Three-dimensional structure of heat shock protein 90 from Plasmodium falciparum: molecular modelling approach to rational drug design against malaria

We have recently implicated heat shock protein 90 from Plasmodium falciparum (PfHsp90) as a potential drug target against malaria. Using inhibitors specific to the nucleotide binding domain of Hsp90, we have shown potent growth inhibitory effects on development of malarial parasite in human erythrocytes. To gain better understanding of the vital role played by PfHsp90 in parasite growth, we have modeled its three dimensional structure using recently described full length structure of yeast Hsp90. Sequence similarity found between PfHsp90 and yeast Hsp90 allowed us to model the core structure with high confidence. The superimposition of the predicted structure with that of the template yeast Hsp90 structure reveals an RMSD of 3.31 angstrom. The N-terminal and middle domains showed the least RMSD (1.76 angstrom) while the more divergent C-terminus showed a greater RMSD (2.84 angstrom) with respect to the template. The structure shows overall conservation of domains involved in nucleotide binding, ATPase activity, co-chaperone binding as well as inter-subunit interactions. Important co-chaperones known to modulate Hsp90 function in other eukaryotes are conserved in malarial parasite as well. An acidic stretch of amino acids found in the linker region, which is uniquely extended in PfHsp90 could not be modeled in this structure suggesting a flexible conformation. Our results provide a basis to compare the overall structure and functional pathways dependent on PfHsp90 in malarial parasite. Further analysis of differences found between human and parasite Hsp90 may make it possible to design inhibitors targeted specifically against malaria.

A dynamical approach to the spatio-temporal features of the Portevin-Le Chatelier effect

We show that the extended Ananthakrishna's model exhibits all the features of the Portevin - Le Chatelier effect including the three types of bands. The model reproduces the recently observed crossover from a low dimensional chaotic state at low and medium strain rates to a high dimensional power law state of stress drops at high strain rates. The dynamics of crossover is elucidated through a study of the Lyapunov spectrum.

A semi-experimental approach to plane problems in elasticity

A semi-experimental approach to solve two-dimensional problems in elasticity is given. The method has been applied to two problems, (i) a square deep beam, and (ii) a bridge pier with a sloping boundary. For the first problem sufficient analytical results are available and hence the accuracy of the method can be verified. Then the method has been extended to the second problem for which sufficient results are not available.

A transputer-based extended hypercube

The Extended Hypercube is a new approach in multiprocessor architectures, which reduces the communication burden on the processor elements. We propose a scheme for implementing such an architecture using INMOS transputers as the processor and controller elements to achieve a very high computation to communication ratio.

A Unified Approach to Encoding and Classification Using Bimodal Projection-Based Features

In general the objective of accurately encoding the input data and the objective of extracting good features to facilitate classification are not consistent with each other. As a result, good encoding methods may not be effective mechanisms for classification. In this paper, an earlier proposed unsupervised feature extraction mechanism for pattern classification has been extended to obtain an invertible map. The method of bimodal projection-based features was inspired by the general class of methods called projection pursuit. The principle of projection pursuit concentrates on projections that discriminate between clusters and not faithful representations. The basic feature map obtained by the method of bimodal projections has been extended to overcome this. The extended feature map is an embedding of the input space in the feature space. As a result, the inverse map exists and hence the representation of the input space in the feature space is exact. This map can be naturally expressed as a feedforward neural network.

A low cost approach for the fabrication of microwave phase shifter on laminates

This paper presents a simple and low cost fabrication approach using extended printed circuit board processing techniques for an electrostatically actuated phase shifter on a common microwave laminate. This approach uses 15 mu m thin copper foils for realizing the bridge structures as well as for a spacer. A polymeric thin film deposited by spin coating and patterned using lithographic process is used as a dielectric layer to improve the reliability of the device. The prototype of the phase shifter for X-band operation is fabricated and tested for electrical and electromechanical performance parameters. The realized devices have a figure of merit of 70 degrees/dB for a maximum applied bias potential of 85 V. Since these phase shifters can be conveniently fabricated directly on microwave substrates used for feed distribution networks of phased arrays, the overall addition in cost, dimensions and processing for including these phase shifters in these arrays is minimal.

Determinant: Old algorithms, new insights (Extended Abstract)

In this paper we approach the problem of computing the characteristic polynomial of a matrix from the combinatorial viewpoint. We present several combinatorial characterizations of the coefficients of the characteristic polynomial, in terms of walks and closed walks of different kinds in the underlying graph. We develop algorithms based on these characterizations, and show that they tally with well-known algorithms arrived at independently from considerations in linear algebra.

