Crystallographic Study of Novel Transthyretin Ligands Exhibiting Negative-Cooperativity between Two Thyroxine Binding Sites

Background: Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports thyroxine (T4) and retinol by binding to retinol binding protein. Rate-limiting tetramer dissociation and rapid monomer misfolding and disassembly of TTR lead to amyloid fibril formation in different tissues causing various amyloid diseases. Based on the current understanding of the pathogenesis of TTR amyloidosis, it is considered that the inhibition of amyloid fibril formation by stabilization of TTR in native tetrameric form is a viable approach for the treatment of TTR amyloidosis. Methodology and Principal Findings: We have examined interactions of the wtTTR with a series of compounds containing various substitutions at biphenyl ether skeleton and a novel compound, previously evaluated for binding and inhibiting tetramer dissociation, by x-ray crystallographic approach. High resolution crystal structures of five ligands in complex with wtTTR provided snapshots of negatively cooperative binding of ligands in two T4 binding sites besides characterizing their binding orientations, conformations, and interactions with binding site residues. In all complexes, the ligand has better fit and more potent interactions in first T4 site i.e. (AC site) than the second T4 site (BD site). Together, these results suggest that AC site is a preferred ligand binding site and retention of ordered water molecules between the dimer interfaces further stabilizes the tetramer by bridging a hydrogen bond interaction between Ser117 and its symmetric copy. Conclusion: Novel biphenyl ether based compounds exhibit negative-cooperativity while binding to two T4 sites which suggests that binding of only single ligand molecule is sufficient to inhibit the TTR tetramer dissociation.

Quantitative interactions between the A-type K+ current and inositol trisphosphate receptors regulate intraneuronal Ca2+ waves and synaptic plasticity

Key points center dot Active calcium signal propagation occurs when an initial calcium trigger elicits calcium release through endoplasmic reticulum (ER) receptors. A high concentration of the calcium trigger in thin-calibre dendrites would suppress release of calcium through hippocampal inositol trisphosphate receptors (InsP3Rs). center dot Could the high-density expression of A-type K+ channels in thin-calibre dendrites be a mechanism for inhibiting this suppression, thereby restoring the utility of the ER as a substrate for active calcium propagation? center dot Quantitative analyses involving experimentally constrained models reveal a bell-shaped dependence of calcium released through InsP3Rs on the A-type K+ channel density, during the propagation of a calcium wave. center dot A-type K+ channels regulated the relative contribution of ER calcium to the induction of synaptic plasticity in the presence of model metabotropic glutamate receptors. center dot These results identify a novel form of interaction between active dendrites and the ER membrane and suggest that A-type K+ channels are ideally placed for inhibiting the suppression of InsP3Rs in thin-calibre dendrites. Abstract The A-type potassium current has been implicated in the regulation of several physiological processes. Here, we explore a role for the A-type potassium current in regulating the release of calcium through inositol trisphosphate receptors (InsP3R) that reside on the endoplasmic reticulum (ER) of hippocampal pyramidal neurons. To do this, we constructed morphologically realistic, conductance-based models equipped with kinetic schemes that govern several calcium signalling modules and pathways, and constrained the distributions and properties of constitutive components by experimental measurements from these neurons. Employing these models, we establish a bell-shaped dependence of calcium release through InsP3Rs on the density ofA-type potassium channels, during the propagation of an intraneuronal calcium wave initiated through established protocols. Exploring the sensitivities of calcium wave initiation and propagation to several underlying parameters, we found that ER calcium release critically depends on dendritic diameter and that wave initiation occurred at branch points as a consequence of a high surface area to volume ratio of oblique dendrites. Furthermore, analogous to the role ofA-type potassium channels in regulating spike latency, we found that an increase in the density ofA-type potassium channels led to increases in the latency and the temporal spread of a propagating calcium wave. Next, we incorporated kinetic models for the metabotropic glutamate receptor (mGluR) signalling components and a calcium-controlled plasticity rule into our model and demonstrate thatthe presence of mGluRs induced a leftward shift in a BienenstockCooperMunro-like synaptic plasticity profile. Finally, we show that the A-type potassium current could regulate the relative contribution of ER calcium to synaptic plasticity induced either through 900 pulses of various stimulus frequencies or through theta burst stimulation. Our results establish a novel form of interaction between active dendrites and the ER membrane, uncovering a powerful mechanism that could regulate biophysical/biochemical signal integration and steer the spatiotemporal spread of signalling microdomains through changes in dendritic excitability.

