Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis

Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organ ` isms. Our findings suggest that compound 10 ``locks'' DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.

Gabapentin: A Stereochemically Constrained gamma Amino Acid Residue in Hybrid Peptide Design

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino adds, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino adds with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino add residue that contains a cyclohexyl ring at the C-beta carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C-7 and C-9 hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alpha gamma sequences, district C-12 hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.

Agents Based Algorithms for Design Parameter Estimation in Contaminant Transport Inverse Problems

A considerable amount of work has been dedicated on the development of analytical solutions for flow of chemical contaminants through soils. Most of the analytical solutions for complex transport problems are closed-form series solutions. The convergence of these solutions depends on the eigen values obtained from a corresponding transcendental equation. Thus, the difficulty in obtaining exact solutions from analytical models encourages the use of numerical solutions for the parameter estimation even though, the later models are computationally expensive. In this paper a combination of two swarm intelligence based algorithms are used for accurate estimation of design transport parameters from the closed-form analytical solutions. Estimation of eigen values from a transcendental equation is treated as a multimodal discontinuous function optimization problem. The eigen values are estimated using an algorithm derived based on glowworm swarm strategy. Parameter estimation of the inverse problem is handled using standard PSO algorithm. Integration of these two algorithms enables an accurate estimation of design parameters using closed-form analytical solutions. The present solver is applied to a real world inverse problem in environmental engineering. The inverse model based on swarm intelligence techniques is validated and the accuracy in parameter estimation is shown. The proposed solver quickly estimates the design parameters with a great precision.

Optimum Design of Bridge Abutments under Seismic Conditions: Reliability-Based Approach

The paper focuses on the reliability-based design optimization of gravity wall bridge abutments when subjected to active condition during earthquakes. An analytical study considering the effect of uncertainties in the seismic analysis of bridge abutments is presented. Planar failure surface has been considered in conjunction with the pseudostatic limit equilibrium method for the calculation of the seismic active earth pressure. Analysis is conducted to evaluate the external stability of bridge abutments when subjected to earthquake loads. Reliability analysis is used to estimate the probability of failure in three modes of failure viz. sliding failure of the wall on its base, overturning failure about its toe (or eccentricity failure of the resultant force) and bearing failure of foundation soil below the base of wall. The properties of backfill and foundation soil below the base of abutment are treated as random variables. In addition, the uncertainties associated with characteristics of earthquake ground motions such as horizontal seismic acceleration and shear wave velocity propagating through backfill soil are considered. The optimum proportions of the abutment needed to maintain the stability are obtained against three modes of failure by targeting various component and system reliability indices. Studies have also been made to study the influence of various parameters on the seismic stability.

An optimal dynamic inversion-based neuro-adaptive approach for treatment of chronic myelogenous leukemia

Combining the advanced techniques of optimal dynamic inversion and model-following neuro-adaptive control design, an innovative technique is presented to design an automatic drug administration strategy for effective treatment of chronic myelogenous leukemia (CML). A recently developed nonlinear mathematical model for cell dynamics is used to design the controller (medication dosage). First, a nominal controller is designed based on the principle of optimal dynamic inversion. This controller can treat the nominal model patients (patients who can be described by the mathematical model used here with the nominal parameter values) effectively. However, since the system parameters for a realistic model patient can be different from that of the nominal model patients, simulation studies for such patients indicate that the nominal controller is either inefficient or, worse, ineffective; i.e. the trajectory of the number of cancer cells either shows non-satisfactory transient behavior or it grows in an unstable manner. Hence, to make the drug dosage history more realistic and patient-specific, a model-following neuro-adaptive controller is augmented to the nominal controller. In this adaptive approach, a neural network trained online facilitates a new adaptive controller. The training process of the neural network is based on Lyapunov stability theory, which guarantees both stability of the cancer cell dynamics as well as boundedness of the network weights. From simulation studies, this adaptive control design approach is found to be very effective to treat the CML disease for realistic patients. Sufficient generality is retained in the mathematical developments so that the technique can be applied to other similar nonlinear control design problems as well.

Design and analysis of ARROW-based racetrack resonator vibration sensor for inertial navigation application

In this paper we propose and analyze a novel racetrack resonator based vibration sensor for inertial grade application. The resonator is formed with an Anti Resonance Reflecting Optical Waveguide (ARROW) structure which offers the advantage of low loss and single mode propagation. The waveguide is designed to operate at 1310nm and TM mode of propagation since the Photo-elastic co-efficient is larger than TE mode in a SiO2/ Si3N4/ SiO2. The longer side of the resonator is placed over a cantilever beam with a proof mass. A single bus waveguide is coupled to the resonator structure. When the beam vibrates the resonator arm at the foot of the cantilever experiences maximum stress. Due to opto-mechanical coupling the effective refractive index of the resonator changes hence the resonance wavelength shifts. The non uniform cantilever beam has a dimension of 1.75mm X 0.45mm X 0.020mm and the proof mass has a dimension of 3mm X 3mm X 0.380mm. The proof mass lowers the natural frequency of vibration to 410Hz, hence designed for inertial navigation application. The operating band of frequency is from DC to 100Hz and acceleration of less than 1g. The resonator has a Free Spectral Range (FSR) of 893pm and produces a phase change of 22.4mrad/g.

