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.

Electromagnetic analysis of novel class of multiple core/multiple clad step index single mode optical fiber by analytical means

General propagation properties and universal curves are given for double clad single mode fibers with inner cladding index higher or lower than the outer cladding index, using the parameter: inner cladding/core radii ratio. Mode cut-off conditions are also examined for the cases. It is shown that dispersion properties largely differ from the single clad single mode fiber case, leading to large new possibilities for extension of single mode operation for large wavelength tange. Paper demonstrates that how substantially we can extend the single mode operation range by using the raised inner cladding fiber. Throughout we have applied our own computations technique to find out the eigenvalue for a given modes. Detail derivations with all trivial mathematics for eigenmode equation are derived for each case. Paper also demonstrates that there is not much use of using depressed inner cladding fiber. We have also concluded that using the large inner cladding/inner core radius we can significantly increase the single mode operation range for the large wavelength region. (C) 2015 Elsevier GmbH. All rights reserved.

Homogeneous Hermitian holomorphic vector bundles and the Cowen-Douglas class over bounded symmetric domains

It is known that all the vector bundles of the title can be obtained by holomorphic induction from representations of a certain parabolic group on finite-dimensional inner product spaces. The representations, and the induced bundles, have composition series with irreducible factors. We write down an equivariant constant coefficient differential operator that intertwines the bundle with the direct sum of its irreducible factors. As an application, we show that in the case of the closed unit ball in C-n all homogeneous n-tuples of Cowen-Douglas operators are similar to direct sums of certain basic n-tuples. (c) 2015 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.

La crónica de la población de Ávila : un estado actual de la cuestión desde su primera publicación

La Crónica de la población de Ávila es un texto de interés para el hispanomedievalismo por diversas razones: se trata del primer texto historiográfico escrito en romance en la península, contiene y da a conocer varios ejemplos de textos de diferentes géneros producidos en la península y muestra con particular nitidez la percepción que tenía de su propia clase un grupo de caballeros villanos. Recién a partir de su primera edición, en 1943, ha empezado a recibir la atención que merece, y la historia de su crítica se encuentra apenas comenzando. Se presenta aquí una revisión de las principales aproximaciones al texto que han aparecido hasta el momento.

Drop migration of middle Reynolds number in a vertical temperature gradient

The experimental investigation of the thermocapillary drop migration in a vertical temperature gradient uns performed on ground. Silicon oil and pure soybean oil were used as experimental medium in drops and as continuous phases, respectively, in the present experiment. The drop migration, under the combined effects of buoyancy: and thermocapillarity, was studied for middle Reynolds numbers in order of magnitude O(10(1)). The drop migration velocities depending on drop diameters were obtained. The present experimental results show relatively small migration velocity in comparison with the one suggested by Young et nl. for linear theory of small Reynolds number. An example of flow patterns inside the drop was observed by PIV method.

A discussion about a class of stress intensity factors and its verification

In this paper, new formulae of a class of stress intensity factors for an infinite plane with two collinear semi-infinite cracks are presented. The formulae differ from those gathered in several handbooks used all over the world. Some experiments and finite element calculations have been developed to verify the new formulae and the results have shown its reliability. Finally, the new formulae and the old are listed to show the differences between them.

Asymptotic solutions to a class of nonlinear oscillation systems

In this paper, we present an asymptotic method for the analysis of a class of strongly nonlinear oscillators, derive second-order approximate solutions to them expressed in terms of their amplitudes and phases, and obtain the equations governing the amplitudes and phases, by which the amplitudes of the corresponding limit cycles and their behaviour can be determined. As an example, we investigate the modified van der Pol oscillator and give the second-order approximate analytical solution of its limit cycle. The comparison with the numerical solutions shows that the two results agree well with each other.

