DNA damage recognition in the normal epithelium of human prostate and seminal vesicles

Prostate cancer is one of the most prevalent cancer types in men. The development of prostate tumors is known to require androgen exposure, and several pathways governing cell growth are deregulated in prostate tumorigenesis. Recent genetic studies have revealed that complex gene fusions and copy - number alterations are frequent in prostate cancer, a unique feature among solid tumors. These chromosomal aberrations are though to arise as a consequence of faulty repair of DNA double strand breaks (DSB). Most repair mechanisms have been studied in detail in cancer cell lines, but how DNA damage is detected and repaired in normal differentiated human cells has not been widely addressed. The events leading to the gene fusions in prostate cancer are under rigorous studies, as they not only shed light on the basic pathobiologic mechanisms but may also produce molecular targets for prostate cancer treatment and prevention. Prostate and seminal vesicles are part of the male reproductive system. They share similar structure and function but differ dramatically in their cancer incidence. Approximately fifty primary seminal vesicle carcinomas have been reported worldwide. Surprisingly, only little is known on why seminal vesicles are resistant to neoplastic changes. As both tissues are androgen dependent, it is a mystery that androgen signaling would only lead to tumors in prostate tissue. In this work, we set up novel ex vivo human tissue culture models of prostate and seminal vesicles, and used them to study how DNA damage is recognized in normal epithelium. One of the major DNA - damage inducible pathways, mediated by the ATM kinase, was robustly activated in all main cell types of both tissues. Interestingly, we discovered that secretory epithelial cells had less histone variant H2A.X and after DNA damage lower levels of H2AX were phosphorylated on serine 139 (γH2AX) than in basal or stromal cells. γH2AX has been considered essential for efficient DSB repair, but as there were no significant differences in the γH2AX levels between the two tissues, it seems more likely that the role of γH2AX is less important in postmitotic cells. We also gained insight into the regulation of p53, an important transcription factor that protects genomic integrity via multiple mechanisms, in human tissues. DSBs did not lead to a pronounced activation of p53, but treatments causing transcriptional stress, on the other hand, were able to launch a notable p53 response in both tissue types. In general, ex vivo culturing of human tissues provided unique means to study differentiated cells in their relevant tissue context, and is suited for testing novel therapeutic drugs before clinical trials. In order to study how prostate and seminal vesicle epithelial cells are able to activate DNA damage induced cell cycle checkpoints, we used primary cultures of prostate and seminal vesicle epithelial cells. To our knowledge, we are the first to report isolation of human primary seminal vesicle cells. Surprisingly, human prostate epithelial cells did not activate cell cycle checkpoints after DSBs in part due to low levels of Wee1A, a kinase regulating CDK activity, while primary seminal vesicle epithelial cells possessed proficient cell cycle checkpoints and expressed high levels of Wee1A. Similarly, seminal vesicle cells showed a distinct activation of the p53 - pathway after DSBs that did not occur in prostate epithelial cells. This indicates that p53 protein function is under different control mechanisms in the two cell types, which together with proficient cell cycle checkpoints may be crucial in protecting seminal vesicles from endogenous and exogenous DNA damaging factors and, as a consequence, from carcinogenesis. These data indicate that two very similar organs of male reproductive system do not respond to DNA damage similarly. The differentiated, non - replicating cells of both tissues were able to recognize DSBs, but under proliferation human prostate epithelial cells had deficient activation of the DNA damage response. This suggests that prostate epithelium is most vulnerable to accumulating genomic aberrations under conditions where it needs to proliferate, for example after inflammatory cellular damage.

Regulation of progesterone biosynthesis in the human placenta by estradiol 17 beta and progesterone

Ex vivo addition of estradiol 17 beta to first trimester or term human placental minces caused a significant increase in the quantity of progesterone produced. Addition of an aromatase inhibitor, CGS 16949 A or the estrogen receptor antagonist, ICI 182780, significantly inhibited progesterone production confirming the role of estradiol 17 beta in the regulation of progesterone synthesis in human placenta. RU 486 and ZK 98299, which are antagonists of progesterone receptor, significantly modulated progesterone synthesis in the human placenta but exhibited paradoxical effects on the first trimester and term placenta We conclude that progesterone synthesis in the human placenta is regulated by estradiol 17 beta and progesterone. This is the first report providing evidence for autoregulation of progesterone synthesis in the human placenta.