Design of mechanism-based inhibitors of transthyretin amyloidosis:Studies with biphenyl ethers and new structural templates

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.

MAC design for heterogeneous application support in OFDM based wireless systems

With the increasing adoption of wireless technology, it is reasonable to expect an increase in file demand for supporting both real-time multimedia and high rate reliable data services. Next generation wireless systems employ Orthogonal Frequency Division Multiplexing (OFDM) physical layer owing, to the high data rate transmissions that are possible without increase in bandwidth. Towards improving file performance of these systems, we look at the design of resource allocation algorithms at medium-access layer, and their impact on higher layers. While TCP-based clastic traffic needs reliable transport, UDP-based real-time applications have stringent delay and rate requirements. The MAC algorithms while catering to the heterogeneous service needs of these higher layers, tradeoff between maximizing the system capacity and providing fairness among users. The novelly of this work is the proposal of various channel-aware resource allocation algorithms at the MAC layer. which call result in significant performance gains in an OFDM based wireless system.

Target reliability based design optimization of anchored cantilever sheet pile walls

In this study, the stability of anchored cantilever sheet pile wall in sandy soils is investigated using reliability analysis. Targeted stability is formulated as an optimization problem in the framework of an inverse first order reliability method. A sensitivity analysis is conducted to investigate the effect of parameters influencing the stability of sheet pile wall. Backfill soil properties, soil - steel pile interface friction angle, depth of the water table from the top of the sheet pile wall, total depth of embedment below the dredge line, yield strength of steel, section modulus of steel sheet pile, and anchor pull are all treated as random variables. The sheet pile wall system is modeled as a series of failure mode combination. Penetration depth, anchor pull, and section modulus are calculated for various target component and system reliability indices based on three limit states. These are: rotational failure about the position of the anchor rod, expressed in terms of moment ratio; sliding failure mode, expressed in terms of force ratio; and flexural failure of the steel sheet pile wall, expressed in terms of the section modulus ratio. An attempt is made to propose reliability based design charts considering the failure criteria as well as the variability in the parameters. The results of the study are compared with studies in the literature.

Design of mechanism-based inhibitors of transthyretin amyloidosis: Studies with biphenyl ethers and new structural templates

Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (> 90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.

Enhancing Physics Education in the National Defence University : A design based research approach in the production of learning material

This research is connected with an education development project for the four-year-long officer education program at the National Defence University. In this curriculum physics was studied in two alternative course plans namely scientific and general. Observations connected to the later one e.g. student feedback and learning outcome gave indications that action was needed to support the course. The reform work was focused on the production of aligned course related instructional material. The learning material project produced a customized textbook set for the students of the general basic physics course. The research adapts phases that are typical in Design Based Research (DBR). The research analyses the feature requirements for physics textbook aimed at a specific sector and frames supporting instructional material development, and summarizes the experiences gained in the learning material project when the selected frames have been applied. The quality of instructional material is an essential part of qualified teaching. The goal of instructional material customization is to increase the product's customer centric nature and to enhance its function as a support media for the learning process. Textbooks are still one of the core elements in physics teaching. The idea of a textbook will remain but the form and appearance may change according to the prevailing technology. The work deals with substance connected frames (demands of a physics textbook according to the PER-viewpoint, quality thinking in educational material development), frames of university pedagogy and instructional material production processes. A wide knowledge and understanding of different frames are useful in development work, if they are to be utilized to aid inspiration without limiting new reasoning and new kinds of models. Applying customization even in the frame utilization supports creative and situation aware design and diminishes the gap between theory and practice. Generally, physics teachers produce their own supplementary instructional material. Even though customization thinking is not unknown the threshold to produce an entire textbook might be high. Even though the observations here are from the general physics course at the NDU, the research gives tools also for development in other discipline related educational contexts. This research is an example of an instructional material development work together the questions it uncovers, and presents thoughts when textbook customization is rewarding. At the same time, the research aims to further creative customization thinking in instruction and development. Key words: Physics textbook, PER (Physics Education Research), Instructional quality, Customization, Creativity

Equivalent constitutive model-based design of wave-absorbing material system and controller

