Oncometabolites: tailoring our genes

Increased glucose metabolism in cancer cells is a phenomenon that has been known for over 90 years, allowing maximal cell growth through faster ATP production and redistribution of carbons towards nucleotide, protein and fatty acid synthesis. Recently, metabolites that can promote tumorigeneis by altering the epigenome have been identified. These ‘oncometabolites’ include the tricarboxylic acid cycle metabolites succinate and fumarate, whose levels are elevated in rare tumours with succinate dehydrogenase and fumarate hydratase mutations, respectively. 2-Hydroxyglutarate is another oncometabolite; it is produced de novo as a result of the mutation of isocitrate dehydrogenase, and is commonly found in gliomas and acute myeloid leukaemia. Interestingly, the structural similarity of these oncometabolites to their precursor metabolite, α-ketoglutarate, explains the tumorigenic potential of these metabolites, by competitive inhibition of a superfamily of enzymes called the α-ketoglutarate-dependent dioxygenases. These enzymes utilize α-ketoglutarate as a cosubstrate, and are involved in fatty acid metabolism, oxygen sensing, collagen biosynthesis, and modulation of the epigenome. They include enzymes that are involved in regulating gene expression via DNA and histone tail demethylation. In this review, we will focus on the link between metabolism and epigenetics, and how we may target oncometabolite-induced tumorigenesis in the future

Metáfora, puesta en escena y público en Calderón

Alejandro Higashi revisa en su artículo los mecanismos desde los cuales un autor como Calderón conseguía escenificar una metáfora y propiciar una sugerente interpretación escénica del texto poético para alentar en el público la construcción del sentido y una comprensión coherente con el tejido histórico. Para lograrlo, Calderón aprovechaba las herramientas del lenguaje, de la representación y los recursos textuales y escénicos

Effects of Dissipation Energy on Vibrational and Sound Energy Flow

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La carta y el papel en la comedia de capa y espada de Calderón: género, enredo y suspenso

En el presente artículo, estudio la función de la carta y el papel en las comedias de capa y espada de Calderón escritas entre 1627 y 1635, con el propósito de mostrar que se trata de un recurso dramático que confiere identidad al género y cuyo estudio panorámico permite advertir un uso que madura y paulatinamente se vuelve más complejo, hasta resultar un eje para la construcción del enredo y del suspenso en obras como No hay burlas con el amor o Con quien vengo, vengo.This article attempts to show the different ways letters and documents are used in Calderon’s cloak and sword plays (1627-1635). The aim is to clarify the contribution of both to a definition of genre and to analyze the use of the letter and the document as a scenic convention that, as will be shown, becomes the principal scenic device which organizes the plot and suspense in plays like No hay burlas como el amor or Con quien vengo, vengo

Vacinas pertussis acelular e pertussis "low": eventos adversos e o papel das mutações

Objective: to discuss the current PAHO recommendation that does not support the substitution of traditional cellular DTP vaccine by acellular DTP, and the role of mutations, in humans, as the main cause of rare adverse events, such as epileptic-like convulsions, triggered by pertussis vaccine. Data review: the main components related to toxic effects of cellular pertussis vaccines are the lipopolysaccharide of bacterial cell wall and pertussis toxin. The removal of part of lipopolysaccharide layer has allowed the creation of a safer cellular pertussis vaccine, with costs comparable to the traditional cellular vaccine, and which may be a substitute for the acellular vaccine. Conclusion: The new methodology introduced by Instituto Butantan allows for the development of a new safer pertussis vaccine with low LPS content (Plow), and the use of the lipopolysaccharide obtained in the process in the production of monophosphoryl lipid A. This component has shown potent adjuvant effect when administered together with influenza inactivated vaccine, making possible to reduce the antigen dose, enhancing the production capacity and lowering costs.Objetivo: Discutir as recomendações da WHO-OPAS que não consideram indicada a substituição da vacina DTP celular clássica pela DTP acelular e o papel de mutações, em humanos, como principal causa dos raros eventos de convulsões epileptiformes desencadeadas pela vacina pertussis. Revisão dos dados: Os principais componentes relacionados aos efeitos tóxicos da vacina pertussis celular são o lipopolissacarídio da parede celular da bactéria e a toxina pertussis. A remoção de parte da camada lipopolissacarídica permitiu a criação de uma vacina pertussis celular, mais segura e de custo comparável ao da vacina celular tradicional, podendo substituir a vacina pertussis acelular. Conclusão: A nova vacina pertussis, com baixo teor de LPS (Plow) desenvolvida pelo Instituto Butantan, além de oferecer uma vacina mais segura, permite o aproveitamento do lipopolissacarídeo para a produção de monofosforil lipídeo A. Esse componente mostrou-se potente como adjuvante e altamente eficiente quando administrado com a vacina de influenza, levando à possibilidade de se reduzir a dose de antígeno, aumentando a capacidade de produção e redução dos custos

