Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease

Half a century ago, chronic granulomatous disease (CGD) was first described as a disease fatally affecting the ability of children to survive infections. Various milestone discoveries have since been made, from an insufficient ability of patients' leucocytes to kill microbes to the underlying genetic abnormalities. In this inherited disorder, phagocytes lack NADPH oxidase activity and do not generate reactive oxygen species, most notably superoxide anion, causing recurrent bacterial and fungal infections. Patients with CGD also suffer from chronic inflammatory conditions, most prominently granuloma formation in hollow viscera. The precise mechanisms of the increased microbial pathogenicity have been unclear, and more so the reasons for the exaggerated inflammatory response. Here we show that a superoxide-dependent step in tryptophan metabolism along the kynurenine pathway is blocked in CGD mice with lethal pulmonary aspergillosis, leading to unrestrained Vgamma1(+) gammadelta T-cell reactivity, dominant production of interleukin (IL)-17, defective regulatory T-cell activity and acute inflammatory lung injury. Although beneficial effects are induced by IL-17 neutralization or gammadelta T-cell contraction, complete cure and reversal of the hyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal to the blockade in the pathway. Effective therapy, which includes co-administration of recombinant interferon-gamma (IFN-gamma), restores production of downstream immunoactive metabolites and enables the emergence of regulatory Vgamma4(+) gammadelta and Foxp3(+) alphabeta T cells. Therefore, paradoxically, the lack of reactive oxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidase deficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet, this condition can be reverted by reactivating the pathway downstream of the superoxide-dependent step.     

DNA repair is limiting for haematopoietic stem cells during ageing

Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of ageing. Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique mouse strain with a hypomorphic Lig4(Y288C) mutation. The Lig4(Y288C) mouse, identified by means of a mutagenesis screening programme, is a mouse model for human LIG4 syndrome, showing immunodeficiency and growth retardation. Diminished DNA double-strand break repair in the Lig4(Y288C) strain causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during ageing, and severely impairs stem cell function in tissue culture and transplantation. The sensitivity of haematopoietic stem cells to non-homologous end-joining deficiency is therefore a key determinant of their ability to maintain themselves against physiological stress over time and to withstand culture and transplantation.     

RNA-Induced immunity against a rat sarcoma

Resumen Se estudió el efecto del ARN proveniente del bazo de ratas inmunizadas a un sarcoma transplantable (Sarcoma E 100) en el crecimiento del mismo. Se inyectó ARN normal y ARN de ratas inmunizadas a dos grupos de animales 5 días antes de la implantación del tumor, tomándose un tercer grupo como testigo normal. Los animales que recibieron el ARN inmune tuvieron tumores más pequeños que los de los dos testigos (p < 0.01), a los 30 días después del injerto. Se formula la hipótesis de que el ARN inmune posee la información (memoria inmunológica) para transformar una respuesta inmunitaria primaria en secundaria.

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This work was supported in part by a grant from the Consejo Nacional de Investigaciones Cientificas y Técnicas.     

A Mere Shadow of an Institution: the Unhappy Story of the Portuguese Geological Survey (PGS) in the Period Between the Two World Wars

In the period between the two World Wars, the Portuguese Geological Survey (Serviços Geológicos de Portugal: PGS) was legally dependent on the General Directorate of Mines and Geological Survey (Direcção Geral de Minas e Serviços Geológicos: GDMGS). Portugal was then living through troubled times, and the PGS struggled with financial problems and a lack of technical personnel. This situation did not allow the PGS to work properly as a scientific institution, and achieve its main function: the making and publication of geological maps and research papers.     

Conversion of Rapid Prototyping Models into Metallic Tools by Ceramic Moulding—an Indirect Rapid Tooling Process

A process to convert models made by rapid prototypi ng techniques like SL (stereolitography) and LOM (laminated object manufacturing) or by conventional techniques (silicones, resins, wax, etc.) into metallic mould s or tools has been developed. The main purpose of this technique is to rapidly obtain the first prototypes of parts, for plastics injection, forging or any oth er manufacturing process using the tools produced by casting a metal into a cera mic mould. Briefly, it can be said that the ceramic...     

A genetically humanized mouse model for hepatitis C virus infection

Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.     

术语和翻译①

文章从专业翻译角度讨论了翻译和术语的关系,分析译者面临的术语问题以及解决这类问题最合适的策略和资源。在此基础上,提出译者在术语工作上不同程度的参与方式。