Avaliação da ação antitumoral in vitro da pterocarpanoquinona LQB 118 e estudo de alguns mecanismos de ação

Tem sido descrito que o acúmulo de mutações em proto-oncogenes e genes supressores de tumor contribui para o direcionamento da célula à carcinogênese. Na maioria dos casos de câncer, as células apresentam proliferação descontrolada devido a alterações na expressão e/ou mutações de ciclinas, quinases dependentes de ciclinas e/ou inibidores do ciclo celular. Os tumores sólidos figuram entre o tipo de câncer mais incidente no mundo, sendo a quimioterapia e/ou hormônio-terapia, radioterapia e cirurgia os tratamentos mais indicados para estes tipos de tumores. Entretanto, o tratamento quimioterápico apresenta diversos efeitos colaterais e muitas vezes é ineficaz. Portanto, a busca por novas moléculas capazes de conter a proliferação destas células e com baixa toxicidade para o organismo se faz necessário. Este trabalho teve por objetivo avaliar a ação antitumoral in vitro de um novo composto sintético, a pterocarpanoquinona LQB118, sobre algumas linhagens tumorais humanas de alta prevalência e estudar alguns dos seus mecanismos de ação. As linhagens tumorais estudadas neste trabalho foram os adenocarcinomas de mama (MCF7) e próstata (PC-3), e carcinoma de pulmão (A549). A citotoxicidade foi avaliada pelo ensaio do MTT e a proliferação celular pela contagem de células vivas (exclusão do corante azul de tripan) e análise do ciclo celular (citometria de fluxo). A expressão gênica foi avaliada por RT-PCR e a apoptose foi avaliada por condensação da cromatina (microscopia de fluorescência-DAPI), fragmentação de DNA (eletroforese) e marcação com anexina V (citometria de fluxo). Das linhagens tumorais testadas, a de próstata (PC3) foi a que se mostrou mais sensível ao LQB 118, e em função deste resultado, os demais experimentos foram realizados com esta linhagem tumoral. O efeito citotóxico do LQB 118 se mostrou tempo e concentração dependente. Esta substância inibiu a proliferação celular e prejudicou a progressão do ciclo celular, acumulando células nas fases S e G2/M. Buscando esclarecer os mecanismos desta ação antitumoral, demonstrou-se que o LQB 118 inibe a expressão do mRNA do fator de transcrição c-Myc e das ciclinas D1 e B1, e induz a apoptose de tais células tumorais. Em suma, o LQB 118 é capaz de inibir a proliferação das células tumorais de próstata, alterando a expressão do mRNA de alguns genes reguladores do ciclo celular, resultando em interrupção do ciclo celular e indução de apoptose, indicando este composto como um potencial candidato a futuro medicamento no tratamento do câncer de próstata.

Web应用服务器自适应配置框架的设计与实现

以Web应用服务器为代表的分布式组件中间件系统(如EJB，CORBA，.NET)已发展为Web计算环境中的主要基础软件。中间件系统通过屏蔽底层平台的异构性，提供大量应用所需要的服务(如事务、安全等)，极大地简化了大规模复杂分布式系统的开发；另外，通过定义良好的组件模型，大量COTS组件能部署到任何与标准兼容的中间件平台实现上，提高了软件复用的程度。 中间件在支持应用的功能性需求方面虽然取得了较好的效果，然而在非功能性支持方面，中间件尚处于“尽力而为”的阶段，缺乏相应的服务质量保障机制，难以满足复杂多变的计算环境的要求。性能是应用系统一种非常关键的非功能特征，基于组件的应用，其性能不但受到应用设计的影响，同时受到应用所部署的中间件系统的影响，而这种影响很大程度上是中间件资源参数配置引起的（下文中如无明确说明，资源配置简称为配置）。目前大部分中间件系统只支持静态配置方式，必须通过反复地试运行来确定手工配置的参数是否能够满足应用的性能需求，该方式效率低下，而且对管理人员的要求很高；同时，对于诸如e-commerce之类的计算环境，负载始终处于高动态变化之中，静态配置方式也难以适应这种负载变化。针对上述问题，本文以EJB中间件为目标平台，提出了一种基于性能模型的自适应配置框架，能够在系统负载变化的情况下，自适应地调整中间件配置参数，更好地满足应用的性能需求。 首先，本文研究了自适应配置框架的总体架构。该框架的核心是一个基于分层排队网络的性能模型，它能够预测在给定中间件配置和负载下的性能度量。在配置决定过程中，性能模型用于评估不同候选配置，指导搜索最优的配置，从而提高性能保障的准确性和有效性。 其次，本文研究了基于分层排队网络模型的EJB性能建模技术。通过分析不同类型组件容器的请求处理行为，我们为不同类型组件建立性能模板。通过基于模型分解/组合的建模方法和模版实例化构建整个EJB应用的完整性能模型。 最后，本文描述了自适应配置框架在OnceAS2.0应用服务器上的原型实现，以及相关实验对该框架有效性的验证。