Multi-Port Network Approach for the Analysis of Dual Band Fractal Microstrip Antennas

The multiport network approach is extended to analyze the behavior of microstrip fractal antennas. The capacitively fedmicrostrip square ring antenna has the side opposite to the feed arm replaced with a fractal Minkowski geometry. Dual frequency operation is achieved by suitably choosing the indentation of this fractal geometry. The width of the two sides adjacent to this is increased to further control the resonant characteristics and the ratio of the two resonance frequencies of this antenna. The impedance matrix for the multiport network model of this antenna is simplified exploiting self-similarity of the geometry with greater accuracy and reduced analysis time. Experimentally validated results confirm utility of the approach in analyzing the input characteristics of similar multi-frequency fractal microstrip antennas with other fractal geometries.

An integrated estimation/guidance approach for seeker-less interceptors

This paper addresses the problem of intercepting highly maneuverable threats using seeker-less interceptors that operate in the command guidance mode. These systems are more prone to estimation errors than standard seeker-based systems. In this paper, an integrated estimation/guidance (IEG) algorithm, which combines interactive multiple model (IMM) estimator with differential game guidance law (DGL), is proposed for seeker-less interception. In this interception scenario, the target performs an evasive bang-bang maneuver, while the sensor has noisy measurements and the interceptor is subject to acceleration bound. The IMM serves as a basis for the synthesis of efficient filters for tracking maneuvering targets and reducing estimation errors. The proposed game-based guidance law for two-dimensional interception, later extended to three-dimensional interception scenarios, is used to improve the endgame performance of the command-guided seeker-less interceptor. The IMM scheme and an optimal selection of filters, to cater to various maneuvers that are expected during the endgame, are also described. Furthermore, a chatter removal algorithm is introduced, thus modifying the differential game guidance law (modified DGL). A comparison between modified DGL guidance law and conventional proportional navigation guidance law demonstrates significant improvement in miss distance in a pursuer-evader scenario. Simulation results are also presented for varying flight path angle errors. A numerical study is provided which demonstrates the performance of the combined interactive multiple model with game-based guidance law (IMM/DGL). Simulation study is also carried out for combined IMM and modified DGL (IMM/modified DGL) which exhibits the superior performance and viability of the algorithm reducing the chattering phenomenon. The results are illustrated by an extensive Monte Carlo simulation study in the presence of estimation errors.

Phase space path integral approach to harmonic oscillator with a time-dependent force constant

The quantum statistical mechanical propagator for a harmonic oscillator with a time-dependent force constant, m omega(2)(t), has been investigated in the past and was found to have only a formal solution in terms of the solutions of certain ordinary differential equations. Such path integrals are frequently encountered in semiclassical path integral evaluations and having exact analytical expressions for such path integrals is of great interest. In a previous work, we had obtained the exact propagator for motion in an arbitrary time-dependent harmonic potential in the overdamped limit of friction using phase space path integrals in the context of Levy flights - a result that can be easily extended to Brownian motion. In this paper, we make a connection between the overdamped Brownian motion and the imaginary time propagator of quantum mechanics and thereby get yet another way to evaluate the latter exactly. We find that explicit analytic solution for the quantum statistical mechanical propagator can be written when the time-dependent force constant has the form omega(2)(t) = lambda(2)(t) - d lambda(t)/dt where lambda(t) is any arbitrary function of t and use it to evaluate path integrals which have not been evaluated previously. We also employ this method to arrive at a formal solution of the propagator for both Levy flights and Brownian subjected to a time-dependent harmonic potential in the underdamped limit of friction. (C) 2015 Elsevier B.V. All rights reserved.

Haloarchaeal gas vesicle nanoparticles displaying Salmonella antigens as a novel approach to vaccine development

