Gang; Wang, Ziwei

2018-05-01

Non-attractor inflation is known as the only single field inflationary scenario that can violate non-Gaussianity consistency relation with the Bunch-Davies vacuum state and generate large local non-Gaussianity. However, it is also known that the non-attractor inflation by itself is incomplete and should be followed by a phase of slow-roll attractor. Moreover, there is a transition process between these two phases. In the past literature, this transition was approximated as instant and the evolution of non-Gaussianity in this phase was not fully studied. In this paper, we follow the detailed evolution of the non-Gaussianity through the transition phase into the slow-roll attractor phase, considering different types of transition. We find that the transition process has important effect on the size of the local non-Gaussianity. We first compute the net contribution of the non-Gaussianities at the end of inflation in canonical non-attractor models. If the curvature perturbations keep evolving during the transition—such as in the case of smooth transition or some sharp transition scenarios—the Script O(1) local non-Gaussianity generated in the non-attractor phase can be completely erased by the subsequent evolution, although the consistency relation remains violated. In extremal cases of sharp transition where the super-horizon modes freeze immediately right after the end of the non-attractor phase, the original non-attractor result can be recovered. We also study models with non-canonical kinetic terms, and find that the transition can typically contribute a suppression factor in the squeezed bispectrum, but the final local non-Gaussianity can still be made parametrically large.

Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs.

PubMed

Dahan, Arik; Amidon, Gordon L

2009-01-01

The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal perfusion model in different regions of the rat small intestine, in the presence or absence of the P-gp inhibitor verapamil. The apical to basolateral (AP-BL) and the BL-AP transport of the compounds in the presence or absence of various efflux transporters inhibitors (verapamil, erythromycin, quinidine, MK-571 and fumitremorgin C) was investigated across Caco-2 cell monolayers. P-gp expression levels in the different intestinal segments were confirmed by immunoblotting. Cimetidine and famotidine exhibited segmental dependent permeability through the gut wall, with decreased P(eff) in the distal ileum in comparison to the proximal regions of the intestine. Coperfusion of verapamil with the drugs significantly increased the permeability in the ileum, while no significant change in the jejunal permeability was observed. Both drugs exhibited significantly greater BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Concentration dependent decrease of this secretion was obtained by the P-gp inhibitors verapamil, erythromycin and quinidine, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC, indicating that P-gp is the transporter mediates the intestinal efflux of cimetidine and famotidine. P-gp levels throughout the intestine were inversely related to the in vivo permeability of the drugs from the different segments. The data demonstrate that for these high-solubility low-permeability P-gp substrates, P-gp limits in vivo intestinal absorption in the distal segments of the small intestine; however P-gp plays a minimal role in the proximal intestinal segments due to significant lower P-gp expression levels in this region.

Random Process Simulation for stochastic fatigue analysis. Ph.D. Thesis - Rice Univ., Houston, Tex.

NASA Technical Reports Server (NTRS)

Larsen, Curtis E.

1988-01-01

A simulation technique is described which directly synthesizes the extrema of a random process and is more efficient than the Gaussian simulation method. Such a technique is particularly useful in stochastic fatigue analysis because the required stress range moment E(R sup m), is a function only of the extrema of the random stress process. The family of autoregressive moving average (ARMA) models is reviewed and an autoregressive model is presented for modeling the extrema of any random process which has a unimodal power spectral density (psd). The proposed autoregressive technique is found to produce rainflow stress range moments which compare favorably with those computed by the Gaussian technique and to average 11.7 times faster than the Gaussian technique. The autoregressive technique is also adapted for processes having bimodal psd's. The adaptation involves using two autoregressive processes to simulate the extrema due to each mode and the superposition of these two extrema sequences. The proposed autoregressive superposition technique is 9 to 13 times faster than the Gaussian technique and produces comparable values for E(R sup m) for bimodal psd's having the frequency of one mode at least 2.5 times that of the other mode.

New Constraints on Gliese 876—Exemplar of Mean-motion Resonance

NASA Astrophysics Data System (ADS)

Millholland, Sarah; Laughlin, Gregory; Teske, Johanna; Butler, R. Paul; Burt, Jennifer; Holden, Bradford; Vogt, Steven; Crane, Jeffrey; Shectman, Stephen; Thompson, Ian

2018-03-01

Gliese 876 harbors one of the most dynamically rich and well-studied exoplanetary systems. The nearby M4V dwarf hosts four known planets, the outer three of which are trapped in a Laplace mean-motion resonance. A thorough characterization of the complex resonant perturbations exhibited by the orbiting planets, and the chaotic dynamics therein, is key to a complete picture of the system’s formation and evolutionary history. Here we present a reanalysis of the system using 6 yr of new radial velocity (RV) data from four instruments. These new data augment and more than double the size of the decades-long collection of existing velocity measurements. We provide updated estimates of the system parameters by employing a computationally efficient Wisdom–Holman N-body symplectic integrator, coupled with a Gaussian process (GP) regression model to account for correlated stellar noise. Experiments with synthetic RV data show that the dynamical characterization of the system can differ depending on whether a white-noise or correlated-noise model is adopted. Despite there being a region of stability for an additional planet in the resonant chain, we find no evidence for one. Our new parameter estimates place the system even deeper into resonance than previously thought and suggest that the system might be in a low-energy, quasi-regular double apsidal corotation resonance. This result and others will be used in a subsequent study on the primordial migration processes responsible for the formation of the resonant chain.

Comprehensive functional analysis of N-linked glycans on Ebola virus GP1.

PubMed

Lennemann, Nicholas J; Rhein, Bethany A; Ndungo, Esther; Chandran, Kartik; Qiu, Xiangguo; Maury, Wendy

2014-01-28

Ebola virus (EBOV) entry requires the virion surface-associated glycoprotein (GP) that is composed of a trimer of heterodimers (GP1/GP2). The GP1 subunit contains two heavily glycosylated domains, the glycan cap and the mucin-like domain (MLD). The glycan cap contains only N-linked glycans, whereas the MLD contains both N- and O-linked glycans. Site-directed mutagenesis was performed on EBOV GP1 to systematically disrupt N-linked glycan sites to gain an understanding of their role in GP structure and function. All 15 N-glycosylation sites of EBOV GP1 could be removed without compromising the expression of GP. The loss of these 15 glycosylation sites significantly enhanced pseudovirion transduction in Vero cells, which correlated with an increase in protease sensitivity. Interestingly, exposing the receptor-binding domain (RBD) by removing the glycan shield did not allow interaction with the endosomal receptor, NPC1, indicating that the glycan cap/MLD domains mask RBD residues required for binding. The effects of the loss of GP1 N-linked glycans on Ca(2+)-dependent (C-type) lectin (CLEC)-dependent transduction were complex, and the effect was unique for each of the CLECs tested. Surprisingly, EBOV entry into murine peritoneal macrophages was independent of GP1 N-glycans, suggesting that CLEC-GP1 N-glycan interactions are not required for entry into this important primary cell. Finally, the removal of all GP1 N-glycans outside the MLD enhanced antiserum and antibody sensitivity. In total, our results provide evidence that the conserved N-linked glycans on the EBOV GP1 core protect GP from antibody neutralization despite the negative impact the glycans have on viral entry efficiency. Filovirus outbreaks occur sporadically throughout central Africa, causing high fatality rates among the general public and health care workers. These unpredictable hemorrhagic fever outbreaks are caused by multiple species of Ebola viruses, as well as Marburg virus. While filovirus vaccines and therapeutics are being developed, there are no licensed products. The sole viral envelope glycoprotein, which is a principal immunogenic target, contains a heavy shield of glycans surrounding the conserved receptor-binding domain. We find that disruption of this shield through targeted mutagenesis leads to an increase in cell entry, protease sensitivity, and antiserum/antibody sensitivity but is not sufficient to allow virion binding to the intracellular receptor NPC1. Therefore, our studies provide evidence that filoviruses maintain glycoprotein glycosylation to protect against proteases and antibody neutralization at the expense of efficient entry. Our results unveil interesting insights into the unique entry process of filoviruses and potential immune evasion tactics of the virus.

Statistical and engineering methods for model enhancement

NASA Astrophysics Data System (ADS)

Chang, Chia-Jung

Models which describe the performance of physical process are essential for quality prediction, experimental planning, process control and optimization. Engineering models developed based on the underlying physics/mechanics of the process such as analytic models or finite element models are widely used to capture the deterministic trend of the process. However, there usually exists stochastic randomness in the system which may introduce the discrepancy between physics-based model predictions and observations in reality. Alternatively, statistical models can be used to develop models to obtain predictions purely based on the data generated from the process. However, such models tend to perform poorly when predictions are made away from the observed data points. This dissertation contributes to model enhancement research by integrating physics-based model and statistical model to mitigate the individual drawbacks and provide models with better accuracy by combining the strengths of both models. The proposed model enhancement methodologies including the following two streams: (1) data-driven enhancement approach and (2) engineering-driven enhancement approach. Through these efforts, more adequate models are obtained, which leads to better performance in system forecasting, process monitoring and decision optimization. Among different data-driven enhancement approaches, Gaussian Process (GP) model provides a powerful methodology for calibrating a physical model in the presence of model uncertainties. However, if the data contain systematic experimental errors, the GP model can lead to an unnecessarily complex adjustment of the physical model. In Chapter 2, we proposed a novel enhancement procedure, named as “Minimal Adjustment”, which brings the physical model closer to the data by making minimal changes to it. This is achieved by approximating the GP model by a linear regression model and then applying a simultaneous variable selection of the model and experimental bias terms. Two real examples and simulations are presented to demonstrate the advantages of the proposed approach. Different from enhancing the model based on data-driven perspective, an alternative approach is to focus on adjusting the model by incorporating the additional domain or engineering knowledge when available. This often leads to models that are very simple and easy to interpret. The concepts of engineering-driven enhancement are carried out through two applications to demonstrate the proposed methodologies. In the first application where polymer composite quality is focused, nanoparticle dispersion has been identified as a crucial factor affecting the mechanical properties. Transmission Electron Microscopy (TEM) images are commonly used to represent nanoparticle dispersion without further quantifications on its characteristics. In Chapter 3, we developed the engineering-driven nonhomogeneous Poisson random field modeling strategy to characterize nanoparticle dispersion status of nanocomposite polymer, which quantitatively represents the nanomaterial quality presented through image data. The model parameters are estimated through the Bayesian MCMC technique to overcome the challenge of limited amount of accessible data due to the time consuming sampling schemes. The second application is to calibrate the engineering-driven force models of laser-assisted micro milling (LAMM) process statistically, which facilitates a systematic understanding and optimization of targeted processes. In Chapter 4, the force prediction interval has been derived by incorporating the variability in the runout parameters as well as the variability in the measured cutting forces. The experimental results indicate that the model predicts the cutting force profile with good accuracy using a 95% confidence interval. To conclude, this dissertation is the research drawing attention to model enhancement, which has considerable impacts on modeling, design, and optimization of various processes and systems. The fundamental methodologies of model enhancement are developed and further applied to various applications. These research activities developed engineering compliant models for adequate system predictions based on observational data with complex variable relationships and uncertainty, which facilitate process planning, monitoring, and real-time control.

Gyrator transform of generalized sine-Gaussian beams and conversion an edge-dislocation into a vortex

NASA Astrophysics Data System (ADS)

Zhu, Kaicheng; Tang, Huiqin; Tang, Ying; Xia, Hui

2014-12-01

We proposed a scheme that converts a sine-Gaussian beam with an edge dislocation into a dark hollow beam with a vortex. Based on the gyrator transform (GT) relation, the closed-form field distribution of generalized sine-Gaussian beams passing through a GT system is derived; the intensity distribution and the corresponding phase distribution associated with the transforming generalized sine-Gaussian beams are analyzed. According to the numerical method, the distributions are graphically demonstrated and found that, for appropriate beam parameters and the GT angle, dark hollow vortex beams with topological charge 1 can be achieved using sine-Gaussian beams carrying an edge dislocation. Moreover, the orbital angular momentum content of a GT sine-Gaussian beam is analyzed. It is proved that the GT retains the odd- or even-order spiral harmonics structures of generalized sine-Gaussian beams in the transform process. In particular, it is wholly possible to convert an edge dislocation embedded in sine-Gaussian beams into a vortex with GT. The study also reveals that to obtain a dark hollow beam making use of GT of cos-Gaussian beams is impossible.

Harnessing the wine dregs: An approach towards a more sustainable synthesis of gold and silver nanoparticles.

PubMed

González-Ballesteros, N; Rodríguez-González, J B; Rodríguez-Argüelles, M C

2018-01-01

In recent years, the management of food waste processing has emerged as a major concern. One such type of food waste, grape pomace, has been shown to be a great source of bioactive compounds which might be used for more environmentally - friendly processes for the synthesis of nanomaterials. In this study, grape pomace of Vitis vinifera has been used for the obtainment of an aqueous extract. Firstly, the reducing activity, total phenolic content and DPPH scavenging activity of the aqueous extract were determined. Then, the aqueous extract was used for the synthesis of gold and silver nanoparticles. The formation of spherical and stable nanoparticles with mean diameters of 35.3±5.2nm for Au@GP and 42.9±6.4nm for Ag@GP was confirmed by UV-vis spectroscopy and transmission electron microscopy. Furthermore, the functional group of biomolecules present in grape pomace extract, Au@GP and Ag@GP, were characterized by Fourier transform infrared spectroscopy prior to and after the synthesis, in order to obtain information about the biomolecules involved in the reducing and stabilization process. This study is the first to deal with the use of Vitis vinifera grape pomace in obtaining gold and silver nanoparticles through an eco-friendly, quick, one-pot synthetic route. Copyright © 2017 Elsevier B.V. All rights reserved.

Effective squeezing enhancement via measurement-induced non-Gaussian operation and its application to the dense coding scheme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kitagawa, Akira; Takeoka, Masahiro; Sasaki, Masahide

2005-08-15

We study the measurement-induced non-Gaussian operation on the single- and two-mode Gaussian squeezed vacuum states with beam splitters and on-off type photon detectors, with which mixed non-Gaussian states are generally obtained in the conditional process. It is known that the entanglement can be enhanced via this non-Gaussian operation on the two-mode squeezed vacuum state. We show that, in the range of practical squeezing parameters, the conditional outputs are still close to Gaussian states, but their second order variances of quantum fluctuations and correlations are effectively suppressed and enhanced, respectively. To investigate an operational meaning of these states, especially entangled states,more » we also evaluate the quantum dense coding scheme from the viewpoint of the mutual information, and we show that non-Gaussian entangled state can be advantageous compared with the original two-mode squeezed state.« less

Evolution of coreceptor utilization to escape CCR5 antagonist therapy.

PubMed

Zhang, Jie; Gao, Xiang; Martin, John; Rosa, Bruce; Chen, Zheng; Mitreva, Makedonka; Henrich, Timothy; Kuritzkes, Daniel; Ratner, Lee

2016-07-01

The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Structure of Epstein-Barr Virus Glycoprotein 42 Suggests a Mechanism for Triggering Receptor-Activated Virus Entry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirschner, Austin N.; Sorem, Jessica; Longnecker, Richard

Epstein-Barr virus requires glycoproteins gH/gL, gB, and gp42 to fuse its lipid envelope with B cells. Gp42 is a type II membrane protein consisting of a flexible N-terminal region, which binds gH/gL, and a C-terminal lectin-like domain that binds to the B-cell entry receptor human leukocyte antigen (HLA) class II. Gp42 triggers membrane fusion after HLA binding, a process that requires simultaneous binding to gH/gL and a functional hydrophobic pocket in the lectin domain adjacent to the HLA binding site. Here we present the structure of gp42 in its unbound form. Comparisons to the previously determined structure of a gp42:HLAmore » complex reveals additional N-terminal residues forming part of the gH/gL binding site and structural changes in the receptor binding domain. Although the core of the lectin domain remains similar, significant shifts in two loops and an {alpha} helix bordering the essential hydrophobic pocket suggest a structural mechanism for triggering fusion.« less

Finding a Vulnerable Spot in HIV’s Armor by Investigating the Structure of HIV | Center for Cancer Research

Cancer.gov

The Human Immunodeficiency Virus (HIV) infects and eventually kills CD4-expressing T cells, which are essential for the immune system to function appropriately. Loss of significant numbers of T cells leads to Acquired Immunodeficiency Syndrome (AIDS), a disease that kills over two million people around the world every year. HIV infection depends on two proteins expressed on the virus surface: gp41, which sits in the virus membrane, and gp120, which sits on top of gp41. Three copies, or trimers, of each gp41/gp120 pair make up the envelope glycoprotein, Env. Env coats the virus surface and interacts with its receptor, CD4, and a co-receptor, either CCR5 or CXCR4, on the T cell. Binding to the receptors is thought to cause a structural reorganization of Env, which exposes a fusion peptide that inserts into the T cell membrane and actually forces the virus and host membranes together, initiating an infection. However, the structural details of this process are lacking.

Protein Interactions in T7 DNA Replisome Facilitate DNA Damage Bypass.

PubMed

Zou, Zhenyu; Chen, Ze; Xue, Qizhen; Xu, Ying; Xiong, Jingyuan; Yang, Ping; Le, Shuai; Zhang, Huidong

2018-06-14

DNA replisome inevitably encounters DNA damage during DNA replication. T7 DNA replisome contains DNA polymerase (gp5), the processivity factor thioredoxin (trx), helicase-primase (gp4), and ssDNA binding protein (gp2.5). T7 protein interactions mediate this DNA replication. However, whether the protein interactions could promote DNA damage bypass is still little addressed. In this study, we investigated the strand-displacement DNA synthesis past 8-oxoG or O6-MeG at the synthetic DNA fork by T7 DNA replisome. DNA damage does not obviously affect the binding affinities among helicase, polymerase, and DNA fork. Relative to unmodified G, both 8-oxoG and O6-MeG, as well as GC-rich template sequence clusters, inhibit the strand-displacement DNA synthesis and produce partial extension products. Relative to gp4 ΔC-tail, gp4 promotes the DNA damage bypass. The presence of gp2.5 further promotes this bypass. Thus, the interactions of polymerase with helicase and ssDNA binidng protein faciliate the DNA damage bypass. Similarly, accessory proteins in other complicated DNA replisomes also facilitate the DNA damage bypass. This work provides the novel mechanism information of DNA damage bypass by DNA replisome. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Glycerophosphate-dependent peroxide production by brown fat mitochondria from newborn rats.

PubMed

Drahota, Z; Rauchova, H; Jesina, P; Vojtísková, A; Houstek, J

2003-03-01

Glycerophosphate (GP)-dependent, ferricyanide-induced hydrogen peroxide production was studied in brown adipose tissue mitochondria from newborn rats. Relations between the rate of hydrogen peroxide production and total amount of hydrogen peroxide produced at different GP and ferricyanide concentrations were determined. It was found that the rate of hydrogen peroxide production increases with increasing GP concentration and decreases with increasing ferricyanide concentration. Total amount of hydrogen peroxide produced increases with increasing ferricyanide concentration, however, not proportionally, and the efficiency of this process (oxygen/ferricyanide ratio) strongly declines. Data presented provide further information on the character and kinetics of hydrogen peroxide production by mammalian mitochondrial glycerophosphate dehydrogenase.

Renyi entropy measures of heart rate Gaussianity.

PubMed

Lake, Douglas E

2006-01-01

Sample entropy and approximate entropy are measures that have been successfully utilized to study the deterministic dynamics of heart rate (HR). A complementary stochastic point of view and a heuristic argument using the Central Limit Theorem suggests that the Gaussianity of HR is a complementary measure of the physiological complexity of the underlying signal transduction processes. Renyi entropy (or q-entropy) is a widely used measure of Gaussianity in many applications. Particularly important members of this family are differential (or Shannon) entropy (q = 1) and quadratic entropy (q = 2). We introduce the concepts of differential and conditional Renyi entropy rate and, in conjunction with Burg's theorem, develop a measure of the Gaussianity of a linear random process. Robust algorithms for estimating these quantities are presented along with estimates of their standard errors.

MuLoG, or How to Apply Gaussian Denoisers to Multi-Channel SAR Speckle Reduction?

PubMed

Deledalle, Charles-Alban; Denis, Loic; Tabti, Sonia; Tupin, Florence

2017-09-01

Speckle reduction is a longstanding topic in synthetic aperture radar (SAR) imaging. Since most current and planned SAR imaging satellites operate in polarimetric, interferometric, or tomographic modes, SAR images are multi-channel and speckle reduction techniques must jointly process all channels to recover polarimetric and interferometric information. The distinctive nature of SAR signal (complex-valued, corrupted by multiplicative fluctuations) calls for the development of specialized methods for speckle reduction. Image denoising is a very active topic in image processing with a wide variety of approaches and many denoising algorithms available, almost always designed for additive Gaussian noise suppression. This paper proposes a general scheme, called MuLoG (MUlti-channel LOgarithm with Gaussian denoising), to include such Gaussian denoisers within a multi-channel SAR speckle reduction technique. A new family of speckle reduction algorithms can thus be obtained, benefiting from the ongoing progress in Gaussian denoising, and offering several speckle reduction results often displaying method-specific artifacts that can be dismissed by comparison between results.

Surface modified carbon nanoparticle papers and applications on polymer composites

NASA Astrophysics Data System (ADS)

Ouyang, Xilian

Free-standing paper like materials are usually employed as protective layers, chemical filters, components of electrical batteries or supercapacitors, adhesive layers, and electronic or optoelectric components. Free-standing papers made from carbon nanoparticles have drawn increased interest because they have a variety of superior chemical and physical characteristics, such as light weight, high intrinsic mechanical properties, and extraordinary high electrical conductivity. Nanopapers fabricated from 1- D shape carbon nanofibers (CNFs) and carbon nanotubes (CNTs) are promising reinforcing materials for polymer composites, because the highly porous CNF and CNT nanopapers (porosity ˜80% and ˜70% respectively) can be impregnated with matrix polymers. In the first part of this work, polyaniline (PANI) was used to functionalize the surface of CNFs, and the resultant carbon nanopapers presented impressive mechanical strength and electrical conductivity that it could be used in the in-mold coating (IMC)/ injection molding process to achieve high electromagnetic interference (EMI) shielding effectiveness. Aniline modified (AF) CNT nanopapers were used as a 3D network in gas separation membranes. The resultant composite membranes demonstrated better and stable CO2 permeance and CO 2/H2 selectivity in a high temperature (107°C) and high pressure (15-30 atm) gas separation process, not achievable by conventional polymer membranes. In the second part, we demonstrated that 2-D graphene (GP) or graphene oxide (GO) nanosheets could be tightly packed into a film which was impermeable to most gases and liquids. GP or GO nanopapers could be coated on polymer composites. In order to achieve well-dispersed single-layer graphene in aqueous medium, we developed a facile approach to synthesize functional GP bearing benzenesulfonic acid groups which allow the preparation of nanopapers by water based assembly. With the optimized processing conditions, our best GP nanopapers could reach a tensile strength of 360 MPa and an electrical conductivity of 4.45x104 S/m, much better than any similar materials reported in the literature. However, they didn't show good gas barrier properties. Since the GO paper presented zero gas permeability for both CO2 and H2, a hybrid paper fabrication approach was proposed to combine the advantages of individual GP and GO papers. This was done by filtering GP and GO layer by layer with GO sandwiched in between two layers of GP. The resulting hybrid papers showed high mechanical tensile strength and EMI shielding effectiveness that are close to GP nanopapers, and excellent gas barrier properties that comparable to GO nanopapers. The GP, GO and GP-Go-GP hybrid nanopapers have been successfully coated onto the thermoplastic surface by thermal lamination and injection molding. In the third part, the effect of PANI-CNF nanopapers and a chelating agent, 2, 4- Pentanedione (2, 4-P) on kinetics of an in-mold coating (IMC) resin was investigated. The results showed that the presence of amine functionalized carbon nanoparticles tended to retard the resin reaction, while 2, 4-P was capable of promoting the redox based free radical polymerization by forming a complex with the cobalt promoter in the initiation step. In order to understand the chemical and physical changes during the resin curing process, kinetics study on two major resin components, i.e. hexanediol diacrylate (HDDA) and styrene (St), were carried out using an integrated analysis design: differential scanning calorimetry (DSC) for overall reaction, Fourier transform infrared spectroscopy (FTIR) for individual component reactions, and rheometry for liquid-solid transition during the reaction. The gel point of this radical polymerization resin system was found to be <2% which implied that most curing was conducted in the solid phase. The results showed that the double bonds in acrylates and St followed an azeotropic polymerization pattern.

Effect of low-fluoride dentifrices supplemented with calcium glycerophosphate on enamel demineralization in situ.

PubMed

do Amaral, Jackeline Gallo; Sassaki, Kikue Takebayashi; Martinhon, Cleide Cristina Rodrigues; Delbem, Alberto Carlos Botazzo

2013-04-01

To evaluate whether a low-fluoride dentifrice with calcium glycerophosphate (CaGP) reduced the demineralization process in situ. A cross-over design with four treatment phases of 7 days each was used. Ten volunteers wore palatal devices containing four blocks of bovine dental enamel. The enamel was treated (ex-vivo) with a placebo, 500 microg-F/g (500), 500 microg-F/g with 0.25%CaGP (500 CaGP), and 1,100 microg-F/g (1,100) dentifrices (twice a day/1 minute) under cariogenic challenge from sucrose solution. To evaluate mineral loss, surface and cross-sectional hardness were performed. The fluoride, calcium, and phosphorus ion concentrations from enamel and dental plaque were determined. The insoluble extracellular polysaccharide (EPS) concentrations were also analyzed. The data were submitted to ANOVA (1-way) followed by the Student-Newman-Keuls test (P < 0.05). The mineral loss and EPS concentration were lowest in the 500 CaGP and 1,100 dentifrice groups. The use of the 500 CaGP and 1,100 dentifrices resulted in similar fluoride, calcium, and phosphorus concentrations in the enamel and in dental plaque (P > 0.05). The ionic activities of calcium phosphate phases for the 500 CaGP and 1,100 dentifrices were similar (P > or = 0.492). The low-fluoride dentifrice with 0.25%CaGP demonstrated efficacy similar to that of the positive control (1,100 dentifrice) with respect to in situ demineralization.

Peptide ligands specific to the oxidized form of escherichia coli thioredoxin.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scholle, M. D.; Banach, B. S.; Hamdan, S. M.

Thioredoxin (Trx) is a highly conserved redox protein involved in several essential cellular processes. In this study, our goal was to isolate peptide ligands to Escherichia coli Trx that mimic protein-protein interactions, specifically the T7 polymerase-Trx interaction. To do this, we subjected Trx to affinity selection against a panel of linear and cysteine-constrained peptides using M13 phage display. A novel cyclized conserved peptide sequence, with a motif of C(D/N/S/T/G)D(S/T)-hydrophobic-C-X-hydrophobic-P, was isolated to Trx. These peptides bound specifically to the E. coli Trx when compared to the human and spirulina homologs. An alanine substitution of the active site cysteines (CGPC) resultedmore » in a significant loss of peptide binding affinity to the Cys-32 mutant. The peptides were also characterized in the context of Trx's role as a processivity factor of the T7 DNA polymerase (gp5). As the interaction between gp5 and Trx normally takes place under reducing conditions, which might interfere with the conformation of the disulfide-bridged peptides, we made use of a 22 residue deletion mutant of gp5 in the thioredoxin binding domain (gp5{Delta}22) that bypassed the requirements of reducing conditions to interact with Trx. A competition study revealed that the peptide selectively inhibits the interaction of gp5{Delta}22 with Trx, under oxidizing conditions, with an IC50 of {approx} 10 {micro}M.« less

Feature generation using genetic programming with application to fault classification.

PubMed

Guo, Hong; Jack, Lindsay B; Nandi, Asoke K

2005-02-01

One of the major challenges in pattern recognition problems is the feature extraction process which derives new features from existing features, or directly from raw data in order to reduce the cost of computation during the classification process, while improving classifier efficiency. Most current feature extraction techniques transform the original pattern vector into a new vector with increased discrimination capability but lower dimensionality. This is conducted within a predefined feature space, and thus, has limited searching power. Genetic programming (GP) can generate new features from the original dataset without prior knowledge of the probabilistic distribution. In this paper, a GP-based approach is developed for feature extraction from raw vibration data recorded from a rotating machine with six different conditions. The created features are then used as the inputs to a neural classifier for the identification of six bearing conditions. Experimental results demonstrate the ability of GP to discover autimatically the different bearing conditions using features expressed in the form of nonlinear functions. Furthermore, four sets of results--using GP extracted features with artificial neural networks (ANN) and support vector machines (SVM), as well as traditional features with ANN and SVM--have been obtained. This GP-based approach is used for bearing fault classification for the first time and exhibits superior searching power over other techniques. Additionaly, it significantly reduces the time for computation compared with genetic algorithm (GA), therefore, makes a more practical realization of the solution.

Structure and Function Study of Phi29 DNA packaging motor

NASA Astrophysics Data System (ADS)

Fang, Huaming

A powerful nanomotor is employed by the tailed dsDNA virus to package the genome into a preformed protein shell during the process of replication. The bacteriophage phi29 is an excellent model for investigating the viral DNA packaging mechanism. The phi29 DNA packaging motor is composed of three ring structures: the dodecameric connector ring, the hexameric pRNA ring and the hexameric ATPase gp16 ring. The connector is the central hub for the DNA to enter and to exit. There are four positively charged lysine rings scattered inside the highly negatively charged connector channel. It is speculated that these positive charged lysine rings may play active roles during DNA packaging in many models. To test this prevalent view, the basic lysine residues were mutated to neutral alanines and the pH environment was altered. Amazingly, the results were beyond expectation. Neither the DNA translocation nor the one-way traffic property of the channel were measurably influenced by the alteration of the charge of lysine residues when the basic lysine residues mutated to neutral alanines or the pH environment changed to acid or basic. The ATPase or the terminase is the central part of the viral DNA packaging motor. The phi29 ATPase is highly hydrophobic and tends to aggregate in solution. A green fluorescent protein tag (eGFP) fused to the N-terminus of gp16 enhanced its solubility and stability. The eGFP-gp16 showed similar activity to wild type gp16 and was easily detected by fluorescent instruments. The interaction between eGFP-gp16 and DNA in the various conditions were investigated by electrophoretic mobility shift assay, FRET and sucrose gradient. gamma-S-ATP dramatically increased gp16 binding affinity to DNA and ATP, ADP, phosphate could release gp16 from gp16-DNA-gamma-S-ATP complex. The sliding of gp16 out of the gp16-DNA-gamma-S-ATP complex could be blocked by addition of Steptavidin to ends of dsDNA which is conjugated with biotins. Also, we found that six eGFP-gp16 molecules were required to bind to one short dsDNA molecule. The inhibitive curve of Walker B mutant gp16 analyzed by binomial distribution model showed that one inactive mutant gp16 in the gp16 ring could block the function of the motor and the stoichiometry of gp16 was six. These findings facilitate our understanding of the molecular mechanism of viral DNA packaging: a novel viral DNA packaging model "push through a one-way valve" was proposed. In this model, the connector functioned as a valve to allow DNA to enter but prevented it from sliding out during DNA packaging; the six subunits in the gp16 ring acted sequentially to push DNA into the connector channel. ATP binding of gp16 induced a conformation change with a high affinity for dsDNA. Then, the ATP was hydrolyzed which resulted in the movement of subdomains in this individual gp16 subunit and DNA was pushed forward, followed by the double helix of dsDNA being brought forward to the adjacent subunit in the gp16 ring. The elucidation of the viral DNA packaging mechanism holds great potential for developing artificial motors for delivering drugs and other molecular cargos.

Period Estimation for Sparsely-sampled Quasi-periodic Light Curves Applied to Miras

NASA Astrophysics Data System (ADS)

He, Shiyuan; Yuan, Wenlong; Huang, Jianhua Z.; Long, James; Macri, Lucas M.

2016-12-01

We develop a nonlinear semi-parametric Gaussian process model to estimate periods of Miras with sparsely sampled light curves. The model uses a sinusoidal basis for the periodic variation and a Gaussian process for the stochastic changes. We use maximum likelihood to estimate the period and the parameters of the Gaussian process, while integrating out the effects of other nuisance parameters in the model with respect to a suitable prior distribution obtained from earlier studies. Since the likelihood is highly multimodal for period, we implement a hybrid method that applies the quasi-Newton algorithm for Gaussian process parameters and search the period/frequency parameter space over a dense grid. A large-scale, high-fidelity simulation is conducted to mimic the sampling quality of Mira light curves obtained by the M33 Synoptic Stellar Survey. The simulated data set is publicly available and can serve as a testbed for future evaluation of different period estimation methods. The semi-parametric model outperforms an existing algorithm on this simulated test data set as measured by period recovery rate and quality of the resulting period-luminosity relations.

Biochemistry and Biophysics of HIV-1 gp41 – membrane interactions

PubMed Central

Cai, Lifeng; Gochin, Miriam; Liu, Keliang

2011-01-01

Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ~2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein – mediated virus-cell fusion. The transmembrane subunit of envelope protein, gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), N-terminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. Subsequent conformational change of the unstable prehairpin results in a coiled-coil 6-helix bundle (6HB) structure formed between NHR and CHR. The energetics of 6HB formation drives membrane apposition and fusion. Drugs targeting gp41 functional domains to prevent 6HB formation inhibit HIV-1 infection. T20 (enfuvirtide, Fuzeon) was approved by the US FDA in 2003 as the first fusion inhibitor. It is a 36-residue peptide from the gp41 CHR, and it inhibits 6HB formation by targeting NHR and lipids. Development of new fusion inhibitors, especially small molecule drugs, is encouraged to overcome the shortcomings of T20 as a peptide drug. Hydrophobic characteristics and membrane association are critical for gp41 function and mechanism of action. Research in gp41-membrane interactions, using peptides corresponding to specific functional domains, or constructs including several interactive domains, are reviewed here to get a better understanding of gp41 mediated virus-cell fusion that can inform or guide the design of new HIV-1 fusion inhibitors. PMID:22044229

Biochemistry and biophysics of HIV-1 gp41 - membrane interactions and implications for HIV-1 envelope protein mediated viral-cell fusion and fusion inhibitor design.

PubMed

Cai, Lifeng; Gochin, Miriam; Liu, Keliang

2011-12-01

Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes ~2 millions death every year and still defies an effective vaccine. HIV-1 infects host cells through envelope protein - mediated virus-cell fusion. The transmembrane subunit of envelope protein, gp41, is the molecular machinery which facilitates fusion. Its ectodomain contains several distinguishing functional domains, fusion peptide (FP), Nterminal heptad repeat (NHR), C-terminal heptad repeat (CHR) and membrane proximal extracellular region (MPER). During the fusion process, FP inserts into the host cell membrane, and an extended gp41 prehairpin conformation bridges the viral and cell membranes through MPER and FP respectively. Subsequent conformational change of the unstable prehairpin results in a coiled-coil 6-helix bundle (6HB) structure formed between NHR and CHR. The energetics of 6HB formation drives membrane apposition and fusion. Drugs targeting gp41 functional domains to prevent 6HB formation inhibit HIV-1 infection. T20 (enfuvirtide, Fuzeon) was approved by the US FDA in 2003 as the first fusion inhibitor. It is a 36-residue peptide from the gp41 CHR, and it inhibits 6HB formation by targeting NHR and lipids. Development of new fusion inhibitors, especially small molecule drugs, is encouraged to overcome the shortcomings of T20 as a peptide drug. Hydrophobic characteristics and membrane association are critical for gp41 function and mechanism of action. Research in gp41-membrane interactions, using peptides corresponding to specific functional domains, or constructs including several interactive domains, are reviewed here to get a better understanding of gp41 mediated virus-cell fusion that can inform or guide the design of new HIV-1 fusion inhibitors.

P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery.

PubMed

Davis, Thomas P; Sanchez-Covarubias, Lucy; Tome, Margaret E

2014-01-01

The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. © 2014 Elsevier Inc. All rights reserved.

Glycoform Analysis of Recombinant and Human Immunodeficiency Virus Envelope Protein gp120 via Higher Energy Collisional Dissociation and Spectral-Aligning Strategy

PubMed Central

2015-01-01

Envelope protein gp120 of human immunodeficiency virus (HIV) is armored with a dense glycan shield, which plays critical roles in envelope folding, immune-evasion, infectivity, and immunogenicity. Site-specific glycosylation profiling of recombinant gp120 is very challenging. Therefore, glycoproteomic analysis of native viral gp120 is still formidable to date. This challenge promoted us to employ a Q-Exactive mass spectrometer to identify low abundant glycopeptides from virion-associated gp120. To search the HCD-MS data for glycopeptides, a novel spectral-aligning strategy was developed. This strategy depends on the observation that glycopeptides and the corresponding deglycosylated peptides share very similar MS/MS pattern in terms of b- and y-ions that do not contain the site of glycosylation. Moreover, glycopeptides with an identical peptide backbone show nearly resembling spectra regardless of the attached glycan structures. For the recombinant gp120, this “copy–paste” spectral pattern of glycopeptides facilitated identification of 2224 spectra using only 18 spectral templates, and after precursor mass correction, 1268 (57%) spectra were assigned to 460 unique glycopeptides accommodating 19 N-linked and one O-linked glycosylation sites (glycosites). Strikingly, we were able to observe five N- and one O-linked glycosites in native gp120. We further revealed that except for Asn276 in the C2 region, glycans were processed to contain both high mannose and hybrid/complex glycans; an additional four N-linked glycosites were decorated with high mannose type. Core 1 O-linked glycan Gal1GalNAc1 was seen for the O-linked glycosite at Thr499. This direct observation of site-specific glycosylation of virion-derived gp120 has implications in HIV glycobiology and vaccine design. PMID:24941220

Directly data processing algorithm for multi-wavelength pyrometer (MWP).

PubMed

Xing, Jian; Peng, Bo; Ma, Zhao; Guo, Xin; Dai, Li; Gu, Weihong; Song, Wenlong

2017-11-27

Data processing of multi-wavelength pyrometer (MWP) is a difficult problem because unknown emissivity. So far some solutions developed generally assumed particular mathematical relations for emissivity versus wavelength or emissivity versus temperature. Due to the deviation between the hypothesis and actual situation, the inversion results can be seriously affected. So directly data processing algorithm of MWP that does not need to assume the spectral emissivity model in advance is main aim of the study. Two new data processing algorithms of MWP, Gradient Projection (GP) algorithm and Internal Penalty Function (IPF) algorithm, each of which does not require to fix emissivity model in advance, are proposed. The novelty core idea is that data processing problem of MWP is transformed into constraint optimization problem, then it can be solved by GP or IPF algorithms. By comparison of simulation results for some typical spectral emissivity models, it is found that IPF algorithm is superior to GP algorithm in terms of accuracy and efficiency. Rocket nozzle temperature experiment results show that true temperature inversion results from IPF algorithm agree well with the theoretical design temperature as well. So the proposed combination IPF algorithm with MWP is expected to be a directly data processing algorithm to clear up the unknown emissivity obstacle for MWP.

Improved Discrete Approximation of Laplacian of Gaussian

NASA Technical Reports Server (NTRS)

Shuler, Robert L., Jr.

2004-01-01

An improved method of computing a discrete approximation of the Laplacian of a Gaussian convolution of an image has been devised. The primary advantage of the method is that without substantially degrading the accuracy of the end result, it reduces the amount of information that must be processed and thus reduces the amount of circuitry needed to perform the Laplacian-of- Gaussian (LOG) operation. Some background information is necessary to place the method in context. The method is intended for application to the LOG part of a process of real-time digital filtering of digitized video data that represent brightnesses in pixels in a square array. The particular filtering process of interest is one that converts pixel brightnesses to binary form, thereby reducing the amount of information that must be performed in subsequent correlation processing (e.g., correlations between images in a stereoscopic pair for determining distances or correlations between successive frames of the same image for detecting motions). The Laplacian is often included in the filtering process because it emphasizes edges and textures, while the Gaussian is often included because it smooths out noise that might not be consistent between left and right images or between successive frames of the same image.

A feedback control strategy for the airfoil system under non-Gaussian colored noise excitation.

PubMed

Huang, Yong; Tao, Gang

2014-09-01

The stability of a binary airfoil with feedback control under stochastic disturbances, a non-Gaussian colored noise, is studied in this paper. First, based on some approximated theories and methods the non-Gaussian colored noise is simplified to an Ornstein-Uhlenbeck process. Furthermore, via the stochastic averaging method and the logarithmic polar transformation, one dimensional diffusion process can be obtained. At last by applying the boundary conditions, the largest Lyapunov exponent which can determine the almost-sure stability of the system and the effective region of control parameters is calculated.

A feedback control strategy for the airfoil system under non-Gaussian colored noise excitation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Yong, E-mail: hy@njust.edu.cn, E-mail: taogang@njust.edu.cn; Tao, Gang, E-mail: hy@njust.edu.cn, E-mail: taogang@njust.edu.cn

2014-09-01

The stability of a binary airfoil with feedback control under stochastic disturbances, a non-Gaussian colored noise, is studied in this paper. First, based on some approximated theories and methods the non-Gaussian colored noise is simplified to an Ornstein-Uhlenbeck process. Furthermore, via the stochastic averaging method and the logarithmic polar transformation, one dimensional diffusion process can be obtained. At last by applying the boundary conditions, the largest Lyapunov exponent which can determine the almost-sure stability of the system and the effective region of control parameters is calculated.

Neural pulse frequency modulation of an exponentially correlated Gaussian process

NASA Technical Reports Server (NTRS)

Hutchinson, C. E.; Chon, Y.-T.

1976-01-01

The effect of NPFM (Neural Pulse Frequency Modulation) on a stationary Gaussian input, namely an exponentially correlated Gaussian input, is investigated with special emphasis on the determination of the average number of pulses in unit time, known also as the average frequency of pulse occurrence. For some classes of stationary input processes where the formulation of the appropriate multidimensional Markov diffusion model of the input-plus-NPFM system is possible, the average impulse frequency may be obtained by a generalization of the approach adopted. The results are approximate and numerical, but are in close agreement with Monte Carlo computer simulation results.

Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger.

PubMed

Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min; Melikyan, Gregory B; Liu, Shan-Lu; Cohen, Fredric S

2016-01-01

Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Currently, how EBOV fuses its envelope membrane within an endosomal membrane to cause infection is poorly understood. We successfully measure cell-cell fusion mediated by the EBOV fusion protein, GP, assayed by the transfer of both cytoplasmic and membrane dyes. A small molecule fusion inhibitor, a neutralizing antibody, as well as mutations in EBOV GP known to reduce viral infection, all greatly reduce fusion. By monitoring redistribution of small aqueous dyes between cells and by electrical capacitance measurements, we discovered that EBOV GP-mediated fusion pores do not readily enlarge-a marked difference from the behavior of other viral fusion proteins. EBOV GP must be cleaved by late endosome-resident cathepsins B or L in order to become fusion-competent. Cleavage of cell surface-expressed GP appears to occur in endosomes, as evidenced by the fusion block imposed by cathepsin inhibitors, agents that raise endosomal pH, or an inhibitor of anterograde trafficking. Treating effector cells with a recombinant soluble cathepsin B or thermolysin, which cleaves GP into an active form, increases the extent of fusion, suggesting that a fraction of surface-expressed GP is not cleaved. Whereas the rate of fusion is increased by a brief exposure to acidic pH, fusion does occur at neutral pH. Importantly, the extent of fusion is independent of external pH in experiments in which cathepsin activity is blocked and EBOV GP is cleaved by thermolysin. These results imply that low pH promotes fusion through the well-known pH-dependent activity of cathepsins; fusion induced by cleaved EBOV GP is a process that is fundamentally independent of pH. The cell-cell fusion system has revealed some previously unappreciated features of EBOV entry, which could not be readily elucidated in the context of endosomal entry.

Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger

PubMed Central

Zheng, Yi-Min; Melikyan, Gregory B.; Liu, Shan-Lu; Cohen, Fredric S.