Monte carlo simulations of parapatric speciation

Parapatric speciation is studied using an individual--based model with sexual reproduction. We combine the theory of mutation accumulation for biological ageing with an environmental selection pressure that varies according to the individuals geographical positions and phenotypic traits. Fluctuations and genetic diversity of large populations are crucial ingredients to model the features of evolutionary branching and are intrinsic properties of the model. Its implementation on a spatial lattice gives interesting insights into the population dynamics of speciation on a geographical landscape and the disruptive selection that leads to the divergence of phenotypes. Our results suggest that assortative mating is not an obligatory ingredient to obtain speciation in large populations at low gene flow.Comment: submitted to Phys.Rev.

Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-beta and Runx2 in bone is required for hearing

Publisher version: http://www.nature.com/embor/journal/v11/n10/full/embor2010135.htmlDA - 20100917 IS - 1469-3178 (Electronic) IS - 1469-221X (Linking) LA - ENG PT - JOURNAL ARTICLEDA - 20100917 IS - 1469-3178 (Electronic) IS - 1469-221X (Linking) LA - ENG PT - JOURNAL ARTICLEDA - 20100917 IS - 1469-3178 (Electronic) IS - 1469-221X (Linking) LA - ENG PT - JOURNAL ARTICLEPhysical cues, such as extracellular matrix stiffness, direct cell differentiation and support tissue-specific function. Perturbation of these cues underlies diverse pathologies, including osteoarthritis, cardiovascular disease and cancer. However, the molecular mechanisms that establish tissue-specific material properties and link them to healthy tissue function are unknown. We show that Runx2, a key lineage-specific transcription factor, regulates the material properties of bone matrix through the same transforming growth factor-beta (TGFbeta)-responsive pathway that controls osteoblast differentiation. Deregulated TGFbeta or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia. In Runx2(+/-) mice, inhibition of TGFbeta signalling rescues both the material properties of the defective matrix, and hearing. This study elucidates the unknown cause of hearing loss in cleidocranial dysplasia, and demonstrates that a molecular pathway controlling cell differentiation also defines material properties of extracellular matrix. Furthermore, our results suggest that the careful regulation of these properties is essential for healthy tissue functio

Cosmic ray tests of a GEM-based TPC prototype operated in Ar-CF4-isobutane gas mixtures

Argon with an admixture of CF4 is expected to be a good candidate for the gas mixture to be used for a time projection chamber (TPC) in the future linear collider experiment because of its small transverse diffusion of drift electrons especially under a strong magnetic field. In order to confirm the superiority of this gas mixture over conventional TPC gases we carried out cosmic ray tests using a GEM-based TPC operated mostly in Ar-CF4-isobutane mixtures under 0 - 1 T axial magnetic fields. The measured gas properties such as gas gain and transverse diffusion constant as well as the observed spatial resolution are presented.Comment: 22 pages, 18 figures. Published in Nuclear Instruments and Methods in Physics Research A. Fig. 3 in the introduction was corrected since it had not been properly normalized. Minor corrections and no changes in the conclusio