针对瞬时故障的控制流容错技术研究

随着微电子器件复杂度的提高，空间辐射对于计算机程序的正确性影响正越来越明显。一般情况下，这些影响并不是永久的，而是瞬时故障。无论是太空中的信息处理系统、嵌入式实时控制系统，还是计算机集群、高性能超级计算机都可能由于错误的输出而导致灾难性的后果。 传统的可靠性系统采用抗辐射部件和冗余的硬件来达到可靠性的要求，但是其价格昂贵，性能落后于今天的商用部件（COTS）。针对COTS在容错能力上存在的不足，软件容错技术可以在不改变硬件结构的情况下，有效的提高计算机系统的可靠性。 瞬时故障在软件层面上主要表现为控制流错误和数据流错误，本文主要针对控制流错误进行容错处理。软件实现的控制流容错技术通过在编译时加入冗余的容错逻辑，在程序执行时进行控制流错误的检测和处理。 如何在保证容错能力的同时，尽量降低冗余逻辑所带来的系统开销，是控制流容错需要解决的主要问题。本文从控制流错误的基本概念，容错单元的选择，签名信息的建立，签名点和检测点的插入位置几个角度对控制流容错进行研究，主要内容有： 1．对常见的控制流容错方法进行了分析比较，对其优点和不足予以说明。 2．对控制流错误进行了分类，以此为基础，提出了基于相关前驱基本块的控制流容错方法（CFCLRB）。 3．提出了一种签名流模型，提出了基于签名流模型的控制流容错方法（CFCSF）。该方法能够对基本块间控制流错误进行检测，具有较低的时间开销、空间开销和较高的错误覆盖率。同时，该方法可以根据容错尺度的要求，灵活的插入和删除签名点与检测点，具有极强的扩展性。该方法还可以应对动态函数指针这种编译时难以确定的控制流情况。 4．基于汇编指令对上述方法予以实现，并实现了国际上常用的控制流容错方法Control Flow Checking by Software Signatures（CFCSS）和Control-flow Error Detection through Assertions（CEDA）做为对比。通过加入冗余的指令逻辑，完成了对原程序的容错功能。 5．基于PIN工具实现了对控制流错误的注入，在相同的实验环境下对CFCLRB ，CFCSF，CFCSS，CEDA进行了对比实验。实验表明, CFCLRB的时间开销为26.9%，空间开销为27.6%，相比不具容错能力的原程序，其错误覆盖率从66.50%提升到97.32%。CFCSF的时间开销为14.7%，空间开销为22.1%，相比不具容错能力的原程序，其错误覆盖率从66.50%提升到96.79%。相比CFCSS，该方法的时间开销从37.2%下降到14.7%，空间开销从31.2%下降到22.1%，错误覆盖率从95.16%提升到96.79%。相比CEDA，该方法的时间开销从26.9%下降到14.7%，空间开销从27.1%下降到22.1%，错误覆盖率仅从97.39%下降到96.79%。 最后，本文对控制流容错的未来研究方向进行了展望。

Relationship between load/unload response ratio and damage variable and its application

The physics-based parameter: load/unload response ratio (LURR) was proposed to measure the proximity of a strong earthquake, which achieved good results in earthquake prediction. As LURR can be used to describe the damage degree of the focal media qualitatively, there must be a relationship between LURR and damage variable (D) which describes damaged materials quantitatively in damage mechanics. Hence, based on damage mechanics and LURR theory, taking Weibull distribution as the probability distribution function, the relationship between LURR and D is set up and analyzed. This relationship directs LURR applied in damage analysis of materials quantitatively from being qualitative earlier, which not only provides the LURR method with a more solid basis in physics, but may also give a new approach to the damage evaluation of big scale structures and prediction of engineering catastrophic failure. Copyright (c) 2009 John Wiley & Sons, Ltd.

