Design, synthesis, and biological activity of rhodium metalloinsertors

Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells.

Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle and induction of necrosis, which occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anti-cancer agents.

In addition, ten distinct metalloinsertors with varying lipophilicities are synthesized and their mismatch binding affinities and biological activities studied. While they are found to have similar binding affinities, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments show that all of these metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. Furthermore, metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cytotoxic and antiproliferative activities that are selective for cells deficient in MMR.

To explore further the basis of the unique selectivity of the metlloinsertors in targeting MMR-deficient cells, experiments were conducted using engineered NCI-H23 lung adenocarcinoma cells that contain a doxycycline-inducible shRNA which suppresses the expression of the MMR gene MLH1. Here we use this new cell line to further validate rhodium metalloinsertors as compounds capable of differentially inhibiting the proliferation of MMR-deficient cancer cells over isogenic MMR-proficient cells. General DNA damaging agents, such as cisplatin and etoposide, in contrast, are less effective in the induced cell line defective in MMR.

Finally, we describe a new subclass of metalloinsertors with enhanced potency and selectivity, in which the complexes show Rh-O coordination. In particular, it has been found that both Δ and Λ enantiomers of [Rh(chrysi)(phen)(DPE)]²⁺ bind to DNA with similar affinities, suggesting a possible different binding conformation than previous metalloinsertors. Remarkably, all members of this new family of compounds have significantly increased potency in a range of cellular assays; indeed, all are more potent than the FDA-approved anticancer drugs cisplatin and MNNG. Moreover, these activities are coupled with high levels of selectivity for MMR-deficient cells.

Understanding Public Support for Externality-Correcting Taxes and Subsidies: A Lab Experiment

31 p.

A Previdência Social no estado contemporâneo Fundamentos, financiamento e regulação

A previdência social brasileira, apesar de constituir um dos modelos mais antigos e tradicionais de proteção social da América Latina, não muito distante dos modelos europeus quanto a sua gênese, passa por momentos difíceis. Em um contexto de rápido envelhecimento populacional, acelerada redução de natalidade e novas realidades de trabalho, nas quais a mão-de-obra assalariada perde seu espaço, o modelo tradicional de cobertura, nos moldes bismarckianos, carece de revisão, de forma a não somente adequar-se às novas premissas demográficas, mas permitir uma universalidade de cobertura efetiva. Para tanto, adota-se, como fundamento de um novo modelo, a justiça social em três dimensões necessidade, igualdade e mérito. A necessidade visa atender e assegurar a qualquer pessoa, dentro das necessidades sociais cobertas, um pagamento mínimo de forma a assegurar o mínimo existencial. A dimensão da igualdade, no viés material, visa preservar nível de bem-estar compatível, em alguma medida, com o usufruído durante a vida ativa. Já o mérito individual implica fornecer prestações mais elevadas aos que, conscientemente, reduziram o consumo presente, preservando parte de suas receitas para o futuro. As duas primeiras dimensões são, na proposta apresentada, organizadas pelo Estado, em pilares compulsórios e financiados, preponderantemente, por repartição simples. O modelo de financiamento adotado, no longo prazo, tem se mostrado mais seguro e isonômico frente a modelos capitalizados. As variantes demográficas podem ser adequadas mediante novos limites de idade para aposentadorias e, em especial, estímulo a natalidade, como novos serviços da previdência social, incluindo creches e pré-escolas. O terceiro pilar, fundado no mérito individual, é a previdência complementar, organizado de forma privada, autônoma e voluntária. Aqui, o financiamento sugerido é a capitalização, de forma a priorizar o rendimento e a eficiência, com as externalidades positivas para a economia e a sociedade, com risco assumido e aceitável em razão do papel subsidiário deste pilar protetivo. Os pilares estatais, no modelo proposto, serão financiados, exclusivamente, por impostos, pondo-se fim às contribuições sociais, que perdem a importância em um modelo universal de proteção. Troca-se a solidariedade do grupo pela solidariedade social e, como conseqüência, saem as contribuições e ingressam os impostos. Mesmo o segundo pilar, que visa prestações correlacionadas com os rendimentos em atividade, será financiado por adicional de imposto de renda. Sistema mais simples, eficaz, e com estímulo à formalização da receita por parte das pessoas. A gestão do modelo previdenciário, em todos os segmentos, contará com forte regulação estatal, mas com efetiva participação dos interessados, afastadas, dentro do possível, as ingerências políticas e formas de captura. A regulação previdenciária, desde adequadamente disciplinada e executada, permitirá que os pilares propostos funcionem em harmonia.