2016-01-01

Ebola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Currently, how EBOV fuses its envelope membrane within an endosomal membrane to cause infection is poorly understood. We successfully measure cell-cell fusion mediated by the EBOV fusion protein, GP, assayed by the transfer of both cytoplasmic and membrane dyes. A small molecule fusion inhibitor, a neutralizing antibody, as well as mutations in EBOV GP known to reduce viral infection, all greatly reduce fusion. By monitoring redistribution of small aqueous dyes between cells and by electrical capacitance measurements, we discovered that EBOV GP-mediated fusion pores do not readily enlarge—a marked difference from the behavior of other viral fusion proteins. EBOV GP must be cleaved by late endosome-resident cathepsins B or L in order to become fusion-competent. Cleavage of cell surface-expressed GP appears to occur in endosomes, as evidenced by the fusion block imposed by cathepsin inhibitors, agents that raise endosomal pH, or an inhibitor of anterograde trafficking. Treating effector cells with a recombinant soluble cathepsin B or thermolysin, which cleaves GP into an active form, increases the extent of fusion, suggesting that a fraction of surface-expressed GP is not cleaved. Whereas the rate of fusion is increased by a brief exposure to acidic pH, fusion does occur at neutral pH. Importantly, the extent of fusion is independent of external pH in experiments in which cathepsin activity is blocked and EBOV GP is cleaved by thermolysin. These results imply that low pH promotes fusion through the well-known pH-dependent activity of cathepsins; fusion induced by cleaved EBOV GP is a process that is fundamentally independent of pH. The cell-cell fusion system has revealed some previously unappreciated features of EBOV entry, which could not be readily elucidated in the context of endosomal entry. PMID:26730950

Corrector VX-809 stabilizes the first transmembrane domain of CFTR.

PubMed

Loo, Tip W; Bartlett, M Claire; Clarke, David M

2013-09-01

Processing mutations that inhibit folding and trafficking of CFTR are the main cause of cystic fibrosis (CF). A potential CF therapy would be to repair CFTR processing mutants. It has been demonstrated that processing mutants of P-glycoprotein (P-gp), CFTR's sister protein, can be efficiently repaired by a drug-rescue mechanism. Many arginine suppressors that mimic drug-rescue have been identified in the P-gp transmembrane (TM) domains (TMDs) that rescue by forming hydrogen bonds with residues in adjacent helices to promote packing of the TM segments. To test if CFTR mutants could be repaired by a drug-rescue mechanism, we used truncation mutants to test if corrector VX-809 interacted with the TMDs. VX-809 was selected for study because it is specific for CFTR, it is the most effective corrector identified to date, but it has limited clinical benefit. Identification of the VX-809 target domain will help to develop correctors with improved clinical benefits. It was found that VX-809 rescued truncation mutants lacking the NBD2 and R domains. When the remaining domains (TMD1, NBD1, TMD2) were expressed as separate polypeptides, VX-809 only increased the stability of TMD1. We then performed arginine mutagenesis on TM6 in TMD1. Although the results showed that TM6 had distinct lipid and aqueous faces, CFTR was different from P-gp as no arginine promoted maturation of CFTR processing mutants. The results suggest that TMD1 contains a VX-809 binding site, but its mechanism differed from P-gp drug-rescue. We also report that V510D acts as a universal suppressor to rescue CFTR processing mutants. Copyright © 2013 Elsevier Inc. All rights reserved.

Modeling Sea-Level Change using Errors-in-Variables Integrated Gaussian Processes

NASA Astrophysics Data System (ADS)

Cahill, Niamh; Parnell, Andrew; Kemp, Andrew; Horton, Benjamin

2014-05-01

We perform Bayesian inference on historical and late Holocene (last 2000 years) rates of sea-level change. The data that form the input to our model are tide-gauge measurements and proxy reconstructions from cores of coastal sediment. To accurately estimate rates of sea-level change and reliably compare tide-gauge compilations with proxy reconstructions it is necessary to account for the uncertainties that characterize each dataset. Many previous studies used simple linear regression models (most commonly polynomial regression) resulting in overly precise rate estimates. The model we propose uses an integrated Gaussian process approach, where a Gaussian process prior is placed on the rate of sea-level change and the data itself is modeled as the integral of this rate process. The non-parametric Gaussian process model is known to be well suited to modeling time series data. The advantage of using an integrated Gaussian process is that it allows for the direct estimation of the derivative of a one dimensional curve. The derivative at a particular time point will be representative of the rate of sea level change at that time point. The tide gauge and proxy data are complicated by multiple sources of uncertainty, some of which arise as part of the data collection exercise. Most notably, the proxy reconstructions include temporal uncertainty from dating of the sediment core using techniques such as radiocarbon. As a result of this, the integrated Gaussian process model is set in an errors-in-variables (EIV) framework so as to take account of this temporal uncertainty. The data must be corrected for land-level change known as glacio-isostatic adjustment (GIA) as it is important to isolate the climate-related sea-level signal. The correction for GIA introduces covariance between individual age and sea level observations into the model. The proposed integrated Gaussian process model allows for the estimation of instantaneous rates of sea-level change and accounts for all available sources of uncertainty in tide-gauge and proxy-reconstruction data. Our response variable is sea level after correction for GIA. By embedding the integrated process in an errors-in-variables (EIV) framework, and removing the estimate of GIA, we can quantify rates with better estimates of uncertainty than previously possible. The model provides a flexible fit and enables us to estimate rates of change at any given time point, thus observing how rates have been evolving from the past to present day.

The learner's perspective in GP teaching practices with multi-level learners: a qualitative study.

PubMed

Thomson, Jennifer S; Anderson, Katrina; Haesler, Emily; Barnard, Amanda; Glasgow, Nicholas

2014-03-19

Medical students, junior hospital doctors on rotation and general practice (GP) registrars are undertaking their training in clinical general practices in increasing numbers in Australia. Some practices have four levels of learner. This study aimed to explore how multi-level teaching (also called vertical integration of GP education and training) is occurring in clinical general practice and the impact of such teaching on the learner. A qualitative research methodology was used with face-to-face, semi-structured interviews of medical students, junior hospital doctors, GP registrars and GP teachers in eight training practices in the region that taught all levels of learners. Interviews were audio-recorded and transcribed. Qualitative analysis was conducted using thematic analysis techniques aided by the use of the software package N-Vivo 9. Primary themes were identified and categorised by the co-investigators. 52 interviews were completed and analysed. Themes were identified relating to both the practice learning environment and teaching methods used.A practice environment where there is a strong teaching culture, enjoyment of learning, and flexible learning methods, as well as learning spaces and organised teaching arrangements, all contribute to positive learning from a learners' perspective.Learners identified a number of innovative teaching methods and viewed them as positive. These included multi-level learner group tutorials in the practice, being taught by a team of teachers, including GP registrars and other health professionals, and access to a supernumerary GP supervisor (also termed "GP consultant teacher"). Other teaching methods that were viewed positively were parallel consulting, informal learning and rural hospital context integrated learning. Vertical integration of GP education and training generally impacted positively on all levels of learner. This research has provided further evidence about the learning culture, structures and teaching processes that have a positive impact on learners in the clinical general practice setting where there are multiple levels of learners. It has also identified some innovative teaching methods that will need further examination. The findings reinforce the importance of the environment for learning and learner centred approaches and will be important for training organisations developing vertically integrated practices and in their training of GP teachers.

The learner’s perspective in GP teaching practices with multi-level learners: a qualitative study

PubMed Central

2014-01-01

Background Medical students, junior hospital doctors on rotation and general practice (GP) registrars are undertaking their training in clinical general practices in increasing numbers in Australia. Some practices have four levels of learner. This study aimed to explore how multi-level teaching (also called vertical integration of GP education and training) is occurring in clinical general practice and the impact of such teaching on the learner. Methods A qualitative research methodology was used with face-to-face, semi-structured interviews of medical students, junior hospital doctors, GP registrars and GP teachers in eight training practices in the region that taught all levels of learners. Interviews were audio-recorded and transcribed. Qualitative analysis was conducted using thematic analysis techniques aided by the use of the software package N-Vivo 9. Primary themes were identified and categorised by the co-investigators. Results 52 interviews were completed and analysed. Themes were identified relating to both the practice learning environment and teaching methods used. A practice environment where there is a strong teaching culture, enjoyment of learning, and flexible learning methods, as well as learning spaces and organised teaching arrangements, all contribute to positive learning from a learners’ perspective. Learners identified a number of innovative teaching methods and viewed them as positive. These included multi-level learner group tutorials in the practice, being taught by a team of teachers, including GP registrars and other health professionals, and access to a supernumerary GP supervisor (also termed “GP consultant teacher”). Other teaching methods that were viewed positively were parallel consulting, informal learning and rural hospital context integrated learning. Conclusions Vertical integration of GP education and training generally impacted positively on all levels of learner. This research has provided further evidence about the learning culture, structures and teaching processes that have a positive impact on learners in the clinical general practice setting where there are multiple levels of learners. It has also identified some innovative teaching methods that will need further examination. The findings reinforce the importance of the environment for learning and learner centred approaches and will be important for training organisations developing vertically integrated practices and in their training of GP teachers. PMID:24645670

Template-directed synthesis on the pentanucleotide CpCpGpCpC

NASA Technical Reports Server (NTRS)

Inoue, T.; Joyce, G. F.; Grzeskowiak, K.; Orgel, L. E.; Brown, J. M.; Reese, C. B.

1984-01-01

Experiments in which CpCpGpCpC is used as a template to facilitate the co-oligomerization of 2-MeImpG and 2-MeImpC are described. It is shown that 3' to 5' prime-linked pGpGpCpGpG, whose sequence is complementary to that of the template, is substantially the most adundant pentameric product of the template-directed reaction. The yield of pGpGpCpGpG is never large (less than 20 percent), presumably becauase off-template reactions consume template-directed products. Thus pGpGpCpGpG is converted to the various isomers of G5C and G4C2 by off-template terminal addition of G or C. The 3' to 5' isomer of GpG is elongated on the template to give GpGpC, GpGpCpG, and GpGpCpGpG, while the 2' to 5' isomer does not initiate the synthesis of detectable amounts of longer oligomers.

Bayesian Computation for Log-Gaussian Cox Processes: A Comparative Analysis of Methods

PubMed Central

Teng, Ming; Nathoo, Farouk S.; Johnson, Timothy D.

2017-01-01

The Log-Gaussian Cox Process is a commonly used model for the analysis of spatial point pattern data. Fitting this model is difficult because of its doubly-stochastic property, i.e., it is an hierarchical combination of a Poisson process at the first level and a Gaussian Process at the second level. Various methods have been proposed to estimate such a process, including traditional likelihood-based approaches as well as Bayesian methods. We focus here on Bayesian methods and several approaches that have been considered for model fitting within this framework, including Hamiltonian Monte Carlo, the Integrated nested Laplace approximation, and Variational Bayes. We consider these approaches and make comparisons with respect to statistical and computational efficiency. These comparisons are made through several simulation studies as well as through two applications, the first examining ecological data and the second involving neuroimaging data. PMID:29200537

Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

PubMed

Wrobel, Jagoda K; Wolff, Gretchen; Xiao, Rijin; Power, Ronan F; Toborek, Michal

2016-08-01

Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.

Initial diagnosis and management of chronic obstructive pulmonary disease in Australia: views from the coal face.

PubMed

Bereznicki, Bonnie; Walters, Haydn; Walters, Julia; Peterson, Gregory; Bereznicki, Luke

2017-07-01

Early diagnosis and management can mitigate the long-term morbidity and mortality of chronic obstructive pulmonary disease (COPD). To gain insights into the initial diagnostic process and early management of COPD by Australian general practitioners (GP). A random sample of Australian GP was invited to complete a postal survey, which assessed familiarity with and use of contemporary practice guidelines, diagnostic criteria and management preferences for COPD. A total of 233 GP completed the survey. While most GP based a COPD diagnosis on smoking history (94.4%), symptoms (91.0%) and spirometry (88.8%), only 39.9% of respondents recorded a formal diagnosis of COPD after the patient's first symptomatic presentation. Tiotropium was the preferred treatment in 77.3% of GP for the initial management of COPD, while only 27.5% routinely recommended pulmonary rehabilitation. GP routinely recorded patients' smoking status and offered smoking cessation advice, but the timing of this advice varied. Less than half of the respondents routinely used COPD management guidelines or tools and resources provided by the Australian Lung Foundation. There is scope for major improvement in GP familiarity with and use of COPD management guidelines and readily available tools and resources. Some systematic issues were highlighted in the Australian primary care setting, such as a reactive and relatively passive and delayed approach to diagnosis, potentially delayed smoking cessation advice and underutilisation of pulmonary rehabilitation. There is an urgent need to devise strategies for improving patient outcomes in COPD using resources that are readily available. © 2017 Royal Australasian College of Physicians.

Structures of Ebola virus GP and sGP in complex with therapeutic antibodies.

PubMed

Pallesen, Jesper; Murin, Charles D; de Val, Natalia; Cottrell, Christopher A; Hastie, Kathryn M; Turner, Hannah L; Fusco, Marnie L; Flyak, Andrew I; Zeitlin, Larry; Crowe, James E; Andersen, Kristian G; Saphire, Erica Ollmann; Ward, Andrew B

2016-08-08

The Ebola virus (EBOV) GP gene encodes two glycoproteins. The major product is a soluble, dimeric glycoprotein (sGP) that is secreted abundantly. Despite the abundance of sGP during infection, little is known regarding its structure or functional role. A minor product, resulting from transcriptional editing, is the transmembrane-anchored, trimeric viral surface glycoprotein (GP). GP mediates attachment to and entry into host cells, and is the intended target of antibody therapeutics. Because large portions of sequence are shared between GP and sGP, it has been hypothesized that sGP may potentially subvert the immune response or may contribute to pathogenicity. In this study, we present cryo-electron microscopy structures of GP and sGP in complex with GP-specific and GP/sGP cross-reactive antibodies undergoing human clinical trials. The structure of the sGP dimer presented here, in complex with both an sGP-specific antibody and a GP/sGP cross-reactive antibody, permits us to unambiguously assign the oligomeric arrangement of sGP and compare its structure and epitope presentation to those of GP. We also provide biophysical evaluation of naturally occurring GP/sGP mutations that fall within the footprints identified by our high-resolution structures. Taken together, our data provide a detailed and more complete picture of the accessible Ebolavirus glycoprotein landscape and a structural basis to evaluate patient and vaccine antibody responses towards differently structured products of the GP gene.

Pseudomonas aeruginosa phage PaP1 DNA polymerase is an A-family DNA polymerase demonstrating ssDNA and dsDNA 3'-5' exonuclease activity.

PubMed

Liu, Binyan; Gu, Shiling; Liang, Nengsong; Xiong, Mei; Xue, Qizhen; Lu, Shuguang; Hu, Fuquan; Zhang, Huidong

2016-08-01

Most phages contain DNA polymerases, which are essential for DNA replication and propagation in infected host bacteria. However, our knowledge on phage-encoded DNA polymerases remains limited. This study investigated the function of a novel DNA polymerase of PaP1, which is the lytic phage of Pseudomonas aeruginosa. PaP1 encodes its sole DNA polymerase called Gp90 that was predicted as an A-family DNA polymerase with polymerase and 3'-5' exonuclease activities. The sequence of Gp90 is homologous but not identical to that of other A-family DNA polymerases, such as T7 DNA polymerases (Pol) and DNA Pol I. The purified Gp90 demonstrated a polymerase activity. The processivity of Gp90 in DNA replication and its efficiency in single-dNTP incorporation are similar to those of T7 Pol with processive thioredoxin (T7 Pol/trx). Gp90 can degrade ssDNA and dsDNA in 3'-5' direction at a similar rate, which is considerably lower than that of T7 Pol/trx. The optimized conditions for polymerization were a temperature of 37 °C and a buffer consisting of 40 mM Tris-HCl (pH 8.0), 30 mM MgCl2, and 200 mM NaCl. These studies on DNA polymerase encoded by PaP1 help advance our knowledge on phage-encoded DNA polymerases and elucidate PaP1 propagation in infected P. aeruginosa.

Darboux transformation of the coupled nonisospectral Gross-Pitaevskii system and its multi-component generalization

NASA Astrophysics Data System (ADS)

Xu, Tao; Chen, Yong

2018-04-01

In this paper, we extend the one-component Gross-Pitaevskii (GP) equation to the two-component coupled GP system including damping term, linear and parabolic density profiles. The Lax pair with nonisospectral parameter and infinitely-many conservation laws of this coupled GP system are presented. Actually, the Darboux transformation (DT) for this kind of nonautonomous system is essentially different from the autonomous case. Consequently, we construct the DT of the coupled GP equations, besides, nonautonomous multi-solitons, one-breather and the first-order rogue wave are also obtained. Various kinds of one-soliton solution are constructed, which include stationary one-soliton and nonautonomous one-soliton propagating along the negative (positive) direction of x-axis. The interaction of two solitons and two-soliton bound state are demonstrated respectively. We get the nonautonomous one-breather on a curved background and this background is completely controlled by the parameter β. Using a limiting process, the nonautonomous first-order rogue wave can be obtained. Furthermore, some dynamic structures of these analytical solutions are discussed in detail. In addition, the multi-component generalization of GP equations are given, then the corresponding Lax pair and DT are also constructed.

Newly synthesized and recycling pools of the apical protein gp135 do not occupy the same compartments.

PubMed

Stoops, Emily H; Hull, Michael; Caplan, Michael J

2016-12-01

Polarized epithelial cells sort newly synthesized and recycling plasma membrane proteins into distinct trafficking pathways directed to either the apical or basolateral membrane domains. While the trans-Golgi network is a well-established site of protein sorting, increasing evidence indicates a key role for endosomes in the initial trafficking of newly synthesized proteins. Both basolateral and apical proteins have been shown to traverse endosomes en route to the plasma membrane. In particular, apical proteins traffic through either subapical early or recycling endosomes. Here we use the SNAP tag system to analyze the trafficking of the apical protein gp135, also known as podocalyxin. We show that newly synthesized gp135 traverses the apical recycling endosome, but not the apical early endosomes (AEEs). In contrast, post-endocytic gp135 is delivered to the AEE before recycling back to the apical membrane. The pathways pursued by the newly synthesized and recycling gp135 populations do not detectably intersect, demonstrating that the biosynthetic and post-endocytic pools of this protein are subjected to distinct sorting processes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of cholesterol on plasma membrane lipid order in MCF-7 cells by two-photon microscopy

NASA Astrophysics Data System (ADS)

Zeng, Yixiu; Chen, Jianling; Yang, Hongqin; Wang, Yuhua; Li, Hui; Xie, Shusen

2014-09-01

Lipid rafts are cholesterol- and glycosphingolipids- enriched microdomains on plasma membrane surface of mammal cells, involved in a variety of cellular processes. Depleting cholesterol from the plasma membrane by drugs influences the trafficking of lipid raft markers. Optical imaging techniques are powerful tools to study lipid rafts in live cells due to its noninvasive feature. In this study, breast cancer cells MCF-7 were treated with different concentrations of MβCD to deplete cholesterol and an environmentally sensitive fluorescence probe, Laurdan was loaded to image lipid order by two-photon microscopy. The generalized polarization (GP) values were calculated to distinguish the lipid order and disorder phase. GP images and GP distributions of native and cholesterol-depleted MCF-7 cells were obtained. Our results suggest that even at low concentration (0.5 mM) of MβCD, the morphology of the MCF-7 cells changes. Small high GP areas (lipid order phase) decrease more rapidly than low GP areas (lipid disorder phase), indicating that lipid raft structure was altered more severely than nonraft domains. The data demonstrates that cholesterol dramatically affect raft coverage and plasma membrane fluidity in living cells.

Entanglement and Wigner Function Negativity of Multimode Non-Gaussian States

NASA Astrophysics Data System (ADS)

Walschaers, Mattia; Fabre, Claude; Parigi, Valentina; Treps, Nicolas

2017-11-01

Non-Gaussian operations are essential to exploit the quantum advantages in optical continuous variable quantum information protocols. We focus on mode-selective photon addition and subtraction as experimentally promising processes to create multimode non-Gaussian states. Our approach is based on correlation functions, as is common in quantum statistical mechanics and condensed matter physics, mixed with quantum optics tools. We formulate an analytical expression of the Wigner function after the subtraction or addition of a single photon, for arbitrarily many modes. It is used to demonstrate entanglement properties specific to non-Gaussian states and also leads to a practical and elegant condition for Wigner function negativity. Finally, we analyze the potential of photon addition and subtraction for an experimentally generated multimode Gaussian state.

Entanglement and Wigner Function Negativity of Multimode Non-Gaussian States.

PubMed

Walschaers, Mattia; Fabre, Claude; Parigi, Valentina; Treps, Nicolas

2017-11-03

Non-Gaussian operations are essential to exploit the quantum advantages in optical continuous variable quantum information protocols. We focus on mode-selective photon addition and subtraction as experimentally promising processes to create multimode non-Gaussian states. Our approach is based on correlation functions, as is common in quantum statistical mechanics and condensed matter physics, mixed with quantum optics tools. We formulate an analytical expression of the Wigner function after the subtraction or addition of a single photon, for arbitrarily many modes. It is used to demonstrate entanglement properties specific to non-Gaussian states and also leads to a practical and elegant condition for Wigner function negativity. Finally, we analyze the potential of photon addition and subtraction for an experimentally generated multimode Gaussian state.

A Nonlinear Framework of Delayed Particle Smoothing Method for Vehicle Localization under Non-Gaussian Environment.

PubMed

Xiao, Zhu; Havyarimana, Vincent; Li, Tong; Wang, Dong

2016-05-13

In this paper, a novel nonlinear framework of smoothing method, non-Gaussian delayed particle smoother (nGDPS), is proposed, which enables vehicle state estimation (VSE) with high accuracy taking into account the non-Gaussianity of the measurement and process noises. Within the proposed method, the multivariate Student's t-distribution is adopted in order to compute the probability distribution function (PDF) related to the process and measurement noises, which are assumed to be non-Gaussian distributed. A computation approach based on Ensemble Kalman Filter (EnKF) is designed to cope with the mean and the covariance matrix of the proposal non-Gaussian distribution. A delayed Gibbs sampling algorithm, which incorporates smoothing of the sampled trajectories over a fixed-delay, is proposed to deal with the sample degeneracy of particles. The performance is investigated based on the real-world data, which is collected by low-cost on-board vehicle sensors. The comparison study based on the real-world experiments and the statistical analysis demonstrates that the proposed nGDPS has significant improvement on the vehicle state accuracy and outperforms the existing filtering and smoothing methods.

Extracting features of Gaussian self-similar stochastic processes via the Bandt-Pompe approach.

PubMed

Rosso, O A; Zunino, L; Pérez, D G; Figliola, A; Larrondo, H A; Garavaglia, M; Martín, M T; Plastino, A

2007-12-01

By recourse to appropriate information theory quantifiers (normalized Shannon entropy and Martín-Plastino-Rosso intensive statistical complexity measure), we revisit the characterization of Gaussian self-similar stochastic processes from a Bandt-Pompe viewpoint. We show that the ensuing approach exhibits considerable advantages with respect to other treatments. In particular, clear quantifiers gaps are found in the transition between the continuous processes and their associated noises.

Functional studies of P-glycoprotein in inside-out plasma membrane vesicles derived from murine erythroleukemia cells overexpressing MDR 3. Properties and kinetics of the interaction of vinblastine with P-glycoprotein and evidence for its active mediated transport.

PubMed

Schlemmer, S R; Sirotnak, F M

1994-12-09

Active [3H]vinblastine (VBL) transport (efflux) was documented for inside-out plasma membrane vesicles from murine erythroleukemia cells (MEL/VCR-6) resistant to vinca alkaloids and overexpressing MDR 3 P-glycoprotein (P-gp) 80-fold. Uptake of [3H]VBL at 37 degrees C by these inside-out vesicles, but not rightside-out vesicles or inside-out vesicles from wild-type cells, was obtained in the form of a rapid, initial phase (0-1 min) and a slower, later phase (> 1 min). The rapidity of each phase correlated with relative P-gp content among different MEL/VCR cell lines. The initial MDR-specific phase was temperature- and pH-dependent (optimum at pH 7), osmotically insensitive, and did not require ATP. The second MDR-specific phase was temperature-dependent, osmotically sensitive, and strictly dependent upon the presence of ATP (Km = 0.37 +/- 0.04 mM). Although other triphosphate nucleotides were partially effective in replacing ATP, the nonhydrolyzable analogue ATP gamma S (adenosine 5'-O-(thiotriphosphate)) was ineffective. This time course appears to represent tandem binding of [3H]VBL by P-gp and its mediated transport, with the latter process representing the rate-limiting step. In support of this conclusion, both binding and transport were inhibited by verapamil, quinidine, and reserpine, all known to be inhibitors of photoaffinity labeling of P-gp, but only transport was inhibited by C219 anti-P-gp antibody or orthovanadate. Although the rate of transport of [3H]VBL was 7-7.5-fold lower than the rate of binding (Vmax = 104 +/- 15 pmol/min/mg protein, Kon = 1.5 - 2 x 10(5) mol-1 s-1) to P-gp, each phase exhibited saturation kinetics and values for apparent Km and KD for each process were approximately the same (215 +/- 35 and 195 +/- 30 nM). Intravesicular accumulation of [3H]VBL was almost completely eliminated by high concentrations of nonradioactive VBL, suggesting that simple diffusion does not contribute appreciably to total accumulation of [3H]VBL in this vesicle system. This could be at least partially explained by the fact that these inside-out vesicles under the conditions employed did not maintain a P-gp mediated pH gradient. However, ATP-dependent, intravesicular accumulation of osmotically sensitive [3H]VBL occurred against a substantial permeant concentration gradient in both a time- and concentration-dependent manner consistent with an active, saturable process.

Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4+ Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

PubMed Central

Li, Tingfeng; Steede, N. Kalaya; Nguyen, Hong-Nam P.; Freytag, Lucy C.; McLachlan, James B.; Mettu, Ramgopal R.; Robinson, James E.

2014-01-01

ABSTRACT Helper T-cell epitope dominance in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is not adequately explained by peptide binding to major histocompatibility complex (MHC) proteins. Antigen processing potentially influences epitope dominance, but few, if any, studies have attempted to reconcile the influences of antigen processing and MHC protein binding for all helper T-cell epitopes of an antigen. Epitopes of gp120 identified in both humans and mice occur on the C-terminal flanks of flexible segments that are likely to be proteolytic cleavage sites. In this study, the influence of gp120 conformation on the dominance pattern in gp120 from HIV strain 89.6 was examined in CBA mice, whose MHC class II protein has one of the most well defined peptide-binding preferences. Only one of six dominant epitopes contained the most conserved element of the I-Ak binding motif, an aspartic acid. Destabilization of the gp120 conformation by deletion of single disulfide bonds preferentially enhanced responses to the cryptic I-Ak motif-containing sequences, as reported by T-cell proliferation or cytokine secretion. Conversely, inclusion of CpG in the adjuvant with gp120 enhanced responses to the dominant CD4+ T-cell epitopes. The gp120 destabilization affected secretion of some cytokines more than others, suggesting that antigen conformation could modulate T-cell functions through mechanisms of antigen processing. IMPORTANCE CD4+ helper T cells play an essential role in protection against HIV and other pathogens. Thus, the sites of helper T-cell recognition, the dominant epitopes, are targets for vaccine design; and the corresponding T cells may provide markers for monitoring infection and immunity. However, T-cell epitopes are difficult to identify and predict. It is also unclear whether CD4+ T cells specific for one epitope are more protective than T cells specific for other epitopes. This work shows that the three-dimensional (3D) structure of an HIV protein partially determines which epitopes are dominant, most likely by controlling the breakdown of HIV into peptides. Moreover, some types of signals from CD4+ T cells are affected by the HIV protein 3D structure; and thus the protectiveness of a particular peptide vaccine could be related to its location in the 3D structure. PMID:24920818

Coherence degree of the fundamental Bessel-Gaussian beam in turbulent atmosphere

NASA Astrophysics Data System (ADS)

Lukin, Igor P.

2017-11-01

In this article the coherence of a fundamental Bessel-Gaussian optical beam in turbulent atmosphere is analyzed. The problem analysis is based on the solution of the equation for the transverse second-order mutual coherence function of a fundamental Bessel-Gaussian optical beam of optical radiation. The behavior of a coherence degree of a fundamental Bessel-Gaussian optical beam depending on parameters of an optical beam and characteristics of turbulent atmosphere is examined. It was revealed that at low levels of fluctuations in turbulent atmosphere the coherence degree of a fundamental Bessel-Gaussian optical beam has the characteristic oscillating appearance. At high levels of fluctuations in turbulent atmosphere the coherence degree of a fundamental Bessel-Gaussian optical beam is described by an one-scale decreasing curve which in process of increase of level of fluctuations on a line of formation of a laser beam becomes closer to the same characteristic of a spherical optical wave.

Radiation pressure acceleration of corrugated thin foils by Gaussian and super-Gaussian beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adusumilli, K.; Goyal, D.; Tripathi, V. K.

Rayleigh-Taylor instability of radiation pressure accelerated ultrathin foils by laser having Gaussian and super-Gaussian intensity distribution is investigated using a single fluid code. The foil is allowed to have ring shaped surface ripples. The radiation pressure force on such a foil is non-uniform with finite transverse component F{sub r}; F{sub r} varies periodically with r. Subsequently, the ripple grows as the foil moves ahead along z. With a Gaussian beam, the foil acquires an overall curvature due to non-uniformity in radiation pressure and gets thinner. In the process, the ripple perturbation is considerably washed off. With super-Gaussian beam, the ripplemore » is found to be more strongly washed out. In order to avoid transmission of the laser through the thinning foil, a criterion on the foil thickness is obtained.« less

Disentangling inhibition-based and retrieval-based aftereffects of distractors: Cognitive versus motor processes.

PubMed

Singh, Tarini; Laub, Ruth; Burgard, Jan Pablo; Frings, Christian

2018-05-01

Selective attention refers to the ability to selectively act upon relevant information at the expense of irrelevant information. Yet, in many experimental tasks, what happens to the representation of the irrelevant information is still debated. Typically, 2 approaches to distractor processing have been suggested, namely distractor inhibition and distractor-based retrieval. However, it is also typical that both processes are hard to disentangle. For instance, in the negative priming literature (for a review Frings, Schneider, & Fox, 2015) this has been a continuous debate since the early 1980s. In the present study, we attempted to prove that both processes exist, but that they reflect distractor processing at different levels of representation. Distractor inhibition impacts stimulus representation, whereas distractor-based retrieval impacts mainly motor processes. We investigated both processes in a distractor-priming task, which enables an independent measurement of both processes. For our argument that both processes impact different levels of distractor representation, we estimated the exponential parameter (τ) and Gaussian components (μ, σ) of the exponential Gaussian reaction-time (RT) distribution, which have previously been used to independently test the effects of cognitive and motor processes (e.g., Moutsopoulou & Waszak, 2012). The distractor-based retrieval effect was evident for the Gaussian component, which is typically discussed as reflecting motor processes, but not for the exponential parameter, whereas the inhibition component was evident for the exponential parameter, which is typically discussed as reflecting cognitive processes, but not for the Gaussian parameter. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Similarity measure and domain adaptation in multiple mixture model clustering: An application to image processing.

PubMed

Leong, Siow Hoo; Ong, Seng Huat

2017-01-01

This paper considers three crucial issues in processing scaled down image, the representation of partial image, similarity measure and domain adaptation. Two Gaussian mixture model based algorithms are proposed to effectively preserve image details and avoids image degradation. Multiple partial images are clustered separately through Gaussian mixture model clustering with a scan and select procedure to enhance the inclusion of small image details. The local image features, represented by maximum likelihood estimates of the mixture components, are classified by using the modified Bayes factor (MBF) as a similarity measure. The detection of novel local features from MBF will suggest domain adaptation, which is changing the number of components of the Gaussian mixture model. The performance of the proposed algorithms are evaluated with simulated data and real images and it is shown to perform much better than existing Gaussian mixture model based algorithms in reproducing images with higher structural similarity index.

Similarity measure and domain adaptation in multiple mixture model clustering: An application to image processing

PubMed Central

Leong, Siow Hoo

2017-01-01

This paper considers three crucial issues in processing scaled down image, the representation of partial image, similarity measure and domain adaptation. Two Gaussian mixture model based algorithms are proposed to effectively preserve image details and avoids image degradation. Multiple partial images are clustered separately through Gaussian mixture model clustering with a scan and select procedure to enhance the inclusion of small image details. The local image features, represented by maximum likelihood estimates of the mixture components, are classified by using the modified Bayes factor (MBF) as a similarity measure. The detection of novel local features from MBF will suggest domain adaptation, which is changing the number of components of the Gaussian mixture model. The performance of the proposed algorithms are evaluated with simulated data and real images and it is shown to perform much better than existing Gaussian mixture model based algorithms in reproducing images with higher structural similarity index. PMID:28686634

PERIOD ESTIMATION FOR SPARSELY SAMPLED QUASI-PERIODIC LIGHT CURVES APPLIED TO MIRAS

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Shiyuan; Huang, Jianhua Z.; Long, James

2016-12-01

We develop a nonlinear semi-parametric Gaussian process model to estimate periods of Miras with sparsely sampled light curves. The model uses a sinusoidal basis for the periodic variation and a Gaussian process for the stochastic changes. We use maximum likelihood to estimate the period and the parameters of the Gaussian process, while integrating out the effects of other nuisance parameters in the model with respect to a suitable prior distribution obtained from earlier studies. Since the likelihood is highly multimodal for period, we implement a hybrid method that applies the quasi-Newton algorithm for Gaussian process parameters and search the period/frequencymore » parameter space over a dense grid. A large-scale, high-fidelity simulation is conducted to mimic the sampling quality of Mira light curves obtained by the M33 Synoptic Stellar Survey. The simulated data set is publicly available and can serve as a testbed for future evaluation of different period estimation methods. The semi-parametric model outperforms an existing algorithm on this simulated test data set as measured by period recovery rate and quality of the resulting period–luminosity relations.« less

Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.

PubMed

Sowalsky, Adam G; Kissick, Haydn T; Gerrin, Sean J; Schaefer, Rachel J; Xia, Zheng; Russo, Joshua W; Arredouani, M Simo; Bubley, Glenn J; Sanda, Martin G; Li, Wei; Ye, Huihui; Balk, Steven P

2017-07-15

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823-33. ©2017 AACR . ©2017 American Association for Cancer Research.

Structural constraints determine the glycosylation of HIV-1 envelope trimers

PubMed Central

Pritchard, Laura K.; Vasiljevic, Snezana; Ozorowski, Gabriel; Seabright, Gemma E.; Cupo, Albert; Ringe, Rajesh; Kim, Helen J.; Sanders, Rogier W.; Doores, Katie J.; Burton, Dennis R.; Wilson, Ian A.; Ward, Andrew B.; Moore, John P.; Crispin, Max

2015-01-01

A highly glycosylated, trimeric envelope glycoprotein (Env) mediates HIV-1 cell entry. The high density and heterogeneity of the glycans shield Env from recognition by the immune system but, paradoxically, many potent broadly neutralizing antibodies (bNAbs) recognize epitopes involving this glycan shield. To better understand Env glycosylation and its role in bNAb recognition, we characterized a soluble, cleaved recombinant trimer (BG505 SOSIP.664) that is a close structural and antigenic mimic of native Env. Large, unprocessed oligomannose-type structures (Man8-9GlcNAc2) are notably prevalent on the gp120 components of the trimer, irrespective of the mammalian cell expression system or the bNAb used for affinity-purification. In contrast, gp41 subunits carry more highly processed glycans. The glycans on uncleaved, non-native oligomeric gp140 proteins are also highly processed. A homogeneous, oligomannose-dominated glycan profile is therefore a hallmark of a native Env conformation and a potential Achilles’ heel that can be exploited for bNAb recognition and vaccine design. PMID:26051934

An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP.

PubMed

Mathieu, Cécile; Duval, Romain; Cocaign, Angélique; Petit, Emile; Bui, Linh-Chi; Haddad, Iman; Vinh, Joelle; Etchebest, Catherine; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

2016-11-11

Brain glycogen and its metabolism are increasingly recognized as major players in brain functions. Moreover, alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. In the brain, both muscle and brain glycogen phosphorylase isozymes regulate glycogen mobilization. However, given their distinct regulatory features, these two isozymes could confer distinct metabolic functions of glycogen in brain. Interestingly, recent proteomics studies have identified isozyme-specific reactive cysteine residues in brain glycogen phosphorylase (bGP). In this study, we show that the activity of human bGP is redox-regulated through the formation of a disulfide bond involving a highly reactive cysteine unique to the bGP isozyme. We found that this disulfide bond acts as a redox switch that precludes the allosteric activation of the enzyme by AMP without affecting its activation by phosphorylation. This unique regulatory feature of bGP sheds new light on the isoform-specific regulation of glycogen phosphorylase and glycogen metabolism. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Ovalbumin-derived precursor peptides are transferred sequentially from gp96 and calreticulin to MHC I in the endoplasmic reticulum

PubMed Central

Kropp, Laura E.; Garg, Manish; Binder, Robert J.

2010-01-01

Cellular peptides generated by proteasomal degradation of proteins in the cytosol and destined for presentation by MHC I are associated with several chaperones. Hsp70, hsp90 and the TCP1-ring complex have been implicated as important cytosolic players for chaperoning these peptides. In this study we report that gp96 and calreticulin are essential for chaperoning peptides in the endoplasmic reticulum. Importantly we demonstrate that cellular peptides are transferred sequentially from gp96 to calreticulin and then to MHC I forming a relay line. Disruption of this relay line by removal of gp96 or calreticulin prevents the binding of peptides by MHC I and hence presentation of the MHC I-peptide complex on the cell surface. Our results are important for understanding how peptides are processed and trafficked within the endoplasmic reticulum before exiting in association with MHC I heavy chains and β2-microglobulin as a trimolecular complex. PMID:20410492

Spectral imaging toolbox: segmentation, hyperstack reconstruction, and batch processing of spectral images for the determination of cell and model membrane lipid order.

PubMed

Aron, Miles; Browning, Richard; Carugo, Dario; Sezgin, Erdinc; Bernardino de la Serna, Jorge; Eggeling, Christian; Stride, Eleanor

2017-05-12

Spectral imaging with polarity-sensitive fluorescent probes enables the quantification of cell and model membrane physical properties, including local hydration, fluidity, and lateral lipid packing, usually characterized by the generalized polarization (GP) parameter. With the development of commercial microscopes equipped with spectral detectors, spectral imaging has become a convenient and powerful technique for measuring GP and other membrane properties. The existing tools for spectral image processing, however, are insufficient for processing the large data sets afforded by this technological advancement, and are unsuitable for processing images acquired with rapidly internalized fluorescent probes. Here we present a MATLAB spectral imaging toolbox with the aim of overcoming these limitations. In addition to common operations, such as the calculation of distributions of GP values, generation of pseudo-colored GP maps, and spectral analysis, a key highlight of this tool is reliable membrane segmentation for probes that are rapidly internalized. Furthermore, handling for hyperstacks, 3D reconstruction and batch processing facilitates analysis of data sets generated by time series, z-stack, and area scan microscope operations. Finally, the object size distribution is determined, which can provide insight into the mechanisms underlying changes in membrane properties and is desirable for e.g. studies involving model membranes and surfactant coated particles. Analysis is demonstrated for cell membranes, cell-derived vesicles, model membranes, and microbubbles with environmentally-sensitive probes Laurdan, carboxyl-modified Laurdan (C-Laurdan), Di-4-ANEPPDHQ, and Di-4-AN(F)EPPTEA (FE), for quantification of the local lateral density of lipids or lipid packing. The Spectral Imaging Toolbox is a powerful tool for the segmentation and processing of large spectral imaging datasets with a reliable method for membrane segmentation and no ability in programming required. The Spectral Imaging Toolbox can be downloaded from https://uk.mathworks.com/matlabcentral/fileexchange/62617-spectral-imaging-toolbox .

GPU-powered Shotgun Stochastic Search for Dirichlet process mixtures of Gaussian Graphical Models

PubMed Central

Mukherjee, Chiranjit; Rodriguez, Abel

2016-01-01

Gaussian graphical models are popular for modeling high-dimensional multivariate data with sparse conditional dependencies. A mixture of Gaussian graphical models extends this model to the more realistic scenario where observations come from a heterogenous population composed of a small number of homogeneous sub-groups. In this paper we present a novel stochastic search algorithm for finding the posterior mode of high-dimensional Dirichlet process mixtures of decomposable Gaussian graphical models. Further, we investigate how to harness the massive thread-parallelization capabilities of graphical processing units to accelerate computation. The computational advantages of our algorithms are demonstrated with various simulated data examples in which we compare our stochastic search with a Markov chain Monte Carlo algorithm in moderate dimensional data examples. These experiments show that our stochastic search largely outperforms the Markov chain Monte Carlo algorithm in terms of computing-times and in terms of the quality of the posterior mode discovered. Finally, we analyze a gene expression dataset in which Markov chain Monte Carlo algorithms are too slow to be practically useful. PMID:28626348

GPU-powered Shotgun Stochastic Search for Dirichlet process mixtures of Gaussian Graphical Models.

PubMed

Mukherjee, Chiranjit; Rodriguez, Abel

2016-01-01

Gaussian graphical models are popular for modeling high-dimensional multivariate data with sparse conditional dependencies. A mixture of Gaussian graphical models extends this model to the more realistic scenario where observations come from a heterogenous population composed of a small number of homogeneous sub-groups. In this paper we present a novel stochastic search algorithm for finding the posterior mode of high-dimensional Dirichlet process mixtures of decomposable Gaussian graphical models. Further, we investigate how to harness the massive thread-parallelization capabilities of graphical processing units to accelerate computation. The computational advantages of our algorithms are demonstrated with various simulated data examples in which we compare our stochastic search with a Markov chain Monte Carlo algorithm in moderate dimensional data examples. These experiments show that our stochastic search largely outperforms the Markov chain Monte Carlo algorithm in terms of computing-times and in terms of the quality of the posterior mode discovered. Finally, we analyze a gene expression dataset in which Markov chain Monte Carlo algorithms are too slow to be practically useful.

Non-Gaussian operations on bosonic modes of light: Photon-added Gaussian channels

NASA Astrophysics Data System (ADS)

Sabapathy, Krishna Kumar; Winter, Andreas

2017-06-01

We present a framework for studying bosonic non-Gaussian channels of continuous-variable systems. Our emphasis is on a class of channels that we call photon-added Gaussian channels, which are experimentally viable with current quantum-optical technologies. A strong motivation for considering these channels is the fact that it is compulsory to go beyond the Gaussian domain for numerous tasks in continuous-variable quantum information processing such as entanglement distillation from Gaussian states and universal quantum computation. The single-mode photon-added channels we consider are obtained by using two-mode beam splitters and squeezing operators with photon addition applied to the ancilla ports giving rise to families of non-Gaussian channels. For each such channel, we derive its operator-sum representation, indispensable in the present context. We observe that these channels are Fock preserving (coherence nongenerating). We then report two examples of activation using our scheme of photon addition, that of quantum-optical nonclassicality at outputs of channels that would otherwise output only classical states and of both the quantum and private communication capacities, hinting at far-reaching applications for quantum-optical communication. Further, we see that noisy Gaussian channels can be expressed as a convex mixture of these non-Gaussian channels. We also present other physical and information-theoretic properties of these channels.

q-Gaussian distributions and multiplicative stochastic processes for analysis of multiple financial time series

NASA Astrophysics Data System (ADS)

Sato, Aki-Hiro

2010-12-01

This study considers q-Gaussian distributions and stochastic differential equations with both multiplicative and additive noises. In the M-dimensional case a q-Gaussian distribution can be theoretically derived as a stationary probability distribution of the multiplicative stochastic differential equation with both mutually independent multiplicative and additive noises. By using the proposed stochastic differential equation a method to evaluate a default probability under a given risk buffer is proposed.

Gaussian process inference for estimating pharmacokinetic parameters of dynamic contrast-enhanced MR images.