A safe, effective, and inexpensive vaccine against typhoid and other Salmonella diseases is urgently needed. In order to address this need, we are developing a novel vaccine platform employing buoyant, self-adjuvanting gas vesicle nanoparticles (GVNPs) from the halophilic archaeon Halobacterium sp. NRC-1, bioengineered to display highly conserved Salmonella enterica antigens. As the initial antigen for testing, we selected SopB, a secreted inosine phosphate effector protein injected by pathogenic S. enterica bacteria during infection into the host cells. Two highly conserved sopB gene segments near the 3'- region, named sopB4 and sopB5, were each fused to the grIpC gene, and resulting SopB-GVNPs were purified by centrifugally accelerated flotation. Display of SopB4 and SopB5 antigenic epitopes on GVNPs was established by Western blotting analysis using antisera raised against short synthetic peptides of SopB. Immunostimulatory activities of the SopB4 and B5 nanoparticles were tested by intraperitoneal administration of SopB-GVNPs to BALB/c mice which had been immunized with S. enterica serovar Typhimurium 14028 ApmrG-H111-D (DV-STM-07), a live attenuated vaccine strain. Proinflammatory cytokines IFN-y, IL-2, and IL-9 were significantly induced in mice boosted with SopB5-GVNPs, consistent with a robust Thl response. After challenge with virulent S. enterica serovar Typhimurium 14028, bacterial burden was found to be diminished in spleen of mice boosted with SopB4-GVNPs and absent or significantly diminished in liver, mesenteric lymph node, and spleen of mice boosted with SopB5GVNPs, indicating that the C-terminal portions of SopB displayed on GVNPs elicit a protective response to Salmonella infection in mice. SopB antigen-GVNPs were also found to be stable at elevated temperatures for extended periods without refrigeration. The results show that bioengineered GVNPs are likely to represent a valuable platform for antigen delivery and development of improved vaccines against Salmonella and other diseases.

Constraints based analysis of extended cybernetic models

The cybernetic modeling framework provides an interesting approach to model the regulatory phenomena occurring in microorganisms. In the present work, we adopt a constraints based approach to analyze the nonlinear behavior of the extended equations of the cybernetic model. We first show that the cybernetic model exhibits linear growth behavior under the constraint of no resource allocation for the induction of the key enzyme. We then quantify the maximum achievable specific growth rate of microorganisms on mixtures of substitutable substrates under various kinds of regulation and show its use in gaining an understanding of the regulatory strategies of microorganisms. Finally, we show that Saccharomyces cerevisiae exhibits suboptimal dynamic growth with a long diauxic lag phase when growing on a mixture of glucose and galactose and discuss on its potential to achieve optimal growth with a significantly reduced diauxic lag period. The analysis carried out in the present study illustrates the utility of adopting a constraints based approach to understand the dynamic growth strategies of microorganisms. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Analysis of optical systems with extended depth of field using the Wigner distribution function

We describe the use of a Wigner distribution function approach for exploring the problem of extending the depth of field in a hybrid imaging system. The Wigner distribution function, in connection with the phase-space curve that formulates a joint phase-space description of an optical field, is employed as a tool to display and characterize the evolving behavior of the amplitude point spread function as a wave propagating along the optical axis. It provides a comprehensive exhibition of the characteristics for the hybrid imaging system in extending the depth of field from both wave optics and geometrical optics. We use it to analyze several well-known optical designs in extending the depth of field from a new viewpoint. The relationships between this approach and the earlier ambiguity function approach are also briefly investigated. (c) 2006 Optical Society of America.

Inference approach to grammar construction

A system of computer assisted grammar construction (CAGC) is presented in this paper. The CAGC system is designed to generate broad-coverage grammars for large natural language corpora by utilizing both an extended inside-outside algorithm and an automatic phrase bracketing (AUTO) system which is designed to provide the extended algorithm with constituent information during learning. This paper demonstrates the capability of the CAGC system to deal with realistic natural language problems and the usefulness of the AUTO system for constraining the inside-outside based grammar re-estimation. Performance results, including coverage, recall and precision, are presented for a grammar constructed for the Wall Street Journal (WSJ) corpus using the Penn Treebank.

Synchronization in climate dynamics and other extended systems

Synchronization is now well established as representing coherent behaviour between two or more otherwise autonomous nonlinear systems subject to some degree of coupling. Such behaviour has mainly been studied to date, however, in relatively low-dimensional discrete systems or networks. But the possibility of similar kinds of behaviour in continuous or extended spatiotemporal systems has many potential practical implications, especially in various areas of geophysics. We review here a range of cyclically varying phenomena within the Earth's climate system for which there may be some evidence or indication of the possibility of synchronized behaviour, albeit perhaps imperfect or highly intermittent. The exploitation of this approach is still at a relatively early stage within climate science and dynamics, in which the climate system is regarded as a hierarchy of many coupled sub-systems with complex nonlinear feedbacks and forcings. The possibility of synchronization between climate oscillations (global or local) and a predictable external forcing raises important questions of how models of such phenomena can be validated and verified, since the resulting response may be relatively insensitive to the details of the model being synchronized. The use of laboratory analogues may therefore have an important role to play in the study of natural systems that can only be observed and for which controlled experiments are impossible. We go on to demonstrate that synchronization can be observed in the laboratory, even in weakly coupled fluid dynamical systems that may serve as direct analogues of the behaviour of major components of the Earth's climate system. The potential implications and observability of these effects in the long-term climate variability of the Earth is further discussed. © 2010 Springer-Verlag Berlin Heidelberg.