A design methodology for wave-absorbing active material system is reported. The design enforces equivalence between an assumed material model having wave-absorbing behavior and a set of target feedback controllers for an array of microelectro-mechanical transducers which are integral part of the active material system. The proposed methodology is applicable to problems involving the control of acoustic waves in passive-active material system with complex constitutive behavior at different length-scales. A stress relaxation type one-dimensional constitutive model involving viscous damping mechanism is considered, which shows asymmetric wave dispersion characteristics about the half-line. The acoustic power flow and asymptotic stability of such material system are studied. A single sensor non-collocated linear feedback control system in a one-dimensional finite waveguide, which is a representative volume element in an active material system, is considered. Equivalence between the exact dynamic equilibrium of these two systems is imposed. It results in the solution space of the design variables, namely the equivalent damping coefficient, the wavelength(s) to be controlled and the location of the sensor. The characteristics of the controller transfer functions and their pole-placement problem are studied. (c) 2005 Elsevier Ltd. All rights reserved.

Optimum Design for External Seismic Stability of Geosynthetic Reinforced Soil Walls: Reliability Based Approach

In this paper, an analytical study considering the effect of uncertainties in the seismic analysis of geosynthetic-reinforced soil (GRS) walls is presented. Using limit equilibrium method and assuming sliding wedge failure mechanism, analysis is conducted to evaluate the external stability of GRS walls when subjected to earthquake loads. Target reliability based approach is used to estimate the probability of failure in three modes of failure, viz., sliding, bearing, and eccentricity failure. The properties of reinforced backfill, retained backfill, foundation soil, and geosynthetic reinforcement are treated as random variables. In addition, the uncertainties associated with horizontal seismic acceleration and surcharge load acting on the wall are considered. The optimum length of reinforcement needed to maintain the stability against three modes of failure by targeting various component and system reliability indices is obtained. Studies have also been made to study the influence of various parameters on the seismic stability in three failure modes. The results are compared with those given by first-order second moment method and Monte Carlo simulation methods. In the illustrative example, external stability of the two walls, Gould and Valencia walls, subjected to Northridge earthquake is reexamined.

Dual-Drug Delivery System Based on In Situ Gel-Forming Nanosuspension of Forskolin to Enhance Antiglaucoma Efficacy

The present study was designed to improve the bioavailability of forskolin by the influence of precorneal residence time and dissolution characteristics. Nanosizing is an advanced approach to overcome the issue of poor aqueous solubility of active pharmaceutical ingredients. Forskolin nanocrystals have been successfully manufactured and stabilized by poloxamer 407. These nanocrystals have been characterized in terms of particle size by scanning electron microscopy and dynamic light scattering. By formulating Noveon AA-1 polycarbophil/poloxamer 407 platforms, at specific concentrations, it was possible to obtain a pH and thermoreversible gel with a pH(gel)/T-gel close to eye pH/temperature. The addition of forskolin nanocrystals did not alter the gelation properties of Noveon AA-1 polycarbophil/poloxamer 407 and nanocrystal properties of forskolin. The formulation was stable over a period of 6 months at room temperature. In vitro release experiments indicated that the optimized platform was able to prolong and control forskolin release for more than 5 h. The in vivo studies on dexamethasone-induced glaucomatous rabbits indicated that the intraocular pressure lowering efficacy for nanosuspension/hydrogel systems was 31% and lasted for 12 h, which is significantly better than the effect of traditional eye suspension (18%, 4-6 h). Hence, our investigations successfully prove that the pH and thermoreversible polymeric in situ gel-forming nanosuspension with ability of controlled drug release exhibits a greater potential for glaucoma therapy.

Optimum Design for External Seismic Stability of Geosynthetic Reinforced Soil Walls: Reliability Based Approach

In this paper, an analytical study considering the effect of uncertainties in the seismic analysis of geosynthetic-reinforced soil (GRS) walls is presented. Using limit equilibrium method and assuming sliding wedge failure mechanism, analysis is conducted to evaluate the external stability of GRS walls when subjected to earthquake loads. Target reliability based approach is used to estimate the probability of failure in three modes of failure, viz., sliding, bearing, and eccentricity failure. The properties of reinforced backfill, retained backfill, foundation soil, and geosynthetic reinforcement are treated as random variables. In addition, the uncertainties associated with horizontal seismic acceleration and surcharge load acting on the wall are considered. The optimum length of reinforcement needed to maintain the stability against three modes of failure by targeting various component and system reliability indices is obtained. Studies have also been made to study the influence of various parameters on the seismic stability in three failure modes. The results are compared with those given by first-order second moment method and Monte Carlo simulation methods. In the illustrative example, external stability of the two walls, Gould and Valencia walls, subjected to Northridge earthquake is reexamined.