Exploring novel methods to achieve sensitivity limits for high operating temperature infrared detectors

A review of high operating temperature (HOT) infrared (IR) photon detector technology vis-a-vis material requirements, device design and state of the art achieved is presented in this article. The HOT photon detector concept offers the promise of operation at temperatures above 120 K to near room temperature. Advantages are reduction in system size, weight, cost and increase in system reliability. A theoretical study of the thermal generation-recombination (g-r) processes such as Auger and defect related Shockley Read Hall (SRH) recombination responsible for increasing dark current in HgCdTe detectors is presented. Results of theoretical analysis are used to evaluate performance of long wavelength (LW) and mid wavelength (MW) IR detectors at high operating temperatures. (C) 2013 Elsevier B.V. All rights reserved.

Analytical Closed-Form Expressions for Harmonic Distortion Corresponding to Novel Switching Sequences for Neutral-Point-Clamped Inverters

Analytical closed-form expressions for harmonic distortion factors corresponding to various pulsewidth modulation (PWM) techniques for a two-level inverter have been reported in the literature. This paper derives such analytical closed-form expressions, pertaining to centered space-vector PWM (CSVPWM) and eight different advanced bus-clamping PWM (ABCPWM) schemes, for a three-level neutral-point-clamped (NPC) inverter. These ABCPWM schemes switch each phase at twice the nominal switching frequency in certain intervals of the line cycle while clamping each phase to one of the dc terminals over certain other intervals. The harmonic spectra of the output voltages, corresponding to the eight ABCPWM schemes, are studied and compared experimentally with that of CSVPWM over the entire modulation range. The measured values of weighted total harmonic distortion (WTHD) of the line voltage V-WTHD are used to validate the analytical closed-form expressions derived. The analytical expressions, pertaining to two of the ABCPWM methods, are also validated by measuring the total harmonic distortion (THD) in the line current I-THD on a 2.2-kW constant volts-per-hertz induction motor drive.

Retinoic Acid and Iron Metabolism: A Step Towards Design of a Novel Antitubercular Drug

The scenario of tuberculosis has gone deadly due to its high prevalence and emergence of widespread drug resistance. It is now high time to develop novel antimycobacterial strategies and to understand novel mechanisms of existing antimycobacterial compounds so that we are equipped with newer tuberculosis controlling molecules in the days to come. Iron has proven to be essential for pathogenesis of tuberculosis and retinoic acid is known to influence the iron metabolism pathway. Retenoic acid is also known to exhibit antitubercular effect in in vivo system. Therefore there is every possibility that retinoic acid by affecting the iron metabolism pathway exhibits its antimycobacterial effect. These aspects are reviewed in the present manuscript for understanding the antimycobacterial role of retinoic acid in the context of iron metabolism and other immunological aspects.

Structural, magnetic and electrochemical investigation of novel binary Na2-x(Fe1-yMny)P2O7 (0 <= y <= 1) pyrophosphate compounds for rechargeable sodium-ion batteries

Pyrophosphate cathodes have been recently reported as a competent family of insertion compounds for sodium-ion batteries. In the current study, we have investigated the binary Na2 - x(Fe1 - yMny)P2O7 (0 <= y <= 1) pyrophosphate family, synthesized by the classical solid-state method. They form a continuous solid solution maintaining triclinic P-1 (#2) symmetry. The local structural coordination differs mainly by different degrees of Na site occupancy and preferential occupation of the Fe2 site by Mn. The structural and magnetic properties of these mixed-metal pyrophosphate phases have been studied. In each case, complete Fe3+/Fe2+ redox activity has been obtained centered at 3 V vs. Na. The Fe3+/Fe2+ redox process involves multiple steps between 2.5 and 3 V owing to Na-cation ordering during electrochemical cycling, which merge to form a broad single Fe3+/Fe2+ redox peak upon progressive Mn-doping. (C) 2014 Elsevier B.V. All rights reserved.

