Crystal structures and binding studies of atovaquone and its derivatives with cytochrome bc(1): a molecular basis for drug design

Crystal structure of trans-atovaquone (antimalarial drug), its polymorph and its stereoisomer (cis) along with five other derivatives with different functional groups have been analyzed. Based on the conformational features of these compounds and the characteristics of the nature of intermolecular interactions, valuable insights into the atomistic details of protein-inhibitor interactions have been derived by docking studies. Atovaquone and its derivatives pack in the crystal lattice using intermolecular O-H center dot center dot center dot O hydrogen bond dimer motifs supported by surrogate weak interactions including C-H center dot center dot center dot O and C-H center dot center dot center dot Cl hydrogen bonds. The docking results of these molecules with cytochrome bc(1) show preferences to form N-H center dot center dot center dot O, O-H center dot center dot center dot O and O-H center dot center dot center dot Cl hydrogen bonds. The involvement of halogen atoms in the binding pocket appears to be significant and is contrary to the theoretically predicted mechanism of protein-ligand docking reported earlier based on mimicking experimental binding results of stigmatellin with cytochrome bc(1). The significance of subtle energy factors controlled by weak intermolecular interactions appears to play a major role in drug binding.

Case for multiple views of function in design based on a common definition

Functions are important in designing. However, several issues hinder progress with the understanding and usage of functions: lack of a clear and overarching definition of function, lack of overall justifications for the inevitability of the multiple views of function, and scarcity of systematic attempts to relate these views with one another. To help resolve these, the objectives of this research are to propose a common definition of function that underlies the multiple views in literature and to identify and validate the views of function that are logically justified to be present in designing. Function is defined as a change intended by designers between two scenarios: before and after the introduction of the design. A framework is proposed that comprises the above definition of function and an empirically validated model of designing, extended generate, evaluate, modify, and select of state-change, and an action, part, phenomenon, input, organ, and effect model of causality (Known as GEMS of SAPPhIRE), comprising the views of activity, outcome, requirement-solution-information, and system-environment. The framework is used to identify the logically possible views of function in the context of designing and is validated by comparing these with the views of function in the literature. Describing the different views of function using the proposed framework should enable comparisons and determine relationships among the various views, leading to better understanding and usage of functions in designing.

The design of polyaniline based sensor for the qualitative estimation of malonaldehyde

The detection of contaminated food in every stage of processing required new technology for fast identification and isolation of toxicity in food. Since effect of food contaminant are severe to human health, the need of pioneer technologies also increasing over last few decades. In the current study, MDA was prepared by hydrolysis of 1,1,3,3-tetramethoxypropane in HCl media and used in the electrochemical studies. The electrochemical sensor was fabricated with modified glassy carbon electrode with polyaniline. These sensors were used for detection of sodium salt of malonaldehyde and observed that a high sensitivity in the concentration range similar to 1 x 10(-1) M and 1 x 10(-2) M. Tafel plots show the variation of over potential from -1.73 V to -3.74 V up to 10(-5) mol/L indicating the lower limit of detection of the system. (C) 2013 Elsevier Ltd. All rights reserved.

Design and development of Fiber Bragg Grating sensing plate for plantar strain measurement and postural stability analysis

This paper describes an ab initio design and development of a novel Fiber Bragg Grating (FBG) sensor based strain sensing plate for the measurement of plantar strain distribution in human foot. The primary aim of this work is to study the feasibility of usage of FBG sensors in the measurement of plantar strain in the foot; in particular, to spatially resolve the strain distribution in the foot at different regions such as fore-foot, mid-foot and hind-foot. This study also provides a method to quantify and compare relative postural stability of different subjects under test; in addition, traditional accelerometers have been used to record the movements of center of gravity (second lumbar vertebra) of the subject and the results obtained have been compared against the outcome of the postural stability studies undertaken using the developed FBG plantar strain sensing plate. (C) 2013 Elsevier Ltd. All rights reserved.

Development of design charts for stress intensity factors at tips of multi-site cracks in unstiffened curved panels

Multi-site damage need to be addressed and evaluated in order to assess the integrity of aging aircraft structures. One of the problems recognized in the recent times is the effect of interaction between two or more cracks in the close neighborhood in such structures. The present paper deals with such a problem and presents numerical estimates of stress intensity factors at a crack tip in an un-stiffened curved panel with a secondary crack in the vicinity of a primary crack. The results are presented in the form of design charts. These results should be useful in evaluation in the damage tolerance evaluation of aircraft structures with multi-site damage. (C) 2014 Elsevier Ltd. All rights reserved.