PubMed

Wang, Shijun; Liu, Peter; Turkbey, Baris; Choyke, Peter; Pinto, Peter; Summers, Ronald M

2012-01-01

In this paper, we propose a new pharmacokinetic model for parameter estimation of dynamic contrast-enhanced (DCE) MRI by using Gaussian process inference. Our model is based on the Tofts dual-compartment model for the description of tracer kinetics and the observed time series from DCE-MRI is treated as a Gaussian stochastic process. The parameter estimation is done through a maximum likelihood approach and we propose a variant of the coordinate descent method to solve this likelihood maximization problem. The new model was shown to outperform a baseline method on simulated data. Parametric maps generated on prostate DCE data with the new model also provided better enhancement of tumors, lower intensity on false positives, and better boundary delineation when compared with the baseline method. New statistical parameter maps from the process model were also found to be informative, particularly when paired with the PK parameter maps.

Multitask visual learning using genetic programming.

PubMed

Jaśkowski, Wojciech; Krawiec, Krzysztof; Wieloch, Bartosz

2008-01-01

We propose a multitask learning method of visual concepts within the genetic programming (GP) framework. Each GP individual is composed of several trees that process visual primitives derived from input images. Two trees solve two different visual tasks and are allowed to share knowledge with each other by commonly calling the remaining GP trees (subfunctions) included in the same individual. The performance of a particular tree is measured by its ability to reproduce the shapes contained in the training images. We apply this method to visual learning tasks of recognizing simple shapes and compare it to a reference method. The experimental verification demonstrates that such multitask learning often leads to performance improvements in one or both solved tasks, without extra computational effort.

Gaussian temporal modulation for the behavior of multi-sinc Schell-model pulses in dispersive media

NASA Astrophysics Data System (ADS)

Liu, Xiayin; Zhao, Daomu; Tian, Kehan; Pan, Weiqing; Zhang, Kouwen

2018-06-01

A new class of pulse source with correlation being modeled by the convolution operation of two legitimate temporal correlation function is proposed. Particularly, analytical formulas for the Gaussian temporally modulated multi-sinc Schell-model (MSSM) pulses generated by such pulse source propagating in dispersive media are derived. It is demonstrated that the average intensity of MSSM pulses on propagation are reshaped from flat profile or a train to a distribution with a Gaussian temporal envelope by adjusting the initial correlation width of the Gaussian pulse. The effects of the Gaussian temporal modulation on the temporal degree of coherence of the MSSM pulse are also analyzed. The results presented here show the potential of coherence modulation for pulse shaping and pulsed laser material processing.

Improved Gaussian Beam-Scattering Algorithm

NASA Technical Reports Server (NTRS)

Lock, James A.

1995-01-01

The localized model of the beam-shape coefficients for Gaussian beam-scattering theory by a spherical particle provides a great simplification in the numerical implementation of the theory. We derive an alternative form for the localized coefficients that is more convenient for computer computations and that provides physical insight into the details of the scattering process. We construct a FORTRAN program for Gaussian beam scattering with the localized model and compare its computer run time on a personal computer with that of a traditional Mie scattering program and with three other published methods for computing Gaussian beam scattering. We show that the analytical form of the beam-shape coefficients makes evident the fact that the excitation rate of morphology-dependent resonances is greatly enhanced for far off-axis incidence of the Gaussian beam.

Gaussian mixture models as flux prediction method for central receivers

NASA Astrophysics Data System (ADS)

Grobler, Annemarie; Gauché, Paul; Smit, Willie

2016-05-01

Flux prediction methods are crucial to the design and operation of central receiver systems. Current methods such as the circular and elliptical (bivariate) Gaussian prediction methods are often used in field layout design and aiming strategies. For experimental or small central receiver systems, the flux profile of a single heliostat often deviates significantly from the circular and elliptical Gaussian models. Therefore a novel method of flux prediction was developed by incorporating the fitting of Gaussian mixture models onto flux profiles produced by flux measurement or ray tracing. A method was also developed to predict the Gaussian mixture model parameters of a single heliostat for a given time using image processing. Recording the predicted parameters in a database ensures that more accurate predictions are made in a shorter time frame.

Continuous and simultaneous estimation of finger kinematics using inputs from an EMG-to-muscle activation model.

PubMed

Ngeo, Jimson G; Tamei, Tomoya; Shibata, Tomohiro

2014-08-14

Surface electromyography (EMG) signals are often used in many robot and rehabilitation applications because these reflect motor intentions of users very well. However, very few studies have focused on the accurate and proportional control of the human hand using EMG signals. Many have focused on discrete gesture classification and some have encountered inherent problems such as electro-mechanical delays (EMD). Here, we present a new method for estimating simultaneous and multiple finger kinematics from multi-channel surface EMG signals. In this study, surface EMG signals from the forearm and finger kinematic data were extracted from ten able-bodied subjects while they were tasked to do individual and simultaneous multiple finger flexion and extension movements in free space. Instead of using traditional time-domain features of EMG, an EMG-to-Muscle Activation model that parameterizes EMD was used and shown to give better estimation performance. A fast feed forward artificial neural network (ANN) and a nonparametric Gaussian Process (GP) regressor were both used and evaluated to estimate complex finger kinematics, with the latter rarely used in the other related literature. The estimation accuracies, in terms of mean correlation coefficient, were 0.85 ± 0.07, 0.78 ± 0.06 and 0.73 ± 0.04 for the metacarpophalangeal (MCP), proximal interphalangeal (PIP) and the distal interphalangeal (DIP) finger joint DOFs, respectively. The mean root-mean-square error in each individual DOF ranged from 5 to 15%. We show that estimation improved using the proposed muscle activation inputs compared to other features, and that using GP regression gave better estimation results when using fewer training samples. The proposed method provides a viable means of capturing the general trend of finger movements and shows a good way of estimating finger joint kinematics using a muscle activation model that parameterizes EMD. The results from this study demonstrates a potential control strategy based on EMG that can be applied for simultaneous and continuous control of multiple DOF(s) devices such as robotic hand/finger prostheses or exoskeletons.

CB2 Receptor Agonists Protect Human Dopaminergic Neurons against Damage from HIV-1 gp120

PubMed Central

Hu, Shuxian; Sheng, Wen S.; Rock, R. Bryan

2013-01-01

Despite the therapeutic impact of anti-retroviral therapy, HIV-1-associated neurocognitive disorder (HAND) remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Recent work suggests that the nigrostriatal dopaminergic area is a critical brain region for the neuronal dysfunction and death seen in HAND and that human dopaminergic neurons have a particular sensitivity to gp120-induced damage, manifested as reduced function (decreased dopamine uptake), morphological changes, and reduced viability. Synthetic cannabinoids inhibit HIV-1 expression in human microglia, suppress production of inflammatory mediators in human astrocytes, and there is substantial literature demonstrating the neuroprotective properties of cannabinoids in other neuropathogenic processes. Based on these data, experiments were designed to test the hypothesis that synthetic cannabinoids will protect dopaminergic neurons against the toxic effects of the HIV-1 protein gp120. Using a human mesencephalic neuronal/glial culture model, which contains dopaminergic neurons, microglia, and astrocytes, we were able to show that the CB1/CB2 agonist WIN55,212-2 blunts gp120-induced neuronal damage as measured by dopamine transporter function, apoptosis and lipid peroxidation; these actions were mediated principally by the CB2 receptor. Adding supplementary human microglia to our cultures enhances gp120-induced damage; WIN55,212-2 is able to alleviate this enhanced damage. Additionally, WIN55,212-2 inhibits gp120-induced superoxide production by purified human microglial cells, inhibits migration of human microglia towards supernatants generated from gp120-stimulated human mesencephalic neuronal/glial cultures and reduces chemokine and cytokine production from the human mesencephalic neuronal/glial cultures. These data suggest that synthetic cannabinoids are capable of protecting human dopaminergic neurons from gp120 in a variety of ways, acting principally through the CB2 receptors and microglia. PMID:24147028

Consulting room computers and their effect on general practitioner-patient communication.

PubMed

Noordman, Janneke; Verhaak, Peter; van Beljouw, Ilse; van Dulmen, Sandra

2010-12-01

in the western medical world, computers form part of the standard equipment in the consulting rooms of most GPs. As the use of a computer requires time and attention from GPs, this may well interfere with the communication process. Yet, the information accessed on the computer may also enhance communication. the present study affords insight into the relationship between computer use and GP-patient communication recorded by the same GPs over two periods. videotaped GP consultations collected in 2001 and 2008 were used to observe computer use and GP-patient communication. In addition, patients questionnaires about their experiences with communication by the GP were analysed using multilevel models with patients (Level 1) nested within GPs (Level 2). both in 2008 and in 2001, GPs used their computer in almost every consultation. Still, our study showed a change in computer use by the GPs over time. In addition, the results indicate that computer use is negatively related to some communication aspects: the patient-directed gaze of the GP and the amount of information given by GPs. There is also a negative association between computer use and the body posture of the GP. Computer use by GPs is not associated with other (analysed) non-verbal and verbal behaviour of GPs and patients. Moreover, computer use is scarcely related to patients' experiences with the communication behaviour of the GP. GPs show greater reluctance to use computers in 2008 compared to 2001. Computer use can indeed affect the communication between GPs and patients. Therefore, GPs ought to remain aware of their computer use during consultations and at the same time keep the interaction with the patient alive.

An endogenous inhibitor of angiogenesis derived from a transitional cell carcinoma: clipped beta2-glycoprotein-I.

PubMed

Beecken, Wolf-Dietrich C; Engl, Tobias; Ringel, Eva M; Camphausen, Kevin; Michaelis, Martin; Jonas, Dietger; Folkman, Judah; Shing, Yuen; Blaheta, Roman A

2006-09-01

Invasive cell carcinoma of the bladder often develops after complete transurethral excision of superficial transitional cell carcinoma. It has been postulated that primary tumors release angiogenesis-blocking proteins which suppress distant metastases. We have identified an endogenous protein which might be responsible for tumor dormancy. A transitional cell carcinoma cell line was developed (UMUC-3i) which inhibits the growth of a tumor implant at a distant site in SCID mice. Conditioned media of UMUC-3i cultured cells was first pooled and then fractioned, and the capacity of individual components to block endothelial cell growth was tested. The protein fraction responsible for blocking endothelial cell growth was identified by N-terminal amino acid sequencing as well as by mass-spectrometry. The effects of the purified protein in preventing endothelial cell proliferation and tube formation in an in vitro angiogenesis assay was investigated. The plasma protein beta(2)-glycoprotein-I (beta(2)gpI) was isolated and identified from conditioned medium of UMUC-3i cultured cells. Based on the in vitro angiogenesis assay, beta(2)gpI strongly inhibited endothelial cell growth and tube formation, whereby the inhibitory activity corresponded to the clipped version of beta(2)gpI (cbeta(2)gpI). Clipping was induced by adding plasmin at a molar ratio 1:15 (plasmin:substrate). Further analysis indicated that cbeta(2)gpI effects were mediated by annexin II surface receptors expressed on endothelial cells. cbeta2gpI may be involved in blocking angiogenic processes and bladder cancer progression. In this case, cbeta2gpI may be a promising tool in bladder cancer therapy.

Diversity and evolution analysis of glycoprotein GP85 from avian leukosis virus subgroup J isolates from chickens of different genetic backgrounds during 1989-2016: Coexistence of five extremely different clusters.

PubMed

Wang, Peikun; Lin, Lulu; Li, Haijuan; Yang, Yongli; Huang, Teng; Wei, Ping

2018-02-01

ALV-J has caused the most serious losses to the poultry industry in China. The gp85-coding sequence of ALV-J is known to be prone to mutation, but any association between the gp85 gene and breed of chicken remains unclear. A comprehensive and systematic study of the evolutionary process of ALV-J in China is needed. In this study, we compared and analyzed gp85 gene sequences from 198 ALV-J isolates, originating from China, USA, UK and France during 1989-2016. These were sorted into five clusters. Cluster 1, 2, 3, 4 and 5 included isolates from chicken types of different genetic backgrounds, e.g. white-feather broiler, Guangxi indigenous chicken breeds, Yellow chickens and layer chickens respectively. A correlation comparison of amino acid sequence similarities in the gp85 protein among the five clusters showed significant differences (P < 0.01) with the exception being when the third and fifth cluster were compared (P > 0.05). Results of entropy analysis of the gp85 sequences revealed that cluster 3 had the largest variation and cluster 1 had the least variation. The N-glycosylation sites in the majority of isolates numbered 14, 16, 17, 16 and 16, respectively, with regards to clusters 1-5. In addition, 5 isolates from cluster 3 had one more glycosylation site than the other isolates from cluster 3. Our study provides evidence that there were five extremely different ALV-J clusters during 1989-2016 and that the gp85 genes isolated from indigenous chicken breed isolates had the largest variation.

Marburg Virus Glycoprotein GP2: pH-Dependent Stability of the Ectodomain α-Helical Bundle†

PubMed Central

Harrison, Joseph S.; Koellhoffer, Jayne F.; Chandran, Kartik; Lai, Jonathan R.

2012-01-01

Marburg virus (MARV) and Ebola virus (EBOV) constitute the family Filoviridae of enveloped viruses (filoviruses) that cause severe hemorrhagic fever. Infection by MARV is required for fusion between the host cell and viral membranes, a process that is mediated by the two subunits of the envelope glycoprotein GP1 (surface subunit) and GP2 (transmembrane subunit). Upon viral attachment and uptake, it is believed that the MARV viral fusion machinery is triggered by host factors and environmental conditions found in the endosome. Next, conformational rearrangements in the GP2 ectodomain result in the formation of a highly stable six-helix bundle; this refolding event provides the energetic driving force for membrane fusion. Both GP1 and GP2 from EBOV have been extensively studied, but there is little information available for the MARV glycoproteins. Here we have expressed two variants of the MARV GP2 ectodomain in Escherichia coli and analyzed their biophysical properties. Circular dichroism indicates that the MARV GP2 ectodomain adopts an α-helical conformation, and one variant sediments as a trimer by equilibrium analytical ultracentrifugation. Denaturation studies indicate the α-helical structure is highly stable at pH 5.3 (unfolding energy, ΔGunf H2O, of 33.4 ± 2.5 kcal/mol and melting temperature, Tm, of 75.3 ± 2.1 °C for one variant). Furthermore, we found the α-helical stability to be strongly dependent on pH with higher stability under lower pH conditions (Tm values ranging from ~92 °C at pH 4.0 to ~38 °C at pH 8.0). Mutational analysis suggests two glutamic acid residues (E579 and E580) are partially responsible for this pH-dependent behavior. Based on these results, we hypothesize that pH-dependent folding stability of the MARV GP2 ectodomain provides a mechanism to control conformational preferences such that the six-helix bundle ‘post-fusion’ state is preferred under conditions of appropriately matured endosomes. PMID:22369502

Research in Stochastic Processes and their Applications

DTIC Science & Technology

1993-01-01

goal is to learn how Gaussian and linear signal processing methodologies should be adapted to deal with non-Gaussian regimes. Part III continues the... smoothi fmictions in /I, ami we have a chain C ... C tir C ... C /I’) C 11_ C ... C 1t_, C_ ... C ¢’, 10 4o = fH,; H =H;, H, (Hilbert space). 4ý is a Fr

Cloning and functional characterization of the guinea pig apoptosis inhibitor protein Survivin.

PubMed

Habtemichael, Negusse; Wünsch, Desiree; Bier, Carolin; Tillmann, Sarah; Unruhe, Britta; Frauenknecht, Katrin; Heinrich, Ulf-Rüdiger; Mann, Wolf J; Stauber, Roland H; Knauer, Shirley K

2010-12-01

The guinea pig is widely used as a model to study (patho)physiological processes, such as neurodegenerative disorders. Survivin's dual function as an apoptosis inhibitor and a mitotic regulator is crucial not only for ordered development but its modulation seems crucial also under disease conditions. However, data on the expression and function of the guinea pig Survivin protein (Survivin(Gp)) are currently lacking. Here, we here report the cloning and functional characterization of Survivin(Gp). The respective cDNA was cloned from spleen mRNA, containing a 426 bp open reading frame encoding for a protein of 142aa. Survivin(Gp) displays a high homology to the human and murine orthologue, especially in domains critical for function, such as binding sites for chromosomal passenger complex (CPC) proteins and the nuclear export signal (NES). Notably, phylogenetic analyses revealed that Survivin(Gp) is more related to humans than to rodents. Ectopic expression studies of a Survivin(Gp)-GFP fusion confirmed its dynamic intracellular localization, analogous to the human and murine counterparts. In interphase cells, Survivin(Gp)-GFP was predominantly cytoplasmic and accumulated in the nucleus following export inhibition with leptomycin B (LMB). A typical CPC protein localization during mitosis was observed for Survivin(Gp)-GFP. Microinjection experiments together with genetic knockout demonstrated that the NES is essential for the anti-apoptotic and regulatory role of Survivin(Gp) during cell division. In vivo protein interaction assays further demonstrated its dimerization with human Survivin and its interaction with human CPC proteins. Importantly, RNAi-depletion studies show that Survivin(Gp) can fully substitute for human Survivin as an apoptosis inhibitor and a mitotic effector. Immunohistochemistry, immunofluorescence, and western blotting were employed to detect Survivin expression in guinea pig tissues. Besides its expression in proliferating tissues, such as spleen and liver, we also found Survivin in terminally differentiated cell types. Importantly, Survivin was detectable also in the cochlea, suggesting a potential role for Survivin in the auditory system. We provide the first experimental evidence for the expression of Survivin in the guinea pig. As Survivin(Gp) can substitute for known functions of human Survivin, the guinea pig model will now also allow investigating Survivin's (patho)physiological role and to test Survivin-directed potential therapeutic strategies. Copyright © 2010 Elsevier B.V. All rights reserved.

Multifunctional PLGA Nanobubbles as Theranostic Agents: Combining Doxorubicin and P-gp siRNA Co-Delivery Into Human Breast Cancer Cells and Ultrasound Cellular Imaging.

PubMed

Yang, Hong; Deng, Liwei; Li, Tingting; Shen, Xue; Yan, Jie; Zuo, Liangming; Wu, Chunhui; Liu, Yiyao

2015-12-01

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. One of the effective approaches to overcome MDR is to use nanoparticle-mediated the gene silence of chemotherapeutic export proteins by RNA interference to increase drug accumulation in drug resistant cancer cells. In this work, a new co-delivery system, DOX-PLGA/PEI/P-gp shRNA nanobubbles (NBs) around 327 nm, to overcome doxorubicin (DOX) resistance in MCF-7 human breast cancer was designed and developed. Positively charged polyethylenimine (PEI) were modified onto the surface of DOX-PLGA NBs through DCC/NHS crosslinking, and could efficiently condense P-gp shRNA into DOX-PLGA/PEI NBs at vector/shRNA weight ratios of 70:1 and above. An in vitro release profile demonstrated an efficient DOX release (more than 80%) from DOX-PLGA/PEI NBs at pH 4.4, suggesting a pH-responsive drug release for the multifunctionalized NBs. Cellular experimental results further showed that DOX-PLGA/PEI/P-gp shRNA NBs could facilitate cellular uptake of DOX into cells and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The IC50 of DOX-PLGA NBs against MCF-7/ADR cells was 2-fold lower than that of free DOX. The increased cellular uptake and nuclear accumulation of DOX delivered by DOX-PLGA/PEI/P-gp shRNA NBs in MCF-7/ADR cells was confirmed by fluorescence microscopy and fluorescence spectrophotometry, and might be owning to the down-regulation of P-gp and reduced the efflux of DOX. The cellular uptake mechanism of DOX-PLGA/PEI/P-gp shRNA NBs indicated that the macropinocytosis was one of the pathways for the uptake of NBs by MCF-7/ADR cells, which was also an energy-dependent process. Furthermore, the in vitro cellular ultrasound imaging suggested that the employment of the DOX-PLGA/PEI/P-gp shRNA NBs could efficiently enhance ultrasound imaging of cancer cells. These results demonstrated that the developed DOX-PLGA/PEI/P-gp shRNA NBs is a potential, safe and efficient theranotic agent for cancer therapy and diagnostics.

Gaussian entanglement generation from coherence using beam-splitters

PubMed Central

Wang, Zhong-Xiao; Wang, Shuhao; Ma, Teng; Wang, Tie-Jun; Wang, Chuan

2016-01-01

The generation and quantification of quantum entanglement is crucial for quantum information processing. Here we study the transition of Gaussian correlation under the effect of linear optical beam-splitters. We find the single-mode Gaussian coherence acts as the resource in generating Gaussian entanglement for two squeezed states as the input states. With the help of consecutive beam-splitters, single-mode coherence and quantum entanglement can be converted to each other. Our results reveal that by using finite number of beam-splitters, it is possible to extract all the entanglement from the single-mode coherence even if the entanglement is wiped out before each beam-splitter. PMID:27892537

The HIV-1 gp41 ectodomain is cleaved by matriptase to produce a chemotactic peptide that acts through FPR2

PubMed Central

Wood, Matthew P; Cole, Amy L; Eade, Colleen R; Chen, Li-Mei; Chai, Karl X; Cole, Alexander M

2014-01-01

Several aspects of HIV-1 virulence and pathogenesis are mediated by the envelope protein gp41. Additionally, peptides derived from the gp41 ectodomain have been shown to induce chemotaxis in monocytes and neutrophils. Whereas this chemotactic activity has been reported, it is not known how these peptides could be produced under biological conditions. The heptad repeat 1 (HR1) region of gp41 is exposed to the extracellular environment and could therefore be susceptible to proteolytic processing into smaller peptides. Matriptase is a serine protease expressed at the surface of most epithelia, including the prostate and mucosal surfaces. Here, we present evidence that matriptase efficiently cleaves the HR1 portion of gp41 into a 22-residue chemotactic peptide MAT-1, the sequence of which is highly conserved across HIV-1 clades. We found that MAT-1 induced migration of primary neutrophils and monocytes, the latter of which act as a cellular reservoir of HIV during early stage infection. We then used formyl peptide receptor 1 (FPR1) and FPR2 inhibitors, along with HEK 293 cells, to demonstrate that MAT-1 can induce chemotaxis specifically using FPR2, a receptor found on the surface of monocytes, macrophages and neutrophils. These findings are the first to identify a proteolytic cleavage product of gp41 with chemotactic activity and highlight a potential role for matriptase in HIV-1 transmission and infection at epithelial surfaces and within tissue reservoirs of HIV-1. PMID:24617769

Distinct requirements for signal peptidase processing and function in the stable signal peptide subunit of the Junin virus envelope glycoprotein

DOE Office of Scientific and Technical Information (OSTI.GOV)

York, Joanne; Nunberg, Jack H.

2007-03-01

The arenavirus envelope glycoprotein (GP-C) retains a cleaved and stable signal peptide (SSP) as an essential subunit of the mature complex. This 58-amino-acid residue peptide serves as a signal sequence and is additionally required to enable transit of the assembled GP-C complex to the Golgi, and for pH-dependent membrane fusion activity. We have investigated the C-terminal region of the Junin virus SSP to study the role of the cellular signal peptidase (SPase) in generating SSP. Site-directed mutagenesis at the cleavage site (positions - 1 and - 3) reveals a pattern of side-chain preferences consistent with those of SPase. Although positionmore » - 2 is degenerate for SPase cleavage, this residue in the arenavirus SSP is invariably a cysteine. In the Junin virus, this cysteine is not involved in disulfide bonding. We show that replacement with alanine or serine is tolerated for SPase cleavage but prevents the mutant SSP from associating with GP-C and enabling transport to the cell surface. Conversely, an arginine mutation at position - 1 that prevents SPase cleavage is fully compatible with GP-C-mediated membrane fusion activity when the mutant SSP is provided in trans. These results point to distinct roles of SSP sequences in SPase cleavage and GP-C biogenesis. Further studies of the unique structural organization of the GP-C complex will be important in identifying novel opportunities for antiviral intervention against arenaviral hemorrhagic disease.« less

A non-gaussian model of continuous atmospheric turbulence for use in aircraft design

NASA Technical Reports Server (NTRS)

Reeves, P. M.; Joppa, R. G.; Ganzer, V. M.

1976-01-01

A non-Gaussian model of atmospheric turbulence is presented and analyzed. The model is restricted to the regions of the atmosphere where the turbulence is steady or continuous, and the assumptions of homogeneity and stationarity are justified. Also spatial distribution of turbulence is neglected, so the model consists of three independent, stationary stochastic processes which represent the vertical, lateral, and longitudinal gust components. The non-Gaussian and Gaussian models are compared with experimental data, and it is shown that the Gaussian model underestimates the number of high velocity gusts which occur in the atmosphere, while the non-Gaussian model can be adjusted to match the observed high velocity gusts more satisfactorily. Application of the proposed model to aircraft response is investigated, with particular attention to the response power spectral density, the probability distribution, and the level crossing frequency. A numerical example is presented which illustrates the application of the non-Gaussian model to the study of an aircraft autopilot system. Listings and sample results of a number of computer programs used in working with the model are included.

Utility of learning plans in general practice vocational training: a mixed-methods national study of registrar, supervisor, and educator perspectives.

PubMed

Garth, Belinda; Kirby, Catherine; Silberberg, Peter; Brown, James

2016-08-19

Learning plans are a compulsory component of the training and assessment requirements of general practice (GP) registrars in Australia. There is a small but growing number of studies reporting that learning plans are not well accepted or utilised in general practice training. There is a lack of research examining this apparent contradiction. The aim of this study was to examine use and perceived utility of formal learning plans in GP vocational training. This mixed-method Australian national research project utilised online learning plan usage data from 208 GP registrars and semi-structured focus groups and telephone interviews with 35 GP registrars, 12 recently fellowed GPs, 16 supervisors and 17 medical educators across three Regional Training Providers (RTPs). Qualitative data were analysed thematically using template analysis. Learning plans were used mostly as a log of activities rather than as a planning tool. Most learning needs were entered and ticked off as complete on the same day. Learning plans were perceived as having little value for registrars in their journey to becoming a competent GP, and as a bureaucratic hurdle serving as a distraction rather than an aid to learning. The process of learning planning was valued more so than the documentation of learning planning. This study provides creditable evidence that mandated learning plans are broadly considered by users to be a bureaucratic impediment with little value as a learning tool. It is more important to support registrars in planning their learning than to enforce documentation of this process in a learning plan. If learning planning is to be an assessed competence, methods of assessment other than the submission of a formal learning plan should be explored.

Comparative immunohistochemical characterization of interstitial cells in the urinary bladder of human, guinea pig and pig.

PubMed

Steiner, Clara; Gevaert, Thomas; Ganzer, Roman; De Ridder, Dirk; Neuhaus, Jochen

2018-05-01

Interstitial cells (ICs) are thought to play a functional role in urinary bladder. Animal models are commonly used to elucidate bladder physiology and pathophysiology. However, inter-species comparative studies on ICs are rare. We therefore analyzed ICs and their distribution in the upper lamina propria (ULP), the deeper lamina propria (DLP) and the detrusor muscular layer (DET) of human, guinea pig (GP) and pig. Paraffin slices were examined by immunohistochemistry and 3D confocal immunofluorescence of the mesenchymal intermediate filament vimentin (VIM), alpha-smooth muscle actin (αSMA), platelet-derived growth factor receptor alpha (PDGFRα) and transient receptor potential cation channel A1 (TRPA1). Image stacks were processed for analysis using Huygens software; quantitative analysis was performed with Fiji macros. ICs were identified by immunoreactivity for VIM (excluding blood vessels). In all species ≥ 75% of ULP ICs were VIM + /PDGFRα + and ≥ 90% were VIM + /TRPA1 + . In human and pig ≥ 74% of ULP ICs were VIM + /αSMA + , while in GP the percentage differed significantly with only 37% VIM + /αSMA + ICs. Additionally, over 90% of αSMA + ICs were also TRPA1 + and PDGFRα + in human, GP and pig. In all three species, TRPA1 + and PDGFRα + ICs point to an active role for these cells in bladder physiology, regarding afferent signaling processes and signal modification. We hypothesize that decline in αSMA-positivity in GP reflects adaptation of bladder histology to smaller bladder size. In our experiments, pig bladder proved to be highly comparable to human urinary bladder and seems to provide safer interpretation of experimental findings than GP.

Replication-defective Friend murine leukemia virus particles containing uncleaved gag polyproteins and decreased levels of envelope glycoprotein.

PubMed Central

Collins, J K; Chesebro, B

1981-01-01

An erythroleukemia cell clone, 7C, which failed to produce reverse transcriptase-containing virions or infectious virus, was found to produce noninfectious virus particles by gradient banding of [3H]leucine- and [3H]uridine-labeled virions. The RNA from the 7C virus was shown to consist of the normal 70S size component, which converted to 35S upon heat denaturation. In contrast, the 7C virion proteins showed multiple defects. Analysis of the virion proteins by gel electrophoresis demonstrated that the pr65 gag precursor was incorporated into the 7C virus and that the processing of this precursor was severely diminished. Polymerase proteins pr180gag-pol and pr120pol were also detected in virions, and a third possible polymerase protein, p70, was reduced in size compared to its normal counterpart, p80. Incorporation of the viral gp70 glycoprotein into particles was also reduced 10-fold, despite synthesis and incorporation of gp70 into the 7C cell membrane in normal amounts. Pulse-chase analysis of the synthesis of the viral gag and env proteins in 7C cells showed greatly reduced amounts of pr180gag-pol, pr65gag, p80gag, and p42gag, whereas pr90env, gp70, and spleen focus-forming virus-specific gp55 were synthesized and processed normally. These results suggested that at least one defect in 7C virus was impaired cleavage of gag or pol proteins or both, most likely due to a lack of the appropriate viral protease, and that this lack of cleavage might affect incorporation of gp70 into virus particles. Images PMID:6163868

Impact of Ebola mucin-like domain on antiglycoprotein antibody responses induced by Ebola virus-like particles.

PubMed

Martinez, Osvaldo; Tantral, Lee; Mulherkar, Nirupama; Chandran, Kartik; Basler, Christopher F

2011-11-01

Ebola virus (EBOV) glycoprotein (GP), responsible for mediating host-cell attachment and membrane fusion, contains a heavily glycosylated mucin-like domain hypothesized to shield GP from neutralizing antibodies. To test whether the mucin-like domain inhibits the production and function of anti-GP antibodies, we vaccinated mice with Ebola virus-like particles (VLPs) that express vesicular stomatitis virus G, wild-type EBOV GP (EBGP), EBOV GP without its mucin-like domain (ΔMucGP), or EBOV GP with a Crimean-Congo hemorrhagic fever virus mucin-like domain substituted for the EBOV mucin-like domain (CMsubGP). EBGP-VLP immunized mice elicited significantly higher serum antibody titers toward EBGP or its mutants, as detected by western blot analysis, than did VLP-ΔMucGP. However, EBGP-, ΔMucGP- and CMsubGP-VLP immunized mouse sera contained antibodies that bound to cell surface-expressed GP at similar levels. Furthermore, low but similar neutralizing antibody titers, measured against a vesicular stomatitis virus (VSV) expressing EBGP or ΔMucGP, were present in EBGP, ΔMucGP, and CMsubGP sera, although a slightly higher neutralizing titer (2- to 2.5-fold) was detected in ΔMucGP sera. We conclude that the EBOV GP mucin-like domain can increase relative anti-GP titers, however these titers appear to be directed, at least partly, to denatured GP. Furthermore, removing the mucin-like domain from immunizing VLPs has modest impact on neutralizing antibody titers in serum.

An Effective Post-Filtering Framework for 3-D PET Image Denoising Based on Noise and Sensitivity Characteristics

NASA Astrophysics Data System (ADS)

Kim, Ji Hye; Ahn, Il Jun; Nam, Woo Hyun; Ra, Jong Beom

2015-02-01

Positron emission tomography (PET) images usually suffer from a noticeable amount of statistical noise. In order to reduce this noise, a post-filtering process is usually adopted. However, the performance of this approach is limited because the denoising process is mostly performed on the basis of the Gaussian random noise. It has been reported that in a PET image reconstructed by the expectation-maximization (EM), the noise variance of each voxel depends on its mean value, unlike in the case of Gaussian noise. In addition, we observe that the variance also varies with the spatial sensitivity distribution in a PET system, which reflects both the solid angle determined by a given scanner geometry and the attenuation information of a scanned object. Thus, if a post-filtering process based on the Gaussian random noise is applied to PET images without consideration of the noise characteristics along with the spatial sensitivity distribution, the spatially variant non-Gaussian noise cannot be reduced effectively. In the proposed framework, to effectively reduce the noise in PET images reconstructed by the 3-D ordinary Poisson ordered subset EM (3-D OP-OSEM), we first denormalize an image according to the sensitivity of each voxel so that the voxel mean value can represent its statistical properties reliably. Based on our observation that each noisy denormalized voxel has a linear relationship between the mean and variance, we try to convert this non-Gaussian noise image to a Gaussian noise image. We then apply a block matching 4-D algorithm that is optimized for noise reduction of the Gaussian noise image, and reconvert and renormalize the result to obtain a final denoised image. Using simulated phantom data and clinical patient data, we demonstrate that the proposed framework can effectively suppress the noise over the whole region of a PET image while minimizing degradation of the image resolution.

Feline immunodeficiency virus envelope glycoprotein mediates apoptosis in activated PBMC by a mechanism dependent on gp41 function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garg, Himanshu; Joshi, Anjali; Tompkins, Wayne A.

2004-12-20

Feline Immunodeficiency Virus (FIV) is a lentivirus that causes immunodeficiency in cats, which parallels HIV-1-induced immunodeficiency in humans. It has been established that HIV envelope (Env) glycoprotein mediates T cell loss via a mechanism that requires CXCR4 binding. The Env glycoprotein of FIV, similar to HIV, requires CXCR4 binding for viral entry, as well as inducing membrane fusion leading to syncytia formation. However, the role of FIV Env in T cell loss and the molecular mechanisms governing this process have not been elucidated. We studied the role of Env glycoprotein in FIV-mediated T cell apoptosis in an in vitro model.more » Our studies demonstrate that membrane-expressed FIV Env induces apoptosis in activated feline peripheral blood mononuclear cells (PBMC) by a mechanism that requires CXCR4 binding, as the process was inhibited by CXCR4 antagonist AMD3100 in a dose-dependent manner. Interestingly, studies regarding the role of CD134, the recently identified primary receptor of FIV, suggest that binding to CD134 may not be important for induction of apoptosis in PBMC. However, inhibiting Env-mediated fusion post CXCR4 binding by FIV gp41-specific fusion inhibitor also inhibited apoptosis. Under similar conditions, a fusion-defective gp41 mutant was unable to induce apoptosis in activated PBMC. Our findings are the first report suggesting the potential of FIV Env to mediate apoptosis in bystander cells by a process that is dependent on gp41 function.« less

A Nonlinear Framework of Delayed Particle Smoothing Method for Vehicle Localization under Non-Gaussian Environment

PubMed Central

Xiao, Zhu; Havyarimana, Vincent; Li, Tong; Wang, Dong

2016-01-01

In this paper, a novel nonlinear framework of smoothing method, non-Gaussian delayed particle smoother (nGDPS), is proposed, which enables vehicle state estimation (VSE) with high accuracy taking into account the non-Gaussianity of the measurement and process noises. Within the proposed method, the multivariate Student’s t-distribution is adopted in order to compute the probability distribution function (PDF) related to the process and measurement noises, which are assumed to be non-Gaussian distributed. A computation approach based on Ensemble Kalman Filter (EnKF) is designed to cope with the mean and the covariance matrix of the proposal non-Gaussian distribution. A delayed Gibbs sampling algorithm, which incorporates smoothing of the sampled trajectories over a fixed-delay, is proposed to deal with the sample degeneracy of particles. The performance is investigated based on the real-world data, which is collected by low-cost on-board vehicle sensors. The comparison study based on the real-world experiments and the statistical analysis demonstrates that the proposed nGDPS has significant improvement on the vehicle state accuracy and outperforms the existing filtering and smoothing methods. PMID:27187405

Computationally efficient algorithm for Gaussian Process regression in case of structured samples

NASA Astrophysics Data System (ADS)

Belyaev, M.; Burnaev, E.; Kapushev, Y.

2016-04-01

Surrogate modeling is widely used in many engineering problems. Data sets often have Cartesian product structure (for instance factorial design of experiments with missing points). In such case the size of the data set can be very large. Therefore, one of the most popular algorithms for approximation-Gaussian Process regression-can be hardly applied due to its computational complexity. In this paper a computationally efficient approach for constructing Gaussian Process regression in case of data sets with Cartesian product structure is presented. Efficiency is achieved by using a special structure of the data set and operations with tensors. Proposed algorithm has low computational as well as memory complexity compared to existing algorithms. In this work we also introduce a regularization procedure allowing to take into account anisotropy of the data set and avoid degeneracy of regression model.

Design of Fusion Proteins for Efficient and Soluble Production of Immunogenic Ebola Virus Glycoprotein in Escherichia coli.

PubMed

Ji, Yang; Lu, Yuan; Yan, Yishu; Liu, Xinxin; Su, Nan; Zhang, Chong; Bi, Shengli; Xing, Xin-Hui

2018-03-03

The Ebola hemorrhagic fever caused by Ebola virus is an extremely dangerous disease, and effective therapeutic agents are still lacking. Platforms for the efficient production of vaccines are crucial to ensure quick response against an Ebola virus outbreak. Ebola virus glycoprotein (EbolaGP) on the virion surface is responsible for membrane binding and virus entry, thus becoming the key target for vaccine development. However, heterologous expression of this protein still faces engineering challenges such as low production levels and insoluble aggregation. Here, the authors design and compare various fusion strategies, attaching great importance to the solubility-enhancing effect, and tag removal process. It is found that a C-terminal intein-based tag greatly enhances the solubility of EbolaGP and allows one-step chromatographic purification of the untagged EbolaGP through thiol-catalyzed self-cleavage. The purified untagged EbolaGP alone or with Freund's adjuvant are highly immunogenic, as confirmed in a mouse model. Consequently, the present study puts forward a new strategy for the efficient and soluble expression of untagged immunogenic EbolaGP. The intein-based protein fusion approach may be of importance for the large-scale production of Ebola virus subunit vaccine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bayesian Analysis of Non-Gaussian Long-Range Dependent Processes

NASA Astrophysics Data System (ADS)

Graves, Timothy; Watkins, Nicholas; Franzke, Christian; Gramacy, Robert

2013-04-01

Recent studies [e.g. the Antarctic study of Franzke, J. Climate, 2010] have strongly suggested that surface temperatures exhibit long-range dependence (LRD). The presence of LRD would hamper the identification of deterministic trends and the quantification of their significance. It is well established that LRD processes exhibit stochastic trends over rather long periods of time. Thus, accurate methods for discriminating between physical processes that possess long memory and those that do not are an important adjunct to climate modeling. As we briefly review, the LRD idea originated at the same time as H-selfsimilarity, so it is often not realised that a model does not have to be H-self similar to show LRD [e.g. Watkins, GRL Frontiers, 2013]. We have used Markov Chain Monte Carlo algorithms to perform a Bayesian analysis of Auto-Regressive Fractionally-Integrated Moving-Average ARFIMA(p,d,q) processes, which are capable of modeling LRD. Our principal aim is to obtain inference about the long memory parameter, d, with secondary interest in the scale and location parameters. We have developed a reversible-jump method enabling us to integrate over different model forms for the short memory component. We initially assume Gaussianity, and have tested the method on both synthetic and physical time series. Many physical processes, for example the Faraday Antarctic time series, are significantly non-Gaussian. We have therefore extended this work by weakening the Gaussianity assumption, assuming an alpha-stable distribution for the innovations, and performing joint inference on d and alpha. Such a modified FARIMA(p,d,q) process is a flexible, initial model for non-Gaussian processes with long memory. We will present a study of the dependence of the posterior variance of the memory parameter d on the length of the time series considered. This will be compared with equivalent error diagnostics for other measures of d.

Key role of glycoprotein Ib/V/IX and von Willebrand factor in platelet activation-dependent fibrin formation at low shear flow

PubMed Central

Cosemans, Judith M. E. M.; Schols, Saskia E. M.; Stefanini, Lucia; de Witt, Susanne; Feijge, Marion A. H.; Hamulyák, Karly; Deckmyn, Hans; Bergmeier, Wolfgang

2011-01-01

A microscopic method was developed to study the role of platelets in fibrin formation. Perfusion of adhered platelets with plasma under coagulating conditions at a low shear rate (250−1) resulted in the assembly of a star-like fibrin network at the platelet surface. The focal fibrin formation on platelets was preceded by rises in cytosolic Ca2+, morphologic changes, and phosphatidylserine exposure. Fibrin formation was slightly affected by αIIbβ3 blockage, but it was greatly delayed and reduced by the following: inhibition of thrombin or platelet activation; interference in the binding of von Willebrand factor (VWF) to glycoprotein Ib/V/IX (GpIb-V-IX); plasma or blood from patients with type 1 von Willebrand disease; and plasma from mice deficient in VWF or the extracellular domain of GpIbα. In this process, the GpIb-binding A1 domain of VWF was similarly effective as full-length VWF. Prestimulation of platelets enhanced the formation of fibrin, which was abrogated by blockage of phosphatidylserine. Together, these results show that, in the presence of thrombin and low shear flow, VWF-induced activation of GpIb-V-IX triggers platelet procoagulant activity and anchorage of a star-like fibrin network. This process can be relevant in hemostasis and the manifestation of von Willebrand disease. PMID:21037087

Models for the Binary Complex of Bacteriophage T4 Gp59 Helicase Loading Protein. GP32 Single-Stranded DNA-Binding Protein and Ternary Complex with Pseudo-Y Junction DNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hinerman, Jennifer M.; Dignam, J. David; Mueser, Timothy C.

2012-04-05

The bacteriophage T4 gp59 helicase assembly protein (gp59) is required for loading of gp41 replicative helicase onto DNA protected by gp32 single-stranded DNA-binding protein. The gp59 protein recognizes branched DNA structures found at replication and recombination sites. Binding of gp32 protein (full-length and deletion constructs) to gp59 protein measured by isothermal titration calorimetry demonstrates that the gp32 protein C-terminal A-domain is essential for protein-protein interaction in the absence of DNA. Sedimentation velocity experiments with gp59 protein and gp32ΔB protein (an N-terminal B-domain deletion) show that these proteins are monomers but form a 1:1 complex with a dissociation constant comparable withmore » that determined by isothermal titration calorimetry. Small angle x-ray scattering (SAXS) studies indicate that the gp59 protein is a prolate monomer, consistent with the crystal structure and hydrodynamic properties determined from sedimentation velocity experiments. SAXS experiments also demonstrate that gp32ΔB protein is a prolate monomer with an elongated A-domain protruding from the core. Moreover, fitting structures of gp59 protein and the gp32 core into the SAXS-derived molecular envelope supports a model for the gp59 protein-gp32ΔB protein complex. Our earlier work demonstrated that gp59 protein attracts full-length gp32 protein to pseudo-Y junctions. A model of the gp59 protein-DNA complex, modified to accommodate new SAXS data for the binary complex together with mutational analysis of gp59 protein, is presented in the accompanying article (Dolezal, D., Jones, C. E., Lai, X., Brister, J. R., Mueser, T. C., Nossal, N. G., and Hinton, D. M. (2012) J. Biol. Chem. 287, 18596–18607).« less

Genuine functions of P-glycoprotein (ABCB1).

PubMed

Mizutani, Takaharu; Masuda, Masatoshi; Nakai, Emi; Furumiya, Kenji; Togawa, Hiroshi; Nakamura, Yutaka; Kawai, Yuko; Nakahira, Keiko; Shinkai, Shigeko; Takahashi, Kazuhiko

2008-02-01

P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.

Improvement of Transmembrane Transport Mechanism Study of Imperatorin on P-Glycoprotein-Mediated Drug Transport.