A Statistical Model of Current Loops and Magnetic Monopoles

We formulate a natural model of loops and isolated vertices for arbitrary planar graphs, which we call the monopole-dimer model. We show that the partition function of this model can be expressed as a determinant. We then extend the method of Kasteleyn and Temperley-Fisher to calculate the partition function exactly in the case of rectangular grids. This partition function turns out to be a square of a polynomial with positive integer coefficients when the grid lengths are even. Finally, we analyse this formula in the infinite volume limit and show that the local monopole density, free energy and entropy can be expressed in terms of well-known elliptic functions. Our technique is a novel determinantal formula for the partition function of a model of isolated vertices and loops for arbitrary graphs.

Novel Alternative Splice Variants of Mouse Cdk5rap2

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by a pronounced reduction of brain volume and intellectual disability. A current model for the microcephaly phenotype invokes a stem cell proliferation and differentiation defect, which has moved the disease into the spotlight of stem cell biology and neurodevelopmental science. Homozygous mutations of the Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 are one genetic cause of MCPH. To further characterize the pathomechanism underlying MCPH, we generated a conditional Cdk5rap2 LoxP/hCMV Cre mutant mouse. Further analysis, initiated on account of a lack of a microcephaly phenotype in these mutant mice, revealed the presence of previously unknown splice variants of the Cdk5rap2 gene that are at least in part accountable for the lack of microcephaly in the mice.

Designing Novel Sulphate-based Ceramic Materials as Insertion Host Compounds for Secondary Batteries

Rechargeable batteries have propelled the wireless revolution and automobiles market over the past 25 years. Developing better batteries with improved energy density demands unveiling of new cathode ceramic materials with suitable diffusion channels and open framework structure. In this pursuit of achieving higher energy density, one approach is to realize enhanced redox voltage of insertion of ceramic compounds. This can be accomplished by incorporating highly electronegative anions in the cathode ceramics. Building on this idea, recently various sulphate- based compounds have been reported as high voltage cathode materials. The current article highlights the use of sulphate (SO4) based cathodes to realize the highest ever Fe3+/Fe2+ redox potentials in Li-ion batteries (LiFeSO4F fluorosulphate: 3.9V vs Li/Li+) and Na-ion batteries (Na2Fe2(SO4)(3) polysulphate: 3.8V vs Na/Na+). These sulphate-based cathode ceramic compounds pave way for newer avenues to design better batteries for future applications.

A novel, sensitive potentiometric hydrocarbon sensor for high-vacuum applications.

A potentiometric device based on interfacing a solid electrolyte oxygen ion conductor with a thin platinum film acts as a robust, reproducible sensor for the detection of hydrocarbons in high- or ultrahigh-vacuum environments. Sensitivities in the order of approximately 5 x 10(-10) mbar are achievable under open circuit conditions, with good selectivity for discrimination between n-butane on one hand and toluene, n-octane, n-hexane, and 1-butene on the other hand. The sensor's sensitivity may be tuned by operating under constant current (closed circuit) conditions; injection of anodic current is also a very effective means of restoring a clean sensing surface at any desired point. XPS data and potentiometric measurements confirm the proposed mode of sensing action: the steady-state coverage of Oa, which sets the potential of the Pt sensing electrode, is determined by the partial pressure and dissociative sticking probability of the impinging hydrocarbon. The principles established here provide the basis for a viable, inherently flexible, and promising means for the sensitive and selective detection of hydrocarbons under demanding conditions.

