The Role of the Glyoxylate Cycle in the Pathogenesis of Mycobacterium tuberculosis

According to the World Health Organization a third of the world\u27s population is infected with Mycobacterium tuberculosis. The unparalleled success of M. tuberculosis as a pathogen reflects the bacterium\u27s extraordinary ability to persist in its host in spite of eliciting a robust immune response. Currently available treatment is inadequate and drug resistance is rapidly spreading. New antibiotics are desperately needed. The substrates and metabolic pathways utilized by pathogens during infection are largely unknown and represent an under-exploited area of investigation. Uniquely, evolution of the genus Mycobacterium has involved extensive duplication of fatty acid metabolism genes, including two homologs encoding prokaryotic- and eukaryotic-like isoforms of the glyoxylate cycle enzyme isocitrate lyase (ICL). The glyoxylate cycle is employed by cells when fatty acids are the main carbon source available. Here, we show that these enzymes are jointly required by M. tuberculosis for growth on fatty acids and for virulence in experimental infections. Although deletion of icll or icl2 had little impact on replication of M. tuberculosis in macrophages and mice, deletion of both genes abrogated intracellular growth, and resulted in rapid bacterial clearance from the lungs. A dual-specificity ICL inhibitor similarly blocked replication of M. tuberculosis on fatty acids in vitro and in macrophages. The absence of ICL orthologs in mammals, and recent findings implicating the glyoxylate pathway in the virulence of other bacterial and fungal pathogens makes this metabolic pathway an attractive novel target for drug development

Analysis of Two Polyhydroxyalkanoate Synthases in Bradyrhizobium japonicum USDA 110

Bradyrhizobium japonicum USDA 110 has five polyhydroxyalkanoate (PHA) synthases (PhaC) annotated in its genome: bll4360 (phaC1), bll6073 (phaC2), blr3732 (phaC3), blr2885 (phaC4), and bll4548 (phaC5). All these proteins possess the catalytic triad and conserved amino acid residues of polyester synthases and are distributed into four different PhaC classes. We obtained mutants in each of these paralogs and analyzed phaC gene expression and PHA production in liquid cultures. Despite the genetic redundancy, only phaC1 and phaC2 were expressed at significant rates, while PHA accumulation in stationary-phase cultures was impaired only in the phaC1 mutant. Meanwhile, the phaC2 mutant produced more PHA than the wild type under this condition, and surprisingly, the phaC3 transcript increased in the phaC2 background. A double mutant, the phaC2 phaC3 mutant, consistently accumulated less PHA than the phaC2 mutant. PHA accumulation in nodule bacteroids followed a pattern similar to that seen in liquid cultures, being prevented in the phaC1 mutant and increased in the phaC2 mutant in relation to the level in the wild type. Therefore, we used these mutants, together with a phaC1 phaC2 double mutant, to study the B. japonicum PHA requirements for survival, competition for nodulation, and plant growth promotion. All mutants, as well as the wild type, survived for 60 days in a carbon-free medium, regardless of their initial PHA contents. When competing for nodulation against the wild type in a 1:1 proportion, the phaC1 and phaC1 phaC2 mutants occupied only 13 to 15% of the nodules, while the phaC2 mutant occupied 81%, suggesting that the PHA polymer is required for successful competitiveness. However, the bacteroid content of PHA did not affect the shoot dry weight accumulation.Fil: Quelas, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Mongiardini, Elias Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Pérez Giménez, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Parisi, Gustavo Daniel. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lodeiro, Anibal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; Argentin

Debunking prevailing explanations for the emergence of classicality in cosmology

The recent Phys. Rev. D 102, 023512 attempts to justify, from first principles, and within the standard framework, the emergence of classical behavior in the post-inflationary cosmological context. Accounting for this emergence is an important issue, as it underlies the extraordinary empirical success of our current understanding of cosmology. In this work, we offer a critique of this and other efforts at explaining the emergence of classical behavior in cosmology within the standard framework. We argue that such endeavors are generically found lacking in conceptual clarity, as they invariably rely, either upon unjustified, implicit assumptions, or on circular logic. We conclude that, within the standard approach, the emergence of classical behavior in cosmology constitutes an unexplained phenomenon

Understanding the Effects of Legalizing Undocumented Immigrants

This paper investigates the consequences of the legalization of around 600,000 immigrants by the unexpectedly elected Spanish government of Zapatero following the terrorist attacks of March 2004 (Garcia-Montalvo, 2011). Using detailed data from payroll-tax revenues, we estimate that each newly legalized immigrant increased local payroll-tax revenues by 4,189 euros on average. This estimate is only 55 percent of what we would have expected from the size of the influx of newly documented immigrants, which suggests that newly legalized immigrants probably earned lower wages than other workers and maybe affected the labor-market outcomes of those other workers. We estimate that the policy change deteriorated the labor-market outcomes of some low-skilled natives and immigrants and improved the outcomes of high-skilled natives and immigrants. This led some low-skilled immigrants to move away from high-immigrant locations. Correcting for internal migration and selection, we obtain that each newly legalized immigrant increased payroll-tax revenues by 4,801 euros, or 15 percent more than the estimates from local raw payroll-tax revenue data. This shows the importance of looking both at public revenue data and the labor market to understand the consequences of amnesty programs fully

