EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats

Objectives: Early weaning (EW) increases proliferation of the gastric epithelium in parallel with higher expression of transforming growth factor alpha and its receptor epidermal growth factor receptor (EGFR). The primary objective of the present study was to examine involvement of EGFR signalling in regulating mucosal cell proliferation during the early weaning period. Materials and methods: Fifteen-day-old rats were split into two groups: suckling (control) and EW, in which pups were separated from the dam. Animals were killed daily until the 18th day, 3 days after onset of treatment. To investigate the role of EGFR in proliferation control, EW pups were injected with AG1478, an EGFR inhibitor; signalling molecules, proliferative indices and cell cycle-related proteins were evaluated. Results: EW increased ERK1/2 and Src phosphorylation at 17 days, but p-Akt levels were unchanged. Moreover, at 17 days, AG1478 administration impaired ERK phosphorylation, whereas p-Src and p-Akt were not altered. AG1478 treatment reduced mitotic and DNA synthesis indices, which were determined on HE-stained and BrdU-labelled sections. Finally, AG1478 injection decreased p21 levels in the gastric mucosa at 17 days, while no changes were detected in p27, cyclin E, CDK2, cyclin D1 and CDK4 concentrations. Conclusions: EGFR is part of the mechanism that regulates cell proliferation in rat gastric mucosa during early weaning. We suggest that such responses might depend on activation of MAPK and/or Src signalling pathways and regulation of p21 levels.

Ciprofibrate quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry for pharmacokinetic studies

A rapid, sensitive and specific method for quantifying ciprofibrate in human plasma using bezafibrate as the internal standard (IS) is described. The sample was acidified prior extraction with formic acid (88%). The analyte and the IS were extracted from plasma by liquid-liquid extraction using an organic solvent (diethyl ether/dichloromethane 70/30 (v/v)). The extracts were analyzed by high performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS). Chromatography was performed using Genesis C18 4 mu m analytical column (4.6 x 150 mm i.d.) and a mobile phase consisting of acetonitrile/water (70/30, v/v) and 1 mM acetic acid. The method had a chromatographic run time of 3.4 min and a linear calibration curve over the range 0.1-60 mu g/mL (r > 0.99). The limit of quantification was 0.1 mu g/mL. The intra- and interday accuracy and precision values of the assay were less than 13.5%. The stability tests indicated no significant degradation. The recovery of ciprofibrate was 81.2%, 73.3% and 76.2% for the 0.3, 5.0 and 48.0 ng/mL standard concentrations, respectively. For ciprofibrate, the optimized parameters of the declustering potential, collision energy and collision exit potential were -51 V, -16 eV and -5 V, respectively. The method was also validated without the use of the internal standard. This HPLC-MS/MS procedure was used to assess the bioequivalence of two ciprofibrate 100 mg tablet formulations in healthy volunteers of both sexes. The following pharmacokinetic parameters were obtained from the ciprofibrate plasma concentration vs. time curves: AUC(last), AUC(0-168 h), C(max) and T(max). The geometric mean with corresponding 90% confidence interval (CI) for test/reference percent ratios were 93.80% (90% CI = 88.16-99.79%) for C(max), 98.31% (90% CI = 94.91-101.83%) for AUC(last) and 97.67% (90% CI = 94.45-101.01%) for AUC(0-168 h). Since the 90% Cl for AUC(last), AUC(0-168 h) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that ciprofibrate (Lipless (R) 100 mg tablet) formulation manufactured by Biolab Sanus Farmaceutica Ltda. is bioequivalent to the Oroxadin (R) (100 mg tablet) formulation for both the rate and the extent of absorption. (C) 2011 Published by Elsevier B.V.

