Luteinizing hormone induction of ovarian tumors: Oligogenic differences between mouse strains dictates tumor disposition

The use of fertility drugs has continued to grow since their introduction in the 1960s. Accompanying this increase has been the speculation that repetitive use of these drugs can cause ovarian tumors or cancer. We recently reported that transgenic mice with chronically elevated luteinizing hormone (LH), an analog of which is commonly used in fertility regimens, develop granulosa cell (GC) tumors. In this report we show that LH induction of these tumors is highly dependent on genetic background. In CF-1 mice, chronically elevated LH invariably causes GC tumors by 5 months of age. However, in hybrid mice generated by crossing CF-1 males with C57BL/6, SJL, or CD-1 females, elevated levels of this same hormone cause a completely different phenotype resembling a luteoma of pregnancy. We also show that three genes likely control these alternative hormonal responses. This clinical correlate of elevated LH reveals remarkably distinct, strain-dependent, ovarian phenotypes. In addition, these results support the rare incidence of GC tumors in the human population, and suggest that the ability of certain fertility drugs to cause ovarian tumors may depend on an individual's genetic predisposition.

Lack of a role for transforming growth factor-β in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation

Similarities in the phenotypes of mice deficient for cytotoxic T lymphocyte antigen-4 (CTLA-4) or transforming growth factor-β1 (TGF-β1) and other observations have led to speculation that CTLA-4 mediates its inhibitory effect on T cell activation via costimulation of TGF-β production. Here, we examine the role of TGF-β in CTLA-4-mediated inhibition of T cell activation and of CTLA-4 in the regulation of TGF-β production. Activation of AND TCR transgenic mouse T cells with costimulatory receptor-specific antigen presenting cells results in efficient costimulation of proliferation by CD28 ligation and inhibition by CTLA-4 ligation. Neutralizing antibody to TGF-β does not reverse CTLA-4-mediated inhibition. Also, CTLA-4 ligation equally inhibits proliferation of wild-type, TGF-β1−/−, and Smad3−/− T cells. Further, CTLA-4 engagement does not result in the increased production of either latent or active TGF-β by CD4+ T cells. These results indicate that CTLA-4 ligation does not regulate TGF-β production and that CTLA-4-mediated inhibition can occur independently of TGF-β. Collectively, these data demonstrate that CTLA-4 and TGF-β represent distinct mechanisms for regulation of T cell responses.

Anticoagulant repertoire of the hookworm Ancylostoma caninum.

Hookworms are hematophagous nematodes that infect a wide range of mammalian hosts, including humans. There has been speculation for nearly a century as to the identity of the anticoagulant substances) used by these organisms to subvert host hemostasis. Using molecular cloning, we describe a family of potent small protein (75-84 amino acids) anticoagulants from the hookworm Ancylostoma caninum termed AcAP (A. caninum anticoagulant protein). Two recombinant AcAP members (AcAP5 and AcAP6) directly inhibited the catalytic activity of blood coagulation factor Xa (fXa), while a third form (AcAPc2) predominantly inhibited the catalytic activity of a complex composed of blood coagulation factor VIIa and tissue factor (fVIIa/TF). The inhibition of fVIIa/TF was by a unique mechanism that required the initial formation of a binary complex of the inhibitor with fXa at a site on the enzyme that is distinct from the catalytic center (exo-site). The sequence of AcAPc2 as well as the utilization of an exo-site on fXa distinguishes this inhibitor from the mammalian anticoagulant TFPI (tissue factor pathway inhibitor), which is functionally equivalent with respect to fXa-dependent inhibition of fIIa/TF. The relative sequence positions of the reactive site residues determined for AcAP5 with the homologous regions in AcAP6 and AcAPc2 as well as the pattern of 10 cysteine residues present in each of the inhibitors suggest that the AcAPs are distantly related to the family of small protein serine protease inhibitors found in the nonhematophagous nematode Ascaris lumbricoides var. suum.

Involvement of cytochrome P450 in oxime production in glucosinolate biosynthesis as demonstrated by an in vitro microsomal enzyme system isolated from jasmonic acid-induced seedlings of Sinapis alba L.

