Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

Final Evaluation Memorandum: Strategies for Resolving Low Dissolved Oxygen and Methylmercury Events in Northern Suisun Marsh

The purpose of the project is to improve our understanding about best management practices that can be utilized on diked managed wetlands in Suisun Marsh for reducing the occurrence of low dissolved oxygen (DO) and high methylmercury (MeHg) events associated primarily with fall flood-up practices. Low DO events are of concern because they can lead to undue stress and even mortality of sensitive aquatic organisms. Elevated MeHg levels are of concern because MeHg is a neurotoxin that bio-magnifies up the food chain and can cause deleterious effects to higher trophic level consumers such as piscivorous fish, birds, and mammals (including humans). This study involved two years (2007-2008) of intensive field data collection at two managed wetland sites in northwest Suisun Marsh and their surrounding tidal sloughs, an area with prior documented low DO events. In addition, the study collected limited soils and water quality field data and mapped vegetation for three managed wetland sites in the central interior of Suisun Marsh, for the purpose of examining whether wetlands at other locations exhibit characteristics that could indicate potential for similar concerns. In Year 1 of the study, the objective was to identify the baseline conditions in the managed wetlands and determine which physical management conditions could be modified for Year 2 to reduce low DO and MeHg production issues most effectively. The objective of Year 2 was to evaluate the effectiveness of these modified management actions at reducing production of low DO and elevated MeHg conditions within the managed wetlands and to continue improving understanding of the underlying biogeochemical processes at play. This Final Evaluation Memorandum examined a total of 19 BMPs, 14 involving modified water management operations and the remaining five involving modified soil and vegetation management practices. Some of these BMPs were previously employed and others have not yet been tested. For each BMP this report assesses its efficacy in improving water quality conditions and potential conflicts with wetland management. It makes recommendations for further study (either feasibility assessments or field testing) and whether to consider for future use. Certain previously used BMPs were found to be important contributors to poor water quality conditions and their continued use is not recommended. Some BMPs that could improve water quality conditions appear difficult to implement in regards to compatibility with wetland management; these BMPs require further elaboration and feasibility assessment to determine whether they should be field tested. In practice for any given wetland, there is likely a combination of BMPs that would together have the greatest potential to address the low DO and high MeHg water quality concerns. Consequently, this report makes no sweeping recommendations applicable to large groups of wetlands but instead promotes a careful consideration of factors at each wetland or small groups of wetlands and from that assessment to apply the most effective suite of BMPs. This report also identifies a number of recommended future actions and studies. These recommendations are geared toward improving the process understanding of factors that promote low DO and high MeHg conditions, the extent of these problems in Suisun Marsh, the regulatory basis for the DO standards for a large estuarine marsh, the economics of BMPs, and alternative approaches to BMPs on diked managed wetlands that may address the water quality issues. The most important of these recommendations is that future BMP implementation should be carried out within the context of rigorous scientific evaluation so as to gain the maximum improvement in how to manage these water quality issues in the diked managed wetlands of Suisun Marsh.

A querela do declínio do simbólico: perspextivas e impasses do pensamento de Slavoj iek