Plasmodium falciparum Accompanied the Human Expansion out of Africa

Plasmodium falciparum is distributed throughout the tropics and is responsible for an estimated 230 million cases of malaria every year, with a further 1.4 billion people at risk of infection [1-3]. Little is known about the genetic makeup of P. falciparum populations, despite variation in genetic diversity being a key factor in morbidity, mortality, and the success of malaria control initiatives. Here we analyze a worldwide sample of 519 P. falciparum isolates sequenced for two housekeeping genes (63 single nucleotide polymorphisms from around 5000 nucleotides per isolate). We observe a strong negative correlation between within-population genetic diversity and geographic distance from sub-Saharan Africa (R(2) = 0.95) over Africa, Asia, and Oceania. In contrast, regional variation in transmission intensity seems to have had a negligible impact on the distribution of genetic diversity. The striking geographic patterns of isolation by distance observed in P. falciparum mirror the ones previously documented in humans [4-7] and point to a joint sub-Saharan African origin between the parasite and its host. Age estimates for the expansion of P. falciparum further support that anatomically modern humans were infected prior to their exit out of Africa and carried the parasite along during their colonization of the world.

Evolutionary dynamics of the immunodominant repeats of the Plasmodium vivax malaria-vaccine candidate circumsporozoite protein (CSP)

The circumsporozoite protein (CSP) of Plasmodium vivax, a major target for malaria vaccine development, has immunodominant B-cell epitopes mapped to central nonapeptide repeat arrays. To determine whether rearrangements of repeat motifs during mitotic DNA replication of parasites create significant CSP diversity under conditions of low effective meiotic recombination rates, we examined csp alleles from sympatric P. vivax isolates systematically sampled from an area of low malaria endemicity in Brazil over a period of 14 months. Nine unique csp types, comprising six different nona peptide repeats, were observed in 45 isolates analyzed. Identical or nearly identical repeats predominated in most arrays, consistent with their recent expansion. We found strong linkage disequilibrium at sites across the chromosome 8 segment flanking the csp locus, consistent with rare meiotic recombination in this region. We conclude that CSP repeat diversity may not be severely constrained by rare meiotic recombination in areas of low malaria endemicity. New repeat variants may be readily created by nonhomologous recombination even when meiotic recombination is rare, with potential implications for CSP-based vaccine development. (C) 2010 Elsevier B.V. All rights reserved.

Gamma-linolenic Acid Alters Ku80, E2F1, and Bax Expression and Induces Micronucleus Formation in C6 Glioma Cells In Vitro

Gamma-linolenic acid (GLA) is an inhibitor of tumor cell proliferation in both in vitro and in vivo conditions. The aim of this study was to investigate the effects of 150 mu M GLA on the expression of E2F1, cyclin D1, bax, bcl2, Ku70, and Ku80 in C6 rat glioma cells. The Ku proteins were chosen as previous studies have shown that loss or reduction in their expression causes increased DNA damage and micronucleus formation in the presence of radiation. The fact that GLA exposure is known to enhance the efficacy of radiation treatment raised the question whether the Ku proteins could be involved in this effect as seen for other molecules such as roscovitine and flavopiridol. GLA altered the mRNA expression of E2F1, cyclin D1, and bax, but no changes were found for bcl2, Ku70, and Ku80. Alterations in protein expression were observed for bax, Ku80, and E2F1. The 45% decrease in E2F1 expression was proportional to decreased cell proliferation (44%). Morphological analysis found a 25% decrease in mitotic activity in the GLA-treated cells, which was accompanied by a 49% decrease in S-phase by FACS analysis. A 39% increase in the number of micronuclei detected by Hoechst fluorescence points to GLA`s effects on cell division even at concentrations that do not produce significant increases in apoptosis. Most important was the finding that Ku80 expression, a critical protein involved in DNA repair as a heterodimer with Ku70, was decreased by 71%. It is probable that reduced Ku80 is responsible for the increase in micronucleus formation in GLA-treated cells in a similar manner to that found in Ku80 null cells exposed to radiation. The decreased expression of Ku80 and E2F1 could make cells more susceptible to radiotherapy and chemotherapy. (C) 2009 IUBMB