Effectors of Salmonella pathogenicity island 2: An island crucial to the life of Salmonella

The tug of war between a pathogen and its host has been one of the most amazing stories in the field of microbial pathogenesis for ages. The strongest known species of all living organisms is the Homo sapiens and yet it is incredible how a pathogen of the size of few microns is smart enough to defeat this mightiest group of survivors. It is of utmost interest to understand the mechanisms behind the successful habitation of a pathogen inside the ever-resisting and complicate human body. Numerous examples of diseases caused by such pathogens exist which intrigues us to venture in the world of host-pathogen interactions.

Total internal reflection (TIR) Raman tribometer: a new tool for in situ study of friction-induced material transfer

The sliding history in friction-induced material transfer of dry 2H-MoS2 particles in a sheared contact was studied. Video images in contact showed fragmentation of lubricant particles and build-up of a transfer film, and were used to measure the speed of fragmented particles in the contact region. Total internal reflection (TIR) Raman spectroscopy was used to follow the build-up of the MoS2 transfer film. A combination of in situ and ex situ analysis of the mating bodies revealed the thickness of the transfer film at steady state to be of the order of 35 nm on the ball surface and 15 nm on the flat substrate. Insights into the mechanism of formation of the transfer film in the early stages of sliding contact are deduced.

Fishery resources of the United States of America

The term “fishery resources” is used in this book with a broad application. It includes the populations of the fishes and other organisms useful to men, the environment that makes life possible for them, the industry that exploits and utilizes them, and our knowledge about them by which we can conserve their productivity. This book aims to survey the present status of all these aspects of those fishery resources that are used or are available for use by United States anglers and commercial fishermen. It is planned primarily for the Congress, at its request, with the idea of giving to busy people, in condensed fashion, a perspective on its subject. (pdf contains 142 pages)

Prevalence Of Shear Banding In Compression Of Zr41Ti14Cu12.5Ni10Be22.5 Pillars As Small As 150 Nm In Diameter

Recently, the size dependence of mechanical behaviors, particularly the yield strength and plastic deformation mode, of bulk metallic glasses (BMG) has created a great deal of interest. Contradicting conclusions have been drawn by different research groups, based on various experiments on different BMG systems. Based on in situ compression transmission electron microscopy (TEM) experiments on Zr41Ti14Cu12.5Ni10Be22.5 (Vit 1) nanopillars, this paper provides strong evidence that shear banding still prevails at specimen length scales as small as 150 nm in diameter. This is supported by in situ and ex situ images of shear bands, and by the carefully recorded displacement bursts under load control its well as load drops under displacement control. Finite element modeling of the stress state within the pillar shows that the unavoidable geometry constraints accompanying such experiments impart a strong effect on the experimental results, including non-uniform stress distributions and high level hydrostatic pressures. The seemingly improved compressive ductility is believed to be due to such geometry constraints. Observations underscore the notion that the mechanical behavior of metallic glasses, including strength and plastic deformation mode, is size independent at least in Vit 1. (C) 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Contribution of women to fisheries development in Kainji Lake basin

The study was carried to examine the contribution of women to fisheries development in the Kainji basin. The sample was drawn in some of the major fishing villages in the sub strata of the basin. A total of 120 respondents were used. The findings revealed that women were involved in fisheries activities most especially in the processing and marketing aspects. Many of the respondents happened to be wives of the fishermen. Few bought fishing equipment with a special arrangement for the supply of fish while some buy from fishermen. This revealed the willingness of the women to be empowered in the economic activities in the area to meet some basic household. Major constrains to the women in this area were the scarcity of fish, no support from the government or private agencies. Recommendations were made on how to enhance women participation in fisheries development