Relationship between load/unload response ratio and damage variable and its application

The physics-based parameter: load/unload response ratio (LURR) was proposed to measure the proximity of a strong earthquake, which achieved good results in earthquake prediction. As LURR can be used to describe the damage degree of the focal media qualitatively, there must be a relationship between LURR and damage variable (D) which describes damaged materials quantitatively in damage mechanics. Hence, based on damage mechanics and LURR theory, taking Weibull distribution as the probability distribution function, the relationship between LURR and D is set up and analyzed. This relationship directs LURR applied in damage analysis of materials quantitatively from being qualitative earlier, which not only provides the LURR method with a more solid basis in physics, but may also give a new approach to the damage evaluation of big scale structures and prediction of engineering catastrophic failure. Copyright (c) 2009 John Wiley & Sons, Ltd.

A Dicer-1 gene from white shrimp Litopenaeus vannamei: Expression pattern in the processes of immune response and larval development

Dicer is a member of the RNAase III family which catalyzes the cleavage of double-stranded RNA to small interfering RNAs and micro RNAs, and then directs sequence-specific gene silencing. In this paper, the full-length cDNA of Dicer-1 was cloned from white shrimp Litopenaeus vannamei (designated as LvDcr1). It was of 7636 bp, including a poly A tail, a 5' UTR of 136 bp, a 3' UTR of 78 bp, and an open reading frame (ORF) of 7422 bp encoding a putative protein of 2473 amino acids. The predicted amino acid sequence comprised all recognized functional domains found in other Dicer-1 homologues and showed the highest (97.7%) similarity to the Dicer-1 from tiger shrimp Penaeus mondon. Quantitative real-time PCR was employed to investigate the tissue distribution of LvDcr1 mRNA, and its expression in shrimps under virus challenge and larvae at different developmental stages. The LvDcr1 mRNA could be detected in all examined tissues with the highest expression level in hemocyte, and was up-regulated in hemocytes and gills after virus injection. These results indicated that LvDcr1 was involved in antiviral defense in adult shrimp. During the developmental stages from fertilized egg to postlarva VII, LvDcr1 was constitutively expressed at all examined development stages, but the expression level varied significantly. The highest expression level was observed in fertilized eggs and followed a decrease from fertilized egg to nauplius I stage. Then, the higher levels of expression were detected at nauplius V and postlarva stages. LvDcr1 expression regularly increased at the upper phase of nauplius, zoea and mysis stages than their prophase. The different expression of LvDcr1 in the larval stages could provide clues for understanding the early innate immunity in the process of shrimp larval development. (C) 2010 Elsevier Ltd. All rights reserved.

Diminishing Returns of Engineering Effort in Telerobotic Systems

Wilson, M.S. and Neal, M.J., 'Diminishing Returns of Engineering Effort in Telerobotic Systems', IEEE Transactions on Systems, Man and Cybernetics - Part A:Systems and Humans, 2001, September, volume 31, number 5, pp 459-465, IEEE Robotics and Automation Society, ed. Dautenhahn,K., Special Issue on Socially Intelligent Agents - The Human in the Loop

Complying with the NIH Public Access Policy - Copyright Considerations and Options