Temporal behaviour of toroidal rotation velocity in the TCABR tokamak

A new method for determining the temporal evolution of plasma rotation is reported in this work. The method is based upon the detection of two different portions of the spectral profile of a plasma impurity line, using a monochromator with two photomultipliers installed at the exit slits. The plasma rotation velocity is determined by the ratio of the two detected signals. The measured toroidal rotation velocities of C III (4647.4 angstrom) and C VI (5290.6 angstrom), at different radial positions in TCABR discharges, show good agreement, within experimental uncertainty, with previous results (Severo et al 2003 Nucl. Fusion 43 1047). In particular, they confirm that the plasma core rotates in the direction opposite to the plasma current, while near the plasma edge (r/a > 0.9) the rotation is in the same direction. This technique was also used to investigate the dependence of toroidal rotation on the poloidal position of gas puffing. The results show that there is no dependence for the plasma core, while for plasma edge (r/a > 0.9) some dependence is observed.

Fragment-Based QSAR and Molecular Modeling Studies on a Series of Discodermolide Analogs as Microtubule-Stabilizing Anticancer Agents

Inhibition of microtubule function is an attractive rational approach to anticancer therapy. Although taxanes are the most prominent among the microtubule-stabilizers, their clinical toxicity, poor pharmacokinetic properties, and resistance have stimulated the search for new antitumor agents having the same mechanism of action. Discodermolide is an example of nontaxane natural product that has the same mechanism of action, demonstrating superior antitumor efficacy and therapeutic index. The extraordinary chemical and biological properties have qualified discodermolide as a lead structure for the design of novel anticancer agents with optimized therapeutic properties. In the present work, we have employed a specialized fragment-based method to develop robust quantitative structure - activity relationship models for a series of synthetic discodermolide analogs. The generated molecular recognition patterns were combined with three-dimensional molecular modeling studies as a fundamental step on the path to understanding the molecular basis of drug-receptor interactions within this important series of potent antitumoral agents.

A quasispecies approach to the evolution of sexual replication in unicellular organisms

This study develops a simplified model describing the evolutionary dynamics of a population composed of obligate sexually and asexually reproducing, unicellular organisms. The model assumes that the organisms have diploid genomes consisting of two chromosomes, and that the sexual organisms replicate by first dividing into haploid intermediates, which then combine with other haploids, followed by the normal mitotic division of the resulting diploid into two new daughter cells. We assume that the fitness landscape of the diploids is analogous to the single-fitness-peak approach often used in single-chromosome studies. That is, we assume a master chromosome that becomes defective with just one point mutation. The diploid fitness then depends on whether the genome has zero, one, or two copies of the master chromosome. We also assume that only pairs of haploids with a master chromosome are capable of combining so as to produce sexual diploid cells, and that this process is described by second-order kinetics. We find that, in a range of intermediate values of the replication fidelity, sexually reproducing cells can outcompete asexual ones, provided the initial abundance of sexual cells is above some threshold value. The range of values where sexual reproduction outcompetes asexual reproduction increases with decreasing replication rate and increasing population density. We critically evaluate a common approach, based on a group selection perspective, used to study the competition between populations and show its flaws in addressing the evolution of sex problem.

An Evaluation of”Middle Ages Dead or Live?”The first interactive exhibition at the National Museum of History

This is a study conducted at, and for, the National Museum of History in Stockholm. The aim of the study was to confirm or disconfirm the hypothesis that visitors in a traditional museum environment might not take part in interactivity in an interactive exhibition. And if they do the visitors might skip the texts and objects on display. To answer this and other questions a multiple method was used. Both non participant observations and exit interviews were conducted. After a description of the interactive exhibits, theory of knowledge and learning is presented before the gathered data is presented. All together 443 visitors were observed. In the observations the visitors were timed on how much time they spent in the room, the time spent on the interactivity, texts and objects. In the 40 interviews information about visitors’ participation in the interactivity was gathered. What interactivity the visitor found easiest, hardest, funniest and most boring.The result did not confirm the hypothesis. All kinds of visitors, children and adults, participated in the interactivities. The visitors took part in the texts and objects and the interactive exhibits.