Growth and characterization of novel, III-V semiconductor heterostructures

The material presented in this thesis concerns the growth and characterization of III-V semiconductor heterostructures. Studies of the interactions between bound states in coupled quantum wells and between well and barrier bound states in AlAs/GaAs heterostructures are presented. We also demonstrate the broad array of novel tunnel structures realizable in the InAs/GaSb/AlSb material system. Because of the unique broken-gap band alignment of InAs/GaSb these structures involve transport between the conduction- and valence-bands of adjacent layers. These devices possess a wide range of electrical properties and are fundamentally different from conventional AlAs/GaAs tunnel devices. We report on the fabrication of a novel tunnel transistor with the largest reported room temperature current gains. We also present time-resolved studies of the growth fronts of InAs/GainSb strained layer superlattices and investigations of surface anion exchange reactions.

Chapter 2 covers tunneling studies of conventional AlAs/GaAs RTD's. The results of two studies are presented: (i) A test of coherent vs. sequential tunneling in triple barrier heterostructures, (ii) An optical measurement of the effect of barrier X-point states on Γ-point well states. In the first it was found if two quantum wells are separated by a sufficiently thin barrier, then the eigenstates of the system extend coherently across both wells and the central barriers. For thicker barriers between the wells, the electrons become localized in the individual wells and transport is best described by the electrons hopping between the wells. In the second, it was found that Γ-point well states and X-point barrier states interact strongly. The barrier X-point states modify the energies of the well states and increase the escape rate for carriers in the quantum well.

The results of several experimental studies of a novel class of tunnel devices realized in the InAs/GaSb/AlSb material system are presented in Chapter 3. These interband tunnel structures involve transport between conduction- and valence-band states in adjacent material layers. These devices are compared and contrasted with the conventional AlAs/GaAs structures discussed in Chapter 2 and experimental results are presented for both resonant and nonresonant devices. These results are compared with theoretical simulations and necessary extensions to the theoretical models are discussed.

In chapter 4 experimental results from a novel tunnel transistor are reported. The measured current gains in this transistor exceed 100 at room temperature. This is the highest reported gain at room temperature for any tunnel transistor. The device is analyzed and the current conduction and gain mechanisms are discussed.

Chapters 5 and 6 are studies of the growth of structures involving layers with different anions. Chapter 5 covers the growth of InAs/GainSb superlattices for far infrared detectors and time resolved, in-situ studies of their growth fronts. It was found that the bandgap of superlattices with identical layer thicknesses and compositions varied by as much as 40 meV depending on how their internal interfaces are formed. The absorption lengths in superlattices with identical bandgaps but whose interfaces were formed in different ways varied by as much as a factor of two. First the superlattice is discussed including an explanation of the device and the complications involved in its growth. The experimental technique of reflection high energy electron diffraction (RHEED) is reviewed, and the results of RHEED studies of the growth of these complicated structures are presented. The development of a time resolved, in-situ characterization of the internal interfaces of these superlattices is described. Chapter 6 describes the result of a detailed study of some of the phenomena described in chapter 5. X-ray photoelectron spectroscopy (XPS) studies of anion exchange reactions on the growth fronts of these superlattices are reported. Concurrent RHEED studies of the same physical systems studied with XPS are presented. Using the RHEED and XPS results, a real-time, indirect measurement of surface exchange reactions was developed.

The impact of molecular biology on assessment of water quality: advantages and limitations of current techniques

The advent of molecular biology has had a dramatic impact on all aspects of biology, not least applied microbial ecology. Microbiological testing of water has traditionally depended largely on culture techniques. Growing understanding that only a small proportion of microbial species are culturable, and that many microorganisms may attain a viable but non-culturable state, has promoted the development of novel approaches to monitoring pathogens in the environment. This has been paralleled by an increased awareness of the surprising genetic diversity of natural microbial populations. By targeting gene sequences that are specific for particular microorganisms, for example genes that encode diagnostic enzymes, or species-specific domains of conserved genes such as 16S ribosomal RNA coding sequences (rrn genes), the problems of culture can be avoided. Technical developments, notably in the area of in vitro amplification of DNA using the polymerase chain reaction (PCR), now permit routine detection and identification of specific microorganisms, even when present in very low numbers. Although the techniques of molecular biology have provided some very powerful tools for environmental microbiology, it should not be forgotten that these have their own drawbacks and biases in sampling. For example, molecular techniques are dependent on efficient lysis and recovery of nucleic acids from both vegetative forms and spores of microbial species that may differ radically when growing in the laboratory compared with the natural environment. Furthermore, PCR amplification can introduce its own bias depending on the nature of the oligonucleotide primers utilised. However, despite these potential caveats, it seems likely that a molecular biological approach, particularly with its potential for automation, will provide the mainstay of diagnostic technology for the foreseeable future.