Strengthening agricultural education and training in Sub-Saharan Africa from an innovation systems perspective: Case studies of Ethiopia and Mozambique

"This paper examines the role of postsecondary agricultural education and training (AET) in Sub-Saharan Africa in the context of the region's agricultural innovation systems. Specifically, the paper looks at how AET in Sub-Saharan Africa can contribute to agricultural development by strengthening innovative capabilities, or the ability to introduce new products and processes that are socially or economically relevant to smallholder farmers and other agents in the agricultural sector. Using AET in Ethiopia and Mozambique as case studies, the paper argues that while AET is conventionally viewed in terms of its role in building human and scientific capital, it also has a vital role to play in building the capacity of organizations and individuals to transmit and adapt new applications of existing information, new products and processes, and new organizational cultures and behaviors. The paper emphasizes the importance of improving AET systems by strengthening the innovative capabilities of AET organizations and professionals; changing organizational cultures, behaviors, and incentives; and building innovation networks and linkages. The paper draws on two main sources of information: the emerging literature on innovation systems in developing-country agriculture, and data gathered from secondary sources and semi-structured key informant interviews conducted in Ethiopia and Mozambique in late 2006. The paper offers several recommendations that can contribute to enhancing the effectiveness of AET's contribution to agricultural innovation and development. Key reforms include aligning the mandates of AET organizations with national development aspirations by promoting new educational programs that are more strategically attuned to the different needs of society; inducing change in the cultures of AET organizations through the introduction of educational programs and linkages beyond the formal AET system; and strengthening individual and organizational capacity by improving incentives to forge stronger linkages between AET and diverse user communities, knowledge sources, and private industry." - from authors' abstract.Agricultural education and training, Innovation systems, Sub-Saharan Africa, case studies, Small farmers, agricultural sector,

Procesos determinativos y exploratorios de la gráfica hacia la definición del espacio arquitectónico

La concepción de paisaje que lo define como la construción integral y dialécticamente de los sistemas políticos, históricos, identitarios, productivos, etc. de un territorio, incorporan la valoración de tales dimensiones en la proyección del mismo. Es por ello que la intangibilidad de ciertos fenómenos territoriales o las evidencias mensurables que generan, hacen necesario mecanismos de observación, significación, registro y producción que vuelvan instrumentales. La producción gráfica -en sus distintas mecánicas, expresiones y productos- conforman procesos constitutivos del pensamiento arquitectónico y de especial relevancia en instancias proyectuales. Este resumen propone demostrar el valor de algunas prácticas gráficas desde sus metodologías de producción y acercando la capacidad instrumental de cada una de ellas, los recursos disciplinares que aportan y, finalmente, las articulaciones entre sí y con otras formas del conocimiento-reflexivo en el que operan. Estas cuatro operaciones gráficas son consecutivas y mantienen autonomía procedimental. Cada paso opera con algunos datos de origen a los cuales se le aplican una acción específica que redescubre nuevos resultados devenidos en estados de “conocimientos” que se transfieren de uno a otros. Ellos son: - El armado de fotocomposiciones - La tridimensionalización de la imagen - Las proyecciones diédricas del objeto - Las geometrización de elementos constitutivos Esta secuencia es sólo un fragmento del proceso proyectual ya que aún no posee cualidad arquitectónica Sin embargo busca provocar un estado de exploración del espacio desde las decisiones que se enmarcan en las lógicas de cada instancia. Es un ejercicio deconstructivo de la forma como origen prefigurativo del proyecto.The intangibility of certain territorial phenomena or the measurable evidences that they generate, necessitate mechanisms of observation, significance, recording and production that return instrumental. The graphic production-in its different mechanics, expressions and products-make up processes constitutive of architectural thought and of special relevance in projecting instances. This summary proposes to demonstrate the value of some graphic practices from their production methodologies and by approaching the instrumental capacity of each one of them, the disciplinary resources they provide and, finally, the articulations between themselves and with other forms of the knowledge-reflective in which they operate.Facultad de Arquitectura y Urbanism

Customer delight: perception of hotel spa consumers

Delighted customers are those whose expectations have been exceeded by the service provider. Competitors in the hotel business need to go beyond what is expected in order to satisfy the guest with an unpredictable positive experience. This study was aimed to clarify the significance of customer delight as an antecedent to customer loyalty, in five-star hotel spas in Portugal. To better understand spa consumers’ perception of delight, the development and testing of an integrated model was undertaken by examining the relationship between perceived service quality, customer satisfaction, loyalty and customer delight. The model was tested using surveyed data from 427 spa consumers and validated using partial least squares (PLS) technique. The results indicated that satisfaction had a direct positive effect on customer delight and, consequently, influences the effect of customer delight on customer loyalty.info:eu-repo/semantics/publishedVersio