Att bli, att vara och att ha varit - om ingångar i och utgångar ur Jehovas vittnen i Sverige

Summary To become, to be and to have been: about the  Jehovah’s Witnesses The Watchtower Bible and Tract Society, in the following text referred to as the Jehovah’s Witnesses or “the organisation”, is a worldwide Christian organisation with about 6.7 million members. The organisation has many times, without any success so far, proclaimed Armageddon when they expect Jehovah to return to Earth. They interpret the Bible in their own, often very literal way, and require their members to live according to these interpretations. Among the consequences of this, members are forbidden to vote, to do military service or to receive blood transfusions. Apart from attending the three weekly meetings, members are expected to be active in missionary work, known as “publishing”. If a member fails to do a certain number of hours’ publishing, he or she risks being deprived of active membership status Sweden in general is considered to be a society where the population is not very religious. The formerly state-governed Lutheran church has lost its influence and the vast majority of ordinary Swedes do not visit church on other occasions than weddings, funerals or christenings. Expressing one’s own religious values has become somewhat of a private matter where publicity is seldom appreciated, which is contrary to the practice of the Jehovah’s Witnesses. This is one of the reasons why the Jehovah’s Witnesses are commonly perceived by average Swedes as a “suspicious” religious organisation. The aim and methods of the study This dissertation seeks to describe and investigate the entering and leaving of a highly structured and hierarchical religious community, exemplified in this case by the Jehovah’s Witnesses. What are the thoughts and aspirations of someone who is considering becoming a Jehovah’s Witness? What are the priorities and what experiences seem important when a person is going through such a process? And when this person has finally reached his or her goal of becoming a member, is it the same motivation that makes him or her stay in the organisation for longer periods of time, possibly for the rest of their lives, or does it change during the process of entering, or does this motivation change its character during the transition from entering to being a regular member? Why do some of the members change their attitude to the Jehovah’s Witnesses from rejoicing to bitterness? And how does this process of exit manifest itself? In what way is it different from the process of entry? The respondents in this study were chosen from both active members of the Jehovah’s Witnesses in Sweden and those who have left the organisation for personal reasons. Repeated interviews with ten active members of the organisation have been conducted in the course of the study and compared to equal numbers of former members. The interviews have been semi-structured to deal with questions of how a person has come into contact with the organisation; how they retrospectively experienced the process of entry; the reasons for becoming a member. Questions have also been asked about life in the organisation. The group of “exiters” have also been asked about the experience of leaving, why they wanted to leave, and how this process was started and carried out. In addition to this I have analysed a four-year diary describing the time inside and the process of leaving the organisation. This has given me an extra psychological insight into the inner experience of someone who has gone through the whole process. The analysis has been done by categorising the content of the transcribed interviews. An attempt to outline a model of an entry and exit process has been made, based on ideas and interpretations presented in the interviews. The analysis of the diary has involved thorough reading, resulting in a division of it into four different parts, where each part has been given a certain key-word, signifying the author’s emotional state when writing it. A great deal of the information about the Jehovah’s Witnesses has been collected through discussion boards on the Internet, informal talks with members and ex-members, interviews with representatives of the organisations during visits to its different offices (Bethels), such as St. Petersburg, Russia, and Brooklyn, New York, USA. The context Each organisation evolves in its own context with its own norms, roles and stories that would not survive outside it. With this as a starting point, there is a chapter dedicated to the description of the organisation’s history, structure and activities. It has been stated that the organisation’s treatment of its critical members and the strategies for recruiting new members have evolved over the years of its history. At the beginning there was an openness allowing members to be critical. As the structure of the organisation has become more rigid and formalised, the treatment of internal critics has become much less tolerated and exclusion has become a frequent option. As a rule many new members have been attracted to the organisation when (1) the day of Armageddon has been pronounced to be approaching; (2) the members of the organisation have been persecuted or threatened with persecution; and (3) the organisation has discovered a “new market”. The processes for entering and exiting How the entering processes manifest themselves depends on whether the person has been brought up in the organisation or not. A person converting as an adult has to pass six phases before being considered a Jehovah’s Witness by the organisation. These are:  Contact with the Jehovah’s Witnesses, Studying the bible with members of the organisation, Questioning, Accepting, Being active as publisher (spreading the belief), Being baptised.  For a person brought up in the organisation, the process to full membership is much shorter:   Upbringing in the organisation, Taking a stand on the belief, Being baptised. The exit process contains of seven phases:   Different levels of doubts, Testing of doubts, Turning points, Different kinds of decisions, Different steps in executing the decisions, Floating, a period of emotional and cognitive consideration of membership and its experiences, Realtive neutrality.   The process in and the process out are both slow and are accompanied with anguish and doubts. When a person is going through the process in or out of the organisation he or she experiences criticism. This is when people around the adept question the decision to continue in the process. The result of the criticism depends on where in the process the person is. If he or she is at the beginning of the process, the criticism will probably make the person insecure and the process will slow down or stop. If the criticism is pronounced in a later phase, the process will probably speed up. The norms of the organisation affect the behaviour of the members. There are techniques for inclusion that both bind members to the organisation and shield them off from the surrounding society. Examples of techniques for inclusion are the “work situation” and “closed doors”. The work situation signifies that members who do as the organisation recommends – doing simple work – often end up in the same branch of industry as many other Jehovah’s Witnesses. This often means that the person has other witnesses as workmates. If the person is unemployed or moves to another town it is easy to find a new job through connections in the organisation. Doubts and exclusions can lead to problems since they entail a risk of losing one’s job. This can also result in problems getting a new job. Jehovah’s Witnesses are not supposed to talk to excluded members, which of course mean difficulties working together. “Closed doors” means that members who do as the organisation recommends – not pursuing higher education, not engaging in civil society, working with a manual or in other way simple job, putting much time into the organisation – will, after a long life in the organisation, have problems starting a new life outside the Jehovah’s Witnesses. The language used in the organisation shows the community among the members, thus the language is one of the most important symbols. A special way of thinking is created through the language. It binds members to the organisation and sometimes it can work as a way to get back into the normative world of the organisation. Randall Collins’s (1990, 2004) thoughts about “emotional energy” have enabled an understanding of the solidarity and unity in the organisation. This also gives an understanding of the way the members treat doubting and critical members. The members who want to exit have to open up the binding/screening off. A possible way to do that is through language, to become aware of the effect the language might have. Another way is to search for emotional energy in another situation. During the exit process, shame might be of some importance. When members become aware of the shame they feel, because they perceive they are “acting a belief”, the exit process might accelerate.