Novel Evidence hat Attributing Affectively Salient Signal to Random Noise Is Associated with Psychosis

We wished to replicate evidence that an experimental paradigm of speech illusions is associated with psychotic experiences. Fifty-four patients with a first episode of psychosis (FEP) and 150 healthy subjects were examined in an experimental paradigm assessing the presence of speech illusion in neutral white noise. Socio-demographic, cognitive function and family history data were collected. The Positive and Negative Syndrome Scale (PANSS) was administered in the patient group and the Structured Interview for Schizotypy-Revised (SIS-R), and the Community Assessment of Psychic Experiences (CAPE) in the control group. Patients had a much higher rate of speech illusions (33.3% versus 8.7%, ORadjusted: 5.1, 95% CI: 2.3-11.5), which was only partly explained by differences in IQ (ORadjusted: 3.4, 95% CI: 1.4-8.3). Differences were particularly marked for signals in random noise that were perceived as affectively salient (ORadjusted: 9.7, 95% CI: 1.8-53.9). Speech illusion tended to be associated with positive symptoms in patients (ORadjusted: 3.3, 95% CI: 0.9-11.6), particularly affectively salient illusions (ORadjusted: 8.3, 95% CI: 0.7-100.3). In controls, speech illusions were not associated with positive schizotypy (ORadjusted: 1.1, 95% CI: 0.3-3.4) or self-reported psychotic experiences (ORadjusted: 1.4, 95% CI: 0.4-4.6). Experimental paradigms indexing the tendency to detect affectively salient signals in noise may be used to identify liability to psychosis.

Investigation of the losses in the stator duct spacers of large A.C. motors using the A -ip 3-D eddy current formulation

This paper describes how the A -if) formulation may be applied to determine the losses in the stator duct spacers of large a.c. motors. The model is described in terms of its geometry and boundary conditions. The novel aspects of the application of the formulation to this problem are explained. These include the modelling of fixed currents sources (the stator windings), the location of the necessary cut surfaces and the determination of their magnetic scalar potential differences, and the implementation of periodic boundary conditions for vector variables. Results are presented showing how the duct spacer losses vary with load, and with the relative permeability of the spacer material. The effects of modelling iron nonlinearity, of both the spacer and the steel laminations, are also illustrated. © 1996 IEEE.

Peptidomics and genomics analysis of novel antimicrobial peptides from the frog, Rana nigrovittata

Much attention has been paid on amphibian peptides for their wide-ranging pharmacological properties, clinical potential, and gene-encoded origin. More than 300 antimicrobial peptides (AMPs) from amphibians have been studied. Peptidomics and genomics analysis combined with functional test including microorganism killing, histamine-releasing, and mast cell degranulation was used to investigate antimicrobial peptide diversity. Thirty-four novel AMPs from skin secretions of Rana nigrovittata were identified in current work, and they belong to 9 families, including 6 novel families. Other three families are classified into rugosin, gaegurin, and temporin family of amphibian AMP, respectively. These AMPs share highly conserved preproregions including signal peptides and spacer acidic peptides, while greatly diversified on mature peptides structures. In this work, peptidomics combined with genomics analysis was confirmed to be an effective way to identify amphibian AMPs, especially novel families. Some AMPs reported here will provide leading molecules for designing novel antimicrobial agents. (C) 2009 Elsevier Inc. All rights reserved