PubMed

Liao, Zheng-Gen; Tang, Tao; Guan, Xue-Jing; Dong, Wei; Zhang, Jing; Zhao, Guo-Wei; Yang, Ming; Liang, Xin-Li

2016-11-24

P-glycoprotein (P-gp) affects the transport of many drugs; including puerarin and vincristine. Our previous study demonstrated that imperatorin increased the intestinal absorption of puerarin and vincristine by inhibiting P-gp-mediated drug efflux. However; the underlying mechanism was not known. The present study investigated the mechanism by which imperatorin promotes P-gp-mediated drug transport. We used molecular docking to predict the binding force between imperatorin and P-gp and the effect of imperatorin on P-gp activity. P-gp efflux activity and P-gp ATPase activity were measured using a rhodamine 123 (Rh-123) accumulation assay and a Pgp-Glo™ assay; respectively. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to assess cellular membrane fluidity in MDCK-MDR1 cells. Western blotting was used to analyze the effect of imperatorin on P-gp expression; and P-gp mRNA levels were assessed by qRT-PCR. Molecular docking results demonstrated that the binding force between imperatorin and P-gp was much weaker than the force between P-gp and verapamil (a P-gp substrate). Imperatorin activated P-gp ATPase activity; which had a role in the inhibition of P-gp activity. Imperatorin promoted Rh-123 accumulation in MDCK-MDR1 cells and decreased cellular membrane fluidity. Western blotting demonstrated that imperatorin inhibited P-gp expression; and qRT-PCR revealed that imperatorin down-regulated P-gp (MDR1) gene expression. Imperatorin decreased P-gp-mediated drug efflux by inhibiting P-gp activity and the expression of P-gp mRNA and protein. Our results suggest that imperatorin could down-regulate P-gp expression to overcome multidrug resistance in tumors.

The glycan-mediated mechanism on the interactions of gp120 with CD4 and antibody: Insights from molecular dynamics simulation.

PubMed

Zhang, Yan; Niu, Yuzhen; Tian, Jiaqi; Liu, Xuewei; Yao, Xiaojun; Liu, Huanxiang

2017-12-01

N-linked glycans such as 234 and 276 gp 120 glycans are vital components of HIV evasion from humoral immunity and important for HIV-1 neutralization of many broadly neutralizing antibodies (bNAbs). However, it is unknown the action mechanism of two glycans. To investigate the roles of the glycans on the interactions of gp120 with CD4 and antibody, molecular dynamic simulations based on gp120-CD4-8ANC195 complex with 234 and 276 gp 120 glycans, 234 gp 120 glycan, 276 gp 120 glycan, and without glycan were performed. Our results reveal that 276 gp 120 glycan can enhance gp120-CD4 and gp120-antibody interactions through the formation of hydrogen bonds of the glycan with CD4 and antibody and make the binding interface of gp120, CD4 and antibody stable; 234 gp 120 glycan primarily reinforces gp120-antibody interactions and weakly affects gp120-CD4 interactions as it mainly lies between gp120 and antibody. The co-operating of two glycans can enhance gp120-CD4 and gp120-antibody associations. Through the structural analysis, it can be seen that 234 gp 120 glycan leads to moving upward of two glycans and the variable region of heavy chain, which is favorable for the interactions of gp120 with CD4 and antibody. The information obtained in this study can provide the guidance for design vaccines and small molecule inhibitors. © 2017 John Wiley & Sons A/S.

PHYSICS OF NON-GAUSSIAN FIELDS AND THE COSMOLOGICAL GENUS STATISTIC

DOE Office of Scientific and Technical Information (OSTI.GOV)

James, J. Berian, E-mail: berian@berkeley.edu

2012-05-20

We report a technique to calculate the impact of distinct physical processes inducing non-Gaussianity on the cosmological density field. A natural decomposition of the cosmic genus statistic into an orthogonal polynomial sequence allows complete expression of the scale-dependent evolution of the topology of large-scale structure, in which effects including galaxy bias, nonlinear gravitational evolution, and primordial non-Gaussianity may be delineated. The relationship of this decomposition to previous methods for analyzing the genus statistic is briefly considered and the following applications are made: (1) the expression of certain systematics affecting topological measurements, (2) the quantification of broad deformations from Gaussianity thatmore » appear in the genus statistic as measured in the Horizon Run simulation, and (3) the study of the evolution of the genus curve for simulations with primordial non-Gaussianity. These advances improve the treatment of flux-limited galaxy catalogs for use with this measurement and further the use of the genus statistic as a tool for exploring non-Gaussianity.« less

Activation rates for nonlinear stochastic flows driven by non-Gaussian noise

NASA Astrophysics Data System (ADS)

van den Broeck, C.; Hänggi, P.

1984-11-01

Activation rates are calculated for stochastic bistable flows driven by asymmetric dichotomic Markov noise (a two-state Markov process). This noise contains as limits both a particular type of non-Gaussian white shot noise and white Gaussian noise. Apart from investigating the role of colored noise on the escape rates, one can thus also study the influence of the non-Gaussian nature of the noise on these rates. The rate for white shot noise differs in leading order (Arrhenius factor) from the corresponding rate for white Gaussian noise of equal strength. In evaluating the rates we demonstrate the advantage of using transport theory over a mean first-passage time approach for cases with generally non-white and non-Gaussian noise sources. For white shot noise with exponentially distributed weights we succeed in evaluating the mean first-passage time of the corresponding integro-differential master-equation dynamics. The rate is shown to coincide in the weak noise limit with the inverse mean first-passage time.

Quantitative comparison of self-healing ability between Bessel–Gaussian beam and Airy beam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wen, Wei; Chu, Xiuxiang, E-mail: xiuxiangchu@yahoo.com

The self-healing ability during propagation process is one of the most important properties of non-diffracting beams. This ability has crucial advantages to light sheet-based microscopy to reduce scattering artefacts, increase the quality of the image and enhance the resolution of microscopy. Based on similarity between two infinite-dimensional complex vectors in Hilbert space, the ability to a Bessel–Gaussian beam and an Airy beam have been studied and compared. Comparing the evolution of the similarity of Bessel–Gaussian beam with Airy beam under the same conditions, we find that Bessel–Gaussian beam has stronger self-healing ability and is more stable than that of Airymore » beam. To confirm this result, the intensity profiles of Bessel–Gaussian beam and Airy beam with different similarities are numerically calculated and compared.« less

Real-time model learning using Incremental Sparse Spectrum Gaussian Process Regression.

PubMed

Gijsberts, Arjan; Metta, Giorgio

2013-05-01

Novel applications in unstructured and non-stationary human environments require robots that learn from experience and adapt autonomously to changing conditions. Predictive models therefore not only need to be accurate, but should also be updated incrementally in real-time and require minimal human intervention. Incremental Sparse Spectrum Gaussian Process Regression is an algorithm that is targeted specifically for use in this context. Rather than developing a novel algorithm from the ground up, the method is based on the thoroughly studied Gaussian Process Regression algorithm, therefore ensuring a solid theoretical foundation. Non-linearity and a bounded update complexity are achieved simultaneously by means of a finite dimensional random feature mapping that approximates a kernel function. As a result, the computational cost for each update remains constant over time. Finally, algorithmic simplicity and support for automated hyperparameter optimization ensures convenience when employed in practice. Empirical validation on a number of synthetic and real-life learning problems confirms that the performance of Incremental Sparse Spectrum Gaussian Process Regression is superior with respect to the popular Locally Weighted Projection Regression, while computational requirements are found to be significantly lower. The method is therefore particularly suited for learning with real-time constraints or when computational resources are limited. Copyright © 2012 Elsevier Ltd. All rights reserved.

Conditional and unconditional Gaussian quantum dynamics

NASA Astrophysics Data System (ADS)

Genoni, Marco G.; Lami, Ludovico; Serafini, Alessio

2016-07-01

This article focuses on the general theory of open quantum systems in the Gaussian regime and explores a number of diverse ramifications and consequences of the theory. We shall first introduce the Gaussian framework in its full generality, including a classification of Gaussian (also known as 'general-dyne') quantum measurements. In doing so, we will give a compact proof for the parametrisation of the most general Gaussian completely positive map, which we believe to be missing in the existing literature. We will then move on to consider the linear coupling with a white noise bath, and derive the diffusion equations that describe the evolution of Gaussian states under such circumstances. Starting from these equations, we outline a constructive method to derive general master equations that apply outside the Gaussian regime. Next, we include the general-dyne monitoring of the environmental degrees of freedom and recover the Riccati equation for the conditional evolution of Gaussian states. Our derivation relies exclusively on the standard quantum mechanical update of the system state, through the evaluation of Gaussian overlaps. The parametrisation of the conditional dynamics we obtain is novel and, at variance with existing alternatives, directly ties in to physical detection schemes. We conclude our study with two examples of conditional dynamics that can be dealt with conveniently through our formalism, demonstrating how monitoring can suppress the noise in optical parametric processes as well as stabilise systems subject to diffusive scattering.

Improving satellite-based PM2.5 estimates in China using Gaussian processes modeling in a Bayesian hierarchical setting.

PubMed

Yu, Wenxi; Liu, Yang; Ma, Zongwei; Bi, Jun

2017-08-01

Using satellite-based aerosol optical depth (AOD) measurements and statistical models to estimate ground-level PM 2.5 is a promising way to fill the areas that are not covered by ground PM 2.5 monitors. The statistical models used in previous studies are primarily Linear Mixed Effects (LME) and Geographically Weighted Regression (GWR) models. In this study, we developed a new regression model between PM 2.5 and AOD using Gaussian processes in a Bayesian hierarchical setting. Gaussian processes model the stochastic nature of the spatial random effects, where the mean surface and the covariance function is specified. The spatial stochastic process is incorporated under the Bayesian hierarchical framework to explain the variation of PM 2.5 concentrations together with other factors, such as AOD, spatial and non-spatial random effects. We evaluate the results of our model and compare them with those of other, conventional statistical models (GWR and LME) by within-sample model fitting and out-of-sample validation (cross validation, CV). The results show that our model possesses a CV result (R 2  = 0.81) that reflects higher accuracy than that of GWR and LME (0.74 and 0.48, respectively). Our results indicate that Gaussian process models have the potential to improve the accuracy of satellite-based PM 2.5 estimates.

The structure of brain glycogen phosphorylase-from allosteric regulation mechanisms to clinical perspectives.

PubMed

Mathieu, Cécile; Dupret, Jean-Marie; Rodrigues Lima, Fernando

2017-02-01

Glycogen phosphorylase (GP) is the key enzyme that regulates glycogen mobilization in cells. GP is a complex allosteric enzyme that comprises a family of three isozymes: muscle GP (mGP), liver GP (lGP), and brain GP (bGP). Although the three isozymes display high similarity and catalyze the same reaction, they differ in their sensitivity to the allosteric activator adenosine monophosphate (AMP). Moreover, inactivating mutations in mGP and lGP have been known to be associated with glycogen storage diseases (McArdle and Hers disease, respectively). The determination, decades ago, of the structure of mGP and lGP have allowed to better understand the allosteric regulation of these two isoforms and the development of specific inhibitors. Despite its important role in brain glycogen metabolism, the structure of the brain GP had remained elusive. Here, we provide an overview of the human brain GP structure and its relationship with the two other members of this key family of the metabolic enzymes. We also summarize how this structure provides valuable information to understand the regulation of bGP and to design specific ligands of potential pharmacological interest. © 2016 Federation of European Biochemical Societies.

Shedding of soluble glycoprotein 1 detected during acute Lassa virus infection in human subjects

PubMed Central

2010-01-01

Background Lassa hemorrhagic fever (LHF) is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. With a high rate of infection that may lead to morbidity and mortality, understanding how the virus interacts with the host's immune system is of great importance for generating vaccines and therapeutics. Previous work by our group identified a soluble isoform of the Lassa virus (LASV) GP1 (sGP1) in vitro resulting from the expression of the glycoprotein complex (GPC) gene [1,2]. Though no work has directly been done to demonstrate the function of this soluble isoform in arenaviral infections, evidence points to immunomodulatory effects against the host's immune system mediated by a secreted glycoprotein component in filoviruses, another class of hemorrhagic fever-causing viruses. A significant fraction of shed glycoprotein isoforms during viral infection and biogenesis may attenuate the host's inflammatory response, thereby enhancing viral replication and tissue damage. Such shed glycoprotein mediated effects were previously reported for Ebola virus (EBOV), a filovirus that also causes hemorrhagic fever with nearly 90% fatality rates [3-5]. The identification of an analogous phenomenon in vivo could establish a new correlate of LHF infection leading to the development of sensitive diagnostics targeting the earliest molecular events of the disease. Additionally, the reversal of potentially untoward immunomodulatory functions mediated by sGP1 could potentiate the development of novel therapeutic intervention. To this end, we investigated the presence of sGP1 in the serum of suspected LASV patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW), in Kenema, Sierra Leone that tested positive for viral antigen or displayed classical signs of Lassa fever. Results It is reasonable to expect that a narrow window exists for detection of sGP1 as the sole protein shed during early arenaviral biogenesis. This phenomenon was clearly distinguishable from virion-associated GP1 only prior to the emergence of de novo viral particles. Despite this restricted time frame, in 2/46 suspected cases in two studies performed in late 2009 and early 2010, soluble glycoprotein component shedding was identified. Differential detection of viral antigens GP1, GP2, and NP by western blot yielded five different scenarios: whole LASV virions (GP1, GP2, NP; i.e. active viremia), different combinations of these three proteins, sGP1 only, NP only, and absence of all three proteins. Four additional samples showed inconclusive evidence for sGP1 shedding due to lack of detection of GP2 and NP by western blot; however, a sensitive LASV NP antigen capture ELISA generated marginally positive signals Conclusions During a narrow window following active infection with LASV, soluble GP1 can be detected in patient sera. This phenomenon parallels other VHF infection profiles, with the actual role of a soluble viral glycoprotein component in vivo remaining largely speculative. The expenditure of energy and cellular resources toward secretion of a critical protein during viral biogenesis without apparent specific function requires further investigation. Future studies will be aimed at systematically identifying the role of LASV sGP1 in the infection process and outcome in vitro and in vivo. PMID:21062490

Shedding of soluble glycoprotein 1 detected during acute Lassa virus infection in human subjects.

PubMed

Branco, Luis M; Grove, Jessica N; Moses, Lina M; Goba, Augustine; Fullah, Mohammed; Momoh, Mambu; Schoepp, Randal J; Bausch, Daniel G; Garry, Robert F

2010-11-09

Lassa hemorrhagic fever (LHF) is a neglected tropical disease with significant impact on the health care system, society, and economy of Western and Central African nations where it is endemic. With a high rate of infection that may lead to morbidity and mortality, understanding how the virus interacts with the host's immune system is of great importance for generating vaccines and therapeutics. Previous work by our group identified a soluble isoform of the Lassa virus (LASV) GP1 (sGP1) in vitro resulting from the expression of the glycoprotein complex (GPC) gene [1, 2]. Though no work has directly been done to demonstrate the function of this soluble isoform in arenaviral infections, evidence points to immunomodulatory effects against the host's immune system mediated by a secreted glycoprotein component in filoviruses, another class of hemorrhagic fever-causing viruses. A significant fraction of shed glycoprotein isoforms during viral infection and biogenesis may attenuate the host's inflammatory response, thereby enhancing viral replication and tissue damage. Such shed glycoprotein mediated effects were previously reported for Ebola virus (EBOV), a filovirus that also causes hemorrhagic fever with nearly 90 percent fatality rates [3 - 5]. The identification of an analogous phenomenon in vivo could establish a new correlate of LHF infection leading to the development of sensitive diagnostics targeting the earliest molecular events of the disease. Additionally, the reversal of potentially untoward immunomodulatory functions mediated by sGP1 could potentiate the development of novel therapeutic intervention. To this end, we investigated the presence of sGP1 in the serum of suspected LASV patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW), in Kenema, Sierra Leone that tested positive for viral antigen or displayed classical signs of Lassa fever. It is reasonable to expect that a narrow window exists for detection of sGP1 as the sole protein shed during early arenaviral biogenesis. This phenomenon was clearly distinguishable from virion-associated GP1 only prior to the emergence of de novo viral particles. Despite this restricted time frame, in 2/46 suspected cases in two studies performed in late 2009 and early 2010, soluble glycoprotein component shedding was identified. Differential detection of viral antigens GP1, GP2, and NP by western blot yielded five different scenarios: whole LASV virions (GP1, GP2, NP; i.e. active viremia), different combinations of these three proteins, sGP1 only, NP only, and absence of all three proteins. Four additional samples showed inconclusive evidence for sGP1 shedding due to lack of detection of GP2 and NP in western blot; however, a sensitive LASV NP antigen capture ELISA generated marginally positive signals. During a narrow window following active infection with LASV, soluble GP1 can be detected in patient sera. This phenomenon parallels other VHF infection profiles, with the actual role of a soluble viral glycoprotein component in vivo remaining largely speculative. The expenditure of energy and cellular resources toward secretion of a critical protein during viral biogenesis without apparent specific function requires further investigation. Future studies will be aimed at systematically identifying the role of LASV sGP1 in the infection process and outcome in vitro and in vivo.

[Patient safety and a culture of responsibility in ambulatory care: strategies for improving practice].

PubMed

Lichte, Thomas; Klement, Andreas; Herrmann, Markus

2009-01-01

The development of a medical safety culture is spreading beyond the hospital into the ambulatory setting. Patient safety defined as "absence of unwanted events" (primum non nocere) can serve as a starting point for the advancement of our ambulatory medical care system. Error analyses conducted in GP and specialist practices will identify gaps and traps in the system and provide ideas for the development and implementation of new safety strategies in ambulatory patient care. In the light of the structures and processes of GP medical care aspects of patient safety will be correlated to the outcome quality and examples will be discussed. Possible strategies for the improvement of patient safety in GP practice will be presented from the perspective of both patient- and practice individuality.

The personal computer and GP-B management. [Gravity Probe experiment

NASA Technical Reports Server (NTRS)

Neighbors, A. K.

1986-01-01

The Gravity Probe-B (GP-B) experiment is one of the most sophisticated and challenging developments to be undertaken by NASA. Its objective is to measure the relativistic drift of gyroscopes in orbit about the earth. In this paper, the experiment is described, and the strategy of phased procurements for accomplishing the engineering development of the hardware is discussed. The microcomputer is a very convenient and powerful tool in the management of GP-B. It is used in creating and monitoring such project data as schedules, budgets, hardware procurements and technical and interface requirements. Commercially available software in word processing, database management, communications, spreadsheet, graphics and program management are used. Examples are described of the efficacy of the application of the computer by the management team.

Digital control for the condensate system in a combined cycle power plant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez Parra, M.; Fuentes Gutierrez, J.E.; Castelo Cuevas, L.

1994-12-31

This paper presents the highlights by means of which development, installation and start up of the digital control system (DCS)for the condenser and hotwell (condensate system) were performed. This system belongs to the distributed control system installed by the Instituto de Investigaciones Electricas (IIE) at the Combined Cycle Power Plant in Gomez Palacio (GP), Durango, Mexico, during the February-March period, in 1993. The main steps for development of the condenser and hotwell control system include: process modeling, definition of control strategies, algorithms, design and software development, PC simulation tests, laboratory tests with an equipment similar to the one installed atmore » the GP Power Plant, installation, and finally, start up, which was a joint effort with the GP Power Plant engineering staff.« less

Recognition of similar epitopes on varicella-zoster virus gpI and gpIV by monoclonal antibodies.

PubMed Central

Vafai, A; Wroblewska, Z; Mahalingam, R; Cabirac, G; Wellish, M; Cisco, M; Gilden, D

1988-01-01

Two monoclonal antibodies, MAb43.2 and MAb79.0, prepared against varicella-zoster virus (VZV) proteins were selected to analyze VZV gpIV and gpI, respectively. MAb43.2 reacted only with cytoplasmic antigens, whereas MAb79.0 recognized both cytoplasmic and membrane antigens in VZV-infected cells. Immunoprecipitation of in vitro translation products with MAb43.2 revealed only proteins encoded by the gpIV gene, whereas MAb79.0 precipitated proteins encoded by the gpIV and gpI genes. Pulse-chase analysis followed by immunoprecipitation of VZV-infected cells indicated reactivity of MAb43.2 with three phosphorylated precursor species of gpIV and reactivity of MAb79.0 with the precursor and mature forms of gpI and gpIV. These results indicated that (i) MAb43.2 and MAb79.0 recognize different epitopes on VZV gpIV, (ii) glycosylation of gpIV ablates recognition by MAb43.2, and (iii) gpIV is phosphorylated. To map the binding site of MAb79.0 on gpI, the pGEM transcription vector, containing the coding region of the gpI gene, was linearized, and three truncated gpI DNA fragments were generated. RNA was transcribed from each truncated fragment by using SP6 RNA polymerase, translated in vitro in a rabbit reticulocyte lysate, and immunoprecipitated with MAb79.0 and human sera. The results revealed the existence of an antibody-binding site within 14 amino acid residues located between residues 109 to 123 on the predicted amino acid sequences of gpI. From the predicted amino acid sequences, 14 residues on gpI (residues 107 to 121) displayed a degree of similarity (36%) to two regions (residues 55 to 69 and 245 to 259) of gp IV. Such similarities may account for the binding of MAb79.0 to both VZV gpI and gpIV. Images PMID:2455814

In vitro evaluation of microleakage under a glass ionomer surface protector cement after different enamel treatment procedures.

PubMed

Haznedaroglu, Eda; Mentes, Ali R; Tanboga, Iknur

2012-03-01

The aim of this in vitrostudy was to evaluate the microleakage of a glass-ionomer surface-protector cement (GC Fuji Triage) placed onto the fissure surfaces of extracted human molars prepared using six different treatment procedures. Ninety-six extracted non-carious human molar teeth were divided into five enamel treatment groups: (Gp1) air-abraded (Micadent II, Medidenta); (Gp2) air-abraded and conditioned with 10% polyacrylic acid (GC dentin conditioner); (Gp3) prepared by a bur designed for enameloplasty (#8833 Komet); (Gp4) prepared with a bur and conditioned; (Gp5) conditioned; and (Gp6) no treatment (control). The teeth were then sealed with GC Fuji Triage. The teeth were thermocycled and left in distilled water or artificial saliva for one week, coated twice with nail varnish, and stained in a dye. They were sectioned and scored for microleakage. All groups showed microleakage. Samples that were kept in saliva had better results than those that were kept in distilled water (P<0.05). Samples conditioned before the treatment were also better than non-conditioned groups (P<0.05). In distilled water and artificial saliva, the range of the groups was, from the best, Gp2

The Genital Tract Virulence Factor pGP3 Is Essential for Chlamydia muridarum Colonization in the Gastrointestinal Tract.

PubMed

Shao, Lili; Zhang, Tianyuan; Melero, Jose; Huang, Yumeng; Liu, Yuanjun; Liu, Quanzhong; He, Cheng; Nelson, David E; Zhong, Guangming

2018-01-01

The cryptic plasmid is essential for Chlamydia muridarum dissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, a C. muridarum strain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical for C. muridarum colonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly, C. muridarum colonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficient C. muridarum strains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinal Chlamydia . Copyright © 2017 American Society for Microbiology.

SU-E-T-20: A Correlation Study of 2D and 3D Gamma Passing Rates for Prostate IMRT Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, D; Sun Yat-sen University Cancer Center, Guangzhou, Guangdong; Wang, B

2015-06-15

Purpose: To investigate the correlation between the two-dimensional gamma passing rate (2D %GP) and three-dimensional gamma passing rate (3D %GP) in prostate IMRT quality assurance. Methods: Eleven prostate IMRT plans were randomly selected from the clinical database and were used to obtain dose distributions in the phantom and patient. Three types of delivery errors (MLC bank sag errors, central MLC errors and monitor unit errors) were intentionally introduced to modify the clinical plans through an in-house Matlab program. This resulted in 187 modified plans. The 2D %GP and 3D %GP were analyzed using different dose-difference and distance-toagreement (1%-1mm, 2%-2mm andmore » 3%-3mm) and 20% dose threshold. The 2D %GP and 3D %GP were then compared not only for the whole region, but also for the PTVs and critical structures using the statistical Pearson’s correlation coefficient (γ). Results: For different delivery errors, the average comparison of 2D %GP and 3D %GP showed different conclusions. The statistical correlation coefficients between 2D %GP and 3D %GP for the whole dose distribution showed that except for 3%/3mm criterion, 2D %GP and 3D %GP of 1%/1mm criterion and 2%/2mm criterion had strong correlations (Pearson’s γ value >0.8). Compared with the whole region, the correlations of 2D %GP and 3D %GP for PTV were better (the γ value for 1%/1mm, 2%/2mm and 3%/3mm criterion was 0.959, 0.931 and 0.855, respectively). However for the rectum, there was no correlation between 2D %GP and 3D %GP. Conclusion: For prostate IMRT, the correlation between 2D %GP and 3D %GP for the PTV is better than that for normal structures. The lower dose-difference and DTA criterion shows less difference between 2D %GP and 3D %GP. Other factors such as the dosimeter characteristics and TPS algorithm bias may also influence the correlation between 2D %GP and 3D %GP.« less

Registration of Seven Sugarbeet Germplasms Selected from Crosses between Cultivated Sugarbeet and Wild Beta Species

USDA-ARS?s Scientific Manuscript database

Seven sugarbeet (Beta vulgaris L.) germplasm lines, F1017 (GP-xxx, PIxxxxxx), F1018 (GP-xxx, PIxxxxxx), F1019 (GP-xxx, PIxxxxxx), F1020 (GP-xxx, PIxxxxxx), F1021 (GP-xxx, PIxxxxxx), F1022 (GP-xxx, PIxxxxxx), and F1023 (GP-xxx, PIxxxxxx) were released 23 February 2009 by the USDA-ARS and the North Da...

N-Glycosylation Profiling of Porcine Reproductive and Respiratory Syndrome Virus Envelope Glycoprotein 5

PubMed Central

Li, Juan; Tao, Shujuan; Orlando, Ron; Murtaugh, Michael P.

2015-01-01

Porcine reproductive and respiratory syndrome virus (PRRSV) is a positive-sense ssRNA virus whose envelope contains four glycoproteins and three nonglycosylated proteins. Glycans of major envelope glycoprotein 5 (GP5) are proposed as important for virus assembly and entry into permissive cells. Structural characterization of GP5 glycans would facilitate the mechanistic understanding of these processes. Thus, we purified the PRRSV type 2 prototype strain, VR2332, and analyzed the virion-associated glycans by both biochemical and mass spectrometric methods. Endoglycosidase digestion showed that GP5 was the primary protein substrate, and that the carbohydrate moieties were primarily complex-type N-glycans. Mass spectrometric analysis (HPLC-ESI-MS/MS) of GP5 N-glycans revealed an abundance of N-acetylglucosamine (GlcNAc) and N-acetyllactosamine (LacNAc) oligomers in addition to sialic acids. GlcNAc and LacNAc accessibility to ligands was confirmed by lectin co-precipitation. Our findings help to explain PRRSV infection of cells lacking sialoadhesin and provide a glycan database to facilitate molecular structural studies of PRRSV. PMID:25726973

Generation of the heterodimeric precursor GP3 of the Chlamydomonas cell wall.

PubMed

Voigt, Jürgen; Kiess, Michael; Getzlaff, Rita; Wöstemeyer, Johannes; Frank, Ronald

2010-09-01

The cell wall of the unicellular green alga Chlamydomonas reinhardtii exclusively consists of hydroxyproline-containing glycoproteins. Protein chemical analysis of its polypeptide constituents was hindered by their cross-linking via peroxidase-catalysed intermolecular isodityrosine formation and transaminase-dependent processes. To overcome this problem, we have identified putative soluble precursors using polyclonal antibodies raised against deglycosylation products of the highly purified insoluble wall fraction and analysed their amino acid sequence. The occurrence of the corresponding polypeptide in the insoluble glycoprotein framework was finally probed by epitope mapping of the polyclonal antibodies using overlapping scan peptides which, together, cover the whole amino acid sequence of the putative precursor. As a control, peptide fragments released from the insoluble wall fraction by trypsin treatment were analysed by mass spectroscopy. By this approach, the heterodimeric, chaotrope-soluble glycoprotein GP3 proved to be a constituent of the insoluble extracellular matrix of Chlamydomonas reinhardtii. Furthermore, we have shown that the polypeptide backbones of both GP3 subunits are encoded by the same gene and differ by a C-terminal truncation in the case of GP3A. © 2010 Blackwell Publishing Ltd.

Depression screening for patients with epilepsy in a primary care setting using the Patient Health Questionnaire-2 and the Neurological Disorders Depression Inventory for Epilepsy.

PubMed

Margrove, Kerrie; Mensah, Seth; Thapar, Ajay; Kerr, Michael

2011-08-01

Depression among people with a diagnosis of epilepsy is under-recognized. General practitioner (GP) screening for depression using a new scale developed specifically for patients with epilepsy, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), has not before been reported. The aims were to examine the process of GP screening for depression in patients with epilepsy employing the widely used Patient Health Questionnaire-2 (PHQ-2) and the NDDI-E; to determine the impact of screening on GP-recognized depression; and to ascertain depression predictors. Patients were screened via their GPs. A subset of participants underwent clinical interview to assess screener accuracy. Use of either instrument almost doubled the proportion of GP-recognized depression. Ninety-four percent of those interviewed found screening acceptable. More recent and frequent seizures predicted screening positive. The results suggest that screening for depression in patients with epilepsy via GPs improves detection of depression and is acceptable to interviewed patients. Copyright © 2011 Elsevier Inc. All rights reserved.

Marker-Dependent Recombination in T4 Bacteriophage. IV. Recombinational Effects of Antimutator T4 DNA Polymerase

PubMed Central

Shcherbakov, V. P.; Plugina, L. A.; Kudryashova, E. A.

1995-01-01

Recombinational effects of the antimutator allele tsL42 of gene 43 of phage T4, encoding DNA polymerase, were studied in crosses between rIIB mutants. Recombination under tsL42-restricted conditions differed from the normal one in several respects: (1) basic recombination was enhanced, especially within very short distances; (2) mismatch repair tracts were shortened, while the contribution of mismatch repair to recombination was not changed; (3) marker interference at very short distances was augmented. We infer that the T4 DNA polymerase is directly involved in mismatch repair, performing both excision of a nonmatched single strand (by its 3' -> 5' exonuclease) and filling the resulting gap. A pathway for the mismatch repair was substantiated; it includes sequential action of endo VII (gp49) -> 3'->5' exonuclease (gp43) -> DNA polymerase (gp43) -> DNA ligase (gp30). It is argued that the marker interference at very short distances may result from the same sequence of events during the final processing of recombinational intermediates. PMID:7635281

Structural and biological mimicry of protein surface recognition by [alpha/beta]-peptide foldamers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horne, W. Seth; Johnson, Lisa M.; Ketas, Thomas J.

Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important protein-protein interactions. Here we evaluate an approach based on combining {alpha}- and {beta}-amino acid residues in the context of a polypeptide sequence from the HIV protein gp41, which represents an excellent testbed because of the wealth of available structural and biological information. We show that {alpha}/{beta}-peptides can mimic structural and functional properties of a critical gp41 subunit. Physical studies in solution, crystallographic data, and results from cell-fusion and virus-infectivity assays collectively indicate that the gp41-mimetic {alpha}/{beta}-peptides effectively block HIV-cell fusion via a mechanism comparablemore » to that of gp41-derived {alpha}-peptides. An optimized {alpha}/{beta}-peptide is far less susceptible to proteolytic degradation than is an analogous {alpha}-peptide. Our findings show how a two-stage design approach, in which sequence-based {alpha} {yields} {beta} replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.« less

A novel thermo-sensitive hydrogel based on thiolated chitosan/hydroxyapatite/beta-glycerophosphate.

PubMed

Liu, Xujie; Chen, Yan; Huang, Qianli; He, Wei; Feng, Qingling; Yu, Bo

2014-09-22

In order to get a water-soluble in situ gel-forming system, a thiolated chitosan, chitosan-4-thio-butylamidine (CS-TBA) conjugate was synthesized and used to replace the unmodified chitosan in the application of the in situ gel-forming system. A novel thermo-sensitive hydrogel was prepared based on CS-TBA/hydroxyapatite (HA)/beta-glycerophosphate disodium (β-GP). The gel formation, rheological properties, morphology, degradation, cytotoxicity, as well as protein release process of the novel gel system were investigated in this study. The CS-TBA/HA/β-GP gel showed a higher storage modulus (G') and loss modulus (G″) and a decreased bovine serum albumin (BSA) release rate which was maintained the protein release for a longer time compared with the unmodified chitosan (CS)/HA/β-GP gel, due to the existence of thiol groups and/or disulfide bonds. The CS-TBA/HA/β-GP gel has a porous structure with a uniform distribution of nano-hydroxyapatite, an appropriate degradation rate and low cytotoxicity, showing potential applications in drug delivery and tissue engineering. Copyright © 2014 Elsevier Ltd. All rights reserved.

Empathy in general practice-the gap between wishes and reality: comparing the views of patients and physicians.

PubMed

Derksen, F A W M; Olde Hartman, Tim; Bensing, Jozien; Lagro-Janssen, Antoine

2018-03-27

Empathy is regarded by patients and general practitioners (GPs) as fundamental in patient-GP communication. Patients do not always experience empathy and GPs encounter circumstances which hamper applying it. To explore why receiving and offering empathy during the encounter in general practice does not always meet the wishes of both patients and GPs. A qualitative research method, based on focus group interviews with patients and in-depth interviews with GPs, was carried out. Within the research process, iterative data collection and analysis were applied. Both patients and GPs perceive a gap between what they wish for with regard to empathy, and what they actually encounter in general practice. Patients report on circumstances which hamper receiving empathy and GPs on circumstances offering it. Various obstacles were mentioned: (i) circumstances related to practice organization, (ii) circumstances related to patient-GP communication or connectedness, (iii) differences between the patient's and the GP's expectations, (iv) time pressure and its causes and (v) the GP's individual capability to offer empathy. When patients do not receive empathy from their GP or practice staff, they feel frustrated. This causes a gap between their expectations on the one hand and their actual experiences on the other. GPs generally want to incorporate empathy; the GP's private, professional and psychological well-being appears to be an important contributing factor in practicing empathy in daily practice. But they encounter various obstacles to offer this. It is up to GPs to take responsibility for showing practice members the importance of an appropriate empathical behaviour towards patients.

Performance Evaluation of Satellite Communication Systems Operating in the Q/V/W Bands

DTIC Science & Technology

2013-06-30

cloud liquid water content (blue line = original MODIS data, red line = underlying Gaussian process) and of rainfall ( NIMROD rain rate data) .. 3-22...correlation of rainfall as obtained from an extensive set of rain field collected by the NIMROD weather radar network [Luini and Capsoni, 2012] has been...underlying Gaussian process) Rain ( NIMROD data) Figure 3-21. Decorrelation with distance of the cloud liquid water content (blue line = original

Event rate and reaction time performance in ADHD: Testing predictions from the state regulation deficit hypothesis using an ex-Gaussian model.

PubMed

Metin, Baris; Wiersema, Jan R; Verguts, Tom; Gasthuys, Roos; van Der Meere, Jacob J; Roeyers, Herbert; Sonuga-Barke, Edmund

2016-01-01

According to the state regulation deficit (SRD) account, ADHD is associated with a problem using effort to maintain an optimal activation state under demanding task settings such as very fast or very slow event rates. This leads to a prediction of disrupted performance at event rate extremes reflected in higher Gaussian response variability that is a putative marker of activation during motor preparation. In the current study, we tested this hypothesis using ex-Gaussian modeling, which distinguishes Gaussian from non-Gaussian variability. Twenty-five children with ADHD and 29 typically developing controls performed a simple Go/No-Go task under four different event-rate conditions. There was an accentuated quadratic relationship between event rate and Gaussian variability in the ADHD group compared to the controls. The children with ADHD had greater Gaussian variability at very fast and very slow event rates but not at moderate event rates. The results provide evidence for the SRD account of ADHD. However, given that this effect did not explain all group differences (some of which were independent of event rate) other cognitive and/or motivational processes are also likely implicated in ADHD performance deficits.

An empirical analysis of the distribution of the duration of overshoots in a stationary gaussian stochastic process

NASA Technical Reports Server (NTRS)

Parrish, R. S.; Carter, M. C.

1974-01-01

This analysis utilizes computer simulation and statistical estimation. Realizations of stationary gaussian stochastic processes with selected autocorrelation functions are computer simulated. Analysis of the simulated data revealed that the mean and the variance of a process were functionally dependent upon the autocorrelation parameter and crossing level. Using predicted values for the mean and standard deviation, by the method of moments, the distribution parameters was estimated. Thus, given the autocorrelation parameter, crossing level, mean, and standard deviation of a process, the probability of exceeding the crossing level for a particular length of time was calculated.

Exploring the membrane fusion mechanism through force-induced disassembly of HIV-1 six-helix bundle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Kai; Beijing Key Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101; University of Chinese Academy of Sciences, Beijing 100049

Enveloped virus, such as HIV-1, employs membrane fusion mechanism to invade into host cell. HIV-1 gp41 ectodomain uses six-helix bundle configuration to accomplish this process. Using molecular dynamic simulations, we confirmed the stability of this six-helix bundle by showing high occupancy of hydrogen bonds and hydrophobic interactions. Key residues and interactions important for the bundle integration were characterized by force-induced unfolding simulations of six-helix bundle, exhibiting the collapse order of these groups of interactions. Moreover, our results in some way concerted with a previous theory that the formation of coiled-coil choose a route which involved cooperative interactions between the N-terminalmore » and C-terminal helix. -- Highlights: •Unfolding of HIV-1 gp41 six-helix bundle is studied by molecular dynamics simulations. •Specific interactions responsible for the stability of HIV-1 envelope post-fusion conformation were identified. •The gp41 six-helix bundle transition inducing membrane fusion might be a cooperative process of the three subunits.« less

Marcus canonical integral for non-Gaussian processes and its computation: pathwise simulation and tau-leaping algorithm.

PubMed

Li, Tiejun; Min, Bin; Wang, Zhiming

2013-03-14

The stochastic integral ensuring the Newton-Leibnitz chain rule is essential in stochastic energetics. Marcus canonical integral has this property and can be understood as the Wong-Zakai type smoothing limit when the driving process is non-Gaussian. However, this important concept seems not well-known for physicists. In this paper, we discuss Marcus integral for non-Gaussian processes and its computation in the context of stochastic energetics. We give a comprehensive introduction to Marcus integral and compare three equivalent definitions in the literature. We introduce the exact pathwise simulation algorithm and give the error analysis. We show how to compute the thermodynamic quantities based on the pathwise simulation algorithm. We highlight the information hidden in the Marcus mapping, which plays the key role in determining thermodynamic quantities. We further propose the tau-leaping algorithm, which advance the process with deterministic time steps when tau-leaping condition is satisfied. The numerical experiments and its efficiency analysis show that it is very promising.

Hierarchical Nearest-Neighbor Gaussian Process Models for Large Geostatistical Datasets.

PubMed

Datta, Abhirup; Banerjee, Sudipto; Finley, Andrew O; Gelfand, Alan E

2016-01-01

Spatial process models for analyzing geostatistical data entail computations that become prohibitive as the number of spatial locations become large. This article develops a class of highly scalable nearest-neighbor Gaussian process (NNGP) models to provide fully model-based inference for large geostatistical datasets. We establish that the NNGP is a well-defined spatial process providing legitimate finite-dimensional Gaussian densities with sparse precision matrices. We embed the NNGP as a sparsity-inducing prior within a rich hierarchical modeling framework and outline how computationally efficient Markov chain Monte Carlo (MCMC) algorithms can be executed without storing or decomposing large matrices. The floating point operations (flops) per iteration of this algorithm is linear in the number of spatial locations, thereby rendering substantial scalability. We illustrate the computational and inferential benefits of the NNGP over competing methods using simulation studies and also analyze forest biomass from a massive U.S. Forest Inventory dataset at a scale that precludes alternative dimension-reducing methods. Supplementary materials for this article are available online.

Hierarchical Nearest-Neighbor Gaussian Process Models for Large Geostatistical Datasets

PubMed Central

Datta, Abhirup; Banerjee, Sudipto; Finley, Andrew O.; Gelfand, Alan E.

2018-01-01

Spatial process models for analyzing geostatistical data entail computations that become prohibitive as the number of spatial locations become large. This article develops a class of highly scalable nearest-neighbor Gaussian process (NNGP) models to provide fully model-based inference for large geostatistical datasets. We establish that the NNGP is a well-defined spatial process providing legitimate finite-dimensional Gaussian densities with sparse precision matrices. We embed the NNGP as a sparsity-inducing prior within a rich hierarchical modeling framework and outline how computationally efficient Markov chain Monte Carlo (MCMC) algorithms can be executed without storing or decomposing large matrices. The floating point operations (flops) per iteration of this algorithm is linear in the number of spatial locations, thereby rendering substantial scalability. We illustrate the computational and inferential benefits of the NNGP over competing methods using simulation studies and also analyze forest biomass from a massive U.S. Forest Inventory dataset at a scale that precludes alternative dimension-reducing methods. Supplementary materials for this article are available online. PMID:29720777

Remaining Useful Life Prediction for Lithium-Ion Batteries Based on Gaussian Processes Mixture

PubMed Central

Li, Lingling; Wang, Pengchong; Chao, Kuei-Hsiang; Zhou, Yatong; Xie, Yang

2016-01-01

The remaining useful life (RUL) prediction of Lithium-ion batteries is closely related to the capacity degeneration trajectories. Due to the self-charging and the capacity regeneration, the trajectories have the property of multimodality. Traditional prediction models such as the support vector machines (SVM) or the Gaussian Process regression (GPR) cannot accurately characterize this multimodality. This paper proposes a novel RUL prediction method based on the Gaussian Process Mixture (GPM). It can process multimodality by fitting different segments of trajectories with different GPR models separately, such that the tiny differences among these segments can be revealed. The method is demonstrated to be effective for prediction by the excellent predictive result of the experiments on the two commercial and chargeable Type 1850 Lithium-ion batteries, provided by NASA. The performance comparison among the models illustrates that the GPM is more accurate than the SVM and the GPR. In addition, GPM can yield the predictive confidence interval, which makes the prediction more reliable than that of traditional models. PMID:27632176

Determination of attenuation parameters and energy absorption build-up factor of amine group materials

NASA Astrophysics Data System (ADS)

Lokhande, Rajkumar M.; More, Chaitali V.; Surung, Bharat S.; Pawar, Pravina P.

2017-12-01

We have computed radiological parameters of some C- H- N- O based amine group bio material in the energy range 122-1330 keV with the gamma ray count by narrow beam geometry. The NaI(Tl) detector with 8 K multichannel analyser was used having resolution 6.8% at 663 keV. The energy absorption buildup factor (EABF) was determined by using Geometric Progression (G-P) fitting method up to penetration depth of 40 mfp at energy 0.015-15 MeV. The NIST XCOM data were compared with the experimental value and we observed (3-5%) difference. The comparative study of effective atomic number and effective electron density in the energy range 122-1330 keV using Gaussian fit for accuracy were performed. The amino acid has the highest EABF value at 0.1 MeV and the variation in EABF with penetration depth up to 1-40 mean free path (mfp). The calculated radiological data of biological material are applicable in medical physics and dosimetry.

Generation and propagation of a sine-azimuthal wavefront modulated Gaussian beam

PubMed Central

Lao, Guanming; Zhang, Zhaohui; Luo, Meilan; Zhao, Daomu

2016-01-01

We introduce a method for modulating the Gaussian beam by means of sine-azimuthal wavefront and carry out the experimental generation. The analytical propagation formula of such a beam passing through a paraxial ABCD optical system is derived, by which the intensity properties of the sine-azimuthal wavefront modulated Gaussian (SWMG) beam are examined both theoretically and experimentally. Both of the experimental and theoretical results show that the SWMG beam goes through the process from beam splitting to a Gaussian-like profile, which is closely determined by the phase factor and the propagation distance. Appropriate phase factor and short distance are helpful for the splitting of beam. However, in the cases of large phase factor and focal plane, the intensity distributions tend to take a Gaussian form. Such unique features may be of importance in particle trapping and medical applications. PMID:27443798

Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization.