Att lämna en värld : Om utgångsprocesser ur Jehovas vittnen

It is an everyday experience to realize that things do not turn out the as expected. But what if you realize that everything you have so far experienced as reality is illusion? This article is about former members of the Jehovah’s Witnesses who have had doubts about what they previously believed to be the Truth. The article also treats the exit process, from being a Jehovah’s Witness to becoming an ex-Jehovah’s Witness. The data consists of twenty qualitative interviews with ten Jehovah’s Witnesses and twenty qualitative interviews with ten former Jehovah’s Witnesses. The data also include a diary written during four years preceding an exit from the organization. The analysis was made through thematic concentration. Ontologically the analysis and the article are based on a constructionist view though it is mainly empirical with no further theoretical assessment. However, to be able to understand the results a contextual frame is sketched with two factors affecting members who make an exit. First there are tying factors that bind the person closer to the organization; these are closeness and friendship and confirmation. A secluding factor is something that secludes the member from the outside society; these factors are the work situation and »closed doors«. With high values on these factors the exit process will be more arduous. The results are presented through a process model in which different phases or steps in the exit process are described. The following steps in the process are: (1) different levels of doubts; (2) trying out doubts; (3) turning points; (4) different decisions; (5) different steps in execution; (6) floating; (7) relative neutrality. The process is defined as an altogether ambivalent and emotionally tough experience, but other parts of life may be affected as well, such as employment, social life, family life and career.