Design and synthesis of new low band gap organic semiconductors for photovoltaic applications

Donor-acceptor (D-A) conjugated polymers have attracted a good deal of attention in recent years. In D-A systems, the introduction of electron withdrawing groups reduces E-g by lowering the LUMO levels whereas, the introduction of electron donating groups reduces E-g by raising the HOMO levels. Also, conjugated polymers with desired HOMO and LUMO energy levels could be obtained by the proper selection of donor and acceptor units. Because of this reason, D-A conjugated polymers are emerging as promising materials particularly for polymer light emitting diodes (PLEDs) and polymer solar cells (PSCs). We report the design and synthesis of four new narrow band gap donor-acceptor (D-A) conjugated polymers, PTCNN, PTCNF, PTCNV and PTCNO, containing electron donating 3,4-didodecyloxythiophene and electron accepting cyanovinylene units. The effects of further addition of electron donating and electron withdrawing groups to the repeating unit of a D-A conjugated polymer (PTCNN) on its optical and electrochemical properties are discussed. The studies revealed that the nature of D and A units as well as the extent of alternate D-A structure influences the optical and the electrochemical properties of the polymers. All the polymers are thermally stable up to a temperature of 300 degrees C under nitrogen atmosphere. The electrochemical studies revealed that the polymers possess low-lying HOMO energy levels and low-lying LUMO energy levels. In the UV-Vis absorption study, the polymer films displayed broad absorption in the wavelength region of 400-700 nm. The polymers exhibited low optical band gaps in the range 1.70 - 1.77 eV.

Use of side-chain for rational design of n-type diketopyrrolopyrrole-based conjugated polymers: what did we find out?

The primary role of substituted side chains in organic semiconductors is to increase their solubility in common organic solvents. In the recent past, many literature reports have suggested that the side chains play a critical role in molecular packing and strongly impact the charge transport properties of conjugated polymers. In this work, we have investigated the influence of side-chains on the charge transport behavior of a novel class of diketopyrrolopyrrole (DPP) based alternating copolymers. To investigate the role of side-chains, we prepared four diketopyrrolopyrrole-diketopyrrolopyrrole (DPP-DPP) conjugated polymers with varied side-chains and carried out a systematic study of thin film microstructure and charge transport properties in polymer thin-film transistors (PTFTs). Combining results obtained from grazing incidence X-ray diffraction (GIXD) and charge transport properties in PTFTs, we conclude side-chains have a strong influence on molecular packing, thin film microstructure, and the charge carrier mobility of DPP-DPP copolymers. However, the influence of side-chains on optical properties was moderate. The preferential ``edge-on'' packing and dominant n-channel behavior with exceptionally high field-effect electron mobility values of >1 cm(2) V-1 s(-1) were observed by incorporating hydrophilic (triethylene glycol) and hydrophobic side-chains of alternate DPP units. In contrast moderate electron and hole mobilities were observed by incorporation of branched hydrophobic side-chains. This work clearly demonstrates that the subtle balance between hydrophobicity and hydrophilicity induced by side-chains is a powerful strategy to alter the molecular packing and improve the ambipolar charge transport properties in DPP-DPP based conjugated polymers. Theoretical analysis supports the conclusion that the side-chains influence polymer properties through morphology changes, as there is no effect on the electronic properties in the gas phase. The exceptional electron mobility is at least partially a result of the strong intramolecular conjugation of the donor and acceptor as evidenced by the unusually wide conduction band of the polymer.

Design and Synthesis of New Benzimidazole-Carbazole Conjugates for the Stabilization of Human Telomeric DNA, Telomerase Inhibition, and Their Selective Action on Cancer Cells

Cell-permeable small molecules that enhance the stability of the G-quadruplex (G4) DNA structures are currently among the most intensively pursued ligands for inhibition of the telomerase activity. Herein we report the design and syntheses of four novel benzimidazole carbazole conjugates and demonstrate their high binding affinity to G4 DNA. Si nuclease assay confirmed the ligand mediated G-quadruplex DNA protection. Additional evidence from Telomeric Repeat Amplification Protocol (TRAP-LIG) assay demonstrated efficient telomerase inhibition activity by the ligands. Two of the ligands showed IC50 values in the sub-micromolar range in the TRAP-LIG assay, which are the best among the benzimidazole derivatives reported so far. The ligands also exhibited cancer cell selective nuclear internalization, nuclear condensation, fragmentation, and eventually antiproliferative activity in long-term cell viability assays. Annexin V-FITC/PI staining assays confirm that the cell death induced by the ligands follows an apoptotic pathway. An insight into the mode of ligand binding was obtained from the molecular dynamics simulations.

Design and Development of Thermoelectric Generator

In this paper we discuss the fabrication, working and characteristics of a thermoelectric generator made up of p and n type semiconductor materials. The device consists of Fe0.2Co3.8Sb11.5Te0.5 (zT = 1.04 at 818 K) as the n-type and Zn4Sb3 (zT= 0.8 at 550 K) as the p-type material synthesized by vacuum hot press method. Carbon paste has been used to join the semiconductor legs to metal (Molybdenum) electrodes to reduce the contact resistance. The multi-couple (4 legs) generator results a maximum output power of 1.083 mW at a temperature difference of 240 K between the hot and cold sides. In this investigation, an I-V characteristic, maximum output power of the thermoelectric module is presented. The efficiency of thermoelectric module is obtained as eta= 0.273 %.