PubMed

Acciani, Marissa; Alston, Jacob T; Zhao, Guohui; Reynolds, Hayley; Ali, Afroze M; Xu, Brian; Brindley, Melinda A

2017-09-15

Lassa virus (LASV) is an enveloped RNA virus endemic to West Africa and responsible for severe cases of hemorrhagic fever. Virus entry is mediated by the glycoprotein complex consisting of a stable-signal peptide, a receptor-binding subunit, GP1, and a viral-host membrane fusion subunit, GP2. Several cellular receptors can interact with the GP1 subunit and mediate viral entry, including alpha-dystroglycan (αDG) and lysosome-associated membrane protein 1 (LAMP1). In order to define the regions within GP1 that interact with the cellular receptors, we implemented insertional mutagenesis, carbohydrate shielding, and alanine scanning mutagenesis. Eighty GP constructs were engineered and evaluated for GP1-GP2 processing, surface expression, and the ability to mediate cell-to-cell fusion after low-pH exposure. To examine virus-to-cell entry, 49 constructs were incorporated onto vesicular stomatitis virus (VSV) pseudoparticles and transduction efficiencies were monitored in HAP1 and HAP1-ΔDAG1 cells that differentially produce the αDG cell surface receptor. Seven constructs retained efficient transduction in HAP1-ΔDAG1 cells yet poorly transduced HAP1 cells, suggesting that they are involved in αDG utilization. Residues H141, N146, F147, and Y150 cluster at the predicted central core of the trimeric interface and are important for GP-αDG interaction. Additionally, H92A-H93A, 150HA, 172HA, and 230HA displayed reduced transduction in both HAP1 and HAP1-ΔDAG1 cells, despite efficient cell-to-cell fusion activity. These mutations may interfere with interactions with the endosomal receptor LAMP1 or interfere at another stage in entry that is common to both cell lines. Insight gained from these data can aid in the development of more-effective entry inhibitors by blocking receptor interactions. IMPORTANCE Countries in which Lassa virus is endemic, such as Nigeria, Sierra Leone, Guinea, and Liberia, usually experience a seasonal outbreak of the virus from December to March. Currently, there is neither a preventative vaccine nor a therapeutic available to effectively treat severe Lassa fever. One way to thwart virus infection is to inhibit interaction with cellular receptors. It is known that the GP1 subunit of the Lassa glycoprotein complex plays a critical role in receptor recognition. Our results highlight a region within the Lassa virus GP1 protein that interacts with the cellular receptor alpha-dystroglycan. This information may be used for future development of new Lassa virus antivirals. Copyright © 2017 American Society for Microbiology.

The Fear Reduction Exercised Early (FREE) approach to low back pain: study protocol for a randomised controlled trial.

PubMed

Darlow, Ben; Stanley, James; Dean, Sarah; Abbott, J Haxby; Garrett, Sue; Mathieson, Fiona; Dowell, Anthony

2017-10-17

Low back pain (LBP) is a major health issue associated with considerable health loss and societal costs. General practitioners (GPs) play an important role in the management of LBP; however, GP care has not been shown to be the most cost-effective approach unless exercise and behavioural counselling are added to usual care. The Fear Reduction Exercised Early (FREE) approach to LBP has been developed to assist GPs to manage LBP by empowering exploration and management of psychosocial barriers to recovery and provision of evidence-based care and information. The aim of the Low Back Pain in General Practice (LBPinGP) trial is to explore whether patients with LBP who receive care from GPs trained in the FREE approach have better outcomes than those who receive usual care. This is a cluster randomised controlled superiority trial comparing the FREE approach with usual care for LBP management with investigator-blinded assessment of outcomes. GPs will be recruited and then cluster randomised (in practice groups) to the intervention or control arm. Intervention arm GPs will receive training in the FREE approach, and control arm GPs will continue to practice as usual. Patients presenting to their GP with a primary complaint of LBP will be allocated on the basis of allocation of the GP they consult. We aim to recruit 60 GPs and 275 patients (assuming patients are recruited from 75% of GPs and an average of 5 patients per GP complete the study, accounting for 20% patient participant dropout). Patient participants and the trial statistician will be blind to group allocation throughout the study. Analyses will be undertaken on an intention-to-treat basis. The primary outcome will be back-related functional impairment 6 months post-initial LBP consultation (interim data at 2 weeks, 6 weeks and 3 months), measured with the Roland-Morris Disability Questionnaire. Secondary patient outcomes include pain, satisfaction, quality of life, days off from work and costs of care. Secondary GP outcomes include beliefs about pain and impairment, GP confidence, and actual and reported clinical behaviour. Health economic and process evaluations will be conducted. In the LBPinGP trial, we will investigate providing an intervention during the first interaction a person with back pain has with their GP. Because the FREE approach is used within a normal GP consultation, if effective, it may be a cost-effective means of improving LBP care. Australian New Zealand Clinical Trials Registry, ACTRN12616000888460 . Registered on 6 July 2016.

Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay

PubMed Central

Jouan, Elodie; Le Vée, Marc; Mayati, Abdullah; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

2016-01-01

In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug–drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs. PMID:27077878

Using qualitative insights to change practice: exploring the culture of antibiotic prescribing and consumption for urinary tract infections

PubMed Central

Duane, Sinead; Domegan, Christine; Callan, Aoife; Galvin, Sandra; Cormican, Martin; Bennett, Kathleen; Murphy, Andrew W

2016-01-01

Objectives The aim of this paper is to explore the culture of antibiotic prescribing and consumption in the community for urinary tract infections (UTI) from the perspective of the general practitioners (GPs) and community member. Design Indepth interviews were conducted with GPs, and focus groups were held with community members. Setting General practice and community setting. Participants 15 GPs practising in rural and urban locations in Ireland participated in the indepth interviews. 6 focus groups (n=42) with participants who had direct or indirect experiences with UTI were also undertaken. Results The decision to prescribe or consume an antibiotic for a UTI is a set of complex processes including need recognition, information search and evaluation processes governed by the relationship and interactions between the GP and the patient. Different GP and patient decision-making profiles emerged emphasising the diversity and variety of general practice in real-life settings. The GP findings showed a requirement for more microbiological information on antibiotic resistance patterns to inform prescribing decisions. Focus group participants wanted a conversation with the GP about their illness and the treatment options available. Conclusions Collectively, this research identified the consultation as a priority intervention environment for stimulating change in relation to antibiotics. This paper demonstrates how qualitative research can identify the interacting processes which are instrumental to the decision to prescribe or consume an antibiotic for a suspected UTI. Qualitative research empowers researchers to investigate the what, how and why of interventions in real-life setting. Qualitative research can play a critical and instrumental role in designing behavioural change strategies with high impact on practice. The results of this research were used to design a complex intervention informed by social marketing. Trial registration number NCT01913860; Pre-results. PMID:26754175

Protective effects of naringin against gp120-induced injury mediated by P2X7 receptors in BV2 microglial cells.

PubMed

Chen, Q; Hu, J; Qin, S S; Liu, C L; Wu, H; Wang, J R; Lu, X M; Wang, J; Chen, G Q; Liu, Y; Liu, B Y; Xu, C S; Liang, S D

2016-05-13

This study was aimed at exploring the effects of P2X7 receptors on gp120-induced injury and naringin's protective effects against gp120-induced injury in BV2 microglia. BV2 microglia injury model was established by gp120 treatment and MTS assay was used to verify whether naringin has a cell-protective effect against gp120-induced injury. Changes in P2X7 receptor expression were assayed using RT-PCR, qPCR, and western blot. Results showed that the ODs of the Ctrl, gp120, gp120+naringin, and gp120+BBG groups were 0.91 ± 0.10, 0.71 ± 0.09, 0.83 ± 0.10, and 0.83 ± 0.10, respectively. Compared to the control group, the gp120 group showed a significantly decreased cell survival rate. Cell survival rates of the gp120+naringin group increased significantly compared to those of the gp120 group, while no difference was observed when compared to the gp120+BBG group. The relative P2X7 mRNA expression levels in the Ctrl, gp120, gp120+naringin, and gp120+BBG groups were 0.73 ± 0.06, 1.05 ± 0.06, 0.78 ± 0.05, and 0.81 ± 0.04, respectively. The corresponding P2X7 protein expression levels were 0.46 ± 0.04, 0.79 ± 0.04, 0.38 ± 0.07, and 0.42 ± 0.06. P2X7 mRNA and protein expression in the gp120 group increased significantly compared to those in the control group, and declined in the gp120+naringin group compared to those in the gp120 group. Therefore, P2X7 receptors might be involved in gp120-induced injury in BV2 microglia, and naringin might play a protective role by inhibiting the up-regulated expression of P2X7 receptors.

Registration of eight six-rowed feed barley germplasm lines resistant to both Russian wheat aphid and greenbug

USDA-ARS?s Scientific Manuscript database

STARS 1006B (Reg. No. GP- , PI 659760), STARS 1007B (Reg. No. GP- , PI 659761), STARS 1008B (Reg. No. GP- , PI 659762), STARS 1009B (Reg. No. GP- , PI 659763), STARS 1010B (Reg. No. GP- , PI 659764), STARS 1011B (Reg. No. GP- , PI 659765), STARS 1012B (Reg. No. GP- , PI 659766), and STARS 1013B (Reg...

A single amino acid substitution modulates low-pH-triggered membrane fusion of GP64 protein in Autographa californica and Bombyx mori nucleopolyhedroviruses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katou, Yasuhiro; Yamada, Hayato; Ikeda, Motoko

2010-09-01

We have previously shown that budded viruses of Bombyx mori nucleopolyhedrovirus (BmNPV) enter the cell cytoplasm but do not migrate into the nuclei of non-permissive Sf9 cells that support a high titer of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) multiplication. Here we show, using the syncytium formation assay, that low-pH-triggered membrane fusion of BmNPV GP64 protein (Bm-GP64) is significantly lower than that of AcMNPV GP64 protein (Ac-GP64). Mutational analyses of GP64 proteins revealed that a single amino acid substitution between Ac-GP64 H155 and Bm-GP64 Y153 can have significant positive or negative effects on membrane fusion activity. Studies using bacmid-based GP64 recombinantmore » AcMNPV harboring point-mutated ac-gp64 and bm-gp64 genes showed that Ac-GP64 H155Y and Bm-GP64 Y153H substitutions decreased and increased, respectively, the multiplication and cell-to-cell spread of progeny viruses. These results indicate that Ac-GP64 H155 facilitates the low-pH-triggered membrane fusion reaction between virus envelopes and endosomal membranes.« less

A real-time multi-scale 2D Gaussian filter based on FPGA

NASA Astrophysics Data System (ADS)

Luo, Haibo; Gai, Xingqin; Chang, Zheng; Hui, Bin

2014-11-01

Multi-scale 2-D Gaussian filter has been widely used in feature extraction (e.g. SIFT, edge etc.), image segmentation, image enhancement, image noise removing, multi-scale shape description etc. However, their computational complexity remains an issue for real-time image processing systems. Aimed at this problem, we propose a framework of multi-scale 2-D Gaussian filter based on FPGA in this paper. Firstly, a full-hardware architecture based on parallel pipeline was designed to achieve high throughput rate. Secondly, in order to save some multiplier, the 2-D convolution is separated into two 1-D convolutions. Thirdly, a dedicate first in first out memory named as CAFIFO (Column Addressing FIFO) was designed to avoid the error propagating induced by spark on clock. Finally, a shared memory framework was designed to reduce memory costs. As a demonstration, we realized a 3 scales 2-D Gaussian filter on a single ALTERA Cyclone III FPGA chip. Experimental results show that, the proposed framework can computing a Multi-scales 2-D Gaussian filtering within one pixel clock period, is further suitable for real-time image processing. Moreover, the main principle can be popularized to the other operators based on convolution, such as Gabor filter, Sobel operator and so on.

Ship Detection in SAR Image Based on the Alpha-stable Distribution

PubMed Central

Wang, Changcheng; Liao, Mingsheng; Li, Xiaofeng

2008-01-01

This paper describes an improved Constant False Alarm Rate (CFAR) ship detection algorithm in spaceborne synthetic aperture radar (SAR) image based on Alpha-stable distribution model. Typically, the CFAR algorithm uses the Gaussian distribution model to describe statistical characteristics of a SAR image background clutter. However, the Gaussian distribution is only valid for multilook SAR images when several radar looks are averaged. As sea clutter in SAR images shows spiky or heavy-tailed characteristics, the Gaussian distribution often fails to describe background sea clutter. In this study, we replace the Gaussian distribution with the Alpha-stable distribution, which is widely used in impulsive or spiky signal processing, to describe the background sea clutter in SAR images. In our proposed algorithm, an initial step for detecting possible ship targets is employed. Then, similar to the typical two-parameter CFAR algorithm, a local process is applied to the pixel identified as possible target. A RADARSAT-1 image is used to validate this Alpha-stable distribution based algorithm. Meanwhile, known ship location data during the time of RADARSAT-1 SAR image acquisition is used to validate ship detection results. Validation results show improvements of the new CFAR algorithm based on the Alpha-stable distribution over the CFAR algorithm based on the Gaussian distribution. PMID:27873794

Relative Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor, Dacarbazine, and Glycoprotein 100 in Metastatic Melanoma: An Indirect Treatment Comparison.

PubMed

Quinn, Casey; Ma, Qiufei; Kudlac, Amber; Palmer, Stephen; Barber, Beth; Zhao, Zhongyun

2017-02-01

Advances in the treatment of metastatic melanoma have been achieved in recent years: immunotherapies and targeted therapies have demonstrated survival benefits over older agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF), dacarbazine, and glycoprotein peptide vaccine (gp100) in pivotal phase 3 trials. It is important to compare therapies to guide the treatment decision-making process, and establishing the relationship between older agents can strengthen the networks of evidence for newer therapies. We report the outcome of an indirect comparison of GM-CSF, dacarbazine, and gp100 in metastatic melanoma through meta-analysis of absolute treatment effect. A systematic literature review identified trials for inclusion in the meta-analysis. A valid network meta-analysis was not feasible: treatment-specific meta-analysis was conducted. A published algorithm was used to adjust overall survival estimates from trials of GM-CSF, dacarbazine, and gp100 for heterogeneity in baseline prognostic factors. Survival estimates were compared in three patient groups: stage IIIB-IV M1c, stage IIIB-IV M1a, and stage IV M1b/c. One trial of GM-CSF, four of dacarbazine, and one of gp100 were included in the analysis. After adjusting for differences in baseline prognostic factors, median overall survival (OS) in all patient groups was longer for those receiving GM-CSF than for those receiving dacarbazine or gp100. The observed survival over time for GM-CSF was similar to the adjusted survival for dacarbazine and greater than for gp100 in all patient groups. The relative treatment effect of GM-CSF, dacarbazine, and gp100 has been reliably estimated by adjusting for differences in baseline prognostic factors. Results suggest that OS with GM-CSF is at least as good as with dacarbazine and greater than with gp100. Given the role of these agents as controls in phase 3 trials of new immunotherapies and targeted agents, these results can be used to contextualize the efficacy of newer therapies. Amgen Inc.

Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility

PubMed Central

Pancera, Marie; Majeed, Shahzad; Ban, Yih-En Andrew; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Stuckey, Jonathan; Zhou, Tongqing; Robinson, James E.; Schief, William R.; Sodroski, Joseph; Wyatt, Richard; Kwong, Peter D.

2009-01-01

The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded β-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate—and structurally plastic—layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated β-sandwich and providing for conformational diversity used in immune evasion. A “layered” gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a β-sandwich clamp maintains gp120–gp41 interaction and regulates gp41 transitions. PMID:20080564

Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility.

PubMed

Pancera, Marie; Majeed, Shahzad; Ban, Yih-En Andrew; Chen, Lei; Huang, Chih-chin; Kong, Leopold; Kwon, Young Do; Stuckey, Jonathan; Zhou, Tongqing; Robinson, James E; Schief, William R; Sodroski, Joseph; Wyatt, Richard; Kwong, Peter D

2010-01-19

The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached noncovalently to three gp41 transmembrane molecules. Viral entry is initiated by binding to the CD4 receptor on the cell surface, which induces large conformational changes in gp120. These changes not only provide a model for receptor-triggered entry, but affect spike sensitivity to drug- and antibody-mediated neutralization. Although some of the details of the CD4-induced conformational change have been visualized by crystal structures and cryoelectron tomograms, the critical gp41-interactive region of gp120 was missing from previous atomic-level characterizations. Here we determine the crystal structure of an HIV-1 gp120 core with intact gp41-interactive region in its CD4-bound state, compare this structure to unliganded and antibody-bound forms to identify structurally invariant and plastic components, and use ligand-oriented cryoelectron tomograms to define component mobility in the viral spike context. Newly defined gp120 elements proximal to the gp41 interface complete a 7-stranded beta-sandwich, which appeared invariant in conformation. Loop excursions emanating from the sandwich form three topologically separate--and structurally plastic--layers, topped off by the highly glycosylated gp120 outer domain. Crystal structures, cryoelectron tomograms, and interlayer chemistry were consistent with a mechanism in which the layers act as a shape-changing spacer, facilitating movement between outer domain and gp41-associated beta-sandwich and providing for conformational diversity used in immune evasion. A "layered" gp120 architecture thus allows movement among alternative glycoprotein conformations required for virus entry and immune evasion, whereas a beta-sandwich clamp maintains gp120-gp41 interaction and regulates gp41 transitions.

Characterization of Ten Heterotetrameric NDP-Dependent Acyl-CoA Synthetases of the Hyperthermophilic Archaeon Pyrococcus furiosus

DOE PAGES

Scott, Joseph W.; Poole, Farris L.; Adams, Michael W. W.

2014-01-01

Tmore » he hyperthermophilic archaeon Pyrococcus furiosus grows by fermenting peptides and carbohydrates to organic acids. In the terminal step, acyl-CoA synthetase (ACS) isoenzymes convert acyl-CoA derivatives to the corresponding acid and conserve energy in the form of AP. ACS1 and ACS2 were previously purified from P. furiosus and have α 2 β 2 structures but the genome contains genes encoding three additional α -subunits. he ten possible combinations of α and β genes were expressed in E. coli and each resulted in stable and active α 2 β 2 isoenzymes. he α -subunit of each isoenzyme determined CoA-based substrate specificity and between them they accounted for the CoA derivatives of fourteen amino acids. he β -subunit determined preference for adenine or guanine nucleotides. he GP-generating isoenzymes are proposed to play a role in gluconeogenesis by producing GP for GP-dependent phosphoenolpyruvate carboxykinase and for other GP-dependent processes. ranscriptional and proteomic data showed that all ten isoenzymes are constitutively expressed indicating that both AP and GP are generated from the metabolism of most of the amino acids. A phylogenetic analysis showed that the ACSs of P. furiosus and other members of the hermococcales are evolutionarily distinct from those found throughout the rest of biology, including those of other hyperthermophilic archaea.« less

Exploration of the nature of a unique natural polymer-based thermosensitive hydrogel.

PubMed

Lu, Shanling; Yang, Yuhong; Yao, Jinrong; Shao, Zhengzhong; Chen, Xin

2016-01-14

The chitosan (CS)/β-glycerol phosphate (GP) system is a heat induced gelling system with a promising potential application, such as an injectable biomedical material. Unlike most thermosensitive gelling systems, the CS/GP system is only partially reversible. That is once the hydrogel is fully matured, it only softens but cannot go back to its initial liquid state when cooled down. Here, we perform both the small and large amplitude oscillatory shear (SAOS and LAOS) tests on the fully matured CS/GP hydrogel samples at a variety of temperatures within the cooling process. The purpose of such tests is to investigate the structural change of the hydrogel network and thus to understand the possible gelation mechanism of this unique thermosensitive hydrogel. From the LAOS results and the further analysis with the Chebyshev expansion method, it shows that the CS/GP hydrogel is composed of a colloidal network dominated by hydrophobic interactions at high temperature, and gradually turns into a flexible network dominated by hydrogen bonding when the temperature goes down. Therefore, we may conclude that LOAS is a powerful tool to study the nonlinear behaviour of a polymer system that is closely related to its structure, and as a practical example, we achieve a clearer vision on the gelation mechanism of the unique CS/GP thermosensitive hydrogel on the basis of considerable previous studies and assumptions in this laboratory and other research groups.

The global financial crisis and Australian general practice.

PubMed

McRae, Ian S; Paolucci, Francesco

2011-02-01

To explore the potential effects of the global financial crisis (GFC) on the market for general practitioner (GP) services in Australia. We estimate the impact of changes in unemployment rates on demand for GP services and the impact of lost asset values on GP retirement plans and work patterns. Combining these supply and demand effects, we estimate the potential effect of the GFC on the market for GP services under various scenarios. If deferral of retirement increases GP availability by 2%, and historic trends to reduce GP working hours are halved, at the current level of ~5.2% unemployment average fees would decline by $0.23 per GP consultation and volumes of GP services would rise by 2.53% with almost no change in average GP gross earnings over what would otherwise have occurred. With 8.5% unemployment, as initially predicted by Treasury, GP fees would increase by $0.91 and GP income by nearly 3%. The GFC is likely to increase activity in the GP market and potentially to reduce fee levels relative to the pre-GFC trends. Net effects on average GP incomes are likely to be small at current unemployment levels.

Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules

PubMed Central

1992-01-01

T cell stimulation by the human immunodeficiency virus 1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules in a cell-free system was found to require proteolytic cleavage. This extracellular processing was mediated by peptidases present in fetal calf serum. In vitro processing of p18 resulted in a distinct reverse phase high performance liquid chromatography profile, from which a biologically active product was isolated and sequenced. This peptide processing can be specifically blocked by the angiotensin- 1 converting enzyme (ACE) inhibitor captopril, and can occur by exposing p18 to purified ACE. The ability of naturally occurring extracellular proteases to convert inactive peptides to T cell antigens has important implications for understanding cytotoxic T lymphocyte responses in vivo, and for rational peptide vaccine design. PMID:1316930

Model-based guiding pattern synthesis for robust assembly of contact layers using directed self-assembly

NASA Astrophysics Data System (ADS)

Mitra, Joydeep; Torres, Andres; Ma, Yuansheng; Pan, David Z.

2018-01-01

Directed self-assembly (DSA) has emerged as one of the most compelling next-generation patterning techniques for sub 7 nm via or contact layers. A key issue in enabling DSA as a mainstream patterning technique is the generation of grapho-epitaxy-based guiding pattern (GP) shapes to assemble the contact patterns on target with high fidelity and resolution. Current GP generation is mostly empirical, and limited to a very small number of via configurations. We propose the first model-based GP synthesis algorithm and methodology for on-target and robust DSA, on general via pattern configurations. The final postoptical proximity correction-printed GPs derived from our original synthesized GPs are resilient to process variations and continue to maintain the same DSA fidelity in terms of placement error and target shape.

A linear goal programming model for human resource allocation in a health-care organization.

PubMed

Kwak, N K; Lee, C

1997-06-01

This paper presents the development of a goal programming (GP) model as an aid to strategic planning and allocation for limited human resources in a health-care organization. The purpose of this study is to assign the personnel to the proper shift hours that enable management to meet the objective of minimizing the total payroll costs while patients are satisfied. A GP model is illustrated using the data provided by a health-care organization in the midwest area. The goals are identified and prioritized. The model result is examined and a sensitivity analysis is performed to improve the model applicability. The GP model application adds insight to the planning functions of resource allocation in the health-care organizations. The proposed model is easily applicable to other human resource planning process.

Porous plug for Gravity Probe B

NASA Astrophysics Data System (ADS)

Wang, Suwen; Everitt, C. W. Francis; Frank, David J.; Lipa, John A.; Muhlfelder, Barry F.

2015-11-01

The confinement of superfluid helium for a Dewar in space poses a unique challenge due to its propensity to minimize thermal gradients by essentially viscous-free counterflow. This poses the risk of losing liquid through a vent pipe, reducing the efficiency of the cooling process. To confine the liquid helium in the Gravity Probe B (GP-B) flight Dewar, a porous plug technique was invented at Stanford University. Here, we review the history of the porous plug and its development, and describe the physics underlying its operation. We summarize a few missions that employed porous plugs, some of which preceded the launch of GP-B. The design, manufacture and flight performance of the GP-B plug are described, and its use resulted in the successful operation of the 2441 l flight Dewar on-orbit for 17.3 months.

Dissociation of the trimeric gp41 ectodomain at the lipid-water interface suggests an active role in HIV-1 Env-mediated membrane fusion.

PubMed

Roche, Julien; Louis, John M; Grishaev, Alexander; Ying, Jinfa; Bax, Adriaan

2014-03-04

The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. The actual fusion process involves a switch from a homotrimeric prehairpin intermediate conformation, consisting of parallel coiled-coil helices, to a postfusion state where the ectodomains are arranged as a trimer of helical hairpins, adopting a six-helix bundle (6HB) state. Here, we show by solution NMR spectroscopy that a water-soluble 6HB gp41 ectodomain binds to zwitterionic detergents that contain phosphocholine or phosphatidylcholine head groups and phospholipid vesicles that mimic T-cell membrane composition. Binding results in the dissociation of the 6HB and the formation of a monomeric state, where its two α-helices, N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), become embedded in the lipid-water interface of the virus and host cell. The atomic structure of the gp41 ectodomain monomer, based on NOE distance restraints and residual dipolar couplings, shows that the NHR and CHR helices remain mostly intact, but they completely lose interhelical contacts. The high affinity of the ectodomain helices for phospholipid surfaces suggests that unzippering of the prehairpin intermediate leads to a state where the NHR and CHR helices become embedded in the host cell and viral membranes, respectively, thereby providing a physical force for bringing these membranes into close juxtaposition before actual fusion.

Gaussian process based intelligent sampling for measuring nano-structure surfaces

NASA Astrophysics Data System (ADS)

Sun, L. J.; Ren, M. J.; Yin, Y. H.

2016-09-01

Nanotechnology is the science and engineering that manipulate matters at nano scale, which can be used to create many new materials and devices with a vast range of applications. As the nanotech product increasingly enters the commercial marketplace, nanometrology becomes a stringent and enabling technology for the manipulation and the quality control of the nanotechnology. However, many measuring instruments, for instance scanning probe microscopy, are limited to relatively small area of hundreds of micrometers with very low efficiency. Therefore some intelligent sampling strategies should be required to improve the scanning efficiency for measuring large area. This paper presents a Gaussian process based intelligent sampling method to address this problem. The method makes use of Gaussian process based Bayesian regression as a mathematical foundation to represent the surface geometry, and the posterior estimation of Gaussian process is computed by combining the prior probability distribution with the maximum likelihood function. Then each sampling point is adaptively selected by determining the position which is the most likely outside of the required tolerance zone among the candidates and then inserted to update the model iteratively. Both simulationson the nominal surface and manufactured surface have been conducted on nano-structure surfaces to verify the validity of the proposed method. The results imply that the proposed method significantly improves the measurement efficiency in measuring large area structured surfaces.

Flexible link functions in nonparametric binary regression with Gaussian process priors.

PubMed

Li, Dan; Wang, Xia; Lin, Lizhen; Dey, Dipak K

2016-09-01

In many scientific fields, it is a common practice to collect a sequence of 0-1 binary responses from a subject across time, space, or a collection of covariates. Researchers are interested in finding out how the expected binary outcome is related to covariates, and aim at better prediction in the future 0-1 outcomes. Gaussian processes have been widely used to model nonlinear systems; in particular to model the latent structure in a binary regression model allowing nonlinear functional relationship between covariates and the expectation of binary outcomes. A critical issue in modeling binary response data is the appropriate choice of link functions. Commonly adopted link functions such as probit or logit links have fixed skewness and lack the flexibility to allow the data to determine the degree of the skewness. To address this limitation, we propose a flexible binary regression model which combines a generalized extreme value link function with a Gaussian process prior on the latent structure. Bayesian computation is employed in model estimation. Posterior consistency of the resulting posterior distribution is demonstrated. The flexibility and gains of the proposed model are illustrated through detailed simulation studies and two real data examples. Empirical results show that the proposed model outperforms a set of alternative models, which only have either a Gaussian process prior on the latent regression function or a Dirichlet prior on the link function. © 2015, The International Biometric Society.

Flexible Link Functions in Nonparametric Binary Regression with Gaussian Process Priors

PubMed Central

Li, Dan; Lin, Lizhen; Dey, Dipak K.

2015-01-01

Summary In many scientific fields, it is a common practice to collect a sequence of 0-1 binary responses from a subject across time, space, or a collection of covariates. Researchers are interested in finding out how the expected binary outcome is related to covariates, and aim at better prediction in the future 0-1 outcomes. Gaussian processes have been widely used to model nonlinear systems; in particular to model the latent structure in a binary regression model allowing nonlinear functional relationship between covariates and the expectation of binary outcomes. A critical issue in modeling binary response data is the appropriate choice of link functions. Commonly adopted link functions such as probit or logit links have fixed skewness and lack the flexibility to allow the data to determine the degree of the skewness. To address this limitation, we propose a flexible binary regression model which combines a generalized extreme value link function with a Gaussian process prior on the latent structure. Bayesian computation is employed in model estimation. Posterior consistency of the resulting posterior distribution is demonstrated. The flexibility and gains of the proposed model are illustrated through detailed simulation studies and two real data examples. Empirical results show that the proposed model outperforms a set of alternative models, which only have either a Gaussian process prior on the latent regression function or a Dirichlet prior on the link function. PMID:26686333

Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases.

PubMed

Wang, Ying; Ha, Seung-Wook; Zhang, Tianpeng; Kho, Dhong-Hyo; Raz, Avraham; Xie, Youming

2014-04-30

gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. The E4-like activity of gp78 was illustrated by an in vitro polyubiquitylation assay using Ub-DHFR as a model substrate. We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78. This study uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation.

Polyubiquitylation of AMF requires cooperation between the gp78 and TRIM25 ubiquitin ligases

PubMed Central

Kho, Dhong-Hyo; Raz, Avraham; Xie, Youming

2014-01-01

gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. The E4-like activity of gp78 was illustrated by an in vitro polyubiquitylation assay using Ub-DHFR as a model substrate. We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78. This study uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation. PMID:24810856

Synergetic Improvement in Thermal Conductivity and Flame Retardancy of Epoxy/Silver Nanowires Composites by Incorporating "Branch-Like" Flame-Retardant Functionalized Graphene.

PubMed

Feng, Yuezhan; Li, Xiongwei; Zhao, Xiaoyu; Ye, Yunsheng; Zhou, Xingping; Liu, Hu; Liu, Chuntai; Xie, Xiaolin

2018-06-27

The significant fire hazards on the polymer-based thermal interface materials (TIM) used in electronic devices are but often neglected. Also, high filler loading with the incident deterioration of mechanical, thermal, and processing properties limits the further application of the traditional polymer-based TIMs. In this work, a ternary TIMs with epoxy resin (EP) matrix, silver nanowires (AgNWs), and a small amount of flame-retardant functionalized graphene (GP-DOPO) were proposed to address the above questions. Briefly, a facile "branch-like" strategy with a polymer as the backbone and flame-retardant molecule as the branch was first used to functionalize reduced graphene oxide (RGO) toward increasing the flame-retardant grafting ratio and RGO's compatibility in matrix, and the resulted GP-DOPO was then in situ introduced into the EP/AgNW composites. As expected, the incorporation of GP-DOPO (2 wt %) can increase the thermal conductivity to 1.413 W/(m K) at a very low AgNW loading (4 vol %), which is 545 and 56% increments compared to pure EP and EP/AgNW, respectively. The prominent improvement in thermal conductivity was put down to the synergetic effect of AgNW and GP-DOPO, i.e., the improving dispersion and bridging effect for AgNWs by adding GP-DOPO. Moreover, the high flame-retardant grafting amount and the excellent compatibility of GP-DOPO resulted in a strong catalytic charring effect on EP matrix, which further formed a robust protective char layer by combining the AgNW and graphene network. Therefore, the flame retardancy of EP/AgNW was significantly improved by introducing GP-DOPO, i.e., the peak heat release rate, total heat release and total smoke production reduced by 27.0, 32.4, and 30.9% reduction compared to EP/AgNW, respectively.

The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport.

PubMed

Dahan, Arik; Sabit, Hairat; Amidon, Gordon L

2009-06-01

The aim of this study was to elucidate the intestinal epithelial cell efflux transport processes that are involved in the intestinal transport of the H(2) receptor antagonist nizatidine. The intestinal epithelial efflux transport mechanisms of nizatidine were investigated and characterized across Caco-2 cell monolayers, in the concentration range 0.05-10 mM in both apical-basolateral (AP-BL) and BL-AP directions, and the transport constants of P-glycoprotein (P-gp) efflux activity were calculated. The concentration-dependent effects of various P-gp (verapamil, quinidine, erythromycin, ketoconazole, and cyclosporine A), multidrug resistant-associated protein 2 (MRP2; MK-571, probenecid, indomethacin, and p-aminohipuric acid), and breast cancer resistance protein (BCRP; Fumitremorgin C) inhibitors on nizatidine bidirectional transport were examined. Nizatidine exhibited 7.7-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. All P-gp inhibitors investigated displayed concentration-dependent inhibition on nizatidine secretion in both directions. The IC(50) of verapamil on nizatidine P-gp secretion was 1.2 x 10(-2) mM. In the absence of inhibitors, nizatidine displayed concentration-dependent secretion, with one saturable (J(max) = 5.7 x 10(-3) nmol cm(-2) s(-1) and K(m) = 2.2 mM) and one nonsaturable component (K(d) = 7 x 10(-4) microL cm(-2) s(-1)). Under complete P-gp inhibition, nizatidine exhibited linear secretory flux, with a slope similar to the nonsaturable component. V(max) and K(m) estimated for nizatidine P-gp-mediated secretion were 4 x 10(-3) nmol cm(-2) s(-1) and 1.2 mM, respectively. No effect was obtained with the MRP2 or the BCRP inhibitors. Being a drug commonly used in pediatrics, adults, and elderly, nizatidine susceptibility to efflux transport by P-gp revealed in this paper may be of significance in its absorption, distribution, and clearance, as well as possible drug-drug interactions.

Permutation entropy of fractional Brownian motion and fractional Gaussian noise

NASA Astrophysics Data System (ADS)

Zunino, L.; Pérez, D. G.; Martín, M. T.; Garavaglia, M.; Plastino, A.; Rosso, O. A.

2008-06-01

We have worked out theoretical curves for the permutation entropy of the fractional Brownian motion and fractional Gaussian noise by using the Bandt and Shiha [C. Bandt, F. Shiha, J. Time Ser. Anal. 28 (2007) 646] theoretical predictions for their corresponding relative frequencies. Comparisons with numerical simulations show an excellent agreement. Furthermore, the entropy-gap in the transition between these processes, observed previously via numerical results, has been here theoretically validated. Also, we have analyzed the behaviour of the permutation entropy of the fractional Gaussian noise for different time delays.

Simulation of the usage of Gaussian mixture models for the purpose of modelling virtual mass spectrometry data.

PubMed

Plechawska, Małgorzata; Polańska, Joanna

2009-01-01

This article presents the method of the processing of mass spectrometry data. Mass spectra are modelled with Gaussian Mixture Models. Every peak of the spectrum is represented by a single Gaussian. Its parameters describe the location, height and width of the corresponding peak of the spectrum. An authorial version of the Expectation Maximisation Algorithm was used to perform all calculations. Errors were estimated with a virtual mass spectrometer. The discussed tool was originally designed to generate a set of spectra within defined parameters.

Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation

PubMed Central

Ringe, Rajesh P.; Sanders, Rogier W.; Yasmeen, Anila; Kim, Helen J.; Lee, Jeong Hyun; Cupo, Albert; Korzun, Jacob; Derking, Ronald; van Montfort, Thijs; Julien, Jean-Philippe; Wilson, Ian A.; Klasse, Per Johan; Ward, Andrew B.; Moore, John P.

2013-01-01

We compare the antigenicity and conformation of soluble, cleaved vs. uncleaved envelope glycoprotein (Env gp)140 trimers from the subtype A HIV type 1 (HIV-1) strain BG505. The impact of gp120–gp41 cleavage on trimer structure, in the presence or absence of trimer-stabilizing modifications (i.e., a gp120–gp41 disulfide bond and an I559P gp41 change, together designated SOSIP), was assessed. Without SOSIP changes, cleaved trimers disintegrate into their gp120 and gp41-ectodomain (gp41ECTO) components; when only the disulfide bond is present, they dissociate into gp140 monomers. Uncleaved gp140s remain trimeric whether SOSIP substitutions are present or not. However, negative-stain electron microscopy reveals that only cleaved trimers form homogeneous structures resembling native Env spikes on virus particles. In contrast, uncleaved trimers are highly heterogeneous, adopting a variety of irregular shapes, many of which appear to be gp120 subunits dangling from a central core that is presumably a trimeric form of gp41ECTO. Antigenicity studies with neutralizing and nonneutralizing antibodies are consistent with the EM images; cleaved, SOSIP-stabilized trimers express quaternary structure-dependent epitopes, whereas uncleaved trimers expose nonneutralizing gp120 and gp41ECTO epitopes that are occluded on cleaved trimers. These findings have adverse implications for using soluble, uncleaved trimers for structural studies, and the rationale for testing uncleaved trimers as vaccine candidates also needs to be reevaluated. PMID:24145402

Comprehensive annotation of Glossina pallidipes salivary gland hypertrophy virus from Ethiopian tsetse flies: a proteogenomics approach

PubMed Central

Kariithi, Henry M.; Cousserans, François; Parker, Nicolas J.; İnce, İkbal Agah; Scully, Erin D.; Boeren, Sjef; Geib, Scott M.; Mekonnen, Solomon; Vlak, Just M.; Parker, Andrew G.; Vreysen, Marc J. B.; Bergoin, Max

2016-01-01

Glossina pallidipes salivary gland hypertrophy virus (GpSGHV; family Hytrosaviridae) can establish asymptomatic and symptomatic infection in its tsetse fly host. Here, we present a comprehensive annotation of the genome of an Ethiopian GpSGHV isolate (GpSGHV-Eth) compared with the reference Ugandan GpSGHV isolate (GpSGHV-Uga; GenBank accession number EF568108). GpSGHV-Eth has higher salivary gland hypertrophy syndrome prevalence than GpSGHV-Uga. We show that the GpSGHV-Eth genome has 190 291 nt, a low G+C content (27.9 %) and encodes 174 putative ORFs. Using proteogenomic and transcriptome mapping, 141 and 86 ORFs were mapped by transcripts and peptides, respectively. Furthermore, of the 174 ORFs, 132 had putative transcriptional signals [TATA-like box and poly(A) signals]. Sixty ORFs had both TATA-like box promoter and poly(A) signals, and mapped by both transcripts and peptides, implying that these ORFs encode functional proteins. Of the 60 ORFs, 10 ORFs are homologues to baculovirus and nudivirus core genes, including three per os infectivity factors and four RNA polymerase subunits (LEF4, 5, 8 and 9). Whereas GpSGHV-Eth and GpSGHV-Uga are 98.1 % similar at the nucleotide level, 37 ORFs in the GpSGHV-Eth genome had nucleotide insertions (n = 17) and deletions (n = 20) compared with their homologues in GpSGHV-Uga. Furthermore, compared with the GpSGHV-Uga genome, 11 and 24 GpSGHV ORFs were deleted and novel, respectively. Further, 13 GpSGHV-Eth ORFs were non-canonical; they had either CTG or TTG start codons instead of ATG. Taken together, these data suggest that GpSGHV-Eth and GpSGHV-Uga represent two different lineages of the same virus. Genetic differences combined with host and environmental factors possibly explain the differential GpSGHV pathogenesis observed in different G. pallidipes colonies. PMID:26801744

Optional part-time and longer GP training modules in GP practices associated with more trainees becoming GPs - a cohort study in Switzerland.

PubMed

Studerus, Lara; Ahrens, Regina; Häuptle, Christian; Goeldlin, Adrian; Streit, Sven

2018-01-05

Switzerland, like many other countries, has a shortage of General Practitioners (GPs). Optional GP training modules in GP practices were offered during the at least 5-year GP training program to increase student and trainee interest in becoming a GP. The training modules had not yet been evaluated. We determined how many Swiss GP trainees became practicing GPs after they completed optional training modules, and if longer modules were associated with higher rates of GP specialization. In this population-based cohort study, we included GP trainees who chose an optional GP training module in GP practice, provided by the Foundation to Promote Training in General Practice (WHM) between 2006 and 2015. GP trainees were invited to complete an online survey to assess the primary outcome (becoming a practicing GP by 2016). Data on non-responders was collected via an internet search. We calculated univariate time-to-event curves to become a practicing GP, stratified by trainee's gender, length, part-time training, and number of years after graduation until training modules were completed. We used a multivariate model to adjust for characteristics of participants, training, and satisfaction with training modules. We assessed primary outcome for 351 (92.1%) of 381 former GP trainees who participated in a WHM program between 2006 and 2015. Of these 218 (57%) were practicing GPs by 2016. When focusing on the trainees who had completed training between 2006 and 2010, the rate of practicing GPs was even 73%. Longer (p = 0.018) and part-time training modules (p = 0.003) were associated with higher rates of being a practicing GP. Most (81%) practicing GPs thought their optional GP training module was (very) important in their choice of specialty. GP trainees who spent more time training in a GP practice, or who trained part-time were more likely to become practicing GPs. Most (80%) rated their training module as (very) important in their choice of career, highlighting that these modules effectively encourage the interests of those already inclined towards the GP specialty. Longer GP training modules and more opportunities for part-time training may attract and retain more interested trainees, and possibly increase the number of practicing GPs.

Extended wavelet transformation to digital holographic reconstruction: application to the elliptical, astigmatic Gaussian beams.

PubMed

Remacha, Clément; Coëtmellec, Sébastien; Brunel, Marc; Lebrun, Denis

2013-02-01

Wavelet analysis provides an efficient tool in numerous signal processing problems and has been implemented in optical processing techniques, such as in-line holography. This paper proposes an improvement of this tool for the case of an elliptical, astigmatic Gaussian (AEG) beam. We show that this mathematical operator allows reconstructing an image of a spherical particle without compression of the reconstructed image, which increases the accuracy of the 3D location of particles and of their size measurement. To validate the performance of this operator we have studied the diffraction pattern produced by a particle illuminated by an AEG beam. This study used mutual intensity propagation, and the particle is defined as a chirped Gaussian sum. The proposed technique was applied and the experimental results are presented.

Parameterization of cloud lidar backscattering profiles by means of asymmetrical Gaussians

NASA Astrophysics Data System (ADS)

del Guasta, Massimo; Morandi, Marco; Stefanutti, Leopoldo

1995-06-01

A fitting procedure for cloud lidar data processing is shown that is based on the computation of the first three moments of the vertical-backscattering (or -extinction) profile. Single-peak clouds or single cloud layers are approximated to asymmetrical Gaussians. The algorithm is particularly stable with respect to noise and processing errors, and it is much faster than the equivalent least-squares approach. Multilayer clouds can easily be treated as a sum of single asymmetrical Gaussian peaks. The method is suitable for cloud-shape parametrization in noisy lidar signatures (like those expected from satellite lidars). It also permits an improvement of cloud radiative-property computations that are based on huge lidar data sets for which storage and careful examination of single lidar profiles can't be carried out.

A GXXXA motif in the transmembrane domain of the Ebola virus glycoprotein is required for tetherin antagonism.

PubMed

González-Hernández, Mariana; Hoffmann, Markus; Brinkmann, Constantin; Nehls, Julia; Winkler, Michael; Schindler, Michael; Pöhlmann, Stefan

2018-04-18

The interferon-induced antiviral host cell protein tetherin can inhibit the release of several enveloped viruses from infected cells. The Ebola virus (EBOV) glycoprotein (GP) antagonizes tetherin but the domains and amino acids in GP that are required for tetherin antagonism have not been fully defined. A GXXXA motif within the transmembrane domain (TMD) of EBOV-GP was previously shown to be important for GP-mediated cellular detachment. Here, we investigated whether this motif also contributes to tetherin antagonism. Mutation of the GXXXA motif did not impact GP expression or particle incorporation and only modestly reduced EBOV-GP-driven entry. In contrast, the GXXXA motif was required for tetherin antagonism in transfected cells. Moreover, alteration of the GXXXA motif increased tetherin-sensitivity of a replication-competent vesicular stomatitis virus (VSV) chimera encoding EBOV-GP. Although these results await confirmation with authentic EBOV, they indicate that a GXXXA motif in the TMD of EBOV-GP is important for tetherin antagonism. Moreover, they provide the first evidence that GP can antagonize tetherin in the context of an infectious EBOV surrogate. IMPORTANCE The glycoprotein (GP) of Ebola virus (EBOV) inhibits the antiviral host cell protein tetherin and may promote viral spread in tetherin-positive cells. However, tetherin antagonism by GP has so far only been demonstrated using virus-like particles and it is unknown whether GP can block tetherin in infected cells. Moreover, a mutation in GP that selectively abrogates tetherin antagonism is unknown. Here, we show that a GXXXA motif in the transmembrane domain of EBOV-GP, which was previously reported to be required for GP-mediated cell rounding, is also important for tetherin counteraction. Moreover, analysis of this mutation in the context of vesicular stomatitis virus chimeras encoding EBOV-GP revealed that GP-mediated tetherin counteraction is operative in infected cells. To our knowledge, these findings demonstrate for the first time that GP can antagonize tetherin in infected cells and provide a tool to study the impact of GP-dependent tetherin counteraction on EBOV spread. Copyright © 2018 American Society for Microbiology.