Synthesis and biological activity of anticoagulant heparan sulfate glycopolymers

Heparin has been used as an anticoagulant drug for more than 70 years. The global distribution of contaminated heparin in 2007, which resulted in adverse clinical effects and over 100 deaths, emphasizes the necessity for safer alternatives to animal-sourced heparin. The structural complexity and heterogeneity of animal-sourced heparin not only impedes safe access to these biologically active molecules, but also hinders investigations on the significance of structural constituents at a molecular level. Efficient methods for preparing new synthetic heparins with targeted biological activity are necessary not only to ensure clinical safety, but to optimize derivative design to minimize potential side effects. Low molecular weight heparins have become a reliable alternative to heparin, due to their predictable dosages, long half-lives, and reduced side effects. However, heparin oligosaccharide synthesis is a challenging endeavor due to the necessity for complex protecting group manipulation and stereoselective glycosidic linkage chemistry, which often result in lengthy synthetic routes and low yields. Recently, chemoenzymatic syntheses have produced targeted ultralow molecular weight heparins with high-efficiency, but continue to be restricted by the substrate specificities of enzymes.

To address the need for access to homogeneous, complex glycosaminoglycan structures, we have synthesized novel heparan sulfate glycopolymers with well-defined carbohydrate structures and tunable chain length through ring-opening metathesis polymerization chemistry. These polymers recapitulate the key features of anticoagulant heparan sulfate by displaying the sulfation pattern responsible for heparin’s anticoagulant activity. The use of polymerization chemistry greatly simplifies the synthesis of complex glycosaminoglycan structures, providing a facile method to generate homogeneous macromolecules with tunable biological and chemical properties. Through the use of in vitro chromogenic substrate assays and ex vivo clotting assays, we found that the HS glycopolymers exhibited anticoagulant activity in a sulfation pattern and length-dependent manner. Compared to heparin standards, our short polymers did not display any activity. However, our longer polymers were able to incorporate in vitro and ex vivo characteristics of both low-molecular-weight heparin derivatives and heparin, displaying hybrid anticoagulant properties. These studies emphasize the significance of sulfation pattern specificity in specific carbohydrate-protein interactions, and demonstrate the effectiveness of multivalent molecules in recapitulating the activity of natural polysaccharides.

Environmental Concerns in Water Pricing Policy: an Application of Data Envelopment Analysis (DEA)

25 p.

Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium

Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids.

Size-composition of Annual Landings in the White Shrimp, Litopenaeus setiferus, Fishery of the Northern Gulf of Mexico, 1960–2006: Its Trend and Relationships with Other Fishery-dependent Variable

The potential for growth overfishing in the white shrimp, Litopenaeus setiferus, fishery of the northern Gulf of Mexico appears to have been of limited concern to Federal or state shrimp management entities, following the cataclysmic drop in white shrimp abundance in the 1940’s. As expected from surplus production theory, a decrease in size of shrimp in the annual landings accompanies increasing fishing effort, and can eventually reduce the value of the landings. Growth overfishing can exacerbate such decline in value of the annual landings. We characterize trends in size-composition of annual landings and other annual fishery-dependent variables in this fishery to determine relationships between selected pairs of these variables and to determine whether growth overfishing occurred during 1960–2006. Signs of growth overfishing were equivocal. For example, as nominal fishing effort increased, the initially upward, decelerating trend in annual yield approached a local maximum in the 1980’s. However, an accelerating upward trend in yield followed as effort continued to increase. Yield then reached its highest point in the time series in 2006, as nominal fishing effort declined due to exogenous factors outside the control of shrimp fishery managers. The quadratic relationship between annual yield and nominal fishing effort exhibited a local maximum of 5.24(107) pounds (≈ MSY) at a nominal fishing effort level of 1.38(105) days fished. However, annual yield showed a continuous increase with decrease in size of shrimp in the landings. Annual inflation-adjusted ex-vessel value of the landings peaked in 1989, preceded by a peak in annual inflation-adjusted ex-vessel value per pound (i.e. price) in 1983. Changes in size composition of shrimp landings and their economic effects should be included among guidelines for future management of this white shrimp

A practical guide for ex-ante impact evaluation in fisheries and aquaculture

This guide provides a framework for ex-ante evaluation of fisheries and aquaculture projects in developing countries. Ex-ante impact evaluations check the potential of a project or program to deliver benefits from proposed interventions. Providing extensive annotated literature citations, this guide is designed for use by practitioners who may not be fisheries or aquaculture specialists. The guide uses concepts from results-based management, organized into five modules that structure the investigation and provide insights regarding alignment of the proposed intervention with stakeholder interests, feasibility of design, potential constraints to implementation, possible impact pathways and distributional effects of the intervention. Separately published case studies of investments in Bangladesh, Malawi and Ghana illustrate application of the guide.

