A carboxy terminal domain of the L protein of rinderpest virus possesses RNA triphosphatase activity - The first enzyme in the viral mRNA capping pathway

The large protein L of negative-sense RNA viruses is a multifunctional protein involved in transcription and replication of genomic RNA. It also possesses enzymatic activities involved in capping and methylation of viral mRNAs. The pathway for mRNA capping followed by the L protein of the viruses in the Morbillivirus genus has not been established, although it has been speculated that these viruses may follow the unconventional capping pathway as has been shown for some viruses of Rhabdoviridae family. We had earlier shown that the large protein L of Rinderpest virus expressed as recombinant L-P complex in insect cells as well as the ribonucleoprotein complex from purified virus possesses RNA triphosphatase (RTPase) and guanylyltransferase activities, in addition to RNA dependent RNA polymerase activity. In the present work, we demonstrate that RTPase as well as nucleoside triphosphatase (NTPase) activities are exhibited by a subdomain of the L protein in the C terminal region (a.a. 1640 1840). The RTPase activity depends absolutely on a divalent cation, either magnesium or manganese. Both the RTPase and NTPase activities of the protein show dual metal specificity. Two mutant proteins having alanine mutations in the glutamic acid residues in motif-A of the RTPase domain did not show RTPase activity, while exhibiting reduced NTPase activity suggesting overlapping active sites for the two enzymatic functions. The RTPase and NTPase activities of the L subdomain resemble those of the Vaccinia capping enzyme D1 and the baculovirus LEF4 proteins. (C) 2015 Elsevier Inc. All rights reserved.

Stability analysis of thick piezoelectric metal based FGM plate using first order and higher order shear deformation theory

This paper presents the stability analysis of functionally graded plate integrated with piezoelectric actuator and sensor at the top and bottom face, subjected to electrical and mechanical loading. The finite element formulation is based on first order and higher order shear deformation theory, degenerated shell element, von-Karman hypothesis and piezoelectric effect. The equation for static analysis is derived by using the minimum energy principle and solutions for critical buckling load is obtained by solving eigenvalue problem. The material properties of the functionally graded plate are assumed to be graded along the thickness direction according to simple power law function. Two types of boundary conditions are used, such as SSSS (simply supported) and CSCS (simply supported along two opposite side perpendicular to the direction of compression and clamped along the other two sides). Sensor voltage is calculated using present analysis for various power law indices and FG (functionally graded) material gradations. The stability analysis of piezoelectric FG plate is carried out to present the effects of power law index, material variations, applied mechanical pressure and piezo effect on buckling and stability characteristics of FG plate.

Multiwavelength features of Fermi bubbles as signatures of a Galactic wind

Using hydrodynamical simulations, we show for the first time that an episode of star formation in the centre of the Milky Way, with a star formation rate (SFR) similar to 0.5 M-circle dot yr(-1) for similar to 30 Myr, can produce bubbles that resemble the Fermi bubbles (FBs), when viewed from the solar position. The morphology, extent and multiwavelength observations of FBs, especially X-rays, constrain various physical parameters such as SFR, age, and the circumgalactic medium (CGM) density. We show that the interaction of the CGM with the Galactic wind driven by star formation in the central region can explain the observed surface brightness and morphological features of X-rays associated with the FBs. Furthermore, assuming that cosmic ray electrons are accelerated in situ by shocks and/or turbulence, the brightness and morphology of gamma-ray emission and the microwave haze can be explained. The kinematics of the cold and warm clumps in our model also matches with recent observations of absorption lines through the bubbles.

Systematic Analysis of Mycobacterial Acylation Reveals First Example of Acylation-mediated Regulation of Enzyme Activity of a Bacterial Phosphatase

Protein lysine acetylation is known to regulate multiple aspects of bacterial metabolism. However, its presence in mycobacterial signal transduction and virulence-associated proteins has not been studied. In this study, analysis of mycobacterial proteins from different cellular fractions indicated dynamic and widespread occurrence of lysine acetylation. Mycobacterium tuberculosis proteins regulating diverse physiological processes were then selected and expressed in the surrogate host Mycobacterium smegmatis. The purified proteins were analyzed for the presence of lysine acetylation, leading to the identification of 24 acetylated proteins. In addition, novel lysine succinylation and propionylation events were found to co-occur with acetylation on several proteins. Protein-tyrosine phosphatase B (PtpB), a secretory phosphatase that regulates phosphorylation of host proteins and plays a critical role in Mycobacterium infection, is modified by acetylation and succinylation at Lys-224. This residue is situated in a lid region that covers the enzyme's active site. Consequently, acetylation and succinylation negatively regulate the activity of PtpB.