An in vitro enzyme system for the conversion of amino acid to oxime in the biosynthesis of glucosinolates has been established by the combined use of an improved isolation medium and jasmonic acid-induced etiolated seedlings of Sinapis alba L. An 8-fold induction of de novo biosynthesis of the L-tyrosine-derived p-hydroxybenzylglucosinolate was obtained in etiolated S. alba seedlings upon treatment with jasmonic acid. Formation of inhibitory glucosinolate degradation products upon tissue homogenization was prevented by inactivation of myrosinase by addition of 100 mM ascorbic acid to the isolation buffer. The biosynthetically active microsomal enzyme system converted L-tyrosine into p-hydroxyphenylacetaldoxime and the production of oxime was strictly dependent on NADPH. The Km and Vmax values of the enzyme system were 346 microM and 538 pmol per mg of protein per h, respectively. The nature of the enzyme catalyzing the conversion of amino acid to oxime in the biosynthesis of glucosinolates has been subject of much speculation. In the present paper, we demonstrate the involvement of cytochrome P450 by photoreversible inhibition by carbon monoxide. The inhibitory effect of numerous cytochrome P450 inhibitors confirms the involvement of cytochrome P450. This provides experimental documentation of similarity between the enzymes converting amino acids into the corresponding oximes in the biosynthesis of glucosinolates and cyanogenic glycosides.

Modulation of c-Myb-induced transcription activation by a phosphorylation site near the negative regulatory domain.

The c-myb protooncogene encodes a highly conserved transcription factor that functions as both an activator and a repressor of transcription. The v-myb oncogenes of E26 leukemia virus and avian myeloblastosis virus encode proteins that are truncated at both the amino and the carboxyl terminus, deleting portions of the c-Myb DNA-binding and negative regulatory domains. This has led to speculation that the deleted regions contain important regulatory sequences. We previously reported that the 42-kDa mitogen-activated protein kinase (p42mapk) phosphorylates chicken and murine c-Myb at multiple sites in the negative regulatory domain in vitro, suggesting that phosphorylation might provide a mechanism to regulate c-Myb function. We now report that three tryptic phosphopeptides derived from in vitro phosphorylated c-Myb comigrate with three tryptic phosphopeptides derived from metabolically labeled c-Myb immunoprecipitated from murine erythroleukemia cells. At least two of these peptides are phosphorylated on serine-528. Replacement of serine-528 with alanine results in a 2- to 7-fold increase in the ability of c-Myb to transactivate a Myb-responsive promoter/reporter gene construct. These findings suggest that phosphorylation serves to regulate c-Myb activity and that loss of this phosphorylation site from the v-Myb proteins may contribute to their transforming potential.

Análise da composição, abundância e distribuição da comunidade fitoplanctônica nos reservatórios do sistema em cascata do Médio e Baixo rio Tietê/SP

Com a finalidade de atender a demanda energética, muitos reservatórios foram construídos no Brasil e, notadamente na região Sudeste, as construções das barragens não somente atenderam aos usos múltiplos (geração de energia, irrigação, lazer e abastecimento público), como também foram elementos propulsores da economia regional, contribuindo para a expansão das atividades industriais e rurais, bem como, um desordenado crescimento urbano. Em conseqüência da falta de planejamento, áreas naturais foram desmatadas, sendo substituídas por formas de plantio inadequadas e por projetos de especulação imobiliária não condizentes com a sustentabilidade ambiental. No decorrer das últimas décadas, os impactos aumentaram em magnitude e extensão, ocasionando sérios problemas aos recursos hídricos, culminando em conflitos pelo uso da água. Dentro deste contexto, destaca-se o rio Tietê, o qual percorre importantes cidades e extensas áreas rurais no Estado de São Paulo, sendo que, neste longo percurso, recebe a contribuição de diversos tributários (poluídos ou não) e efluentes urbanos, industriais e aqueles derivados de fontes não pontuais, além do processo de fragmentação que foi instalado a partir da construção de inúmeras barragens. De forma conjunta, todos os fatores promoveram alterações significativas no sistema e, procurando avaliar a situação atual dos reservatórios, desenvolveu-se uma pesquisa direcionada à análise da composição, densidade e distribuição da comunidade fitoplanctônica e sua relação com as variáveis limnológicas, climatológicas e hidrodinâmicas dos reservatórios da Barra Bonita, Bariri, Ibitinga, Promissão, Nova Avanhandava, Três Irmãos, além dos rios Tietê e Piracicaba e parte do rio Paraná (reservatório de Jupiá e a Jusante do reservatório de Ilha Solteira). Para tanto, foram realizadas coletas nos meses de fevereiro, maio, julho e outubro de 2000 e os resultados obtidos demonstram uma elevada concentração de nutrientes, com redução na seqüência dos reservatórios, além da variabilidade temporal, com efeito significativo da precipitação no transporte de materiais, promovendo alterações no estado trófico de cada sistema. A disponibilidade de nutrientes, transparência da água, vazão e tempo de residência, associados aos fatores climatológicos, foram elementos importantes no estabelecimento das populações, influenciando a composição, densidade e distribuição da comunidade fitoplanctônica, a qual apresentou maior dominância das classes Cyanophyceae e Chlorophyceae, com maior contribuição em densidade e riqueza de espécies, respectivamente.