O Protocolo de Kyoto e o mercado de crédito de carbono: estudo de caso das emissões de gases de efeito estufa da fábrica de combustível nuclear pertencente às Indústrias Nucleares do Brasil no ano de 2008

A presente dissertação discute as questões relacionadas à intensificação das mudanças climáticas por causas antrópicas conforme a evolução no uso dos recursos naturais, inovações nos processos produtivos, transformações econômicas, sociais, culturais, políticas e, especialmente ambientais. Aborda a comercialização dos créditos de carbono através de projetos de Mecanismo de Desenvolvimento Limpo (MDL), um dos mecanismos de flexibilização criados pelo Protocolo de Kyoto. No contexto de mudanças climáticas, uma matriz energética que utilize fontes de energia que não emitam gases causadores do efeito estufa (GEE) se mostra uma importante estratégia de desenvolvimento sustentável. Sob essa perspectiva, a energia nucleoelétrica é apresentada como uma alternativa viável aos combustíveis fósseis, considerando que esta é uma energia limpa e compatível com a perspectiva de desenvolvimento sustentável. A Fábrica de Combustível Nuclear (FCN), localizada em Resende (Rio de Janeiro), pertencente às Indústrias Nucleares do Brasil (INB), é um conjunto de sofisticadas fábricas nas quais se processam etapas importantes do ciclo do combustível nuclear. Na FCN, o Centro Zoobotânico realiza a gestão das atividades voltadas para a conservação da natureza tais como o Programa de Recuperação de Mata Ciliar, Reflorestamento e Fauna. O Relatório de inventário das emissões diretas e indiretas de GEE da FCN, elaborado pela INB para o ano de 2008, permite a auto-avaliação da empresa, retratando a preocupação corporativa com as questões relativas às mudanças climáticas. Segundo este Relatório, o total de emissões de GEE quantificado corresponde a 12,14% da capacidade total de sequestro de dióxido de carbono, no período de Janeiro a Dezembro de 2008. A proteção de florestas e a plantação de árvores são componentes essenciais de qualquer estratégia global para mitigação da mudança climática, e a participação da INB no mercado de crédito de carbono pode proporcionar externalidades positivas, tais como ganhos de imagem, adequação a padrões ambientais e melhoria do relacionamento com a sociedade.

A Low-level Geographic Information System for coastal zone management, with application to Brunei Darussalam. Part II:: Economic analysis of trawling in Brunei Darussalam

Economic analysis of the trawl fishery of Brunei Darussalam was conducted using cost and returns analysis and based on an economic survey of trawlers and B:RUN, a low-level geographic information system. Profitability indicators were generated for the trawl fleet under various economic and operational scenarios. The results show that financial profits are earned by trawlers which operate off Muara, particularly those with high vessel capacity, and that these profits could be further enhanced. On the other hand, a similar fleet operating off Tutong would generate profits due mainly to high fish biomass. Trawling operations offshore are deemed financially unfeasible. Incorporating realistic opportunity costs and externalities for existing trawl operations off Muara results in economic losses.

O impacto da cláusula de raio nas relações entre o lojista e o empreendedor e seus efeitos no direito da concorrência

A pesquisa analisa a validade da cláusula de raio no aspecto do direito civil-empresarial (privado) e da concorrência (público). No âmbito do direito civil-empresarial analisa-se a cláusula de raio em conjunto com a cláusula de aluguel percentual e possível lesão à boa-fé objetiva. No aspecto do direito da concorrência é analisado o mercado relevante na dimensão produto e geográfica, bem como as externalidades positivas e negativas produzidas pela cláusula de raio. Para a realização da pesquisa adota-se o método dedutivo, realizado a partir de pesquisa bibliográfica e jurisprudencial sobre o tema. Traz como resultado os parâmetros que devem ser utilizados para a análise da cláusula de raio e a hipótese em que ela pode ser prevista.

O princípio da reparação integral à atividade negocial

Neste trabalho estuda-se a aplicação do princípio da reparação integral do dano causado às atividades negociais. Como a teoria da responsabilidade civil está calcada na doutrina liberal clássica, a reparação do dano, muitas vezes, não recebe, por parte da doutrina e da jurisprudência, tratamento adequado às características e vicissitudes do mercado. O objetivo principal é tratar de uma das vertentes que o Direito exerce no seu papel de corretor das chamadas falhas de mercado. Analisam-se os preceitos jurídicos da responsabilidade civil em relação a essas falhas de mercado e a implicação que isto tem na solução de questões jurídicas envolvendo a atividade negocial.