1D Tight-Binding Models Render Quantum First Passage Time ``Speakable''

The calculation of First Passage Time (moreover, even its probability density in time) has so far been generally viewed as an ill-posed problem in the domain of quantum mechanics. The reasons can be summarily seen in the fact that the quantum probabilities in general do not satisfy the Kolmogorov sum rule: the probabilities for entering and non-entering of Feynman paths into a given region of space-time do not in general add up to unity, much owing to the interference of alternative paths. In the present work, it is pointed out that a special case exists (within quantum framework), in which, by design, there exists one and only one available path (i.e., door-way) to mediate the (first) passage -no alternative path to interfere with. Further, it is identified that a popular family of quantum systems - namely the 1d tight binding Hamiltonian systems - falls under this special category. For these model quantum systems, the first passage time distributions are obtained analytically by suitably applying a method originally devised for classical (stochastic) mechanics (by Schroedinger in 1915). This result is interesting especially given the fact that the tight binding models are extensively used in describing everyday phenomena in condense matter physics.

First Structural View of a Peptide Interacting with the Nucleotide Binding Domain of Heat Shock Protein 90

The involvement of Hsp90 in progression of diseases like cancer, neurological disorders and several pathogen related conditions is well established. Hsp90, therefore, has emerged as an attractive drug target for many of these diseases. Several small molecule inhibitors of Hsp90, such as geldanamycin derivatives, that display antitumor activity, have been developed and are under clinical trials. However, none of these tested inhibitors or drugs are peptide-based compounds. Here we report the first crystal structure of a peptide bound at the ATP binding site of the N-terminal domain of Hsp90. The peptide makes several specific interactions with the binding site residues, which are comparable to those made by the nucleotide and geldanamycin. A modified peptide was designed based on these interactions. Inhibition of ATPase activity of Hsp90 was observed in the presence of the modified peptide. This study provides an alternative approach and a lead peptide molecule for the rational design of effective inhibitors of Hsp90 function.

First principles DFT investigation Of Yttrium-decorated Boron-Nitride Nanotube: Electronic Structure and Hydrogen Storage

The electronic structure and hydrogen storage capability of Yttrium-doped BNNTs has been theoretically investigated using first principles density functional theory (DFT). Yttrium atom prefers the hollow site in the center of the hexagonal ring with a binding energy of 0.8048eV. Decorating by Y makes the system half-metallic and magnetic with a magnetic moment of 1.0 mu(B). Y decorated Boron-Nitride (8,0) nanotube can adsorb up to five hydrogen molecules whose average binding energy is computed as 0.5044eV. All the hydrogen molecules are adsorbed with an average desorption temperature of 644.708 K. Taking that the Y atoms can be placed only in alternate hexagons, the implied wt% comes out to be 5.31%, a relatively acceptable value for hydrogen storage materials. Thus, this system can serve as potential hydrogen storage medium.

First-in-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M-tuberculosis

Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters. Here, we establish a first functional HTS platform for identification of APS reductase (APSR) inhibitors, a critical enzyme in the assimilation of sulfate for the biosynthesis of cysteine and other essential sulfur-containing molecules. Our HTS campaign involving 38?350 compounds led to the discovery of three distinct structural classes of APSR inhibitors. A class of bioactive compounds with known pharmacology displayed potent bactericidal activity in wild-type Mtb as well as MDR and XDR clinical isolates. Top compounds showed markedly diminished potency in a conditional Delta APSR mutant, which could be restored by complementation with Mtb APSR. Furthermore, ITC studies on representative compounds provided evidence for direct engagement of the APSR target. Finally, potent APSR inhibitors significantly decreased the cellular levels of key reduced sulfur-containing metabolites and also induced an oxidative shift in mycothiol redox potential of live Mtb, thus providing functional validation of our screening data. In summary, we have identified first-in-class inhibitors of APSR that can serve as molecular probes in unraveling the links between Mtb persistence, antibiotic tolerance, and sulfate assimilation, in addition to their potential therapeutic value.

High temperature thermoelectric properties of Zr and Hf based transition metal dichalcogenides: A first principles study

We investigate the electronic and thermal transport properties of bulk MX2 compounds (M = Zr, Hf and X = S, Se) by first-principles calculations and semi-classical Boltzmann transport theory. The band structure shows the confinement of heavy and light bands along the out of plane and in-plane directions, respectively. This results in high electrical conductivity (sigma) and large thermopower leading to a high power factor (S-2 sigma) for moderate n-type doping. The phonon dispersion demonstrates low frequency flat acoustical modes, which results in low group velocities (v(g)). Consequently, lowering the lattice thermal conductivity (kappa(latt)) below 2 W/m K. Low kappa(latt) combined with high power factor results in ZT > 0.8 for all the bulk MX2 compounds at high temperature of 1200 K. In particular, the ZT(max) of HfSe2 exceeds 1 at 1400 K. Our results show that Hf/Zr based dichalcogenides are very promising for high temperature thermoelectric application. (C) 2015 AIP Publishing LLC.