Glycoprotein 5 of porcine reproductive and respiratory syndrome virus strain SD16 inhibits viral replication and causes G2/M cell cycle arrest, but does not induce cellular apoptosis in Marc-145 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mu, Yang, E-mail: muyang@nwsuaf.edu.cn; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture of the People's Republic of China, No. 22 Xinong Road, Yangling, Shaanxi 712100; Li, Liangliang, E-mail: lifeiyang2007@126.com

Cell apoptosis is common after infection with porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV GP5 has been reported to induce cell apoptosis. To further understand the role of GP5 in PRRSV induced cell apoptosis, we established Marc-145 cell lines stably expressing full-length GP5, GP5{sup Δ84-96} (aa 84-96 deletion), and GP5{sup Δ97-119} (aa 97-119 deletion). Cell proliferation, cell cycle progression, cell apoptosis and virus replication in these cell lines were evaluated. Neither truncated nor full-length GP5 induced cell apoptosis in Marc-145 cells. However, GP5{sup Δ97-119}, but not full-length or GP5{sup Δ84-96}, induced a cell cycle arrest at the G2/M phasemore » resulting in a reduction in the growth of Marc-145 cells. Additionally, GP5{sup Δ84-96} inhibited the replication of PRRSV in Marc-145 cells through induction of IFN-β. These findings suggest that PRRSV GP5 is not responsible for inducing cell apoptosis in Marc-145 cells under these experimental conditions; however it has other important roles in virus/host cell biology. - Highlights: • Marc-145 cell lines stable expression PRRSV GP5 or truncated GP5 were constructed. • GP5{sup Δ97-119} expression in Marc-145 cell induced cell cycle arrest at G2/M phase. • Expression of GP5 and truncated GP5 could not induce Marc-145 cells apoptosis. • PRRSV replication in Marc-145-GP5{sup Δ84-96} was significantly inhibited.« less

Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage.

PubMed

Ploss, Martin; Kuhn, Andreas

2011-09-26

Filamentous M13 phage extrude from infected Escherichia coli with a tip structure composed of gp7 and gp9. This tip structure is extended by the assembly of the filament composed of the major coat protein gp8. Finally, gp3 and gp6 terminate the phage structure at the proximal end. Up to now, gp3 has been the primary tool for phage display technology. However, gp7, gp8 and gp9 could also be used for phage display and these phage particles should bind to two different or more surfaces when the modified coat proteins are combined. Therefore, we tested here if the amino-terminal end of gp9 can be modified and whether the modified portion is exposed and detectable on the M13 phage particles. The amino-terminal region of gp9 was modified by inserting short sequences that encode antigenic epitopes. We show here that the modified gp9 proteins correctly integrate into the membrane using the membrane insertase YidC exposing the modified epitope into the periplasm. The proteins are then efficiently assembled onto the phage particles. Also extensions up to 36 amino acid residues at the amino-terminal end of gp9 did not interfere with membrane integration and phage assembly. The exposure of the antigenic tags on the phage was visualised with immunogold labelling by electron microscopy and verified by dot blotting with antibodies to the tags. Our results suggest that gp9 at the phage tip is suitable for the phage display technology. The modified gp9 can be supplied in trans from a plasmid and fully complements M13 phage with an amber mutation in gene 9. The modified phage tip is very well accessible to antibodies.

Membrane insertion and assembly of epitope-tagged gp9 at the tip of the M13 phage

PubMed Central

2011-01-01

Background Filamentous M13 phage extrude from infected Escherichia coli with a tip structure composed of gp7 and gp9. This tip structure is extended by the assembly of the filament composed of the major coat protein gp8. Finally, gp3 and gp6 terminate the phage structure at the proximal end. Up to now, gp3 has been the primary tool for phage display technology. However, gp7, gp8 and gp9 could also be used for phage display and these phage particles should bind to two different or more surfaces when the modified coat proteins are combined. Therefore, we tested here if the amino-terminal end of gp9 can be modified and whether the modified portion is exposed and detectable on the M13 phage particles. Results The amino-terminal region of gp9 was modified by inserting short sequences that encode antigenic epitopes. We show here that the modified gp9 proteins correctly integrate into the membrane using the membrane insertase YidC exposing the modified epitope into the periplasm. The proteins are then efficiently assembled onto the phage particles. Also extensions up to 36 amino acid residues at the amino-terminal end of gp9 did not interfere with membrane integration and phage assembly. The exposure of the antigenic tags on the phage was visualised with immunogold labelling by electron microscopy and verified by dot blotting with antibodies to the tags. Conclusions Our results suggest that gp9 at the phage tip is suitable for the phage display technology. The modified gp9 can be supplied in trans from a plasmid and fully complements M13 phage with an amber mutation in gene 9. The modified phage tip is very well accessible to antibodies. PMID:21943062

Localization of the Houdinisome (Ejection Proteins) inside the Bacteriophage P22 Virion by Bubblegram Imaging

PubMed Central

Wu, Weimin; Leavitt, Justin C.; Cheng, Naiqian; Gilcrease, Eddie B.; Motwani, Tina; Teschke, Carolyn M.; Casjens, Sherwood R.

2016-01-01

ABSTRACT The P22 capsid is a T=7 icosahedrally symmetric protein shell with a portal protein dodecamer at one 5-fold vertex. Extending outwards from that vertex is a short tail, and putatively extending inwards is a 15-nm-long α-helical barrel formed by the C-terminal domains of portal protein subunits. In addition to the densely packed genome, the capsid contains three “ejection proteins” (E-proteins [gp7, gp16, and gp20]) destined to exit from the tightly sealed capsid during the process of DNA delivery into target cells. We estimated their copy numbers by quantitative SDS-PAGE as approximately 12 molecules per virion of gp16 and gp7 and 30 copies of gp20. To localize them, we used bubblegram imaging, an adaptation of cryo-electron microscopy in which gaseous bubbles induced in proteins by prolonged irradiation are used to map the proteins’ locations. We applied this technique to wild-type P22, a triple mutant lacking all three E-proteins, and three mutants each lacking one E-protein. We conclude that all three E-proteins are loosely clustered around the portal axis, in the region displaced radially inwards from the portal crown. The bubblegram data imply that approximately half of the α-helical barrel seen in the portal crystal structure is disordered in the mature virion, and parts of the disordered region present binding sites for E-proteins. Thus positioned, the E-proteins are strategically placed to pass down the shortened barrel and through the portal ring and the tail, as they exit from the capsid during an infection. PMID:27507825

The ATPase domain of the large terminase protein, gp17, from bacteriophage T4 binds DNA: implications to the DNA packaging mechanism.

PubMed

Alam, Tanfis I; Rao, Venigalla B

2008-03-07

Translocation of double-stranded DNA into a preformed capsid by tailed bacteriophages is driven by powerful motors assembled at the special portal vertex. The motor is thought to drive processive cycles of DNA binding, movement, and release to package the viral genome. In phage T4, there is evidence that the large terminase protein, gene product 17 (gp17), assembles into a multisubunit motor and translocates DNA by an inchworm mechanism. gp17 consists of two domains; an N-terminal ATPase domain (amino acids 1-360) that powers translocation of DNA, and a C-terminal nuclease domain (amino acids 361-610) that cuts concatemeric DNA to generate a headful-size viral genome. While the functional motifs of ATPase and nuclease have been well defined and the ATPase atomic structure has been solved, the DNA binding motif(s) responsible for viral DNA recognition, cutting, and translocation are unknown. Here we report the first evidence for the presence of a double-stranded DNA binding activity in the gp17 ATPase domain. Binding to DNA is sensitive to Mg(2+) and salt, but not the type of DNA used. DNA fragments as short as 20 bp can bind to the ATPase but preferential binding was observed to DNA greater than 1 kb. A high molecular weight ATPase-DNA complex was isolated by gel filtration, suggesting oligomerization of ATPase following DNA interaction. DNA binding was not observed with the full-length gp17, or the C-terminal nuclease domain. The small terminase protein, gp16, inhibited DNA binding, which was further accentuated by ATP. The presence of a DNA binding site in the ATPase domain and its binding properties implicate a role in the DNA packaging mechanism.

Re-Audit of the Contents of GP Referral letters to General Adult Community Psychiatrists.

PubMed

Odelola, Catherine; Jabbar, Farid

2017-09-01

The quality of information provided by referring general practitioners to secondary care mental health services are crucial elements in the effective management of patients. In order to establish effective communication, both primary and secondary care health professionals should contribute to planning and organising this process taking into account their different opinions and views. Anonymous questionnaire was designed to collect information on items that GPs and psychiatrist rated as most important items in GP referral letters to psychiatrists. The questionnaires were sent out electronically. Each item was scored using a rating scale where 0 was least important and 10 was most important. Items that scored 8 and above were agreed by all as the most important items. 76 GP letters were audited using a devised checklist of the identified most important items. Data was collected and analysed using a devised data collection tool. A re-audit was done 6months later. A response rate of 70% was obtained for both psychiatrists and GPs. Reasons for referral were described in almost all GP referral letters (95%). Only 24% referral letters had details about current physical health which improved to 59%. Concerns about risk were described in only 47% of letters and treatment provided by GP in 50% of letters. These improved in 79% and 71% of letters respectively in the re-audit. The involvement of professionals in devising a standardised approach for referral letters has improved communication in this re-audit between GPs and Psychiatrists. This is evident in the improvement in key aspects of the referral letters: past medical history, past psychiatric history, current physical health, treatment provided by GP. Efficient communication between GPs and psychiatrists improves the quality of health care for patients.

Specific and non-specific symptoms of colorectal cancer and contact to general practice.

PubMed

Rasmussen, Sanne; Larsen, Pia V; Søndergaard, Jens; Elnegaard, Sandra; Svendsen, Rikke P; Jarbøl, Dorte E

2015-08-01

To improve survival rates for colorectal cancer, referral guidelines have been implemented. First step in the diagnostic process is for the individual to recognize the symptoms and contact his/her general practitioner (GP) for evaluation. To determine (i) the prevalence of specific and non-specific symptom experiences indicative of colorectal cancer, (ii) the proportion of subsequent contacts to GPs, (iii) to explore the possible differences in symptom experience and contact to GPs between age and sex. A nationwide study of 100000 adults, aged 20 years and older, were randomly selected in the general population and invited to participate in an internet-based survey. Items regarding experience of specific and non-specific alarm symptoms of colorectal cancer within the preceding 4 weeks and contact to GP were included. A total of 49706 subjects completed the questionnaire. Abdominal pain was the most common specific alarm symptom (19.7%) and tiredness was the most common non-specific symptom (49.8%). The experiences of symptoms were more common among women and more common in the youngest age groups for both sexes. The symptom leading to the highest proportion of GP contacts was rectal bleeding (33.8%). When experiencing any combination of two specific alarm symptoms, the proportion who contacted a GP was less than 50%. The combination of a non-specific and a specific alarm symptom gave rise to the highest proportion of GP contacts. Although specific and non-specific alarm symptoms of colorectal cancer are common in the general population, the proportion of GP contacts is low. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Exposing the Secrets of Two Well-Known Lactobacillus casei Phages, J-1 and PL-1, by Genomic and Structural Analysis

PubMed Central

Dieterle, Maria Eugenia; Bowman, Charles; Batthyany, Carlos; Lanzarotti, Esteban; Turjanski, Adrián; Hatfull, Graham

2014-01-01

Bacteriophage J-1 was isolated in 1965 from an abnormal fermentation of Yakult using Lactobacillus casei strain Shirota, and a related phage, PL-1, was subsequently recovered from a strain resistant to J-1. Complete genome sequencing shows that J-1 and PL-1 are almost identical, but PL-1 has a deletion of 1.9 kbp relative to J-1, resulting in the loss of four predicted gene products involved in immunity regulation. The structural proteins were identified by mass spectrometry analysis. Similarly to phage A2, two capsid proteins are generated by a translational frameshift and undergo proteolytic processing. The structure of gene product 16 (gp16), a putative tail protein, was modeled based on the crystal structure of baseplate distal tail proteins (Dit) that form the baseplate hub in other Siphoviridae. However, two regions of the C terminus of gp16 could not be modeled using this template. The first region accounts for the differences between J-1 and PL-1 gp16 and showed sequence similarity to carbohydrate-binding modules (CBMs). J-1 and PL-1 GFP-gp16 fusions bind specifically to Lactobacillus casei/paracasei cells, and the addition of l-rhamnose inhibits binding. J-1 gp16 exhibited a higher affinity than PL-1 gp16 for cell walls of L. casei ATCC 27139 in phage adsorption inhibition assays, in agreement with differential adsorption kinetics observed for both phages in this strain. The data presented here provide insights into how Lactobacillus phages interact with their hosts at the first steps of infection. PMID:25217012

B cell recognition of the conserved HIV-1 co-receptor binding site is altered by endogenous primate CD4.

PubMed

Forsell, Mattias N E; Dey, Barna; Mörner, Andreas; Svehla, Krisha; O'dell, Sijy; Högerkorp, Carl-Magnus; Voss, Gerald; Thorstensson, Rigmor; Shaw, George M; Mascola, John R; Karlsson Hedestam, Gunilla B; Wyatt, Richard T

2008-10-03

The surface HIV-1 exterior envelope glycoprotein, gp120, binds to CD4 on the target cell surface to induce the co-receptor binding site on gp120 as the initial step in the entry process. The binding site is comprised of a highly conserved region on the gp120 core, as well as elements of the third variable region (V3). Antibodies against the co-receptor binding site are abundantly elicited during natural infection of humans, but the mechanism of elicitation has remained undefined. In this study, we investigate the requirements for elicitation of co-receptor binding site antibodies by inoculating rabbits, monkeys and human-CD4 transgenic (huCD4) rabbits with envelope glycoprotein (Env) trimers possessing high affinity for primate CD4. A cross-species comparison of the antibody responses showed that similar HIV-1 neutralization breadth was elicited by Env trimers in monkeys relative to wild-type (WT) rabbits. In contrast, antibodies against the co-receptor site on gp120 were elicited only in monkeys and huCD4 rabbits, but not in the WT rabbits. This was supported by the detection of high-titer co-receptor antibodies in all sera from a set derived from human volunteers inoculated with recombinant gp120. These findings strongly suggest that complexes between Env and (high-affinity) primate CD4 formed in vivo are responsible for the elicitation of the co-receptor-site-directed antibodies. They also imply that the naïve B cell receptor repertoire does not recognize the gp120 co-receptor site in the absence of CD4 and illustrate that conformational stabilization, imparted by primary receptor interaction, can alter the immunogenicity of a type 1 viral membrane protein.

Understanding the molecular mechanism of the broad and potent neutralization of HIV-1 by antibody VRC01 from the perspective of molecular dynamics simulation and binding free energy calculations.

PubMed

Zhang, Yan; Pan, Dabo; Shen, Yulin; Jin, Nengzhi; Liu, Huanxiang; Yao, Xiaojun

2012-09-01

VRC01 is one of the most broadly and potently neutralizing HIV-1 antibodies known-it has been shown to neutralize 91 % of the tested primary isolate Env pseudoviruses by recognizing the viral envelope glycoprotein gp120. To explore the mechanism of HIV-1 neutralization by VRC01 and thus obtain valuable information for vaccine design, we performed molecular dynamics simulations and binding free energy calculations for apo-VRC01, apo-gp120, and the gp120-VRC01 complex. For gp120, residue energy decomposition analysis showed that the hotspot residues Asn280, Lys282, Asp368, Ile371, and Asp457 are located in three primary loops, including the CD4-binding loop, loop D, and loop V5. For VRC01, the hotspot residues Trp47, Trp50, Asn58, Arg61, Gln64, Trp100, and Tyr91 mainly come from CDR2 of the heavy chain. By decomposing the binding free energy into different components, intermolecular van der Waals interactions and nonpolar solvation were found to dominate the binding process. Principal component analysis of loops D and V5, which are related to neutralization resistance, indicated that these two areas have a larger conformational space in apo-gp120 compared to bound gp120. A comparison of three representative structures from the cluster analysis of loops D and V5 indicated that changes primarily occur at the tip of loop V5, and are caused by fluctuations in the terminal Glu1 residue of the antibody. This information can be used to guide the design of vaccines and small molecule inhibitors.

A fast elitism Gaussian estimation of distribution algorithm and application for PID optimization.

PubMed

Xu, Qingyang; Zhang, Chengjin; Zhang, Li

2014-01-01

Estimation of distribution algorithm (EDA) is an intelligent optimization algorithm based on the probability statistics theory. A fast elitism Gaussian estimation of distribution algorithm (FEGEDA) is proposed in this paper. The Gaussian probability model is used to model the solution distribution. The parameters of Gaussian come from the statistical information of the best individuals by fast learning rule. A fast learning rule is used to enhance the efficiency of the algorithm, and an elitism strategy is used to maintain the convergent performance. The performances of the algorithm are examined based upon several benchmarks. In the simulations, a one-dimensional benchmark is used to visualize the optimization process and probability model learning process during the evolution, and several two-dimensional and higher dimensional benchmarks are used to testify the performance of FEGEDA. The experimental results indicate the capability of FEGEDA, especially in the higher dimensional problems, and the FEGEDA exhibits a better performance than some other algorithms and EDAs. Finally, FEGEDA is used in PID controller optimization of PMSM and compared with the classical-PID and GA.

A Fast Elitism Gaussian Estimation of Distribution Algorithm and Application for PID Optimization

PubMed Central

Xu, Qingyang; Zhang, Chengjin; Zhang, Li

2014-01-01

Estimation of distribution algorithm (EDA) is an intelligent optimization algorithm based on the probability statistics theory. A fast elitism Gaussian estimation of distribution algorithm (FEGEDA) is proposed in this paper. The Gaussian probability model is used to model the solution distribution. The parameters of Gaussian come from the statistical information of the best individuals by fast learning rule. A fast learning rule is used to enhance the efficiency of the algorithm, and an elitism strategy is used to maintain the convergent performance. The performances of the algorithm are examined based upon several benchmarks. In the simulations, a one-dimensional benchmark is used to visualize the optimization process and probability model learning process during the evolution, and several two-dimensional and higher dimensional benchmarks are used to testify the performance of FEGEDA. The experimental results indicate the capability of FEGEDA, especially in the higher dimensional problems, and the FEGEDA exhibits a better performance than some other algorithms and EDAs. Finally, FEGEDA is used in PID controller optimization of PMSM and compared with the classical-PID and GA. PMID:24892059

A brain MRI bias field correction method created in the Gaussian multi-scale space

NASA Astrophysics Data System (ADS)

Chen, Mingsheng; Qin, Mingxin

2017-07-01

A pre-processing step is needed to correct for the bias field signal before submitting corrupted MR images to such image-processing algorithms. This study presents a new bias field correction method. The method creates a Gaussian multi-scale space by the convolution of the inhomogeneous MR image with a two-dimensional Gaussian function. In the multi-Gaussian space, the method retrieves the image details from the differentiation of the original image and convolution image. Then, it obtains an image whose inhomogeneity is eliminated by the weighted sum of image details in each layer in the space. Next, the bias field-corrected MR image is retrieved after the Υ correction, which enhances the contrast and brightness of the inhomogeneity-eliminated MR image. We have tested the approach on T1 MRI and T2 MRI with varying bias field levels and have achieved satisfactory results. Comparison experiments with popular software have demonstrated superior performance of the proposed method in terms of quantitative indices, especially an improvement in subsequent image segmentation.

'Just a GP': a mixed method study of undermining of general practice as a career choice in the UK.

PubMed

Alberti, Hugh; Banner, Kimberley; Collingwood, Helen; Merritt, Kymberlee

2017-11-03

Failure to recruit sufficient applicants to general practice (GP) training has been a problem both nationally and internationally for many years and undermining of GP is one possible contributing factor. The aim of our study was to ascertain what comments, both negative and positive, are being made in UK clinical settings to GP trainees about GP and to further explore these comments and their influence on career choice. We conducted a mixed methods study. We surveyed all foundation doctors and GP trainees within one region of Health Education England regarding any comments they experienced relating to a career in GP. We also conducted six focus groups with early GP trainees to discuss any comments that they experienced and whether these comments had any influence on their or others career choice. Positive comments reported by trainees centred around the concept that choosing GP is a positive, family-focused choice which facilities a good work-life balance. Workload was the most common negative comment, alongside the notion of being 'just a GP'; the belief that GP is boring, a waste of training and a second-class career choice. The reasons for and origin of the comments are multifactorial in nature. Thematic analysis of the focus groups identified key factors such as previous exposure to and experience of GP, family members who were GPs, GP role models, demographics of the clinician and referral behaviour. Trainees perceived that negative comments may be discouraging others from choosing GP as a career. Our study demonstrates that negative comments towards GP as a career do exist within clinical settings and are having a potential impact on poor recruitment rates to GP training. We have identified areas in which further negative comments could be prevented by changing perceptions of GP as a career. Additional time spent in GP as undergraduates and postgraduates, and positive GP role models, could particularly benefit recruitment. We recommend that undermining of GP as a career choice be approached with a zero-tolerance policy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model.

PubMed

Hatting, M; Spannbauer, M; Peng, J; Al Masaoudi, M; Sellge, G; Nevzorova, Y A; Gassler, N; Liedtke, C; Cubero, F J; Trautwein, C

2015-03-05

Chronic liver inflammation is a crucial event in the development and growth of hepatocellular carcinoma (HCC). Compelling evidence has shown that interleukin-6 (IL-6)/gp130-dependent signaling has a fundamental role in liver carcinogenesis. Thus, in the present study we aimed to investigate the role of gp130 in hepatocytes for the initiation and progression of HCC. Hepatocyte-specific gp130 knockout mice (gp130(Δhepa)) and control animals (gp130(f/f)) were treated with diethylnitrosamine (DEN). The role of gp130 for acute injury (0-144 h post treatment), tumor initiation (24 weeks) and progression (40 weeks) was analyzed. After acute DEN-induced liver injury we observed a reduction in the inflammatory response in gp130(Δhepa) animals as reflected by decreased levels of IL-6 and oncostatin M. The loss of gp130 slightly attenuated the initiation of HCC 24 weeks after DEN treatment. In contrast, 40 weeks after DEN treatment, male and female gp130(Δhepa) mice showed smaller tumors and reduced tumor burden, indicating a role for hepatocyte-specific gp130 expression during HCC progression. Oxidative stress and DNA damage were substantially and similarly increased by DEN in both gp130(f/f) and gp130(Δhepa) animals. However, gp130(Δhepa) livers revealed aberrant STAT5 activation and decreased levels of transforming growth factor-β (TGFβ), pSMAD2/3 and SMAD2, whereas phosphorylation of STAT3 at Tyr705 and Ser727 was absent. Our results indicate that gp130 deletion in hepatocytes reduces progression, but not HCC initiation in the DEN model. Gp130 deletion resulted in STAT3 inhibition but increased STAT5 activation and diminished TGF-dependent signaling. Hence, blocking gp130 in hepatocytes might be an interesting therapeutic target to inhibit the growth of HCC.

Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2.

PubMed

Roggenbuck, Dirk; Goihl, Alexander; Hanack, Katja; Holzlöhner, Pamela; Hentschel, Christian; Veiczi, Miklos; Schierack, Peter; Reinhold, Dirk; Schulz, Hans-Ulrich

2017-05-01

Glycoprotein 2 (GP2), the pancreatic major zymogen granule membrane glycoprotein, was reported to be elevated in acute pancreatitis in animal models. Enzyme-linked immunosorbent assays (ELISAs) were developed to evaluate human glycoprotein 2 isoform alpha (GP2a) and total GP2 (GP2t) as specific markers for acute pancreatitis in sera of 153 patients with acute pancreatitis, 26 with chronic pancreatitis, 125 with pancreatic neoplasms, 324 with non-pancreatic neoplasms, 109 patients with liver/biliary disease, 67 with gastrointestinal disease, and 101 healthy subjects. GP2a and GP2t levels were correlated with procalcitonin and C-reactive protein in 152 and 146 follow-up samples of acute pancreatitis patients, respectively. The GP2a ELISA revealed a significantly higher assay accuracy in contrast to the GP2t assay (sensitivity ≤3 disease days: 91.7%, specificity: 96.7%, positive likelihood ratio [LR+]: 24.6, LR-: 0.09). GP2a and GP2t levels as well as prevalences were significantly elevated in early acute pancreatitis (≤3 disease days) compared to all control cohorts (p<0.05, respectively). GP2a and GP2t levels were significantly higher in patients with severe acute pancreatitis at admission compared with mild cases (p<0.05, respectively). Odds ratio for GP2a regarding mild vs. severe acute pancreatitis with lethal outcome was 7.8 on admission (p=0.0222). GP2a and GP2t levels were significantly correlated with procalcitonin [Spearman's rank coefficient of correlation (ρ)=0.21, 0.26; p=0.0110, 0.0012; respectively] and C-reactive protein (ρ=0.37, 0.40; p<0.0001; respectively). Serum GP2a is a specific marker of acute pancreatitis and analysis of GP2a can aid in the differential diagnosis of acute upper abdominal pain and prognosis of severe acute pancreatitis.

Chemical synthesis of 5'-pyrophosphate and triphosphate derivatives of 3'-5' ApA, ApG, GpA and GpG. CD study of the effect of 5'-phosphate groups on the conformation of 3'-5' GpG.

PubMed Central

Tomasz, J; Simoncsits, A; Kajtár, M; Krug, R M; Shatkin, A J

1978-01-01

A simple, two-step method is described for the synthesis of the 5'-pyro- and triphosphate derivatives of 3'-5' ApA, ApG, GpA and GpG. The readily accessible 2'(3')-5' ApA, ApG, GpA and GpG were converted in one step to the corresponding 5'-phosphoramidate derivatives which were then transformed to the 5'-pyro- and triphosphates. CD spectra of 3'-5' pn GpG (n = 0,1,2 or 3) derivatives, measured at pH 1, indicated stabilization of the (syn) G+p (anti)G conformation by the 5'-phosphate groups. PMID:211490

Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes

PubMed Central

Xin Liu, Gong; Derst, Christian; Schlichthörl, Günter; Heinen, Steffen; Seebohm, Guiscard; Brüggemann, Andrea; Kummer, Wolfgang; Veh, Rüdiger W; Daut, Jürgen; Preisig-Müller, Regina

2001-01-01

The aim of the study was to compare the properties of cloned Kir2 channels with the properties of native rectifier channels in guinea-pig (gp) cardiac muscle. The cDNAs of gpKir2.1, gpKir2.2, gpKir2.3 and gpKir2.4 were obtained by screening a cDNA library from guinea-pig cardiac ventricle. A partial genomic structure of all gpKir2 genes was deduced by comparison of the cDNAs with the nucleotide sequences derived from a guinea-pig genomic library. The cell-specific expression of Kir2 channel subunits was studied in isolated cardiomyocytes using a multi-cell RT-PCR approach. It was found that gpKir2.1, gpKir2.2 and gpKir2.3, but not gpKir2.4, are expressed in cardiomyocytes. Immunocytochemical analysis with polyclonal antibodies showed that expression of Kir2.4 is restricted to neuronal cells in the heart. After transfection in human embryonic kidney cells (HEK293) the mean single-channel conductance with symmetrical K+ was found to be 30.6 pS for gpKir2.1, 40.0 pS for gpKir2.2 and 14.2 pS for Kir2.3. Cell-attached measurements in isolated guinea-pig cardiomyocytes (n = 351) revealed three populations of inwardly rectifying K+ channels with mean conductances of 34.0, 23.8 and 10.7 pS. Expression of the gpKir2 subunits in Xenopus oocytes showed inwardly rectifying currents. The Ba2+ concentrations required for half-maximum block at -100 mV were 3.24 μm for gpKir2.1, 0.51 μm for gpKir2.2, 10.26 μm for gpKir2.3 and 235 μm for gpKir2.4. Ba2+ block of inward rectifier channels of cardiomyocytes was studied in cell-attached recordings. The concentration and voltage dependence of Ba2+ block of the large-conductance inward rectifier channels was virtually identical to that of gpKir2.2 expressed in Xenopus oocytes. Our results suggest that the large-conductance inward rectifier channels found in guinea-pig cardiomyocytes (34.0 pS) correspond to gpKir2.2. The intermediate-conductance (23.8 pS) and low-conductance (10.7 pS) channels described here may correspond to gpKir2.1 and gpKir2.3, respectively. PMID:11283229

SU-G-IeP3-08: Image Reconstruction for Scanning Imaging System Based On Shape-Modulated Point Spreading Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Ruixing; Yang, LV; Xu, Kele

Purpose: Deconvolution is a widely used tool in the field of image reconstruction algorithm when the linear imaging system has been blurred by the imperfect system transfer function. However, due to the nature of Gaussian-liked distribution for point spread function (PSF), the components with coherent high frequency in the image are hard to restored in most of the previous scanning imaging system, even the relatively accurate PSF is acquired. We propose a novel method for deconvolution of images which are obtained by using shape-modulated PSF. Methods: We use two different types of PSF - Gaussian shape and donut shape -more » to convolute the original image in order to simulate the process of scanning imaging. By employing deconvolution of the two images with corresponding given priors, the image quality of the deblurred images are compared. Then we find the critical size of the donut shape compared with the Gaussian shape which has similar deconvolution results. Through calculation of tightened focusing process using radially polarized beam, such size of donut is achievable under same conditions. Results: The effects of different relative size of donut and Gaussian shapes are investigated. When the full width at half maximum (FWHM) ratio of donut and Gaussian shape is set about 1.83, similar resolution results are obtained through our deconvolution method. Decreasing the size of donut will favor the deconvolution method. A mask with both amplitude and phase modulation is used to create a donut-shaped PSF compared with the non-modulated Gaussian PSF. Donut with size smaller than our critical value is obtained. Conclusion: The utility of donutshaped PSF are proved useful and achievable in the imaging and deconvolution processing, which is expected to have potential practical applications in high resolution imaging for biological samples.« less

Molecular cloning and sequence analysis of the Anticarsia gemmatalis multicapsid nuclear polyhedrosis virus GP64 glycoprotein.

PubMed

Pilloff, Marcela Gabriela; Bilen, Marcos Fabián; Belaich, Mariano Nicolás; Lozano, Mario Enrique; Ghiringhelli, Pablo Daniel

2003-01-01

The gp64 locus of Anticarsia gemmatalis multicapsid nucleopolyhedrovirus isolate Santa Fe (AgMNPV-SF) was characterised molecularly in our laboratory. To this end, we have located and cloned a AgMNPV-SF genomic DNA fragment containing the gp64 gene and sequenced the complete gp64 locus. Nucleotide sequence analysis indicated that the AgMNPV gp64 gene consists of a 1500 nucleotide open reading frame (ORF), encoding a protein of 499 amino acids. Of the seven gp64 homologues identified to date, the AgMNPV gp64 ORF shared most sequence similarity with the gp64 gene of Orgyia pseudotsugata MNPV. The GP64 from AgMNPV is the smallest baculoviral envelope glycoprotein found to date, differing in 10 or more residues from the other group I nucleopolyhedroviruses. The biological activity of AgMNPV GP64 protein was assessed by cell fusion assays in UFL-AG-286 cells using the obtained recombinant plasmids. In the upstream and downstream regions, relative to the gp64 ORF, we found different conserved transcriptional and post-transcriptional regulatory elements, respectively.

‘Just a GP’: a mixed method study of undermining of general practice as a career choice in the UK

PubMed Central

Alberti, Hugh; Collingwood, Helen; Merritt, Kymberlee

2017-01-01

Objectives Failure to recruit sufficient applicants to general practice (GP) training has been a problem both nationally and internationally for many years and undermining of GP is one possible contributing factor. The aim of our study was to ascertain what comments, both negative and positive, are being made in UK clinical settings to GP trainees about GP and to further explore these comments and their influence on career choice. Methodology We conducted a mixed methods study. We surveyed all foundation doctors and GP trainees within one region of Health Education England regarding any comments they experienced relating to a career in GP. We also conducted six focus groups with early GP trainees to discuss any comments that they experienced and whether these comments had any influence on their or others career choice. Results Positive comments reported by trainees centred around the concept that choosing GP is a positive, family-focused choice which facilities a good work–life balance. Workload was the most common negative comment, alongside the notion of being ‘just a GP’; the belief that GP is boring, a waste of training and a second-class career choice. The reasons for and origin of the comments are multifactorial in nature. Thematic analysis of the focus groups identified key factors such as previous exposure to and experience of GP, family members who were GPs, GP role models, demographics of the clinician and referral behaviour. Trainees perceived that negative comments may be discouraging others from choosing GP as a career. Conclusion Our study demonstrates that negative comments towards GP as a career do exist within clinical settings and are having a potential impact on poor recruitment rates to GP training. We have identified areas in which further negative comments could be prevented by changing perceptions of GP as a career. Additional time spent in GP as undergraduates and postgraduates, and positive GP role models, could particularly benefit recruitment. We recommend that undermining of GP as a career choice be approached with a zero-tolerance policy. PMID:29102997

Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine

PubMed Central

2018-01-01

ABSTRACT Current evidence supports a protective role for virus-neutralizing antibodies in immunity against hepatitis C virus (HCV) infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to provide protection or to clear infection in animal models. Previous clinical trials have shown that a gpE1/gpE2 vaccine can induce antibodies that neutralize the in vitro infectivity of all the major cell culture-derived HCV (HCVcc) genotypes around the world. However, cross-neutralization appeared to favor certain genotypes, with significant but lower neutralization against others. HCV may employ epitope masking to avoid antibody-mediated neutralization. Hypervariable region 1 (HVR1) at the amino terminus of glycoprotein E2 has been shown to restrict access to many neutralizing antibodies. Consistent with this, other groups have reported that recombinant viruses lacking HVR1 are hypersensitive to neutralization. It has been proposed that gpE1/gpE2 lacking this domain could be a better vaccine antigen to induce broadly neutralizing antibodies. In this study, we examined the immunogenicity of recombinant gpE1/gpE2 lacking HVR1 (ΔHVR1). Our results indicate that wild-type (WT) and ΔHVR1 gpE1/gpE2 antigens induced antibodies targeting many well-characterized cross-genotype-neutralizing epitopes. However, while the WT gpE1/gpE2 vaccine can induce cross-genotype protection against various genotypes of HCVcc and/or HCV-pseudotyped virus (HCVpp), antisera from ΔHVR1 gpE1/gpE2-immunized animals exhibited either reduced homologous neutralization activity compared to that of the WT or heterologous neutralization activity similar to that of the WT. These data suggest that ΔHVR1 gpE1/gpE2 is not a superior vaccine antigen. Based on previously reported chimpanzee protection data using WT gpE1/gpE2 and our current findings, we are preparing a combination vaccine including wild-type recombinant gpE1/gpE2 for clinical testing in the future. IMPORTANCE An HCV vaccine is an unmet medical need. Current evidence suggests that neutralizing antibodies play an important role in virus clearance, along with cellular immune responses. Previous clinical data showed that gpE1/gpE2 can effectively induce cross-neutralizing antibodies, although they favor certain genotypes. HCV employs HVR1 within gpE2 to evade host immune control. It has been hypothesized that the removal of this domain would improve the production of cross-neutralizing antibodies. In this study, we compared the immunogenicities of WT and ΔHVR1 gpE1/gpE2 antigens as vaccine candidates. Our results indicate that the ΔHVR1 gpE1/gpE2 antigen confers no advantages in the neutralization of HCV compared with the WT antigen. Previously, we showed that this WT antigen remains the only vaccine candidate to protect chimpanzees from chronic infection, contains multiple cross-neutralizing epitopes, and is well tolerated and immunogenic in humans. The current data support the further clinical development of this vaccine antigen component. PMID:29540595

Functional characterization of Autographa californica multiple nucleopolyhedrovirus gp16 (ac130)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Ming; Huang, Cui; Qian, Duo-Duo

2014-09-15

To investigate the function of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) gp16, multiple gp16-knockout and repair mutants were constructed and characterized. No obvious difference in productivity of budded virus, DNA synthesis, late gene expression and morphogenesis was observed between gp16-knockout and repair viruses, but gp16 deletion resulted in six hours of lengthening in ST{sub 50} to the third instar Spodoptera exigua larvae in bioassays. GP16 was fractionated mainly in the light membrane fraction, by subcellular fractionation. A GP16-EGFP fusion protein was predominantly localized close around the nuclear membrane in infected cells, being coincident with formation of the vesicles associated with themore » nuclear membrane, which hosted nucleocapsids released from the nucleus. These data suggest that gp16 is not required for viral replication, but may be involved in membrane trafficking associated with the envelopment/de-envelopment of budded viruses when they cross over the nuclear membrane and pass through cytoplasm. - Highlights: • gp16 knockout and repair mutants of AcMNPV were constructed and characterized. • AcMNPV gp16 is not essential to virus replication. • Deletion of gp16 resulted in time lengthening to kill S. exigua larvae. • GP16 was localized close around the nuclear membrane of infected cells. • GP16 was fractionated in the light membrane fraction in subcellular fractionation.« less

Investigating intermolecular forces associated with thrombus initiation using optical tweezers

NASA Astrophysics Data System (ADS)

Arya, Maneesh; Lopez, Jose A.; Romo, Gabriel M.; Dong, Jing-Fei; McIntire, Larry V.; Moake, Joel L.; Anvari, Bahman

2002-05-01

Thrombus formation occurs when a platelet membrane receptor, glycoprotein (GP) Ib-IX-V complex, binds to its ligand, von Willebrand factor (vWf), in the subendothelium or plasma. To determine which GP Ib-IX-V amino acid sequences are critical for bond formation, we have used optical tweezers to measure forces involved in the binding of vWf to GP Ib-IX-V variants. Inasmuch as GP Ib(alpha) subunit is the primary component in human GP Ib-IX-V complex that binds to vWf, and that canine GP Ib(alpha) , on the other hand, does not bind to human vWf, we progressively replaced human GP Ib(alpha) amino acid sequences with canine GP Ib(alpha) sequences to determine the sequences essential for vWf/GP Ib(alpha) binding. After measuring the adhesive forces between optically trapped, vWf-coated beads and GP Ib(alpha) variants expressed on mammalian cells, we determined that leucine- rich repeat 2 of GP Ib(alpha) was necessary for vWf/GP Ib-IX- V bond formation. We also found that deletion of the N- terminal flanking sequence and leucine-rich repeat 1 reduced adhesion strength to vWf but did not abolish binding. While divalent cations are known to influence binding of vWf, addition of 1mM CaCl2 had no effect on measured vWf/GP Ib(alpha) bond strengths.

Strain-level genetic diversity of Methylophaga nitratireducenticrescens confers plasticity to denitrification capacity in a methylotrophic marine denitrifying biofilm.

PubMed

Geoffroy, Valérie; Payette, Geneviève; Mauffrey, Florian; Lestin, Livie; Constant, Philippe; Villemur, Richard

2018-01-01

The biofilm of a methanol-fed, fluidized denitrification system treating a marine effluent is composed of multi-species microorganisms, among which Hyphomicrobium nitrativorans NL23 and Methylophaga nitratireducenticrescens JAM1 are the principal bacteria involved in the denitrifying activities. Strain NL23 can carry complete nitrate (NO[Formula: see text]) reduction to N 2 , whereas strain JAM1 can perform 3 out of the 4 reduction steps. A small proportion of other denitrifiers exists in the biofilm, suggesting the potential plasticity of the biofilm in adapting to environmental changes. Here, we report the acclimation of the denitrifying biofilm from continuous operating mode to batch operating mode, and the isolation and characterization from the acclimated biofilm of a new denitrifying bacterial strain, named GP59. The denitrifying biofilm was batch-cultured under anoxic conditions. The acclimated biofilm was plated on Methylophaga specific medium to isolate denitrifying Methylophaga isolates. Planktonic cultures of strains GP59 and JAM1 were performed, and the growth and the dynamics of NO[Formula: see text], nitrite (NO[Formula: see text]) and N 2 O were determined. The genomes of strains GP59 and JAM1 were sequenced and compared. The transcriptomes of strains GP59 and JAM1 were derived from anoxic cultures. During batch cultures of the biofilm, we observed the disappearance of H. nitrativorans NL23 without affecting the denitrification performance. From the acclimated biofilm, we isolated strain GP59 that can perform, like H. nitrativorans NL23, the complete denitrification pathway. The GP59 cell concentration in the acclimated biofilm was 2-3 orders of magnitude higher than M. nitratireducenticrescens JAM1 and H. nitrativorans NL23. Genome analyses revealed that strain GP59 belongs to the species M. nitratireducenticrescens . The GP59 genome shares more than 85% of its coding sequences with those of strain JAM1. Based on transcriptomic analyses of anoxic cultures, most of these common genes in strain GP59 were expressed at similar level than their counterparts in strain JAM1. In contrast to strain JAM1, strain GP59 cannot reduce NO[Formula: see text] under oxic culture conditions, and has a 24-h lag time before growth and NO[Formula: see text] reduction start to occur in anoxic cultures, suggesting that both strains regulate differently the expression of their denitrification genes. Strain GP59 has the ability to reduce NO[Formula: see text] as it carries a gene encoding a NirK-type NO[Formula: see text] reductase. Based on the CRISPR sequences, strain GP59 did not emerge from strain JAM1 during the biofilm batch cultures but rather was present in the original biofilm and was enriched during this process. These results reinforce the unique trait of the species M. nitratireducenticrescens among the Methylophaga genus as facultative anaerobic bacterium. These findings also showed the plasticity of denitrifying population of the biofilm in adapting to anoxic marine environments of the bioreactor.

Mean-square state and parameter estimation for stochastic linear systems with Gaussian and Poisson noises

NASA Astrophysics Data System (ADS)

Basin, M.; Maldonado, J. J.; Zendejo, O.

2016-07-01

This paper proposes new mean-square filter and parameter estimator design for linear stochastic systems with unknown parameters over linear observations, where unknown parameters are considered as combinations of Gaussian and Poisson white noises. The problem is treated by reducing the original problem to a filtering problem for an extended state vector that includes parameters as additional states, modelled as combinations of independent Gaussian and Poisson processes. The solution to this filtering problem is based on the mean-square filtering equations for incompletely polynomial states confused with Gaussian and Poisson noises over linear observations. The resulting mean-square filter serves as an identifier for the unknown parameters. Finally, a simulation example shows effectiveness of the proposed mean-square filter and parameter estimator.

Brownian motion under dynamic disorder: effects of memory on the decay of the non-Gaussianity parameter

NASA Astrophysics Data System (ADS)

Tyagi, Neha; Cherayil, Binny J.

2018-03-01

The increasingly widespread occurrence in complex fluids of particle motion that is both Brownian and non-Gaussian has recently been found to be successfully modeled by a process (frequently referred to as ‘diffusing diffusivity’) in which the white noise that governs Brownian diffusion is itself stochastically modulated by either Ornstein–Uhlenbeck dynamics or by two-state noise. But the model has so far not been able to account for an aspect of non-Gaussian Brownian motion that is also commonly observed: a non-monotonic decay of the parameter that quantifies the extent of deviation from Gaussian behavior. In this paper, we show that the inclusion of memory effects in the model—via a generalized Langevin equation—can rationalise this phenomenon.

Dynamics of a Landau-Zener non-dissipative system with fluctuating energy levels

NASA Astrophysics Data System (ADS)

Fai, L. C.; Diffo, J. T.; Ateuafack, M. E.; Tchoffo, M.; Fouokeng, G. C.