Os fatores determinantes do boom do mercado imobiliário residencial do Rio de Janeiro entre 2005 e 2010

O mercado imobiliário brasileiro está passando pelo maior boom que já ocorreu no mundo que, por sua vez, envolve uma complexa interação entre os agentes de oferta e de demanda. Os principais fatores que têm impactado a demanda por imóveis no período recente são o aumento da renda média e a expansão do mercado de crédito. Pelo lado da oferta, é a escassez de terrenos edificáveis, dificultada, ainda, pela legislação de proteção ao meio ambiente, justificando o alto déficit habitacional. O resultado dos três fatores que, juntos, pressionam a demanda para cima e a oferta para baixo, acarreta no aumento dos preços dos imóveis residenciais em todo o país. No caso específico do Rio de Janeiro, levam-se em conta as externalidades positivas geradas pelo aumento dos investimentos em infraestrutura para a realização da Copa do Mundo de 2014 e dos Jogos Olímpicos de 2016, incluindo a redução da violência em determinadas áreas com a implantação das Unidades de Polícia Pacificadora (UPPs).

Water budgeting studies on the hatchery and nursery rearing practices for the common carp, Cyprinus carpio (Linnaeus, 1758)

Aquaculture systems are an integral element of rural development and therefore should be environment friendly as well as socially and economically designed. From the economic standpoint, one of the major constraints for the development of sustainable aquaculture includes externalities generated by competition in access to a limited resource. This study was conducted as an investigation into the water requirement for the hatchery and nursery production phases of common carp, Cyprinus carpio (Linnaeus, 1758) at the Maharashtra State Fish Seed Farm at Khopoli in Raigad Dist. of Maharashtra during the winter months from November to February. The water budgeting study involves the quantification of water used in every stage of production in hatchery and nursery systems and aimed at becoming a foundation for the minimization of water during production without affecting the yield; thereby conserving water and upholding the theme of sustainable aquaculture. The total water used in a single operation cycle was estimated to be 11,25,040 L [sic]. Out of the total water consumed, 4.74% water was used in the pre-operational management steps, 4.48% was consumed during breeding, 62.72% was consumed in the hatching phase, 21.50% was used for hatchery rearing and 6.56% was consumed during conditioning. In the nursery ponds, the water gain was primarily the regulated inflow coming through the irrigation channel. The total quantum of water used in the nursery rearing was 31,60,800 L [sic]. The initial filling and regulated inflow formed 42.60% and 57.40% respectively of water gain, while evaporation, seepage and discharge contributed 20.71%, 36.46% and 42.82% respectively to the water loss. The total water expended for the entire operation was 1,21,61,120 L [sic]. Water expense occurred to produce a single spawn in the hatchery system was calculated and found to be 0.56 L while the water expended to produce one fry was calculated as 4.86 L. The study fulfills the hydrological equation described by Winter (1981) and Boyd (1985). It also validates the water budget simulation model that can be used for forecasting water requirements for aquaculture ponds (Nath and Bolte, 1998).

Full cost accounting for the life cycle of coal.

Each stage in the life cycle of coal-extraction, transport, processing, and combustion-generates a waste stream and carries multiple hazards for health and the environment. These costs are external to the coal industry and are thus often considered "externalities." We estimate that the life cycle effects of coal and the waste stream generated are costing the U.S. public a third to over one-half of a trillion dollars annually. Many of these so-called externalities are, moreover, cumulative. Accounting for the damages conservatively doubles to triples the price of electricity from coal per kWh generated, making wind, solar, and other forms of nonfossil fuel power generation, along with investments in efficiency and electricity conservation methods, economically competitive. We focus on Appalachia, though coal is mined in other regions of the United States and is burned throughout the world.