Optimal bounded control of first-passage failure of quasi-integrable Hamiltonian systems with wide-band random excitation

The optimal bounded control of quasi-integrable Hamiltonian systems with wide-band random excitation for minimizing their first-passage failure is investigated. First, a stochastic averaging method for multi-degrees-of-freedom (MDOF) strongly nonlinear quasi-integrable Hamiltonian systems with wide-band stationary random excitations using generalized harmonic functions is proposed. Then, the dynamical programming equations and their associated boundary and final time conditions for the control problems of maximizinig reliability and maximizing mean first-passage time are formulated based on the averaged It$\ddot{\rm o}$ equations by applying the dynamical programming principle. The optimal control law is derived from the dynamical programming equations and control constraints. The relationship between the dynamical programming equations and the backward Kolmogorov equation for the conditional reliability function and the Pontryagin equation for the conditional mean first-passage time of optimally controlled system is discussed. Finally, the conditional reliability function, the conditional probability density and mean of first-passage time of an optimally controlled system are obtained by solving the backward Kolmogorov equation and Pontryagin equation. The application of the proposed procedure and effectiveness of control strategy are illustrated with an example.

First human hNT neurons patterned on parylene-C/silicon dioxide substrates: Combining an accessible cell line and robust patterning technology for the study of the pathological adult human brain

In this communication, we describe a new method which has enabled the first patterning of human neurons (derived from the human teratocarcinoma cell line (hNT)) on parylene-C/silicon dioxide substrates. We reveal the details of the nanofabrication processes, cell differentiation and culturing protocols necessary to successfully pattern hNT neurons which are each key aspects of this new method. The benefits in patterning human neurons on silicon chip using an accessible cell line and robust patterning technology are of widespread value. Thus, using a combined technology such as this will facilitate the detailed study of the pathological human brain at both the single cell and network level. © 2010 Elsevier B.V.

First demonstration on the non-transparency of FWM and its application of 40 Gbit/s all-optical CSRZ-to-RZ format conversion

We report first experimental demonstration on the non-transparent characteristic of FWM using NRZ-DPSK, RZ-DPSK, CSRZ-DPSK, and CSRZ signals. One potential non-transparency application of 40Gbit/s CSRZ-to-RZ format conversion is experimentally demonstrated. © 2008 IEEE.

First-passage failure and its feedback minimization of quasi-partially integrable Hamiltonian systems

An n degree-of-freedom Hamiltonian system with r (1¡r¡n) independent 0rst integrals which are in involution is calledpartially integrable Hamiltonian system. A partially integrable Hamiltonian system subject to light dampings andweak stochastic excitations is called quasi-partially integrable Hamiltonian system. In the present paper, the procedures for studying the 0rst-passage failure and its feedback minimization of quasi-partially integrable Hamiltonian systems are proposed. First, the stochastic averaging methodfor quasi-partially integrable Hamiltonian systems is brie4y reviewed. Then, basedon the averagedIt ˆo equations, a backwardKolmogorov equation governing the conditional reliability function, a set of generalized Pontryagin equations governing the conditional moments of 0rst-passage time and their boundary and initial conditions are established. After that, the dynamical programming equations and their associated boundary and 0nal time conditions for the control problems of maximization of reliability andof maximization of mean 0rst-passage time are formulated. The relationship between the backwardKolmogorov equation andthe dynamical programming equation for reliability maximization, andthat between the Pontryagin equation andthe dynamical programming equation for maximization of mean 0rst-passage time are discussed. Finally, an example is worked out to illustrate the proposed procedures and the e9ectiveness of feedback control in reducing 0rst-passage failure.

Fuesse paral Papa et contól la sua fazienda : la escritura ejemplar del viaje en el Conde Lucanor

Resumen: Tomando como precepto la idea de que el motivo del viaje sirve de elemento organizador de la materia narrativa en textos como los Cuentos del papagayo, Canterbury Tales o Las mil y una noches, el autor se propone analizar la estructura de El conde Lucanor a la luz del mencionado motivo. El viaje aparece explicitado en el primero y en el último de los relatos, a los que se suma el exemplo XXV, episodio central en el diálogo entre el conde y su ayo. Su análisis lo llevará a develar en los restantes exemplos que este motivo central sirve de nexo de unión entre cada cuento, organiza la trama general en forma de episodios y configura distintos tipos de viajes: escatológico, de ultratumba, iniciático, alegórico, celestial o fantástico. El viaje se ofrece, así, como instrumento portador de sentido, de forma y de estructura en la trama general del marco y, en particular, de cada episodio.

The “Centre for Child Protection” of the Gregorian University/Rome. First experiences, results and reflections in setting up a global e-learning-program for the prevention of sexual abuse of minors

Resumen: El Centro para la Protección Infantil ha sido fundado en cooperación con el Instituto de Psicología de la Universidad Gregoriana (Roma, Italia), el Departamento para la Psiquiatría/Psicoterapia Infantil y Adolescente del Hospital de la Universidad de Ulm (Alemania) y la Arquidiócesis de Múnich (Alemania). Su tarea principal es la creación de un centro global de entrenamiento e-learning para profesiones de pastoral que respondan al abuso sexual de los menores, tomando en consideración asuntos multilingüísticos e interculturales. Dentro de tres años el Centro desarrollado e implementado un programa e-learning en cuatro lenguas. Ocho socios del proyecto internacional asumen un papel en el reclutamiento de participantes y en la evaluación en curso del programa. En esta fase, personas-test son incluidas en el desarrollo y la evaluación del programa, como parte de la formación (en curso) de sacerdotes y de otros coagentes de pastoral