2014-12-01

This paper considers a Landau-Zener (two-level) system influenced by a three-dimensional Gaussian and non-Gaussian coloured noise and finds a general form of the time dependent diabatic quantum bit (qubit) flip transition probabilities in the fast, intermediate and slow noise limits. The qubit flip probability is observed to mimic (for low-frequencies noise) that of the standard LZ problem. The qubit flip probability is also observed to be the measure of quantum coherence of states. The transition probability is observed to be tailored by non-Gaussian low-frequency noise and otherwise by Gaussian low-frequency coloured noise. Intermediate and fast noise limits are observed to alter the memory of the system in time and found to improve and control quantum information processing.

Deciliation Is Associated with Dramatic Remodeling of Epithelial Cell Junctions and Surface Domains

PubMed Central

Overgaard, Christian E.; Sanzone, Kaitlin M.; Spiczka, Krystle S.; Sheff, David R.; Sandra, Alexander

2009-01-01

Stress-induced shedding of motile cilia (autotomy) has been documented in diverse organisms and likely represents a conserved cellular reaction. However, little is known about whether primary cilia are shed from mammalian epithelial cells and what impact deciliation has on polarized cellular organization. We show that several chemically distinct agents trigger autotomy in epithelial cells. Surprisingly, deciliation is associated with a significant, but reversible increase in transepithelial resistance. This reflects substantial reductions in tight junction proteins associated with “leaky” nephron segments (e.g., claudin-2). At the same time, apical trafficking of gp80/clusterin and gp114/CEACAM becomes randomized, basal-lateral delivery of Na,K-ATPase is reduced, and expression of the nonciliary apical protein gp135/podocalyxin is greatly decreased. However, ciliogenesis-impaired MDCK cells do not undergo continual junction remodeling, and mature cilia are not required for autotomy-associated remodeling events. Deciliation and epithelial remodeling may be mechanistically linked processes, because RNAi-mediated reduction of Exocyst subunit Sec6 inhibits ciliary shedding and specifically blocks deciliation-associated down-regulation of claudin-2 and gp135. We propose that ciliary autotomy represents a signaling pathway that impacts the organization and function of polarized epithelial cells. PMID:19005211

Mechanochemical Phosphorylation and Solubilisation of β-D-Glucan from Yeast Saccharomyces cerevisiae and Its Biological Activities

PubMed Central

Shi, Feng; Shi, Jikui; Li, Yongfu

2014-01-01

To obtain a water-soluble β-D-glucan derivative cleanly and conveniently, a highly efficient mechanochemical method, planetary ball milling, was used to phosphorylate β-D-glucan isolated from yeast Saccharomyces cerevisiae in solid state. Soluble β-D-glucan phosphate (GP) with a high degree of substitution (0.77–2.09) and an apparent PEAK molecular weight of 6.6–10.0 kDa was produced when β-D-glucan was co-milled with sodium hexametaphosphate at 139.5–186.0 rad/s for 12–20 min. The energy transferred was 3.03–11.98 KJ/g. The phosphorylation of GPs was demonstrated by Fourier transform infrared spectroscopy and 13C and 31P Nuclear magnetic resonance spectroscopy. Three GP products with different degree of substitution (DS) and degree of polymerisation (DP) were able to upregulate the functional events mediated by activated murine macrophage RAW264.7 cells, among which GP-2 with a DS of 1.24 and DP of 30.5 exerted the highest immunostimulating activity. Our results indicate that mechanochemical processing is an efficient method for preparing water-soluble and biologically active GP with high DS. PMID:25075740

Controlled release behaviors of chitosan/α, β-glycerophosphate thermo-sensitive hydrogels

NASA Astrophysics Data System (ADS)

Liu, Wei-Fang; Kang, Chuan-Zhen; Kong, Ming; Li, Yang; Su, Jing; Yi, An; Cheng, Xiao-Jie; Chen, Xi-Guang

2012-09-01

Chitosan/α, β-glycerophosphate (CS/α, β-GP) thermo-sensitive hydrogels presented flowable solution state at low temperature and semisolid hydrogel when the ambient temperature increased. In this research, different concentrations of metronidazole encapsulated, CS and α, β-GP, as well as different acid solvents, were chosen to evaluate their influences on the drug release behaviors from CS/α, β-GP hydrogels. It was found that there was a sustaining release during the first 3 h followed by a plateau. SEM images showed that drugs were located both on the surface and in the interior of hydrogels. The optimal preparation conditions of this hydrogel for drug release were as follows: 1.8% (w/v) CS in HAc solvent, 5.6% (w/v) α, β-GP and 5 g/L metronidazole encapsulation. Cytotoxicity evaluation found no toxic effect. In order to control the release rate, 2.5 g/L chitosan microspheres with spherical shape and smooth surface were incorporated, and it was found that the initial release process was alleviated, while drug concentration had no obvious effect on the release rate. It could be concluded that the metronidzole release behaviors could be optimized according to practical applications.

Up close - reasons why parents attend their general practitioner when their child is sick.

PubMed

Sharma, Mohna; Usherwood, Tim

2014-04-01

This study aimed to explore the reasons prompting Australian parents to seek medical advice for their sick children, and to define the factors influencing their decision. International data suggest non-clinical reasons for general practitioner (GP) visits. Twenty-two parents from eight general practices were interviewed using a semi-structured questionnaire while they waited to see their GP. The interviews were tape-recorded, de-identified, transcribed and analysed thematically. Five emergent themes were fears about possible scenarios; personal and vicarious experiences; resources and convenience; being seen to do the right thing; and reassurance and guidance about management. Parents reported several reasons for seeking medical advice for their sick child and often a combination of factors influenced their decision, consistent with research findings from other countries. Awareness and understanding of this decision-making process could significantly improve primary care for patients in Australia and contribute to training of medical students and GP registrars.

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth.

PubMed

Roselló-Díez, Alberto; Stephen, Daniel; Joyner, Alexandra L

2017-07-25

Regulation of organ growth is a poorly understood process. In the long bones, the growth plates (GPs) drive elongation by generating a scaffold progressively replaced by bone. Although studies have focused on intrinsic GP regulation, classic and recent experiments suggest that local signals also modulate GP function. We devised a genetic mouse model to study extrinsic long bone growth modulation, in which injury is specifically induced in the left hindlimb, such that the right hindlimb serves as an internal control. Remarkably, when only mesenchyme cells surrounding postnatal GPs were killed, left bone growth was nevertheless reduced. GP signaling was impaired by altered paracrine signals from the knee joint, including activation of the injury response and, in neonates, dampened IGF1 production. Importantly, only the combined prevention of both responses rescued neonatal growth. Thus, we identified signals from the knee joint that modulate bone growth and could underlie establishment of body proportions.

Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation.

PubMed

Xu, Yang; Lu, Hong; Kennedy, Jack P; Yan, Xuxia; McAllister, Laura A; Yamamoto, Noboru; Moss, Jason A; Boldt, Grant E; Jiang, Shibo; Janda, Kim D

2006-01-01

Protein-protein interactions are of critical importance in biological systems, and small molecule modulators of such protein recognition and intervention processes are of particular interest. To investigate this area of research, we have synthesized small-molecule libraries that can disrupt a number of biologically relevant protein-protein interactions. These library members are designed upon planar motif, appended with a variety of chemical functions, which we have termed "credit-card" structures. From two of our "credit-card" libraries, a series of molecules were uncovered which act as inhibitors against the HIV-1 gp41 fusogenic 6-helix bundle core formation, viral antigen p24 formation, and cell-cell fusion at low micromolar concentrations. From the high-throughput screening assays we utilized, a selective index (SI) value of 4.2 was uncovered for compound 2261, which bodes well for future structure activity investigations and the design of more potent gp41 inhibitors.

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

PubMed

Zhang, Xiaoping; Nieforth, Keith; Lang, Jean-Marie; Rouzier-Panis, Regine; Reynes, Jacques; Dorr, Albert; Kolis, Stanley; Stiles, Mark R; Kinchelow, Tosca; Patel, Indravadan H

2002-07-01

Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

Stable radiation pressure acceleration of ions by suppressing transverse Rayleigh-Taylor instability with multiple Gaussian pulses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, M. L.; Liu, B.; Hu, R. H.

In the case of a thin plasma slab accelerated by the radiation pressure of an ultra-intense laser pulse, the development of Rayleigh-Taylor instability (RTI) will destroy the acceleration structure and terminate the acceleration process much sooner than theoretical limit. In this paper, a new scheme using multiple Gaussian pulses for ion acceleration in a radiation pressure acceleration regime is investigated with particle-in-cell simulation. We found that with multiple Gaussian pulses, the instability could be efficiently suppressed and the divergence of the ion bunch is greatly reduced, resulting in a longer acceleration time and much more collimated ion bunch with highermore » energy than using a single Gaussian pulse. An analytical model is developed to describe the suppression of RTI at the laser-plasma interface. The model shows that the suppression of RTI is due to the introduction of the long wavelength mode RTI by the multiple Gaussian pulses.« less

An unbiased risk estimator for image denoising in the presence of mixed poisson-gaussian noise.

PubMed

Le Montagner, Yoann; Angelini, Elsa D; Olivo-Marin, Jean-Christophe

2014-03-01

The behavior and performance of denoising algorithms are governed by one or several parameters, whose optimal settings depend on the content of the processed image and the characteristics of the noise, and are generally designed to minimize the mean squared error (MSE) between the denoised image returned by the algorithm and a virtual ground truth. In this paper, we introduce a new Poisson-Gaussian unbiased risk estimator (PG-URE) of the MSE applicable to a mixed Poisson-Gaussian noise model that unifies the widely used Gaussian and Poisson noise models in fluorescence bioimaging applications. We propose a stochastic methodology to evaluate this estimator in the case when little is known about the internal machinery of the considered denoising algorithm, and we analyze both theoretically and empirically the characteristics of the PG-URE estimator. Finally, we evaluate the PG-URE-driven parametrization for three standard denoising algorithms, with and without variance stabilizing transforms, and different characteristics of the Poisson-Gaussian noise mixture.

'A device for being able to book P&L': the organizational embedding of the Gaussian copula.

PubMed

MacKenzie, Donald; Spears, Taylor

2014-06-01

This article, the second of two articles on the Gaussian copula family of models, discusses the attitude of 'quants' (modellers) to these models, showing that contrary to some accounts, those quants were not 'model dopes' who uncritically accepted the outputs of the models. Although sometimes highly critical of Gaussian copulas - even 'othering' them as not really being models --they nevertheless nearly all kept using them, an outcome we explain with reference to the embedding of these models in inter- and intra-organizational processes: communication, risk control and especially the setting of bonuses. The article also examines the role of Gaussian copula models in the 2007-2008 global crisis and in a 2005 episode known as 'the correlation crisis'. We end with the speculation that all widely used derivatives models (and indeed the evaluation culture in which they are embedded) help generate inter-organizational co-ordination, and all that is special in this respect about the Gaussian copula is that its status as 'other' makes this role evident.

Pathway and rate-limiting step of glyphosate degradation by Aspergillus oryzae A-F02.

PubMed

Fu, Gui-Ming; Chen, Yan; Li, Ru-Yi; Yuan, Xiao-Qiang; Liu, Cheng-Mei; Li, Bin; Wan, Yin

2017-09-14

Aspergillus oryzae A-F02, a glyphosate-degrading fungus, was isolated from an aeration tank in a pesticide factory. The pathway and rate-limiting step of glyphosate (GP) degradation were investigated through metabolite analysis. GP, aminomethylphosphonic acid (AMPA), and methylamine were detected in the fermentation liquid of A. oryzae A-F02, whereas sarcosine and glycine were not. The pathway of GP degradation in A. oryzae A-F02 was revealed: GP was first degraded into AMPA, which was then degraded into methylamine. Finally, methylamine was further degraded into other products. Investigating the effects of the exogenous addition of substrates and metabolites showed that the degradation of GP to AMPA is the rate-limiting step of GP degradation by A. oryzae A-F02. In addition, the accumulation of AMPA and methylamine did not cause feedback inhibition in GP degradation. Results showed that degrading GP to AMPA was a crucial step in the degradation of GP, which determines the degradation rate of GP by A. oryzae A-F02.

Ensilage and bioconversion of grape pomace into fuel ethanol.

PubMed

Zheng, Yi; Lee, Christopher; Yu, Chaowei; Cheng, Yu-Shen; Simmons, Christopher W; Zhang, Ruihong; Jenkins, Bryan M; VanderGheynst, Jean S

2012-11-07

Two types of grape pomace were ensiled with eight strains of lactic acid bacteria (LAB). Both fresh grape pomace (FrGP) and fermented grape pomace (FeGP) were preserved through alcoholic fermentation but not malolactic conversion. Water leaching prior to storage was used to reduce water-soluble carbohydrates and ethanol from FrGP and FeGP, respectively, to increase malolactic conversion. Leached FeGP had spoilage after 28 days of ensilage, whereas FrGP was preserved. Dilute acid pretreatment was examined for increasing the conversion of pomace to ethanol via Escherichia coli KO11 fermentation. Dilute acid pretreatment doubled the ethanol yield from FeGP, but it did not improve the ethanol yield from FrGP. The ethanol yields from raw pomace were nearly double the yields from the ensiled pomace. For this reason, the recovery of ethanol produced during winemaking from FeGP and ethanol produced during storage of FrGP is critical for the economical conversion of grape pomace to biofuel.

Structure of the Ebola Virus Glycoprotein Bound to An Antibody From a Human Survivor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, J.E.; Fusco, M.L.; Hessell, A.J.

2009-05-20

Ebola virus (EBOV) entry requires the surface glycoprotein (GP) to initiate attachment and fusion of viral and host membranes. Here we report the crystal structure of EBOV GP in its trimeric, pre-fusion conformation (GP1+GP2) bound to a neutralizing antibody, KZ52, derived from a human survivor of the 1995 Kikwit outbreak. Three GP1 viral attachment subunits assemble to form a chalice, cradled by the GP2 fusion subunits, while a novel glycan cap and projected mucin-like domain restrict access to the conserved receptor-binding site sequestered in the chalice bowl. The glycocalyx surrounding GP is likely central to immune evasion and may explainmore » why survivors have insignificant neutralizing antibody titres. KZ52 recognizes a protein epitope at the chalice base where it clamps several regions of the pre-fusion GP2 to the amino terminus of GP1. This structure provides a template for unraveling the mechanism of EBOV GP-mediated fusion and for future immunotherapeutic development.« less

Evaluation of the immunogenicity of a transgenic tobacco plant expressing the recombinant fusion protein of GP5 of porcine reproductive and respiratory syndrome virus and B subunit of Escherichia coli heat-labile enterotoxin in pigs.

PubMed

Chia, Min-Yuan; Hsiao, Shih-Hsuan; Chan, Hui-Ting; Do, Yi-Yin; Huang, Pung-Ling; Chang, Hui-Wen; Tsai, Yi-Chieh; Lin, Chun-Ming; Pang, Victor Fei; Jeng, Chian-Ren

2011-04-15

Escherichia coli heat-labile enterotoxin B subunit (LTB) can be used as an adjuvant for co-administered antigens. Our previous study showed that the expression of neutralizing epitope GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) in transgenic tobacco plant (GP5-T) could induce PRRSV-specific immune responses in pigs. A transgenic tobacco plant co-expressing LTB and PRRSV GP5 as a fusion protein (LTB-GP5-T) was further constructed and its immunogenicity was evaluated. Pigs were given orally three consecutive doses of equal concentration of recombinant GP5 protein expressed in leaves of LTB-GP5-T or GP5-T at a 2-week interval and challenged with PRRSV at 7 weeks post-initial immunization. Pigs receiving LTB-GP5-T or GP5-T developed PRRSV-specific antibody- and cell-mediated immunity and showed significantly lower viremia and tissue viral load and milder lung lesions than wild type tobacco plant (W-T). The LTB-GP5-T-treated group had relatively higher immune responses than the GP5-T-treated group, although the differences were not statistically significant. Copyright © 2011 Elsevier B.V. All rights reserved.

A Gaussian Processes Technique for Short-term Load Forecasting with Considerations of Uncertainty

NASA Astrophysics Data System (ADS)

Ohmi, Masataro; Mori, Hiroyuki

In this paper, an efficient method is proposed to deal with short-term load forecasting with the Gaussian Processes. Short-term load forecasting plays a key role to smooth power system operation such as economic load dispatching, unit commitment, etc. Recently, the deregulated and competitive power market increases the degree of uncertainty. As a result, it is more important to obtain better prediction results to save the cost. One of the most important aspects is that power system operator needs the upper and lower bounds of the predicted load to deal with the uncertainty while they require more accurate predicted values. The proposed method is based on the Bayes model in which output is expressed in a distribution rather than a point. To realize the model efficiently, this paper proposes the Gaussian Processes that consists of the Bayes linear model and kernel machine to obtain the distribution of the predicted value. The proposed method is successively applied to real data of daily maximum load forecasting.

Gaussian process tomography for soft x-ray spectroscopy at WEST without equilibrium information

NASA Astrophysics Data System (ADS)

Wang, T.; Mazon, D.; Svensson, J.; Li, D.; Jardin, A.; Verdoolaege, G.

2018-06-01

Gaussian process tomography (GPT) is a recently developed tomography method based on the Bayesian probability theory [J. Svensson, JET Internal Report EFDA-JET-PR(11)24, 2011 and Li et al., Rev. Sci. Instrum. 84, 083506 (2013)]. By modeling the soft X-ray (SXR) emissivity field in a poloidal cross section as a Gaussian process, the Bayesian SXR tomography can be carried out in a robust and extremely fast way. Owing to the short execution time of the algorithm, GPT is an important candidate for providing real-time reconstructions with a view to impurity transport and fast magnetohydrodynamic control. In addition, the Bayesian formalism allows quantifying uncertainty on the inferred parameters. In this paper, the GPT technique is validated using a synthetic data set expected from the WEST tokamak, and the results are shown of its application to the reconstruction of SXR emissivity profiles measured on Tore Supra. The method is compared with the standard algorithm based on minimization of the Fisher information.

Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

PubMed

Shi, J Q; Wang, B; Will, E J; West, R M

2012-11-20

We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime. Copyright © 2012 John Wiley & Sons, Ltd.

Assessment of DPOAE test-retest difference curves via hierarchical Gaussian processes.

PubMed

Bao, Junshu; Hanson, Timothy; McMillan, Garnett P; Knight, Kristin

2017-03-01

Distortion product otoacoustic emissions (DPOAE) testing is a promising alternative to behavioral hearing tests and auditory brainstem response testing of pediatric cancer patients. The central goal of this study is to assess whether significant changes in the DPOAE frequency/emissions curve (DP-gram) occur in pediatric patients in a test-retest scenario. This is accomplished through the construction of normal reference charts, or credible regions, that DP-gram differences lie in, as well as contour probabilities that measure how abnormal (or in a certain sense rare) a test-retest difference is. A challenge is that the data were collected over varying frequencies, at different time points from baseline, and on possibly one or both ears. A hierarchical structural equation Gaussian process model is proposed to handle the different sources of correlation in the emissions measurements, wherein both subject-specific random effects and variance components governing the smoothness and variability of each child's Gaussian process are coupled together. © 2016, The International Biometric Society.

Log-normal distribution from a process that is not multiplicative but is additive.

PubMed

Mouri, Hideaki

2013-10-01

The central limit theorem ensures that a sum of random variables tends to a Gaussian distribution as their total number tends to infinity. However, for a class of positive random variables, we find that the sum tends faster to a log-normal distribution. Although the sum tends eventually to a Gaussian distribution, the distribution of the sum is always close to a log-normal distribution rather than to any Gaussian distribution if the summands are numerous enough. This is in contrast to the current consensus that any log-normal distribution is due to a product of random variables, i.e., a multiplicative process, or equivalently to nonlinearity of the system. In fact, the log-normal distribution is also observable for a sum, i.e., an additive process that is typical of linear systems. We show conditions for such a sum, an analytical example, and an application to random scalar fields such as those of turbulence.

Recovering Galaxy Properties Using Gaussian Process SED Fitting

NASA Astrophysics Data System (ADS)

Iyer, Kartheik; Awan, Humna

2018-01-01

Information about physical quantities like the stellar mass, star formation rates, and ages for distant galaxies is contained in their spectral energy distributions (SEDs), obtained through photometric surveys like SDSS, CANDELS, LSST etc. However, noise in the photometric observations often is a problem, and using naive machine learning methods to estimate physical quantities can result in overfitting the noise, or converging on solutions that lie outside the physical regime of parameter space.We use Gaussian Process regression trained on a sample of SEDs corresponding to galaxies from a Semi-Analytic model (Somerville+15a) to estimate their stellar masses, and compare its performance to a variety of different methods, including simple linear regression, Random Forests, and k-Nearest Neighbours. We find that the Gaussian Process method is robust to noise and predicts not only stellar masses but also their uncertainties. The method is also robust in the cases where the distribution of the training data is not identical to the target data, which can be extremely useful when generalized to more subtle galaxy properties.

Robust radio interferometric calibration using the t-distribution

NASA Astrophysics Data System (ADS)

Kazemi, S.; Yatawatta, S.

2013-10-01

A major stage of radio interferometric data processing is calibration or the estimation of systematic errors in the data and the correction for such errors. A stochastic error (noise) model is assumed, and in most cases, this underlying model is assumed to be Gaussian. However, outliers in the data due to interference or due to errors in the sky model would have adverse effects on processing based on a Gaussian noise model. Most of the shortcomings of calibration such as the loss in flux or coherence, and the appearance of spurious sources, could be attributed to the deviations of the underlying noise model. In this paper, we propose to improve the robustness of calibration by using a noise model based on Student's t-distribution. Student's t-noise is a special case of Gaussian noise when the variance is unknown. Unlike Gaussian-noise-model-based calibration, traditional least-squares minimization would not directly extend to a case when we have a Student's t-noise model. Therefore, we use a variant of the expectation-maximization algorithm, called the expectation-conditional maximization either algorithm, when we have a Student's t-noise model and use the Levenberg-Marquardt algorithm in the maximization step. We give simulation results to show the robustness of the proposed calibration method as opposed to traditional Gaussian-noise-model-based calibration, especially in preserving the flux of weaker sources that are not included in the calibration model.

Antigenicity and Immunogenicity of RV144 Vaccine AIDSVAX Clade E Envelope Immunogen Is Enhanced by a gp120 N-Terminal Deletion

PubMed Central

Liao, Hua-Xin; Tomaras, Georgia D.; Bonsignori, Mattia; Tsao, Chun-Yen; Hwang, Kwan-Ki; Chen, Haiyan; Lloyd, Krissey E.; Bowman, Cindy; Sutherland, Laura; Jeffries, Thomas L.; Kozink, Daniel M.; Stewart, Shelley; Anasti, Kara; Jaeger, Frederick H.; Parks, Robert; Yates, Nicole L.; Overman, R. Glenn; Sinangil, Faruk; Berman, Phillip W.; Pitisuttithum, Punnee; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Karasavva, Nicos; Rerks-Ngarm, Supachai; Kim, Jerome H.; Michael, Nelson L.; Zolla-Pazner, Susan; Santra, Sampa; Letvin, Norman L.; Harrison, Stephen C.

2013-01-01

An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity. PMID:23175357

A binary genetic programing model for teleconnection identification between global sea surface temperature and local maximum monthly rainfall events

NASA Astrophysics Data System (ADS)

Danandeh Mehr, Ali; Nourani, Vahid; Hrnjica, Bahrudin; Molajou, Amir

2017-12-01

The effectiveness of genetic programming (GP) for solving regression problems in hydrology has been recognized in recent studies. However, its capability to solve classification problems has not been sufficiently explored so far. This study develops and applies a novel classification-forecasting model, namely Binary GP (BGP), for teleconnection studies between sea surface temperature (SST) variations and maximum monthly rainfall (MMR) events. The BGP integrates certain types of data pre-processing and post-processing methods with conventional GP engine to enhance its ability to solve both regression and classification problems simultaneously. The model was trained and tested using SST series of Black Sea, Mediterranean Sea, and Red Sea as potential predictors as well as classified MMR events at two locations in Iran as predictand. Skill of the model was measured in regard to different rainfall thresholds and SST lags and compared to that of the hybrid decision tree-association rule (DTAR) model available in the literature. The results indicated that the proposed model can identify potential teleconnection signals of surrounding seas beneficial to long-term forecasting of the occurrence of the classified MMR events.

Gaussian process based independent analysis for temporal source separation in fMRI.

PubMed

Hald, Ditte Høvenhoff; Henao, Ricardo; Winther, Ole

2017-05-15

Functional Magnetic Resonance Imaging (fMRI) gives us a unique insight into the processes of the brain, and opens up for analyzing the functional activation patterns of the underlying sources. Task-inferred supervised learning with restrictive assumptions in the regression set-up, restricts the exploratory nature of the analysis. Fully unsupervised independent component analysis (ICA) algorithms, on the other hand, can struggle to detect clear classifiable components on single-subject data. We attribute this shortcoming to inadequate modeling of the fMRI source signals by failing to incorporate its temporal nature. fMRI source signals, biological stimuli and non-stimuli-related artifacts are all smooth over a time-scale compatible with the sampling time (TR). We therefore propose Gaussian process ICA (GPICA), which facilitates temporal dependency by the use of Gaussian process source priors. On two fMRI data sets with different sampling frequency, we show that the GPICA-inferred temporal components and associated spatial maps allow for a more definite interpretation than standard temporal ICA methods. The temporal structures of the sources are controlled by the covariance of the Gaussian process, specified by a kernel function with an interpretable and controllable temporal length scale parameter. We propose a hierarchical model specification, considering both instantaneous and convolutive mixing, and we infer source spatial maps, temporal patterns and temporal length scale parameters by Markov Chain Monte Carlo. A companion implementation made as a plug-in for SPM can be downloaded from https://github.com/dittehald/GPICA. Copyright © 2017 Elsevier Inc. All rights reserved.

Reduced Wiener Chaos representation of random fields via basis adaptation and projection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsilifis, Panagiotis, E-mail: tsilifis@usc.edu; Department of Civil Engineering, University of Southern California, Los Angeles, CA 90089; Ghanem, Roger G., E-mail: ghanem@usc.edu

2017-07-15

A new characterization of random fields appearing in physical models is presented that is based on their well-known Homogeneous Chaos expansions. We take advantage of the adaptation capabilities of these expansions where the core idea is to rotate the basis of the underlying Gaussian Hilbert space, in order to achieve reduced functional representations that concentrate the induced probability measure in a lower dimensional subspace. For a smooth family of rotations along the domain of interest, the uncorrelated Gaussian inputs are transformed into a Gaussian process, thus introducing a mesoscale that captures intermediate characteristics of the quantity of interest.

Reduced Wiener Chaos representation of random fields via basis adaptation and projection

NASA Astrophysics Data System (ADS)

Tsilifis, Panagiotis; Ghanem, Roger G.

2017-07-01

A new characterization of random fields appearing in physical models is presented that is based on their well-known Homogeneous Chaos expansions. We take advantage of the adaptation capabilities of these expansions where the core idea is to rotate the basis of the underlying Gaussian Hilbert space, in order to achieve reduced functional representations that concentrate the induced probability measure in a lower dimensional subspace. For a smooth family of rotations along the domain of interest, the uncorrelated Gaussian inputs are transformed into a Gaussian process, thus introducing a mesoscale that captures intermediate characteristics of the quantity of interest.

Risk factors for and management of graft pancreatitis.

PubMed

Nadalin, Silvio; Girotti, Paolo; Königsrainer, Alfred

2013-02-01

Systematic and detailed analysis of risk factors, pathophysiology, clinical manifestation, diagnosis and management of graft pancreatitis in its different forms, that is acute and chronic graft pancreatitis (A-GP and C-GP), and A-GP being further distinguished into: physiological (P-AGP), early (E-AGP) and late AP (L-AGP). Graft pancreatitis is the second most-frequent complication following pancreas transplantation. P-AGP is an unavoidable entity related to ischemic reperfusion injury. It is usually clinically silent. It is a timely and prognostically self-limited process. E-AGP occurs within 3 months after pancreas transplantation (PTx) in 35% of cases and is associated with high rates of graft loss (78-91%). Clinical signs are pain, systemic inflammatory response (SIRS) and haematuria. Therapy can be medical, interventional and surgical. L-AGP occurs 3 months following PTx in 14-25% of cases and represents an uncommon cause of graft loss. Typical clinical signs are pain, abdominal tenderness and fever. Typical laboratory signs are hyperamylasaemia, hyperglycaemia and hypercreatininaemia. Therapy is usually conservative. C-GP is difficult to be distinguished from chronic rejection and is associated to graft loss in 4-10% of cases. Recurrent A-GPs and infections are the main risk factors. Specific symptoms are chronic abdominal malaise, constipation and recurrence of DM. Isolated hyperglycaemia is typical of C-GP. The therapy is usually conservative. This systematic analysis of different manifestations of graft pancreatitis provides the basis for a clinical approach to tackling this complex entity.

Comparison of Gaussian and non-Gaussian Atmospheric Profile Retrievals from Satellite Microwave Data

NASA Astrophysics Data System (ADS)

Kliewer, A.; Forsythe, J. M.; Fletcher, S. J.; Jones, A. S.

2017-12-01

The Cooperative Institute for Research in the Atmosphere at Colorado State University has recently developed two different versions of a mixed-distribution (lognormal combined with a Gaussian) based microwave temperature and mixing ratio retrieval system as well as the original Gaussian-based approach. These retrieval systems are based upon 1DVAR theory but have been adapted to use different descriptive statistics of the lognormal distribution to minimize the background errors. The input radiance data is from the AMSU-A and MHS instruments on the NOAA series of spacecraft. To help illustrate how the three retrievals are affected by the change in the distribution we are in the process of creating a new website to show the output from the different retrievals. Here we present initial results from different dynamical situations to show how the tool could be used by forecasters as well as for educators. However, as the new retrieved values are from a non-Gaussian based 1DVAR then they will display non-Gaussian behaviors that need to pass a quality control measure that is consistent with this distribution, and these new measures are presented here along with initial results for checking the retrievals.

Determining the Gaussian Modulus and Edge Properties of 2D Materials: From Graphene to Lipid Bilayers

NASA Astrophysics Data System (ADS)

Zelisko, Matthew; Ahmadpoor, Fatemeh; Gao, Huajian; Sharma, Pradeep

2017-08-01

The dominant deformation behavior of two-dimensional materials (bending) is primarily governed by just two parameters: bending rigidity and the Gaussian modulus. These properties also set the energy scale for various important physical and biological processes such as pore formation, cell fission and generally, any event accompanied by a topological change. Unlike the bending rigidity, the Gaussian modulus is, however, notoriously difficult to evaluate via either experiments or atomistic simulations. In this Letter, recognizing that the Gaussian modulus and edge tension play a nontrivial role in the fluctuations of a 2D material edge, we derive closed-form expressions for edge fluctuations. Combined with atomistic simulations, we use the developed approach to extract the Gaussian modulus and edge tension at finite temperatures for both graphene and various types of lipid bilayers. Our results possibly provide the first reliable estimate of this elusive property at finite temperatures and appear to suggest that earlier estimates must be revised. In particular, we show that, if previously estimated properties are employed, the graphene-free edge will exhibit unstable behavior at room temperature. Remarkably, in the case of graphene, we show that the Gaussian modulus and edge tension even change sign at finite temperatures.

Entanglement sensitivity to signal attenuation and amplification

NASA Astrophysics Data System (ADS)

Filippov, Sergey N.; Ziman, Mário

2014-07-01

We analyze general laws of continuous-variable entanglement dynamics during the deterministic attenuation and amplification of the physical signal carrying the entanglement. These processes are inevitably accompanied by noises, so we find fundamental limitations on noise intensities that destroy entanglement of Gaussian and non-Gaussian input states. The phase-insensitive amplification Φ1⊗Φ2⊗⋯ΦN with the power gain κi≥2 (≈3 dB, i =1,...,N) is shown to destroy entanglement of any N-mode Gaussian state even in the case of quantum-limited performance. In contrast, we demonstrate non-Gaussian states with the energy of a few photons such that their entanglement survives within a wide range of noises beyond quantum-limited performance for any degree of attenuation or gain. We detect entanglement preservation properties of the channel Φ1⊗Φ2, where each mode is deterministically attenuated or amplified. Gaussian states of high energy are shown to be robust to very asymmetric attenuations, whereas non-Gaussian states are at an advantage in the case of symmetric attenuation and general amplification. If Φ1=Φ2, the total noise should not exceed 1/2√κ2+1 to guarantee entanglement preservation.

Quantitative separation of murine leukemia virus proteins by reversed-phase high-pressure liquid chromatography reveals newly described gag and env cleavage products.

PubMed Central

Henderson, L E; Sowder, R; Copeland, T D; Smythers, G; Oroszlan, S

1984-01-01

The structural proteins of murine type C retroviruses are proteolytic cleavage products of two different precursor polyproteins coded by the viral gag and env genes. To further investigate the nature and number of proteolytic cleavages involved in virus maturation, we quantitatively isolated the structural proteins of the Rauscher and Moloney strains of type C murine leukemia virus (R-MuLV and M-MuLV, respectively) by reversed-phase high-pressure liquid chromatography. Proteins and polypeptides isolated from R-MuLV included p10, p12, p15, p30, p15(E), gp69, and gp71 and three previously undescribed virus components designated here as p10', p2(E), and p2(E). Homologous proteins and polypeptides were isolated from M-MuLV. Complete or partial amino acid sequences of all the proteins listed above were either determined in this study or were available in previous reports from this laboratory. These data were compared with those from the translation of the M-MuLV proviral DNA sequence (Shinnick et al., Nature [London] 293:543-548, 1981) to determine the exact nature of proteolytic cleavages for all the structural proteins described above and to determine the origin of p10' and p2(E)s. The results showed that, during proteolytic processing of gp80env from M-MuLV (M-gp 80env), a single Arg residue was excised between gp70 and p15(E) and a single peptide bond was cleaved between p15(E) and p2(E). The structure of M-gPr80env is gp70-(Arg)-p15(E)-p2(E). The data suggest that proteolytic cleavage sites in R-gp85env are identical to corresponding cleavage sites in M-gp80env. The p2(E)s are shown to be different genetic variants of p2(E) present in the uncloned-virus preparations. The data for R- and M-p10's shows that they are cleavage products of the gag precursor with the structure p10-Thr-Leu-Asp-Asp-OH. The complete structure of Pr65gag is p15-p12-p30-p10'. Stoichiometries of the gag and env cleavage products in mature R- and M-MuLV were determined. In each virus, gag cleavage products (p15, p12, p30, and p10 plus p10') were found in equimolar amounts and p15(E)s were equimolar with p2(E)s. The stoichiometry of gag to env cleavage products was 4:1. These data are consistent with the proposal that proteolytic processing of precursor polyproteins occurs after virus assembly and that the C-terminal portion of Pr15(E) [i.e., p15(E)-p2(E)] is located on the inner side of the lipid bilayer of the virus. Images PMID:6333515

Designing a Soluble Near Full-Length HIV-1 GP41 Trimer

DTIC Science & Technology

2012-11-26

envelope; gp41 trimer; bacteriophage T4 display; prehairpin fusion intermediate. Background: The envelope glycoprotein gp41 is a key component of...protein into trimers and defined oligomers. These gp41 trimers were displayed on bacteriophage T4 capsid nanoparticles by attaching to the small...Construction of the Expression Vectors —All the gp41 constructs were generated by splicing-by- overlap extension PCR using wild-type HXB2 gp41 DNA

Rheological, mechanical and degradable properties of injectable chitosan/silk fibroin/hydroxyapatite/glycerophosphate hydrogels.

PubMed

Wu, Jingjing; Liu, Jiaoyan; Shi, Yanmei; Wan, Ying

2016-12-01

Silk fibroin (SF) and hydroxyapatite (HA) were incorporated into chitosan/glycerophosphate (GP) system to prepare new types of hydrogels. The formulated chitosan/SF/GP and chitosan/SF/HA/GP solutions were found to be injectable at room temperature, and able to form into hydrogels at near-physiological temperature and pH. Rheological measurements showed that elastic modulus of certain chitosan/SF/GP and chitosan/SF/HA/GP gels could reach around 1.8 and 15kPa, respectively, and was much higher than their respective viscous modulus. Compressive measurements revealed that some chitosan/SF/GP and chitosan/SF/HA/GP gels had 8 and 20-fold modulus and strength higher than the chitosan/GP gel, respectively, confirming that compressive properties of these gels were greatly improved. Results obtained from in vivo degradation demonstrated that degradation endurance of the optimized chitosan/SF/GP and chitosan/SF/HA/GP gels was significantly enhanced as compared to the chitosan/GP gel, and the degradation rate of the gels could be regulated by the SF component alone or by the combination of SF and HA components. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Effects of IGF-1 on Trk Expressing DRG Neurons with HIV-gp120- Induced Neurotoxicity.

PubMed

Li, Hao; Liu, Zhen; Chi, Heng; Bi, Yanwen; Song, Lijun; Liu, Huaxiang

2016-01-01

HIV envelope glycoprotein gp120 is the main protein that causes HIVassociated sensory neuropathy. However, the underlying mechanisms of gp120-induced neurotoxicity are still unclear. There are lack effective treatments for relieving HIV-related neuropathic symptoms caused by gp120-induced neurotoxicity. In the present study, tyrosine kinase receptor (Trk)A, TrkB, and TrkC expression in primary cultured dorsal root ganglion (DRG) neurons with gp120-induced neurotoxicity was investigated. The effects of IGF-1 on distinct Trk-positive DRG neurons with gp120-induced neurotoxicity were also determined. The results showed that gp120 not only dose-dependently induced DRG neuronal apoptosis and inhibited neuronal survival and neurite outgrowth, but also decreased distinct Trk expression levels. IGF-1 rescued DRG neurons from apoptosis and improved neuronal survival of gp120 neurotoxic DRG neurons in vitro. IGF-1 also improved TrkA and TrkB, but not TrkC, expression in gp120 neurotoxic conditions. The effects of IGF-1 could be blocked by preincubation with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results suggested that gp120 may have a wide range of neurotoxicity on different subpopulations of DRG neurons, while IGF-1 might only relieve some subpopulations of DRG neurons with gp120-induced neurotoxicity. These data provide novel information of mechanisms of gp120 neurotoxicity on primary sensory neurons and the potential therapeutic effects of IGF-1 on gp120-induced neurotoxicity.

Direct interaction of the bacteriophage SPP1 packaging ATPase with the portal protein.

PubMed

Oliveira, Leonor; Cuervo, Ana; Tavares, Paulo

2010-03-05

DNA packaging in tailed bacteriophages and other viruses requires assembly of a complex molecular machine at a specific vertex of the procapsid. This machine is composed of the portal protein that provides a tunnel for DNA entry, an ATPase that fuels DNA translocation (large terminase subunit), and most frequently, a small terminase subunit. Here we characterized the interaction between the terminase ATPase subunit of bacteriophage SPP1 (gp2) and the procapsid portal vertex. We found, by affinity pulldown assays with purified proteins, that gp2 interacts with the portal protein, gp6, independently of the terminase small subunit gp1, DNA, or ATP. The gp2-procapsid interaction via the portal protein depends on gp2 concentration and requires the presence of divalent cations. Competition experiments showed that isolated gp6 can only inhibit gp2-procapsid interactions and DNA packaging at gp6:procapsid molar ratios above 10-fold. Assays with gp6 carrying mutations in distinct regions of its structure that affect the portal-induced stimulation of ATPase and DNA packaging revealed that none of these mutations impedes gp2-gp6 binding. Our results demonstrate that the SPP1 packaging ATPase binds directly to the portal and that the interaction is stronger with the portal embedded in procapsids. Identification of mutations in gp6 that allow for assembly of the ATPase-portal complex but impair DNA packaging support an intricate cross-talk between the two proteins for activity of the DNA translocation motor.

The Role of Conserved N-Linked Glycans on Ebola Virus Glycoprotein 2.

PubMed

Lennemann, Nicholas J; Walkner, Madeline; Berkebile, Abigail R; Patel, Neil; Maury, Wendy

2015-10-01

N-linked glycosylation is a common posttranslational modification found on viral glycoproteins (GPs) and involved in promoting expression, cellular attachment, protection from proteases, and antibody evasion. The GP subunit GP2 of filoviruses contains 2 completely conserved N-linked glycosylation sites (NGSs) at N563 and N618, suggesting that they have been maintained through selective pressures. We assessed mutants lacking these glycans for expression and function to understand the role of these sites during Ebola virus entry. Elimination of either GP2 glycan individually had a modest effect on GP expression and no impact on antibody neutralization of vesicular stomatitis virus pseudotyped with Ebola virus GP. However, loss of the N563 glycan enhanced entry by 2-fold and eliminated GP detection by a well-characterized monoclonal antibody KZ52. Loss of both sites dramatically decreased GP expression and abolished entry. Surprisingly, a GP that retained a single NGS at N563, eliminating the remaining 16 NGSs from GP1 and GP2, had detectable expression, a modest increase in entry, and pronounced sensitivity to antibody neutralization. Our findings support the importance of the GP2 glycans in GP expression/structure, transduction efficiency, and antibody neutralization, particularly when N-linked glycans are also removed from GP1. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Single-Chain Soluble BG505.SOSIP gp140 Trimers as Structural and Antigenic Mimics of Mature Closed HIV-1 Env.

PubMed

Georgiev, Ivelin S; Joyce, M Gordon; Yang, Yongping; Sastry, Mallika; Zhang, Baoshan; Baxa, Ulrich; Chen, Rita E; Druz, Aliaksandr; Lees, Christopher R; Narpala, Sandeep; Schön, Arne; Van Galen, Joseph; Chuang, Gwo-Yu; Gorman, Jason; Harned, Adam; Pancera, Marie; Stewart-Jones, Guillaume B E; Cheng, Cheng; Freire, Ernesto; McDermott, Adrian B; Mascola, John R; Kwong, Peter D

2015-05-01

Similar to other type I fusion machines, the HIV-1 envelope glycoprotein (Env) requires proteolytic activation; specifically, cleavage of a gp160 precursor into gp120 and gp41 subunits creates an N-terminal gp41 fusion peptide and permits folding from an immature uncleaved state to a mature closed state. While the atomic-level consequences of cleavage for HIV-1 Env are still being determined, the uncleaved state is antigenically distinct from the mature closed state, and cleavage has been reported to be essential for mimicry of the mature viral spike by soluble versions of Env. Here we report the redesign of a current state-of-the-art soluble Env mimic, BG505.SOSIP, to make it cleavage independent. Specifically, we replaced the furin cleavage site between gp120 and gp41 with Gly-Ser linkers of various lengths. The resultant linked gp120-gp41 constructs, termed single-chain gp140 (sc-gp140), exhibited different levels of structural and antigenic mimicry of the parent cleaved BG505.SOSIP. When constructs were subjected to negative selection to remove subspecies recognized by poorly neutralizing antibodies, trimers of high antigenic mimicry of BG505.SOSIP could be obtained; negative-stain electron microscopy indicated these to resemble the mature closed state. Higher proportions of BG505.SOSIP-trimer mimicry were observed in sc-gp140s with linkers of 6 or more residues, with a linker length of 15 residues exhibiting especially promising traits. Overall, flexible linkages between gp120 and gp41 in BG505.SOSIP can thus substitute for cleavage, and sc-gp140s that closely mimicked the vaccine-preferred mature closed state of Env could be obtained. The trimeric HIV-1 envelope glycoprotein (Env) is the sole target of virus-directed neutralizing antibody responses and a primary focus of vaccine design. Soluble mimics of Env have proven challenging to obtain and have been thought to require proteolytic cleavage into two-component subunits, gp120 and gp41, to achieve structural and antigenic mimicry of mature Env spikes on virions. Here we show that replacement of the cleavage site between gp120 and gp41 in a lead soluble gp140 construct, BG505.SOSIP, with flexible linkers can result in molecules that do not require cleavage to fold efficiently into the mature closed state. Our results provide insights into the impact of cleavage on HIV-1 Env folding. In some contexts such as genetic immunization, optimized cleavage-independent soluble gp140 constructs may have utility over the parental BG505.SOSIP, as they would not require furin cleavage to achieve mimicry of mature Env spikes on virions. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

How do trained raters take context factors into account when assessing GP trainee communication performance? An exploratory, qualitative study.