Ex-ante impact evaluation: case studies from Malawi, Bangladesh and Ghana

This document presents ex-ante impact evaluations of research for development projects related to aquaculture in Bangladesh, Malawi and Ghana. The Ghana chapter also includes an ex-ante evaluation of a fisheries project. The case studies utilized preliminary versions of guidelines developed specifically for ex-ante evaluations of aquaculture and fisheries projects. The guidelines, found in A Practical Guide for Ex-Ante Impact Evaluations in Fisheries and Aquaculture, are designed to provide an approach for a qualitative examination of the potential for a project to deliver impacts. Using a conceptual framework based on the outcome focus of results-based management, the guidelines stress careful examination of the setting, internal consistency, a sound theory of change, and an examination of stakeholders’ interests and potential partnerships. The case study reports illustrate the variability with which the guidelines may be interpreted and applied. The different teams, operating with limited time and budget that constrained the collection of new data, were forced to utilize existing secondary data and information and consult with key stakeholders to complete their analyses. The varying levels of reporting reflect the differences among the cases in the amounts of existing information and variety of stakeholders potentially involved in the projects being examined.

As representações de Justiça no Complexo do Alemão: uma área pacificada na cidade do Rio de Janeiro

O trabalho se refere ao processo e tomada do Complexo do Alemão pelas forças militares na cidade do Rio de Janeiro, para implantação das Unidades de Polícia Pacificadora (UPP), que aconteceu em novembro de 2010. Tem como objetivo levantar hipóteses sobre a relação do que se entende por Justiça a partir da ocupação da favela pelos militares, e como a convivência com a UPP tem influenciado a ideia de Justiça nos moradores do Alemão. A pesquisa ocupa-se em elucidar ao leitor sobre as abordagens de justiça mais comuns, conceituando e explicando quais os princípios de justiça em que cada uma delas se sustenta. A pesquisa descreve duas teorias que explicam o surgimento das favelas na cidade do Rio de Janeiro. O Complexo do Alemão é considerado uma das maiores favelas do Rio de Janeiro, e a mais violenta, por isso a tomada da área se deu através do ataque dos militares que utilizaram táticas de guerra e cerco, tiveram o Caveirão como suporte, e assim deram início a invasão. A Rede Globo de Televisão também aparece na pesquisa, pois a emissora ganhou o prêmio Emmy de jornalismo, com a cobertura da invasão no Alemão. Considerando que uma das condições básicas de uma sociedade democrática é o direito a participação nas decisões políticas, sociais e econômicas, as questões investigadas foram: A megaoperação de pacificação no Alemão foi justa? Do ponto de vista de quem? Qual o parâmetro para uma sociedade justa? Qual representação de justiça tem feito parte da rotina dos moradores do Alemão? Por que ainda se tem a ideia de que Bandido bom é bandido morto? As contribuições da pesquisa se deram no campo social, filosófico e político e nos convida a refletir sobre o que é considerado justo em uma sociedade como a nossa, onde as desigualdades sociais são tão fortes.

Low-temperature growth of InN by MOCVD and its characterization

Metalorganic chemical vapor deposition growth of InN on sapphire substrate has been investigated between 400 degrees C and 500 degrees C to seek the growth condition of InN buffer layer, i.e. the first step of realization of the two-step growth method. Ex situ characterization of the epilayers by means of atomic force microscope, scanning electron microscope and X-ray diffraction, coupled with in situ reflectance curves, has revealed different growth circumstances at these temperatures, and conclusion has been reached that the most suitable temperature for buffer growth is around 450 degrees C. In addition, the growth rate of InN at the optimized temperature with regard to different precursor flow rates is studied at length. (c) 2004 Elsevier B.V. All rights reserved.