Latin America major player in the international financial markets, agony and ecstasy

This study deals with the complex relationship between the International Financial Markets (IFMs) and the countries of the Latin America Group, emphasizing the entrance and the exit conditions for these countries in the last two indebtedness cycles - 1967/1982 and 1990/1994. Finally, it makes some considerations about the consequences of these Latin America countries of being linking economic policies to the external financing abtained in the IFMs.

Proposta de modelo integrado de gestão financeira para empresas de pequeno porte

O mercado exige cada vez mais o aperfeiçoamento das organizações, inclusive às de pequeno porte, haja visto que as empresas de pequeno porte estão aumentando sua área de atingimento e consequêntemente necessitam de maiores controles gerenciais. No que tange ao controle econômico-financeiro, não basta o administrador apenas prestar atenção nos valores movimentados, mas sim ter cuidado especial em sua base de dados que gera as informações para as decisões, isso recai sobre o sistema de custos na empresa. O sistema de custos é formado pelos princípios e métodos que auxiliarão na formação de preços, que também além do mercado, sofre influência do fluxo de caixa que por sua vez decorre em função do ciclo operacional realizado. Por isso da necessidade do aperfeiçoamento do administrado da empresa de pequeno porte, para poder implementar uma Gestão Financeira eficaz que possua controle sobre todas essas nunces citadas. O presente trablho buscou discernir de forma objetiva a parte teórica e tembém através de um modelo a parte prática dessa integração de informações criando um modelo de Gestão Financeira.

REPETRO - Regime Aduaneiro Especial de Importação e Exportação de Bens Destinados à Pesquisa e Lavra de Petróleo e Gás: análise dos entraves e propostas de soluções

REPETRO, the special tax regime for importing and exporting goods for the exploration and drilling of oil and gas, aims at bringing foreign assets to Brazil enjoying a suspension or even an exemption of taxes, so that Brazilian industry may profit from about 8 billion American dollars in investments. The creation of normative devices as well as the management of the REPETRO model are under the exclusive responsibility of the Brazilian Internal Revenue Services. REPETRO was created in 1999 and is composed of the following customs treatments: importation of goods with suspension of taxes by use of the drawback special regime, suspension mode for national exporting industry; exportation with fictitious exit for the national industry; temporary admission of goods or assets used in oil exploration and production, attending to the needs of both the national and foreign market. Considering the inability of the Brazilian government in restructuring its foreign trade model so that a strong investment in technology could provide for the sector¿s needs, we must ask how we can change REPETRO to help the various companies in the oil business? The issue is very important for one of our main economic activities, though not enough studied. The energy sector has a strategic importance for the development and the economic independence of any country. The winds of globalization lead Brazil to open its economy in the last decade and the national policy for exploration and drilling (E&D) was altered. The government created a new agency dedicated to market control and energy policies, the National Agency for Oil and Biofuels (ANP). With the opening of the market, Petróleo Brasileiro S.A. - Petrobras, the Brazilian giant, lost the monopoly of the oil business. The P-50 Platform, with a capacity for 180,000 barrels per day, was imported based on REPETRO. When it began operating on April 21st, 2006, Brazil achieved self-sufficiency in oil production. The present work intends to estimate the main variables affecting the importation and exportation of goods and assets for E&D, showing how REPETRO works. We also intend to look at the results yielded by the REPETRO model for the development of the production of oil and gas in Brazil, as well as show proposals for its modernization. It has been established that even though since its implementation the REPETRO model has brought fiscal advantages through the reduction of tax costs relating to foreign commerce operations and the incentive of investments in the E&D area with the increase in the national oil production there remain the following limitations: lack of preparation and of knowledge of the model; lack of adjustement of the model to the reality of actitity of E&D of oil and gas; taxes over the pre-operational stage or investment in oil production stage; non-allowance of full access by the national industry to the supply of goods and products relating to the industrialization of goods allowed by REPETRO; other fiscal and administrative difficulties. We conclude that the REPETRO model is important for the development of the area of E&D of oil and gas, but not completely effective. It is necessary to change it or create a new model based on a new perspective of the customs treatment of the activities of exploration and production, minimizing administrative procedures relating to the operations of exportation and importation.