PubMed

Essers, Geurt; Dielissen, Patrick; van Weel, Chris; van der Vleuten, Cees; van Dulmen, Sandra; Kramer, Anneke

2015-03-01

Communication assessment in real-life consultations is a complex task. Generic assessment instruments help but may also have disadvantages. The generic nature of the skills being assessed does not provide indications for context-specific behaviour required in practice situations; context influences are mostly taken into account implicitly. Our research questions are: 1. What factors do trained raters observe when rating workplace communication? 2. How do they take context factors into account when rating communication performance with a generic rating instrument? Nineteen general practitioners (GPs), trained in communication assessment with a generic rating instrument (the MAAS-Global), participated in a think-aloud protocol reflecting concurrent thought processes while assessing videotaped real-life consultations. They were subsequently interviewed to answer questions explicitly asking them to comment on the influence of predefined contextual factors on the assessment process. Results from both data sources were analysed. We used a grounded theory approach to untangle the influence of context factors on GP communication and on communication assessment. Both from the think-aloud procedure and from the interviews we identified various context factors influencing communication, which were categorised into doctor-related (17), patient-related (13), consultation-related (18), and education-related factors (18). Participants had different views and practices on how to incorporate context factors into the GP(-trainee) communication assessment. Raters acknowledge that context factors may affect communication in GP consultations, but struggle with how to take contextual influences into account when assessing communication performance in an educational context. To assess practice situations, raters need extra guidance on how to handle specific contextual factors.

A Pareto-optimal moving average multigene genetic programming model for daily streamflow prediction

NASA Astrophysics Data System (ADS)

Danandeh Mehr, Ali; Kahya, Ercan

2017-06-01

Genetic programming (GP) is able to systematically explore alternative model structures of different accuracy and complexity from observed input and output data. The effectiveness of GP in hydrological system identification has been recognized in recent studies. However, selecting a parsimonious (accurate and simple) model from such alternatives still remains a question. This paper proposes a Pareto-optimal moving average multigene genetic programming (MA-MGGP) approach to develop a parsimonious model for single-station streamflow prediction. The three main components of the approach that take us from observed data to a validated model are: (1) data pre-processing, (2) system identification and (3) system simplification. The data pre-processing ingredient uses a simple moving average filter to diminish the lagged prediction effect of stand-alone data-driven models. The multigene ingredient of the model tends to identify the underlying nonlinear system with expressions simpler than classical monolithic GP and, eventually simplification component exploits Pareto front plot to select a parsimonious model through an interactive complexity-efficiency trade-off. The approach was tested using the daily streamflow records from a station on Senoz Stream, Turkey. Comparing to the efficiency results of stand-alone GP, MGGP, and conventional multi linear regression prediction models as benchmarks, the proposed Pareto-optimal MA-MGGP model put forward a parsimonious solution, which has a noteworthy importance of being applied in practice. In addition, the approach allows the user to enter human insight into the problem to examine evolved models and pick the best performing programs out for further analysis.

Bayesian non-parametric inference for stochastic epidemic models using Gaussian Processes.

PubMed

Xu, Xiaoguang; Kypraios, Theodore; O'Neill, Philip D

2016-10-01

This paper considers novel Bayesian non-parametric methods for stochastic epidemic models. Many standard modeling and data analysis methods use underlying assumptions (e.g. concerning the rate at which new cases of disease will occur) which are rarely challenged or tested in practice. To relax these assumptions, we develop a Bayesian non-parametric approach using Gaussian Processes, specifically to estimate the infection process. The methods are illustrated with both simulated and real data sets, the former illustrating that the methods can recover the true infection process quite well in practice, and the latter illustrating that the methods can be successfully applied in different settings. © The Author 2016. Published by Oxford University Press.

Alphavirus Replicon DNA Vectors Expressing Ebola GP and VP40 Antigens Induce Humoral and Cellular Immune Responses in Mice

PubMed Central

Ren, Shoufeng; Wei, Qimei; Cai, Liya; Yang, Xuejing; Xing, Cuicui; Tan, Feng; Leavenworth, Jianmei W.; Liang, Shaohui; Liu, Wenquan

2018-01-01

Ebola virus (EBOV) causes severe hemorrhagic fevers in humans, and no approved therapeutics or vaccine is currently available. Glycoprotein (GP) is the major protective antigen of EBOV, and can generate virus-like particles (VLPs) by co-expression with matrix protein (VP40). In this study, we constructed a recombinant Alphavirus Semliki Forest virus (SFV) replicon vector DREP to express EBOV GP and matrix viral protein (VP40). EBOV VLPs were successfully generated and achieved budding from 293 cells after co-transfection with DREP-based GP and VP40 vectors (DREP-GP+DREP-VP40). Vaccination of BALB/c mice with DREP-GP, DREP-VP40, or DREP-GP+DREP-VP40 vectors, followed by immediate electroporation resulted in a mixed IgG subclass production, which recognized EBOV GP and/or VP40 proteins. This vaccination regimen also led to the generation of both Th1 and Th2 cellular immune responses in mice. Notably, vaccination with DREP-GP and DREP-VP40, which produces both GP and VP40 antigens, induced a significantly higher level of anti-GP IgG2a antibody and increased IFN-γ secreting CD8+ T-cell responses relative to vaccination with DREP-GP or DREP-VP40 vector alone. Our study indicates that co-expression of GP and VP40 antigens based on the SFV replicon vector generates EBOV VLPs in vitro, and vaccination with recombinant DREP vectors containing GP and VP40 antigens induces Ebola antigen-specific humoral and cellular immune responses in mice. This novel approach provides a simple and efficient vaccine platform for Ebola disease prevention. PMID:29375526

P-glycoprotein induction in Caco-2 cells by newly synthetized thioxanthones prevents paraquat cytotoxicity.

PubMed

Silva, Renata; Palmeira, Andreia; Carmo, Helena; Barbosa, Daniel José; Gameiro, Mariline; Gomes, Ana; Paiva, Ana Mafalda; Sousa, Emília; Pinto, Madalena; Bastos, Maria de Lourdes; Remião, Fernando

2015-10-01

The induction of P-glycoprotein (P-gp), an ATP-dependent efflux pump, has been proposed as a strategy against the toxicity induced by P-gp substrates such as the herbicide paraquat (PQ). The aim of this study was to screen five newly synthetized thioxanthonic derivatives, a group known to interact with P-gp, as potential inducers of the pump's expression and/or activity and to evaluate whether they would afford protection against PQ-induced toxicity in Caco-2 cells. All five thioxanthones (20 µM) caused a significant increase in both P-gp expression and activity as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, it was demonstrated that the tested compounds, when present only during the efflux of rhodamine 123, rapidly induced an activation of P-gp. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, indicating that all derivatives acted as P-gp substrates. PQ cytotoxicity was significantly reduced in the presence of four thioxanthone derivatives, and this protective effect was reversed upon incubation with a specific P-gp inhibitor. In silico studies showed that all the tested thioxanthones fitted onto a previously described three-feature P-gp induction pharmacophore. Moreover, in silico interactions between thioxanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. Based on the in vitro activation results, a pharmacophore model for P-gp activation was built, which will be of further use in the screening for new P-gp activators. In conclusion, the study demonstrated the potential of the tested thioxanthonic compounds in protecting against toxic effects induced by P-gp substrates through P-gp induction and activation.

Enhancing field GP engagement in hospital-based studies. Rationale, design, main results and participation in the Diagest 3-GP motivation study.

PubMed

Berkhout, Christophe; Vandaele-Bétancourt, Marie; Robert, Stéphane; Lespinasse, Solène; Mitha, Gamil; Bradier, Quentin; Vambergue, Anne; Fontaine, Pierre

2012-06-21

Diagest 3 was a study aimed at lowering the risk of developing type 2 diabetes within 3 years after childbirth. Women with gestational diabetes were enrolled in the study. After childbirth, the subjects showed little interest in the structured education programme and did not attend workshops. Their general practitioners (GPs) were approached to help motivate the subjects to participate in Diagest 3, but the GPs were reluctant. The present study aimed to understand field GPs' attitudes towards hospital-based studies, and to develop strategies to enhance their involvement and reduce subject drop-out rates. We used a three-step process: step one used a phenomenological approach exploring the beliefs, attitudes, motivations and environmental factors contributing to the GPs' level of interest in the study. Data were collected in face-to-face interviews and coded by hand and with hermeneutic software to develop distinct GP profiles. Step two was a cross-sectional survey by questionnaire to determine the distribution of the profiles in the GP study population and whether completion of an attached case report form (CRF) was associated with a particular GP profile. In step three, we assessed the impact of the motivation study on participation rates in the main study. Fifteen interviews were conducted to achieve data saturation. Theorisation led to the definition of 4 distinct GP profiles. The response rate to the questionnaire was 73%, but dropped to 52% when a CRF was attached. The link between GP profiles and the rate of CRF completion remains to be verified. The GPs provided data on the CRF that was of comparable quality to those collected in the main trial. Our analysis showed that the motivation study increased overall participation in the main study by 23%, accounting for 16% (24/152) of all final visits for 536 patients who were initially enrolled in the Diagest 3 study. When a hospital-led study explores issues in primary care, its design must anticipate GP participation early in the trial. Based on our questionnaire response rates, we found that one in two GPs were willing to participate in our hospital-led study, regardless of their initial attitudes.

Registration of NE Trailblazer C-1, NE Trailblazer C0, NE Trailblazer C2, NE Trailblazer C3, NE Trailblazer C4, and NE Trailblazer C5 Switchgrass Germplasms

USDA-ARS?s Scientific Manuscript database

NE Trailblazer C-1 (GP-101, PI 672015), NE Trailblazer C0 (GP-100, PI 672014), NE Trailblazer C2 (GP-102, PI 672016), NE Trailblazer C3 (GP-103, PI 672017), NE Trailblazer C4 (GP-104, PI 672018), and NE Trailblazer C5 (GP-105, PI 672019) switchgrass (Panicum virgatum L.) germplasms were released by ...

Abcb1 in Pigs: Molecular cloning, tissues distribution, functional analysis, and its effect on pharmacokinetics of enrofloxacin

PubMed Central

Guo, Tingting; Huang, Jinhu; Zhang, Hongyu; Dong, Lingling; Guo, Dawei; Guo, Li; He, Fang; Bhutto, Zohaib Ahmed; Wang, Liping

2016-01-01

P-glycoprotein (P-gp) is one of the best-known ATP-dependent efflux transporters, contributing to differences in pharmacokinetics and drug-drug interactions. Until now, studies on pig P-gp have been scarce. In our studies, the full-length porcine P-gp cDNA was cloned and expressed in a Madin-Darby Canine Kidney (MDCK) cell line. P-gp expression was then determined in tissues and its role in the pharmacokinetics of oral enrofloxacin in pigs was studied. The coding region of pig Abcb1 gene was 3,861 bp, encoding 1,286 amino acid residues (Mw = 141,966). Phylogenetic analysis indicated a close evolutionary relationship between porcine P-gp and those of cow and sheep. Pig P-gp was successfully stably overexpressed in MDCK cells and had efflux activity for rhodamine 123, a substrate of P-gp. Tissue distribution analysis indicated that P-gp was highly expressed in brain capillaries, small intestine, and liver. In MDCK-pAbcb1 cells, enrofloxacin was transported by P-gp with net efflux ratio of 2.48 and the efflux function was blocked by P-gp inhibitor verapamil. High expression of P-gp in the small intestine could modify the pharmacokinetics of orally administrated enrofloxacin by increasing the Cmax, AUC and Ka, which was demonstrated using verapamil, an inhibitor of P-gp. PMID:27572343

Investigation of the function of the putative self-association site of Epstein-Barr virus (EBV) glycoprotein 42 (gp42)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rowe, Cynthia L., E-mail: c-rowe@northwestern.edu; Matsuura, Hisae, E-mail: hisaem@stanford.edu; Interdepartmental Biological Sciences Program, Northwestern University, Evanston, IL 60208

The Epstein-Barr virus (EBV) glycoprotein 42 (gp42) is a type II membrane protein essential for entry into B cells but inhibits entry into epithelial cells. X-ray crystallography suggests that gp42 may form dimers when bound to human leukocyte antigen (HLA) class II receptor (Mullen et al., 2002) or multimerize when not bound to HLA class II (Kirschner et al., 2009). We investigated this self-association of gp42 using several different approaches. We generated soluble mutants of gp42 containing mutations within the self-association site and found that these mutants have a defect in fusion. The gp42 mutants bound to gH/gL and HLAmore » class II, but were unable to bind wild-type gp42 or a cleavage mutant of gp42. Using purified gp42, gH/gL, and HLA, we found these proteins associate 1:1:1 by gel filtration suggesting that gp42 dimerization or multimerization does not occur or is a transient event undetectable by our methods.« less

[NF-kappaB-induced gp96 up-regulation promotes hepatocyte growth, cell cycle progression and transition].

PubMed

Feng, Cong; Wu, Bo; Fan, Hongxia; Li, Changfei; Meng, Songdong

2014-10-04

To investigate the mechanism of gp96 raised during hepatitis B virus (HBV) infection and the pathological mechanism. The mechanism of NF-KB activating gp96 expression was determined by bioinformatics analysis, luciferase reporter assay, real-time PCR and Western blot. The effect of over-expression and knockdown gp96 expression by transfection or RNA interference on hepatocyte proliferation, apoptosis and cell cycle was examined by CCK-8 and flow cytometry. The role of gp96 for HCC development was determined by epithelial-mesenchymal transition (EMT) and colony formation assay. NF-kB significantly increased the gp96 expression by binding to the NF-kappaB binding site. Over-expression and knockdown studies both show that gp96 promoted hepatocyte proliferation, inhibited apoptosis, and induced G0/G1 to S phase cell cycle progression. Moreover, gp96 induced epithelial-mesenchymal transition and increased colony formation ability of hepatocytes. Our results therefore provide insights in chronic HBV infection-induced gp96 expression, and indicate that elevated gp96 may contribute to HCC development during chronic inflammation.

Enhanced Immune Responses to HIV-1 Envelope Elicited by a Vaccine Regimen Consisting of Priming with Newcastle Disease Virus Expressing HIV gp160 and Boosting with gp120 and SOSIP gp140 Proteins.

PubMed

Khattar, Sunil K; DeVico, Anthony L; LaBranche, Celia C; Panda, Aruna; Montefiori, David C; Samal, Siba K

2016-02-01

Newcastle disease virus (NDV) expressing HIV-1 BaL gp160 was evaluated either alone or with monomeric BaL gp120 and BaL SOSIP gp140 protein in a prime-boost combination in guinea pigs to enhance envelope (Env)-specific humoral and mucosal immune responses. We showed that a regimen consisting of an NDV prime followed by a protein boost elicited stronger serum and mucosal Th-1-biased IgG responses and neutralizing antibody responses than NDV-only immunizations. Additionally, these responses were higher after the gp120 than after the SOSIP gp140 protein boost. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

GP3 is a structural component of the PRRSV type II (US) virion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lima, M. de; Departamento de Microbiologia e Parasitologia, Universidade Federal Fluminense, Niteroi, RJ; Ansari, I.H.

2009-07-20

Glycoprotein 3 (GP3) is a highly glycosylated PRRSV envelope protein which has been reported as being present in the virions of PRRSV type I, while missing in the type II PRRSV (US) virions. We herein present evidence that GP3 is indeed incorporated in the virus particles of a North American strain of PRRSV (FL12), at a density that is consistent with the minor structural role assigned to GP3 in members of the Arterivirus genus. Two 15aa peptides corresponding to two different immunodominant linear epitopes of GP3 derived from the North American strain of PRRSV (FL12) were used as antigen tomore » generate a rabbit monospecific antiserum to this protein. The specificity of this anti-GP3 antiserum was confirmed by radioimmunoprecipitation (RIP) assay using BHK-21 cells transfected with GP3 expressing plasmid, MARC-145 cells infected with FL12 PRRSV, as well as by confocal microscopy on PRRSV-infected MARC-145 cells. To test if GP3 is a structural component of the virion, {sup 35}S-labelled PRRSV virions were pelleted through a 30% sucrose cushion, followed by a second round of purification on a sucrose gradient (20-60%). Virions were detected in specific gradient fractions by radioactive counts and further confirmed by viral infectivity assay in MARC 145 cells. The GP3 was detected in gradient fractions containing purified virions by RIP using anti-GP3 antiserum. Predictably, the GP3 was less abundant in purified virions than other major structural envelope proteins such as GP5 and M. Further evidence of the presence of GP3 at the level of PRRSV FL12 envelope was obtained by immunogold staining of purified virions from the supernatant of infected cells with anti-GP3 antiserum. Taken together, these results indicate that GP3 is a minor structural component of the PRRSV type II (FL12 strain) virion, as had been previously described for PRRSV type I.« less

Identification and Characterization of a Broadly Cross-Reactive HIV-1 Human Monoclonal Antibody That Binds to Both gp120 and gp41

PubMed Central

Zhang, Mei-Yun; Yuan, Tingting; Li, Jingjing; Rosa Borges, Andrew; Watkins, Jennifer D.; Guenaga, Javier; Yang, Zheng; Wang, Yanping; Wilson, Richard; Li, Yuxing; Polonis, Victoria R.; Pincus, Seth H.; Ruprecht, Ruth M.; Dimitrov, Dimiter S.

2012-01-01

Identification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics. PMID:22970187

Innate immunity glycoprotein gp-340 variants may modulate human susceptibility to dental caries

PubMed Central

Jonasson, Anette; Eriksson, Christer; Jenkinson, Howard F; Källestål, Carina; Johansson, Ingegerd; Strömberg, Nicklas

2007-01-01

Background Bacterial adhesion is an important determinant of colonization and infection, including dental caries. The salivary scavenger receptor cysteine-rich glycoprotein gp-340, which mediates adhesion of Streptococcus mutans (implicated in caries), harbours three major size variants, designated gp-340 I to III, each specific to an individual saliva. Here we have examined the association of the gp-340 I to III polymorphisms with caries experience and adhesion of S. mutans. Methods A case-referent study was performed in 12-year-old Swedish children with high (n = 19) or low (n = 19) caries experiences. We measured the gp-340 I to III saliva phenotypes and correlated those with multiple outcome measures for caries experience and saliva adhesion of S. mutans using the partial least squares (PLS) multivariate projection technique. In addition, we used traditional statistics and 2-year caries increment to verify the established PLS associations, and bacterial adhesion to purified gp-340 I to III proteins to support possible mechanisms. Results All except one subject were typed as gp-340 I to III (10, 23 and 4, respectively). The gp-340 I phenotype correlated positively with caries experience (VIP = 1.37) and saliva adhesion of S. mutans Ingbritt (VIP = 1.47). The gp-340 II and III phenotypes tended to behave in the opposite way. Moreover, the gp-340 I phenotype tended to show an increased 2-year caries increment compared to phenotypes II/III. Purified gp-340 I protein mediated markedly higher adhesion of S. mutans strains Ingbritt and NG8 and Lactococcus lactis expressing AgI/II adhesins (SpaP or PAc) compared to gp-340 II and III proteins. In addition, the gp-340 I protein appeared over represented in subjects positive for Db, an allelic acidic PRP variant associated with caries, and subjects positive for both gp-340 I and Db tended to experience more caries than those negative for both proteins. Conclusion Gp-340 I behaves as a caries susceptibility protein. PMID:17562017

Robustness analysis of superpixel algorithms to image blur, additive Gaussian noise, and impulse noise

NASA Astrophysics Data System (ADS)

Brekhna, Brekhna; Mahmood, Arif; Zhou, Yuanfeng; Zhang, Caiming

2017-11-01

Superpixels have gradually become popular in computer vision and image processing applications. However, no comprehensive study has been performed to evaluate the robustness of superpixel algorithms in regard to common forms of noise in natural images. We evaluated the robustness of 11 recently proposed algorithms to different types of noise. The images were corrupted with various degrees of Gaussian blur, additive white Gaussian noise, and impulse noise that either made the object boundaries weak or added extra information to it. We performed a robustness analysis of simple linear iterative clustering (SLIC), Voronoi Cells (VCells), flooding-based superpixel generation (FCCS), bilateral geodesic distance (Bilateral-G), superpixel via geodesic distance (SSS-G), manifold SLIC (M-SLIC), Turbopixels, superpixels extracted via energy-driven sampling (SEEDS), lazy random walk (LRW), real-time superpixel segmentation by DBSCAN clustering, and video supervoxels using partially absorbing random walks (PARW) algorithms. The evaluation process was carried out both qualitatively and quantitatively. For quantitative performance comparison, we used achievable segmentation accuracy (ASA), compactness, under-segmentation error (USE), and boundary recall (BR) on the Berkeley image database. The results demonstrated that all algorithms suffered performance degradation due to noise. For Gaussian blur, Bilateral-G exhibited optimal results for ASA and USE measures, SLIC yielded optimal compactness, whereas FCCS and DBSCAN remained optimal for BR. For the case of additive Gaussian and impulse noises, FCCS exhibited optimal results for ASA, USE, and BR, whereas Bilateral-G remained a close competitor in ASA and USE for Gaussian noise only. Additionally, Turbopixel demonstrated optimal performance for compactness for both types of noise. Thus, no single algorithm was able to yield optimal results for all three types of noise across all performance measures. Conclusively, to solve real-world problems effectively, more robust superpixel algorithms must be developed.

Non-Gaussian effects, space-time decoupling, and mobility bifurcation in glassy hard-sphere fluids and suspensions.

PubMed

Saltzman, Erica J; Schweizer, Kenneth S

2006-12-01

Brownian trajectory simulation methods are employed to fully establish the non-Gaussian fluctuation effects predicted by our nonlinear Langevin equation theory of single particle activated dynamics in glassy hard-sphere fluids. The consequences of stochastic mobility fluctuations associated with the space-time complexities of the transient localization and barrier hopping processes have been determined. The incoherent dynamic structure factor was computed for a range of wave vectors and becomes of an increasingly non-Gaussian form for volume fractions beyond the (naive) ideal mode coupling theory (MCT) transition. The non-Gaussian parameter (NGP) amplitude increases markedly with volume fraction and is well described by a power law in the maximum restoring force of the nonequilibrium free energy profile. The time scale associated with the NGP peak becomes much smaller than the alpha relaxation time for systems characterized by significant entropic barriers. An alternate non-Gaussian parameter that probes the long time alpha relaxation process displays a different shape, peak intensity, and time scale of its maximum. However, a strong correspondence between the classic and alternate NGP amplitudes is predicted which suggests a deep connection between the early and final stages of cage escape. Strong space-time decoupling emerges at high volume fractions as indicated by a nondiffusive wave vector dependence of the relaxation time and growth of the translation-relaxation decoupling parameter. Displacement distributions exhibit non-Gaussian behavior at intermediate times, evolving into a strongly bimodal form with slow and fast subpopulations at high volume fractions. Qualitative and semiquantitative comparisons of the theoretical results with colloid experiments, ideal MCT, and multiple simulation studies are presented.

Parametrization and Optimization of Gaussian Non-Markovian Unravelings for Open Quantum Dynamics

NASA Astrophysics Data System (ADS)

Megier, Nina; Strunz, Walter T.; Viviescas, Carlos; Luoma, Kimmo

2018-04-01

We derive a family of Gaussian non-Markovian stochastic Schrödinger equations for the dynamics of open quantum systems. The different unravelings correspond to different choices of squeezed coherent states, reflecting different measurement schemes on the environment. Consequently, we are able to give a single shot measurement interpretation for the stochastic states and microscopic expressions for the noise correlations of the Gaussian process. By construction, the reduced dynamics of the open system does not depend on the squeezing parameters. They determine the non-Hermitian Gaussian correlation, a wide range of which are compatible with the Markov limit. We demonstrate the versatility of our results for quantum information tasks in the non-Markovian regime. In particular, by optimizing the squeezing parameters, we can tailor unravelings for improving entanglement bounds or for environment-assisted entanglement protection.

Restoration of Static JPEG Images and RGB Video Frames by Means of Nonlinear Filtering in Conditions of Gaussian and Non-Gaussian Noise

NASA Astrophysics Data System (ADS)

Sokolov, R. I.; Abdullin, R. R.

2017-11-01

The use of nonlinear Markov process filtering makes it possible to restore both video stream frames and static photos at the stage of preprocessing. The present paper reflects the results of research in comparison of these types image filtering quality by means of special algorithm when Gaussian or non-Gaussian noises acting. Examples of filter operation at different values of signal-to-noise ratio are presented. A comparative analysis has been performed, and the best filtered kind of noise has been defined. It has been shown the quality of developed algorithm is much better than quality of adaptive one for RGB signal filtering at the same a priori information about the signal. Also, an advantage over median filter takes a place when both fluctuation and pulse noise filtering.

Interaction of pyridostigmine bromide and N,N-diethyl-m-toluamide alone and in combination with P-glycoprotein expressed in Escherichia coli leaky mutant.

PubMed

El-Masry, Eman M; Abou-Donia, Mohamed B

2006-05-01

P-glycoprotein (P-gp), the most extensively studied ATP-binding transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of the cell. This study was carried out to determine the effect of N,N-diethyl-m-toluamide (DEET) and pyridostigmine bromide (PB), alone and in combination, on P-gp expression using Escherichia coli leaky mutant transformed with Mdr1 gene (pT5-7/mdr1), which codes for P-gp or lactose permease (pT5-7/lacY) as negative control. Also, daunomycin (a known P-gp sustrate) was used as a positive control and reserpine (a known P-gp inhibitor) served as a negative control. An in vitro cell-resistant assay was used to monitor the potential of test compounds to interact with P-gp. Following exposure of the cells to pyridostigmine bromide or daunomycin, P-gp conferred significant resistance against both compounds, while reserpine and DEET significantly inhibited the glycoprotein. Cells were grown in the presence of noncytotoxic concentrations of daunomycin, pyridostigmine bromide, reserpine, or DEET, and membrane fractions were examined by Western immunoblotting for expression of P-gp. Daunomycin induced P-gp expression quantitatively more than pyridostigmine bromide, while reserpine and DEET significantly inhibited P-gp expression in cells harboring mdr1. Photoaffinity labeling experiment performed with the P-gp ligand [125I]iodoarylazidoprazosin demonstrated that compounds that induced or inhibited P-gp transport activity also bound to P-gp. DEET was also found to be a potent inhibitor of P-gp-mediated ATPase activity, whereas pyridostigmine bromide increased P-gp ATPase activity. Cells expressing P-gp or lac permease were exposed to pyridostigmine bromide and DEET, alone and in combination. Noncytotoxic concentrations of DEET significantly inhibited P-gp-mediated resistance against pyridostigmine bromide, resulting in a reduction of the number of effective drug interactions with biological targets. An explanation of these results might be that DEET is a third-generation inhibitor of P-gp; it has high potency and specificity for P-gp, it inhibits hydrolysis of ATP, it exerts no appreciable impact on cytochrome P-450 3A4, and it prevents transport of xenobiotics, such as pyridostigmine bromide, out of the cell. This conclusion explains, at least in part, the increased toxicity and bioavailability of pyridostigmine bromide following combined administration with DEET. This study improves our understanding of the basis of chemical interactions with DEET by defining the ability of drugs to interact with P-gp either as inhibitors or substrates, which may in turn lead to altered efficacy or toxicity.

General practitioners' perceptions of their ability to identify and refer patients with suspected axial spondyloarthritis: a qualitative study.

PubMed

van Onna, Marloes; Gorter, Simone; van Meerendonk, Aniek; van Tubergen, Astrid

2014-05-01

To explore the knowledge, beliefs, and experiences of general practitioners (GP) about inflammatory back pain (IBP) and axial spondyloarthritis (axSpA) and potential barriers for referral of patients suspected of having axSpA. A qualitative study involving semistructured interviews with GP was conducted. Transcripts of the interviews were independently read and annotated by 2 readers. Illustrative themes were identified and a coding system to categorize the data was developed. Ten GP (all men; mean age 49 yrs) were interviewed. All could adequately describe "classic" ankylosing spondylitis (AS) and mentioned chronic back pain and/or stiffness as key features. All GP thought that AS is almost exclusively diagnosed in men. Six GP knew that there is a difference between mechanical back pain and IBP, but could recall only a limited number of variables indicative of IBP, such as awakening night pain (4 GP), insidious onset of back pain (1 GP), improvement with movement (1 GP), and (morning) stiffness (2 GP). Two GP mentioned peripheral arthritis as other SpA features, none mentioned dactylitis or enthesitis. GP awareness of associated extraarticular manifestations was low. Most GP expressed that (practical) referral measures would be useful. GP are aware of "classic", but longterm features of axSpA. Knowledge about the disease spectrum and early detection is, however, limited. Addressing these issues in training programs may improve recognition of axSpA in primary care. This may ultimately contribute to earlier referral, diagnosis, and initiation of effective treatment in patients with axSpA.

Advances in PET Imaging of P-Glycoprotein Function at the Blood-Brain Barrier

PubMed Central

2012-01-01

Efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance observed in patient groups with refractory epilepsy and HIV. Altered P-gp function has also been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Positron emission tomography (PET), a molecular imaging modality, has become a promising method to study the role of P-gp at the BBB. The first PET study of P-gp function was conducted in 1998, and during the past 15 years two main categories of P-gp PET tracers have been investigated: tracers that are substrates of P-gp efflux and tracers that are inhibitors of P-gp function. PET, as a noninvasive imaging technique, allows translational research. Examples of this are preclinical investigations of P-gp function before and after administering P-gp modulating drugs, investigations in various animal and disease models, and clinical investigations regarding disease and aging. The objective of the present review is to give an overview of available PET radiotracers for studies of P-gp and to discuss how such studies can be designed. Further, the review summarizes results from PET studies of P-gp function in different central nervous system disorders. PMID:23421673

Cramer-Rao Bound for Gaussian Random Processes and Applications to Radar Processing of Atmospheric Signals

NASA Technical Reports Server (NTRS)

Frehlich, Rod

1993-01-01

Calculations of the exact Cramer-Rao Bound (CRB) for unbiased estimates of the mean frequency, signal power, and spectral width of Doppler radar/lidar signals (a Gaussian random process) are presented. Approximate CRB's are derived using the Discrete Fourier Transform (DFT). These approximate results are equal to the exact CRB when the DFT coefficients are mutually uncorrelated. Previous high SNR limits for CRB's are shown to be inaccurate because the discrete summations cannot be approximated with integration. The performance of an approximate maximum likelihood estimator for mean frequency approaches the exact CRB for moderate signal to noise ratio and moderate spectral width.

Fusion proteins of HIV-1 envelope glycoprotein gp120 with CD4-induced antibodies showed enhanced binding to CD4 and CD4 binding site antibodies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Weizao, E-mail: chenw3@mail.nih.gov; Feng, Yang; Wang, Yanping

Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibitmore » decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.« less

Evaluation of humoral, mucosal, and cellular immune responses following co-immunization of HIV-1 Gag and Env proteins expressed by Newcastle disease virus

PubMed Central

Khattar, Sunil K; Palaniyandi, Senthilkumar; Samal, Sweety; LaBranche, Celia C; Montefiori, David C; Zhu, Xiaoping; Samal, Siba K

2015-01-01

The combination of multiple HIV antigens in a vaccine can broaden antiviral immune responses. In this study, we used NDV vaccine strain LaSota to generate rNDV (rLaSota/optGag) expressing human codon optimized p55 Gag protein of HIV-1. We examined the effect of co-immunization of rLaSota/optGag with rNDVs expressing different forms of Env protein gp160, gp120, gp140L [a version of gp140 that lacked cytoplasmic tail and contained complete membrane-proximal external region (MPER)] and gp140S (a version of gp140 that lacked cytoplasmic tail and distal half of MPER) on magnitude and breadth of humoral, mucosal and cellular immune responses in guinea pigs and mice. Our results showed that inclusion of rLaSota/optGag with rNDVs expressing different forms of Env HIV Gag did not affect the Env-specific humoral and mucosal immune responses in guinea pigs and that the potent immune responses generated against Env persisted for at least 13 weeks post immunization. The highest Env-specific humoral and mucosal immune responses were observed with gp140S+optGag group. The neutralizing antibody responses against HIV strains BaL.26 and MN.3 induced by gp140S+optGag and gp160+optGag were higher than those elicited by other groups. Inclusion of Gag with gp160, gp140S and gp140L enhanced the level of Env-specific IFN-γ-producing CD8+ T cells in mice. Inclusion of Gag with gp160 and gp140L also resulted in increased Env-specific CD4+ T cells. The level of Gag-specific CD8+ and CD4+ T cells was also enhanced in mice immunized with Gag along with gp140S and gp120. These results indicate lack of antigen interference in a vaccine containing rNDVs expressing Env and Gag proteins. PMID:25695657

Shedding of Ebola Virus Surface Glycoprotein Is a Mechanism of Self-regulation of Cellular Cytotoxicity and Has a Direct Effect on Virus Infectivity.

PubMed

Dolnik, Olga; Volchkova, Valentina A; Escudero-Perez, Beatriz; Lawrence, Philip; Klenk, Hans-Dieter; Volchkov, Viktor E

2015-10-01

The surface glycoprotein (GP) is responsible for Ebola virus (EBOV) attachment and membrane fusion during virus entry. Surface expression of highly glycosylated GP causes marked cytotoxicity via masking of a wide range of cellular surface molecules, including integrins. Considerable amounts of surface GP are shed from virus-infected cells in a soluble truncated form by tumor necrosis factor α-converting enzyme. In this study, the role of GP shedding was investigated using a reverse genetics approach by comparing recombinant viruses possessing amino acid substitutions at the GP shedding site. Virus with an L635V substitution showed a substantial decrease in shedding, whereas a D637V substitution resulted in a striking increase in the release of shed GP. Variations in shedding efficacy correlated with observed differences in the amounts of shed GP in the medium, GP present in virus-infected cells, and GP present on virions. An increase in shedding appeared to be associated with a reduction in viral cytotoxicity, and, vice versa, the virus that shed less was more cytotoxic. An increase in shedding also resulted in a reduction in viral infectivity, whereas a decrease in shedding efficacy enhanced viral growth characteristics in vitro. Differences in shedding efficacy and, as a result, differences in the amount of mature GP available for incorporation into budding virions did not equate to differences in overall release of viral particles. Likewise, data suggest that the resulting differences in the amount of mature GP on the cell surface led to variations in the GP content of released particles and, as a consequence, in infectivity. In conclusion, fine-tuning of the levels of EBOV GP expressed at the surface of virus-infected cells via GP shedding plays an important role in EBOV replication by orchestrating the balance between optimal virion GP content and cytotoxicity caused by GP. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Energy pumping in electrical circuits under avalanche noise.

PubMed

Kanazawa, Kiyoshi; Sagawa, Takahiro; Hayakawa, Hisao

2014-07-01

We theoretically study energy pumping processes in an electrical circuit with avalanche diodes, where non-Gaussian athermal noise plays a crucial role. We show that a positive amount of energy (work) can be extracted by an external manipulation of the circuit in a cyclic way, even when the system is spatially symmetric. We discuss the properties of the energy pumping process for both quasistatic and finite-time cases, and analytically obtain formulas for the amounts of the work and the power. Our results demonstrate the significance of the non-Gaussianity in energetics of electrical circuits.

An Imager Gaussian Process Machine Learning Methodology for Cloud Thermodynamic Phase classification

NASA Astrophysics Data System (ADS)

Marchant, B.; Platnick, S. E.; Meyer, K.

2017-12-01

The determination of cloud thermodynamic phase from MODIS and VIIRS instruments is an important first step in cloud optical retrievals, since ice and liquid clouds have different optical properties. To continue improving the cloud thermodynamic phase classification algorithm, a machine-learning approach, based on Gaussian processes, has been developed. The new proposed methodology provides cloud phase uncertainty quantification and improves the algorithm portability between MODIS and VIIRS. We will present new results, through comparisons between MODIS and CALIOP v4, and for VIIRS as well.

Dimension from covariance matrices.

PubMed

Carroll, T L; Byers, J M

2017-02-01

We describe a method to estimate embedding dimension from a time series. This method includes an estimate of the probability that the dimension estimate is valid. Such validity estimates are not common in algorithms for calculating the properties of dynamical systems. The algorithm described here compares the eigenvalues of covariance matrices created from an embedded signal to the eigenvalues for a covariance matrix of a Gaussian random process with the same dimension and number of points. A statistical test gives the probability that the eigenvalues for the embedded signal did not come from the Gaussian random process.

Screening programme to select a resin for Gravity Probe-B composites

NASA Technical Reports Server (NTRS)

Will, E. T.

1992-01-01

The Gravity Probe-B (GP-B) program undertook a screening program to select a possible replacement resin for the E-787 resin currently used in composite neck tubes and support struts. The goal was to find a resin with good cryogenic and structural properties, low-helium permeation and an easily repeatable fabrication process. Cycom 92, SCI REZ 081 and RS-3 were selected for comparison with E-787. Identical composite tubes made from each resin and gamma-alumina fiber (85 percent Al2O3, 15 percent SiO2) were evaluated for cryogenic and structural performance and for processability. Cryogenic performance was evaluated by measuring low-temperature permeation and leaks to determine cryogenic strain behavior. Structural performance was evaluated by comparing the resin-dominated shear strength of the composites. Processability was evaluated from fabrication comments and GP-B's own experience. SCI REZ 081 was selected as the best overall resin with superior strength and cryogenic performance and consistent processability.

Internalization and Axonal Transport of the HIV Glycoprotein gp120

PubMed Central

Berth, Sarah; Caicedo, Hector Hugo; Sarma, Tulika; Morfini, Gerardo

2015-01-01

The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity. PMID:25636314

Synthetic polymers as substrates for a DNA-sliding clamp protein.

PubMed

van Dongen, S F M; Clerx, J; van den Boomen, O I; Pervaiz, M; Trakselis, M A; Ritschel, T; Schoonen, L; Schoenmakers, D C; Nolte, R J M

2018-04-26

The clamp protein (gp45) of the DNA polymerase III of the bacteriophage T4 is known to bind to DNA and stay attached to it in order to facilitate the process of DNA copying by the polymerase. As part of a project aimed at developing new biomimetic data-encoding systems we have investigated the binding of gp45 to synthetic polymers, that is, rigid, helical polyisocyanopeptides. Molecular modelling studies suggest that the clamp protein may interact with the latter polymers. Experiments aimed at verifying these interactions are presented and discussed. © 2018 The Authors Biopolymers Published by Wiley Periodicals, Inc.

A qualitative assessment of a random process proposed as an atmospheric turbulence model

NASA Technical Reports Server (NTRS)

Sidwell, K.

1977-01-01

A random process is formed by the product of two Gaussian processes and the sum of that product with a third Gaussian process. The resulting total random process is interpreted as the sum of an amplitude modulated process and a slowly varying, random mean value. The properties of the process are examined, including an interpretation of the process in terms of the physical structure of atmospheric motions. The inclusion of the mean value variation gives an improved representation of the properties of atmospheric motions, since the resulting process can account for the differences in the statistical properties of atmospheric velocity components and their gradients. The application of the process to atmospheric turbulence problems, including the response of aircraft dynamic systems, is examined. The effects of the mean value variation upon aircraft loads are small in most cases, but can be important in the measurement and interpretation of atmospheric turbulence data.

Three-photon Gaussian-Gaussian-Laguerre-Gaussian excitation of a localized atom to a highly excited Rydberg state

NASA Astrophysics Data System (ADS)

Mashhadi, L.

2017-12-01

Optical vortices are currently one of the most intensively studied topics in light-matter interaction. In this work, a three-step axial Doppler- and recoil-free Gaussian-Gaussian-Laguerre-Gaussian (GGLG) excitation of a localized atom to the highly excited Rydberg state is presented. By assuming a large detuning for intermediate states, an effective quadrupole excitation related to the Laguerre-Gaussian (LG) excitation to the highly excited Rydberg state is obtained. This special excitation system radially confines the single highly excited Rydberg atom independently of the trapping system into a sharp potential landscape into the so-called ‘far-off-resonance optical dipole-quadrupole trap’ (FORDQT). The key parameters of the Rydberg excitation to the highly excited state, namely the effective Rabi frequency and the effective detuning including a position-dependent AC Stark shift, are calculated in terms of the basic parameters of the LG beam and of the polarization of the excitation lasers. It is shown that the obtained parameters can be tuned to have a precise excitation of a single atom to the desired Rydberg state as well. The features of transferring the optical orbital and spin angular momentum of the polarized LG beam to the atom via quadrupole Rydberg excitation offer a long-lived and controllable qudit quantum memory. In addition, in contrast to the Gaussian laser beam, the doughnut-shaped LG beam makes it possible to use a high intensity laser beam to increase the signal-to-noise ratio in quadrupole excitation with minimized perturbations coming from stray light broadening in the last Rydberg excitation process.

DIFFERENT PROTOCOLS OF POSTCONDITIONING DOES NOT ATTENUATE MESENTERIC ISCHEMIA-REPERFUSION INJURY AFTER SHORT-TERM REPERFUSION

PubMed Central

BRITO, Marcus Vinicius Henriques; YASOJIMA, Edson Yuzur; MACHADO, Andressa Abnader; SILVEIRA, Matheus Paiva Pacheco Reis; TEIXEIRA, Renan Kleber Costa; YAMAKI, Vitor Nagai; COSTA, Felipe Lobato da Silva

2017-01-01

ABSTRACT Background: Mesenteric ischemia is a challenging diagnosis. Delay in diagnosis can lead to extent bowel necrosis and poor outcomes. Ischemia and reperfusion syndrome plays an important role in this scenario. Aim: To access effects of different post-conditioning cycles on mesenteric ischemia-reperfusion syndrome. Method: Twenty-five rats were assigned into five groups: Sham, used to establish normal parameters; control group, submitted to mesenteric ischemia for 30 min; in groups GP3, GP1 and GP30, ischemia was followed by post-conditioning protocol, which consisted of 1 cycle of 3 min (GP3), 3 cycles of 1 min (GP1) or 6 cycles of 30 s (GP30), respectively. Ileum samples were harvested after one hour of reperfusion. Intestinal mucosal injury was evaluated through histopathological analysis. Results: The average of mesenteric injury degree was 0 in the sham group, 3.6 in the control group, 3.4 in GP3, 3.2 in GP1, and 3.0 in GP30; villous length average was 161.59 in sham group, 136.27 in control group, 135.89 in GP3, 129.46 in GP1, and 135.18 in GP30. Was found significant difference between sham and other groups (p<0.05); however, there was no difference among post-conditioning groups. Conclusion: Post-conditioning adopted protocols were not able to protect intestinal mucosa integrity after mesenteric ischemia and short term reperfusion. PMID:28489164

Generation and Characterization of Inhibitory Antibodies Specific to Guinea Pig CXCR1 and CXCR2.

PubMed

Tanaka, Kento; Yoshimura, Chigusa; Shiina, Tetsuo; Terauchi, Tomoko; Yoshitomi, Tomomi; Hirahara, Kazuki

2017-04-01

CXCR1 and CXCR2 are chemokine receptors that have different selectivity of chemokine ligands, but the distinct role of each receptor is not clearly understood. This is due to the absence of specific inhibitors in guinea pigs, which are the appropriate species for investigation of CXCR1 and CXCR2 because of their functional similarity to humans. In this study, we generated and evaluated monoclonal antibodies that specifically bound to guinea pig CXCR1 (gpCXCR1) and guinea pig CXCR2 (gpCXCR2) for acquisition of specific inhibitors. To assess the activity of antibodies, we established CHO-K1 cells stably expressing either gpCXCR1 or gpCXCR2 (CHO/gpCXCR1 or CHO/gpCXCR2). CHO/gpCXCR1 showed migration in response to guinea pig interleukin (IL)-8, and CHO/gpCXCR2 showed migration in response to both guinea pig IL-8 and guinea pig growth-regulated oncogene α. The receptor selectivities of the chemokines of guinea pigs were the same as the human orthologs. The inhibitory activities of the anti-gpCXCR1 and anti-gpCXCR2 monoclonal antibodies on cell migration were observed in a concentration-dependent manner. In conclusion, we successfully obtained inhibitory antibodies specific to gpCXCR1 and gpCXCR2. These inhibitory antibodies will be useful to clarify the physiological roles of CXCR1 and CXCR2 in guinea pigs.