Human Rights in the Democratic People's Republic of Korea and the Future of the Troubled State after Kim Jong-Il

Since 2008, international speculation about the viability of Kim Jong-Il's leadership in North Korea has been at the forefront of diplomatic discussions. North Korea is known to be a secretive state where human rights violations abound. This paper discusses the history of leadership and government in North Korea since World War II, the current human rights situation in the country, the role of China, and potential successors to Kim Jong-Il. The ramifications of impending regime change are discussed in terms of North Korea's human rights issues and economic problems. While current efforts at diplomacy have proved ineffective, the need for concerned nations, intergovernmental organizations, and non-governmental organizations to be prepared to engage North Korea after Kim Jong-Il is imperative.

Corn Liberalization in Mexico: The Effects of Neoliberal Policies on Campesino Food Security

Mexico has a long history of structuralized violence against its most vulnerable socioeconomic strata, the peasantry, also referred to as Campesinos. From the Spanish invasion, to the contemporary neoliberal development project, corn production has been intimately associated with disparate power relations both within Mexican society, and without, particularly in relations with the United States. This study sheds light on the incongruities of modernism implicit within neoliberal policy instruments such as Structural Adjustment Programs (SAP) and free trade agreements. It will demonstrate that while such policies benefit some, they principally exacerbate existing power disparities via disarticulated trade economics, subordinating rather than liberating Mexico's most vulnerable citizenry.

La arquitectura de la Obra Sindical del Hogar en la ciudad de Albacete: 1941-1981

En este estudio se presenta y analiza, proyectándola en su contexto, la producción de vivienda protegida acometida por la Obra Sindical del Hogar en la ciudad de Albacete, desde la creación de este organismo hasta su disolución, es decir, a lo largo de la dictadura franquista. La investigación viene, por un lado, a llenar el vacío que, en la bibliografía de referencia, existía, habida cuenta de que se trata de una arquitectura en su mayoría modesta, generalmente mal conservada, periférica y, en ocasiones, injustamente marginada que apenas ha interesado ni a los eruditos ni a los críticos. Por otro lado, el trabajo se alinea con el interés disciplinar que, desde hace ya bastante tiempo, despierta en el panorama nacional la vivienda social, tema clave tanto en el quehacer profesional de los arquitectos como en el conocimiento del devenir de la historia de la arquitectura moderna española y sus relaciones, intercambios e influencias con el ámbito internacional. Así, se estudian y documentan seis promociones que abarcan desde la escala del barrio (Barrio Hogar Nacional Sindicalista, al oeste del casco urbano), hasta la actuación puntual en un solar (Gabriel Ciscar, al norte), pasando por actuaciones que juegan con varios bloques y su composición (grupos San Juan Bautista, Emperador Carlos V o Lope de Vega, al sur), culminando con la construcción de un nuevo barrio (Hermanos Falcó), al dictado tanto de los aires que respira el urbanismo europeo (1ª fase), como de la entrega sin reservas a la especulación inmobiliaria (2ª fase, no realizada).

Letters from William Tudor to Thomas Handasyd Perkins,

Four letters on topics including the capture of an American ship, the General Carrington, at Callao, Peru, and the loss and damage incurred; the movements of Simón Bolívar and the state of the conflicts with Spain; the impact of the war on trade, with details on prices and speculation in goods like foodstuffs and domestic quicksilver; and the "deteriorating" condition of American merchant seamen.