Immunogen design for HIV-1 and influenza

Vaccines provide the most cost effective defense against pathogens. Although vaccines have been designed for a number of viral diseases, a vaccine against HIV-1 still remains elusive. In contrast while there are excellent influenza vaccines, these need to be changed every few years because of antigenic drift and shift The recent discovery of a large number of broadly neutralizing antibodies (bNAbs) and structural characterization of the conserved epitopes targeted by them presents an opportunity for structure based HIV-1 and influenza A vaccine design. We discuss strategies to design immunogens either targeting a particular antigenic region or focusing on native structure stabilization. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody. (C) 2014 Elsevier B.V. All rights reserved.

Design, Development and Calibration of HTS Wire Based LOX Level Sensor Probe

For space applications, the weight of the liquid level sensors are of major concern as they affect the payload fraction and hence the cost. An attempt is made to design and test a light weight High Temperature Superconductor (HTS) wire based liquid level sensor for Liquid Oxygen (LOX) tank used in the cryostage of the spacecraft. The total resistance value measured of the HTS wire is inversely proportional to the liquid level. A HTS wire (SF12100) of 12mm width and 2.76m length without copper stabilizer has been used in the level sensor. The developed HTS wire based LOX level sensor is calibrated against a discrete diode array type level sensor. Liquid Nitrogen (LN2) and LOX has been used as cryogenic fluid for the calibration purpose. The automatic data logging for the system has been done using LabVIEW11. The net weight of the developed sensor is less than 1 kg.

An empirical understanding of use of internal analogies in conceptual design

Internal analogies are created if the knowledge of source domain is obtained only from the cognition of designers. In this paper, an understanding of the use of internal analogies in conceptual design is developed by studying: the types of internal analogies; the roles of internal analogies; the influence of design problems on the creation of internal analogies; the role of experience of designers on the use of internal analogies; the levels of abstraction at which internal analogies are searched in target domain, identified in source domain, and realized in the target domain; and the effect of internal analogies from the natural and artificial domains on the solution space created using these analogies. To facilitate this understanding, empirical studies of design sessions from earlier research, each involving a designer solving a design problem by identifying requirements and developing conceptual solutions, without using any support, are used. The following are the important findings: designers use analogies from the natural and artificial domains; analogies are used for generating requirements and solutions; the nature of the design problem influences the use of analogies; the role of experience of designers on the use of analogies is not clearly ascertained; analogical transfer is observed only at few levels of abstraction while many levels remain unexplored; and analogies from the natural domain seem to have more positive influence than the artificial domain on the number of ideas and variety of idea space.

Hemagglutinin sequence conservation guided stem immunogen design from influenza A H3 subtype

Seasonal epidemics caused by influenza A (H1 and H3 subtypes) and B viruses are a major global health threat. The traditional, trivalent influenza vaccines have limited efficacy because of rapid antigenic evolution of the circulating viruses. This antigenic variability mediates viral escape from the host immune responses, necessitating annual vaccine updates. Influenza vaccines elicit a protective antibody response, primarily targeting the viral surface glycoprotein hemagglutinin (HA). However, the predominant humoral response is against the hypervariable head domain of HA, thereby restricting the breadth of protection. In contrast, the conserved, subdominant stem domain of HA is a potential ``universal'' vaccine candidate. We designed an HA stem-fragment immunogen from the 1968 pandemic H3N2 strain (A/Hong Kong/1/68) guided by a comprehensive H3 HA sequence conservation analysis. The biophysical properties of the designed immunogen were further improved by C-terminal fusion of a trimerization motif, ``isoleucine-zipper'', or ``foldon''. These immunogens elicited cross-reactive, antiviral antibodies and conferred partial protection against a lethal, homologous HK68 virus challenge in vivo. Furthermore, bacterial expression of these immunogens is economical and facilitates rapid scale-up.

Part I: High-Voltage MOS Device Design for Improved Static and RF Performance

In this paper, for the first time, the key design parameters of a shallow trench isolation-based drain-extended MOS transistor are discussed for RF power applications in advanced CMOS technologies. The tradeoff between various dc and RF figures of merit (FoMs) is carefully studied using well-calibrated TCAD simulations. This detailed physical insight is used to optimize the dc and RF behavior, and our work also provides a design window for the improvement of dc as well as RF FoMs, without affecting the breakdown voltage. An improvement of 50% in R-ON and 45% in RF gain is achieved at 1 GHz. Large-signal time-domain analysis is done to explore the output power capability of the device.

Part II: A Fully Integrated RF PA in 28-nm CMOS With Device Design for Optimized Performance and ESD Robustness

In this paper, we report drain-extended MOS device design guidelines for the RF power amplifier (RF PA) applications. A complete RF PA circuit in a 28-nm CMOS technology node with the matching and biasing network is used as a test vehicle to validate the RF performance improvement by a systematic device design. A complete RF PA with 0.16-W/mm power density is reported experimentally. By simultaneous improvement of device-circuit performance, 45% improvement in the circuit RF power gain, 25% improvement in the power-added efficiency at 1-GHz frequency, and 5x improvement in the electrostatic discharge robustness are reported experimentally.