Cruise Report: Spring 2006 Survey of ecological conditions of the U.S. Middle Atlantic Bight NOAA Ship Nancy Foster NF-06-06-NCCOS (May 12 - May 21, 2006)

This cruise report is a summary of a field survey conducted in coastal-ocean waters of the Mid-Atlantic Bight from Nags Head, North Carolina to Cape Cod, Massachusetts and from approximately 1 nautical mile (nm) of shore seaward to the shelf break (100 m). The survey was conducted May 12 - May 21, 2006 on NOAA Ship NANCY FOSTER Cruise NF-06-06-NCCOS. Multiple indicators of ecological condition were sampled synoptically at each of 49 stations throughout the region using a random probabilistic sampling design. Samples were collected for the analysis of benthic community structure and composition; concentrations of chemical contaminants (metals, pesticides, PAHs, PCBs, PBDEs) in sediments and target demersal biota; nutrient and chlorophyll levels in the water column; and other basic habitat characteristics such as depth, salinity, temperature, dissolved oxygen, pH, sediment grain size, and organic carbon content. The overall purpose of the survey was to collect data to assess the status of ecological condition in coastal-ocean waters of the region, based on these various indicators, and to provide this information as a baseline for determining how environmental conditions may be changing with time. The results will be of value in helping to broaden our understanding of the status of ecological resources and their controlling factors, including impacts of potential ecosystem stressors, in such strategic coastal areas. (18pp.) (PDF contains 24 pages)

Fixed Points of Closed and Compact Composite Sequences of Operators and Projectors in a Class of Banach Spaces

Some results on fixed points related to the contractive compositions of bounded operators in a class of complete metric spaces which can be also considered as Banach's spaces are discussed through the paper. The class of composite operators under study can include, in particular, sequences of projection operators under, in general, oblique projective operators. In this paper we are concerned with composite operators which include sequences of pairs of contractive operators involving, in general, oblique projection operators. The results are generalized to sequences of, in general, nonconstant bounded closed operators which can have bounded, closed, and compact limit operators, such that the relevant composite sequences are also compact operators. It is proven that in both cases, Banach contraction principle guarantees the existence of unique fixed points under contractive conditions.

Southend Adult Community College: Walk like an Egyptian - A new reflection

Southend Adult Community College hosts a regular Middle Eastern and Egyptian dance class for all ages and abilities. For a performing art such as dance, learning and self-review aids such as mirrors are essential for improving technique and attainment. The Egyptian Dance course is very popular with many students enrolled. Therefore, sessions need to take place in a large hall within the college. Through inspired innovation and improvisation, the class now have an extremely useful reflective teaching aid using cameras and projectors.

Size and year class composition of catch, age and growth of yellowfin tuna in the Eastern Tropical Pacific Ocean for the years 1954-1958

ENGLISH: Data on the size composition of catch for the years 1954-1958 have been studied to determine year class composition, age and growth of yellowfin tuna in the Eastern Tropical Pacific Ocean. Direct age determination of tropical tunas has not yet proven reliable; however, this analysis has shown that the length-frequency distributions themselves are adequate to determine year class structure and growth rates. Absolute age has been estimated by comparing the average time of spawning with the time at which age groups initially appear in the catch. SPANISH: Los datos sobre la composición del tamaño de la pesca durante los años 1954-1958 han sido estudiados con el objeto de determinar la composición de las clases anuales, la edad y el crecimiento del atún aleta amarilla en el Océano Pacífico Oriental Tropical. Las determinaciones directas de la edad de los atunes tropicales no han probado todavía ser de confianza; sin embargo, este análisis ha demostrado que las distribuciones de la frecuencia de las longitudes son adecuadas para determinar la estructura de las clases anuales y de las tasas de crecimiento. La edad absoluta ha sido estimada mediante la comparación de la época promedio de desove con la epoca en que los grupos de edades comienzan a aparecer en la pesca.

应用力学进展：祝贺郑哲敏先生八十华诞应用力学报告会

    本书为祝贺郑哲敏先生八十华诞的学术报告会的文集，其中收录邀请报告12篇，定向征文58篇。这些论文涉及爆炸力学、岩土力学、冲击力学、材料力学性能、生物力学、物理力学、海洋工程力学、环境流体力学等几大方面，绝大多数为论文作者科研项目的最新成果。

 

 

力学2000

本书收录关于力学领域的论文301篇。内容包括：回顾20世纪力学在中国的发展，描绘了2000年中国和世界在力学各主要领域的发展现状；展望力学在21世纪的发展方向，探论新世纪中可能面临的新的重大力学等问题。