Letter from William Tudor to Thomas Handasyd Perkins,

One letter in which Tudor writes of his relief at the acquittal of his brother-in-law Charles Stewart at a court martial. He also discusses speculation and trade, his shares in silver mines at Bella Vista and Chanca, Peru, and the political climate. He additionally references his role in planning the monument at Bunker Hill in Charlestown, writing, "I had something to do in originating and preparing the way for the Bunker Hill monunument, a truly patriotic object, which I believed was a proper way to excite public enthusiasm."

Letter from John Belknap to William Tudor,

One letter in which Belknap declines Tudor’s offer to partner in business speculation.

Letters from Strobel & Martini to William Tudor,

Four letters regarding prices current, the impact of tensions between England and France on speculation, and market demands for items like cocoa, cochineal, and codfish.

The Financialization of Food: An Inquiry into the 2008-2011 Food Price Spikes

This dissertation investigates the question: has financial speculation contributed to global food price volatility since the mid 2000s? I problematize the mainstream academic literature on the 2008-2011 food price spikes as being dominated by neoclassical economic perspectives and offer new conceptual and empirical insights into the relationship between financial speculation and food. Presented in three journal style manuscripts, manuscript one uses circuits of capital to conceptualize the link between financial speculators in the global north and populations in the global south. Manuscript two argues that what makes commodity index speculation (aka ‘index funds’ or index swaps) novel is that it provides institutional investors with what Clapp (2014) calls “financial distance” from the biopolitical implications of food speculation. Finally, manuscript three combines Gramsci’s concepts of hegemony and ‘the intellectual’ with the concept of performativity to investigate the ideological role that public intellectuals and the rhetorical actor the market play in the proliferation and governance of commodity index speculation. The first two manuscripts take an empirically mixed method approach by combining regression analysis with discourse analysis, while the third relies on interview data and discourse analysis. The findings show that financial speculation by index swap dealers and hedge funds did indeed significantly contribute to the price volatility of food commodities between June 2006 and December 2014. The results from the interview data affirm these findings. The discourse analysis of the interview data shows that public intellectuals and rhetorical characters such as ‘the market’ play powerful roles in shaping how food speculation is promoted, regulated and normalized. The significance of the findings is three-fold. First, the empirical findings show that a link does exist between financial speculation and food price volatility. Second, the findings indicate that the post-2008 CFTC and the Dodd-Frank reforms are unlikely to reduce financial speculation or the price volatility that it causes. Third, the findings suggest that institutional investors (such as pension funds) should think critically about how they use commodity index speculation as a way of generating financial earnings.

A importância da liberdade na correspomdência entre Gottfried Leibniz e Samuel Clarke, 1717/1716: análise temática da totalidade da polémica

A presente dissertação tem como objetivo analisar tematicamente a polémica de 1715/16 entre Leibniz e Clarke, não apenas, como é usual, no âmbito das conceções do espaço e do tempo, mas no conjunto dos seus temas metafísicos, teológicos, gnosiológicos e físicos. Na estruturação da dissertação, adquiriu um papel central o confronto dos autores em torno da noção de liberdade, cuja importância é evidente na utilização do princípio da razão suficiente e seus corolários, na distinção entre verdades de razão e verdades de facto, entre os diversos tipos de necessidade, nas conceções alternativas de espaço e de tempo, na alternativa entre átomos e mónadas, na questão dos limites do universo, na relação entre a alma e o corpo, nas teses relativas à providência divina, na forma como se concebe a relação de Deus com a sua máquina, na noção de milagre e nas próprias noções de força e de movimento, pelo menos no que respeita à sua relação com Deus, isto sem desprezar a abordagem direta da própria noção de liberdade. Com este enquadramento, pretende-se mostrar, através de um eloquente exemplo histórico, que as teorias científicas naturais se podem alicerçar em teorias metafísicas e que esses alicerces não têm que se esgotar, mesmo no seio da metafísica, nas questões estritamente cosmológicas, isto para lá de poderem existir influências nunca menosprezáveis de domínios não filosóficos, como é o caso da teologia dogmática. Apesar disto ser evidente na abordagem dos textos, existe uma sistemática menorização contemporânea desta determinação, como se fosse uma idiossincrasia da época ou uma deferência que a ciência tinha de ter numa época ainda obscurecida pela autoridade das igrejas e pela especulação filosófica. Esta abordagem pretende compreender todos os aspetos do pensamento expresso pelos autores na polémica, na sua integralidade, sem reservas de qualquer tipo.