Esse estudo tem por objetivo principal analisar as reflexões do filósofo e psicanalista teórico esloveno Slavoj iek acerca dos impactos subjetivos das transformações normativas ocorridas no Ocidente nos últimos cinqüenta anos. O problema do chamado declínio do Simbólico passou a ser amplamente discutido pela comunidade de psicanalistas lacanianos na qual se insere o filósofo a partir do final da década de 1990, o que constituiu uma inovação em um campo fortemente influenciado pela concepção estruturalista da subjetividade. Situando o autor como pioneiro na utilização de ferramentas conceituais lacanianas para a análise do social, o estudo divide-se em duas partes. Na primeira delas, exponho as bases teóricas do pensamento de iek, contextualizando o seu itinerário intelectual e político, e abordando as suas três linhas fundamentais de investigação: a filosofia política, a discussão sobre o ato ético e a ontologia do sujeito. Assim, o primeiro capítulo retraça o percurso que vai dos primeiros estudos sobre o funcionamento ideológico nos regimes totalitários à abordagem pop filosófica da ideologia na atualidade. Em seguida, apresento a sua redescrição da noção de comunismo à luz da tese dos novos antagonismos do capitalismo tardio. Por fim, trato da perspectiva universalista do filósofo a partir de sua leitura materialista do cristianismo, lançando mão sobretudo dos estudos de Alain Badiou sobre São Paulo. No segundo capítulo, delineamos as coordenadas centrais da concepção de sujeito em iek, cuja originalidade reside na articulação das formulações de Lacan e Hegel. As noções de grande Outro, objeto pequeno a, pulsão de morte e negatividade são tomadas como os pilares nos quais se assenta a descrição do sujeito iekiano. Na segunda parte do estudo, examinamos as teses de iek a respeito das relações entre subjetividade e cultura, com ênfase nos novos impasses que daí decorrem. As inibições que sucedem à injunção de gozar sem entraves, a melancolização do laço social, as metamorfoses da culpa, a vitimologia e a culpabilização do Outro são os tópicos centrais que sobressaem desse recorte. Nessa parte do trabalho, as reflexões de iek são cotejadas com as análises de autores de orientação lacaniana, considerados representativos desse tipo de discussão, como Jean-Pierre Lebrun, Charles Melman, Dany-Robert Dufour e Roland Chemama. Pretende-se com isso enriquecer a discussão, apontando as aproximações e distâncias que o pensamento de iek entretém com os referidos autores. O capítulo final do trabalho é consagrado ao exame crítico da démarche iekiana acerca do declínio do Simbólico. Dois tópicos de seu discurso são analisados, a saber: a) seu posicionamento ambivalente no que tange à crítica do catastrofismo; b) seu esforço de expurgar da noção de ato ético na qual ele quer encontrar saídas para os embaraços engendrados pelo dito declínio do Simbólico qualquer traço de pertencimento à tradição moral judaico-cristã, guardando dessa tradição apenas o exemplo do aspecto formal do ato. Para empreender tal exame, nos servimos, de um lado, do estudo crítico do sociólogo francês Alain Ehrenberg sobre a declinologia noção por ele cunhada para se referir ao conjunto de estudos que enfatizam o atual risco da dissolução dos laços sociais , e de outro lado, nos apoiamos na concepção de ética do filósofo neo-pragmatista Richard Rorty.

Plastic Analysis and Testing of multidirectional SFRC flag slabs

This paper presents a theoretical and experimental study of multidirectional steel fibers reinforced concrete slabs (SFRC). The study is based on a real building application using SFRC flag slabs. For the evaluation of the slabs bearing capacity, plastic calculations are performed both at section and structure levels. The section analysis uses the perfect plastic stress-strain diagram, with reference to the values of the strength characteristics of SFRC based on previous jobs that used similar fibers and dosages. In the structure analysis the plastic yield lines method has been used. This method relates the section last bearing moment and the plastic collapse load. The experimental campaign has consisted of the testing of six 2 m. diameter circular shaped slabs prototypes, and has allowed to verify the reference resistance used in the calculations.

外差干涉仪混频误差分析

共光路外差干涉仪具有很高的分辨率．但因为安装、调试误差会产生非线性误差．影响系统的测量精度。着重分析了在共光路外差干涉仪中由激光光源的椭圆偏振化和沃拉斯顿棱镜的安装方位角误差同时存在的情况下，引起的频率混叠综合误差的大小及变化规律。结果发现其造成的非线性误差可达2．2nm，同时还发现两者造成的误差在某些情况下存在一定程度的相互抵消作用。讨论了提高测量系统精度的有效措施，对正确设计和调试激光外差测试系统、提高测量系统精度具有重要意义。