森林生态系统服务功能评估及效益补偿分析-以长白山白河林业局为例

森林生态服务功能的评价及在人类采伐活动及对其影响的研究，是生态服务功能研究的重点内容，也是当前研究的重点方向。本文以白河林业局为研究区域，选择三个林场为典型代表，利用已有的模型，充分利用森林二类调查数据并结合FORESTAR决策支持系统，综合运用GIS技术和统计方法，研究了森林生态服务功能的时空变化，并通过采伐模拟决策，预测不同采伐方案对其服务功能的影响，旨在揭示采伐与森林生态服务功能间的关系；同时将经济补偿作为解决森林生态效益外部性问题的手段，建立了经济补偿的概念模型，较深入的探讨了补偿标准问题，得出以下主要结论：①森林的涵养水源、固土保肥、吸收二氧化碳、净化空气和抑制风沙的效益中，水源涵养功能单位价值量在各项效益价值量中贡献最大，在森林生态服务功能中占有极其重要的地位。②黄松蒲林场1987年和2000年森林服务功能变化主要是由于郁闭度和林龄的改变，森林资源空间分布的变化导致了生态服务功能的经济价值在20年间减少了近40％。③运用FORESTAR森林决策支持系统模拟不同采伐方案，采伐小班的各项单位效益值都有明显的下降；三个林场经过模拟采伐后总的经济价值分别减少了353.83元／hm~2、448.62元／hm~2和457.13元／hm~2。④将补偿标准用补偿系数和森林服务的价值量来表示，充分反映了在一定社会生产条件下人民生活水平下对森林这种公共产品的支付意愿和森林本身的性质，计算出的补偿系数为0.412，三个林场的补偿费年均分别为1067元/hm~2，1161元/hm~2和1314元/hm~2，同时对其与机会成本比较是单位面积机会成本的近3倍。⑤在补偿政策的实施中，建议建立和健全多层次的经济补偿制度，通过国家财政拨款、跨区域补偿以及当地税收调节等多种途径取得补偿资金，形成跨区域补偿以及在税收中加入生态税这一个项目，可以保证补偿资金来源。

Agglomeration effects in foreign direct investment and the pollution haven hypothesis

Does environmental regulation impair international competitiveness of pollution-intensive industries to the extent that they relocate to countries with less stringent regulation, turning those countries into "pollution havens"? We test this hypothesis using panel data on outward foreign direct investment (FDI) flows of various industries in the German manufacturing sector and account for several econometric issues that have been ignored in previous studies. Most importantly, we demonstrate that externalities associated with FDI agglomeration can bias estimates away from finding a pollution haven effect if omitted from the analysis. We include the stock of inward FDI as a proxy for agglomeration and employ a GMM estimator to control for endogenous time-varying determinants of FDI flows. Furthermore, we propose a difference estimator based on the least polluting industry to break the possible correlation between environmental regulatory stringency and unobservable attributes of FDI recipients in the cross-section. When accounting for these issues we find robust evidence of a pollution haven effect for the chemical industry. © 2008 Springer Science+Business Media B.V.

Parimutuel betting under asymmetric information

This paper examines simple parimutuel betting games under asymmetric information, with particular attention to differences between markets in which bets are submitted simultaneously versus sequentially. In the simultaneous parimutuel betting market, all (symmetric and asymmetric) Bayesian-Nash equilibria are generically characterized as a function of the number of bettors and the quality of their private information. There always exists a separating equilibrium, in which all bettors follow their private signals. This equilibrium is unique if the number of bettors is sufficiently large. In the sequential framework, earlier bets have information externalities, because they may reveal private information of bettors. They also have payoff externalities, because they affect the betting odds. One effect of these externalities is that the separating equilibrium disappears if the number of betting periods is sufficiently large. (C) 2006 Elsevier B.V. All rights reserved.

Structural Capital of University Spin-Out Firms: The Moderating Role of University Incubators

University incubators (UI) are generally believed to be important in the successful commercialisation of university spin-outs (USO) with over half of all UK Universities having established an on-campus UI. In this chapter we examine the value of UIs in the spin-out process, focusing on the structural networks of USOs located in a UI as compared to USOs in a University with no access to a UI. Our primary research question is therefore: to what extent does the structural network of USOs with access to an on-campus UI differ from USOs without? The research therefore con-tributes to a growing critique of the effectiveness of UIs in commercialis-ing academic research and the recognition of positive direct and indirect externalities from participation in networks. Through network mapping of all USOs from two research intensive universities, we profile and ana-lyse the formal and informal network ties of USOs to various partners in-ternal and external to the host university. Through interviews we also consider how these networks enhance the resources and capabilities of USOs. Our findings highlight significant differences, with USOs located in a UI having more informal but fewer formal ties, both to other USOs as well as within the host University. In contrast, location in an incuba-tor was not found to affect the extent and nature of ties with external or-ganisations. Reasons for these differences are examined through inter-views with the USOs and point to various factors including the proactive brokering role of incubator and university staff, university bureaucracy, the hidden networks of executive board members across USOs, university equity investment policy and complementary technologies.

Business Intelligence and Multi-market Competition

We consider a multi-market framework where a set of firms compete on two oligopolistic markets. The cost of production of each firm allows for spillovers across markets, ensuring that output decisions for both markets have to be made jointly. Prior to competing in these markets, firms can establish links gathering business intelligence about other firms. A link formed by a firm generates two types of externalities for competitors and consumers. We characterize the business intelligence equilibrium networks and networks that maximize social welfare. By contrast with single market competition, we show that in multi-market competition there exist situations where intelligence gathering activities are underdeveloped with regard to social welfare and should be tolerated, if not encouraged, by public authorities.