On January 11, 2008, the National Institutes of Health ('NIH') adopted a revised Public Access Policy for peer-reviewed journal articles reporting research supported in whole or in part by NIH funds. Under the revised policy, the grantee shall ensure that a copy of the author's final manuscript, including any revisions made during the peer review process, be electronically submitted to the National Library of Medicine's PubMed Central ('PMC') archive and that the person submitting the manuscript will designate a time not later than 12 months after publication at which NIH may make the full text of the manuscript publicly accessible in PMC. NIH adopted this policy to implement a new statutory requirement under which: The Director of the National Institutes of Health shall require that all investigators funded by the NIH submit or have submitted for them to the National Library of Medicine's PubMed Central an electronic version of their final, peer-reviewed manuscripts upon acceptance for publication to be made publicly available no later than 12 months after the official date of publication: Provided, That the NIH shall implement the public access policy in a manner consistent with copyright law. This White Paper is written primarily for policymaking staff in universities and other institutional recipients of NIH support responsible for ensuring compliance with the Public Access Policy. The January 11, 2008, Public Access Policy imposes two new compliance mandates. First, the grantee must ensure proper manuscript submission. The version of the article to be submitted is the final version over which the author has control, which must include all revisions made after peer review. The statutory command directs that the manuscript be submitted to PMC 'upon acceptance for publication.' That is, the author's final manuscript should be submitted to PMC at the same time that it is sent to the publisher for final formatting and copy editing. Proper submission is a two-stage process. The electronic manuscript must first be submitted through a process that requires input of additional information concerning the article, the author(s), and the nature of NIH support for the research reported. NIH then formats the manuscript into a uniform, XML-based format used for PMC versions of articles. In the second stage of the submission process, NIH sends a notice to the Principal Investigator requesting that the PMC-formatted version be reviewed and approved. Only after such approval has grantee's manuscript submission obligation been satisfied. Second, the grantee also has a distinct obligation to grant NIH copyright permission to make the manuscript publicly accessible through PMC not later than 12 months after the date of publication. This obligation is connected to manuscript submission because the author, or the person submitting the manuscript on the author's behalf, must have the necessary rights under copyright at the time of submission to give NIH the copyright permission it requires. This White Paper explains and analyzes only the scope of the grantee's copyright-related obligations under the revised Public Access Policy and suggests six options for compliance with that aspect of the grantee's obligation. Time is of the essence for NIH grantees. As a practical matter, the grantee should have a compliance process in place no later than April 7, 2008. More specifically, the new Public Access Policy applies to any article accepted for publication on or after April 7, 2008 if the article arose under (1) an NIH Grant or Cooperative Agreement active in Fiscal Year 2008, (2) direct funding from an NIH Contract signed after April 7, 2008, (3) direct funding from the NIH Intramural Program, or (4) from an NIH employee. In addition, effective May 25, 2008, anyone submitting an application, proposal or progress report to the NIH must include the PMC reference number when citing articles arising from their NIH funded research. (This includes applications submitted to the NIH for the May 25, 2008 and subsequent due dates.) Conceptually, the compliance challenge that the Public Access Policy poses for grantees is easily described. The grantee must depend to some extent upon the author(s) to take the necessary actions to ensure that the grantee is in compliance with the Public Access Policy because the electronic manuscripts and the copyrights in those manuscripts are initially under the control of the author(s). As a result, any compliance option will require an explicit understanding between the author(s) and the grantee about how the manuscript and the copyright in the manuscript are managed. It is useful to conceptually keep separate the grantee's manuscript submission obligation from its copyright permission obligation because the compliance personnel concerned with manuscript management may differ from those responsible for overseeing the author's copyright management. With respect to copyright management, the grantee has the following six options: (1) rely on authors to manage copyright but also to request or to require that these authors take responsibility for amending publication agreements that call for transfer of too many rights to enable the author to grant NIH permission to make the manuscript publicly accessible ('the Public Access License'); (2) take a more active role in assisting authors in negotiating the scope of any copyright transfer to a publisher by (a) providing advice to authors concerning their negotiations or (b) by acting as the author's agent in such negotiations; (3) enter into a side agreement with NIH-funded authors that grants a non-exclusive copyright license to the grantee sufficient to grant NIH the Public Access License; (4) enter into a side agreement with NIH-funded authors that grants a non-exclusive copyright license to the grantee sufficient to grant NIH the Public Access License and also grants a license to the grantee to make certain uses of the article, including posting a copy in the grantee's publicly accessible digital archive or repository and authorizing the article to be used in connection with teaching by university faculty; (5) negotiate a more systematic and comprehensive agreement with the biomedical publishers to ensure either that the publisher has a binding obligation to submit the manuscript and to grant NIH permission to make the manuscript publicly accessible or that the author retains sufficient rights to do so; or (6) instruct NIH-funded authors to submit manuscripts only to journals with binding deposit agreements with NIH or to journals whose copyright agreements permit authors to retain sufficient rights to authorize NIH to make manuscripts publicly accessible.

Task Assignment in a Distributed System: Improving Performance by Unbalancing Load

We consider the problem of task assignment in a distributed system (such as a distributed Web server) in which task sizes are drawn from a heavy-tailed distribution. Many task assignment algorithms are based on the heuristic that balancing the load at the server hosts will result in optimal performance. We show this conventional wisdom is less true when the task size distribution is heavy-tailed (as is the case for Web file sizes). We introduce a new task assignment policy, called Size Interval Task Assignment with Variable Load (SITA-V). SITA-V purposely operates the server hosts at different loads, and directs smaller tasks to the lighter-loaded hosts. The result is that SITA-V provably decreases the mean task slowdown by significant factors (up to 1000 or more) where the more heavy-tailed the workload, the greater the improvement factor. We evaluate the tradeoff between improvement in slowdown and increase in waiting time in a system using SITA-V, and show conditions under which SITA-V represents a particularly appealing policy. We conclude with a discussion of the use of SITA-V in a distributed Web server, and show that it is attractive because it has a simple implementation which requires no communication from the server hosts back to the task router.

UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity.

The receptor deleted in colorectal cancer (DCC) directs dynamic polarizing activities in animals toward its extracellular ligand netrin. How DCC polarizes toward netrin is poorly understood. By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin). Time-lapse analyses revealed that UNC-40 clusters assemble, disassemble, and reform at periodic intervals in different regions of the cell membrane. This oscillatory behavior indicates that UNC-40 clusters through a mechanism involving interlinked positive (formation) and negative (disassembly) feedback. We show that endogenous UNC-6 and ectopically provided UNC-6 orient and stabilize UNC-40 clustering. Furthermore, the UNC-40-binding protein MADD-2 (a TRIM family protein) promotes ligand-independent clustering and robust UNC-40 polarization toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering. We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.

Metal oxide photoanodes for solar hydrogen production

The development of sustainable hydrogen production is a key target in the further facilitation of a hydrogen economy. Solar hydrogen generation through the photolytic splitting of water sensitised by semiconductor materials is attractive as it is both renewable and does not lead to problematic by-products, unlike current hydrogen sources such as natural gas. Consequently, the development of these semiconductor materials has undergone considerable research since their discovery over 30 years ago and it would seem prescient to review the more practical results of this research. Among the critical factors influencing the choice of semiconductor material for photoelectrolysis of water are the band-gap energies, flat band potentials and stability towards photocorrosion; the latter of these points directs us to focus on metal oxides. Careful design of thin films of photocatalyst material can eliminate potential routes of losses in performance, i.e., recombination at grain boundaries. Methods to overcome these problems are discussed such as coupling a photoanode for photolysis of water to a photovoltaic cell in a 'tandem cell' device.

Las infraestructuras de recarga y el despegue del vehículo eléctrico.

Este trabajo revisa la evolución y estado actual de la automoción eléctrica; analiza las ventajas ambientales, de eficiencia energética y de costes del motor eléctrico frente al de combustión interna; y presenta como limitaciones para el uso del vehículo eléctrico, el desarrollo actual de las baterías recargables y la lenta implantación de electrolineras. Con el objetivo de contribuir al desarrollo de una actividad económica respetuosa con el medio ambiente y basada en nuevas tecnologías, se proyecta, a partir de experiencias previas, una instalación de puntos de recarga para una ciudad de 50.000 habitantes con un parque de 100 vehículos eléctricos que dispone de dos plazas de recarga rápida (poste trifásico 400V CA), siete plazas de recarga lenta (postes monofásicos 230V CA) y de 50 módulos fotovoltaicos que producen diariamente la energía equivalente a la recarga lenta de un vehículo en los meses fríos y de dos en los meses cálidos.

Pupil participation in school life: an approach from the educational community

The Convention on the Rights of the Child (CRC, 1989) is currently the most ratified international treaty. Several authors have highlighted its potential for both a moral education and citizenship. However, paradoxically, different studies report its limited or occasional incorporation into school practices. This article explores experiences of participation in schools,the third P of the CRC, from the plurality of voices and actors of the educational community,by means of 14 discussion groups in 11 autonomous communities in Spain. Discourse analysis evidence low levels of student participation in school life. But, at the same time, a favorable educational environment for the development of projects that contribute to child participation is found, as well as for the incorporation of the CRC as a mover and a referential integrator of the different schools projects. However, it is also an educational background conductive to projects for its development, such as the incorporation of the CRC as a referential integrator of the schools projects.

Parent-offspring conflict and motivational control of brooding in an amphipod (Crustacea)

Models of parent - offspring conflict concerning levels of caregiving centre on conflict resolution by offspring control, compromise or offspring 'honest signalling' that parents use to maximize their own fitness. Recent empirical studies on motivational control of parental feeding of offspring are interpreted as supporting the latter model. Here, we examine parental care in an amphipod, Crangonyx pseudogracilis, which directs care to embryos in a brood pouch. Embryo removal and transplantation elucidated causal factors that determine levels of caregiving. In the short-term, females with all embryos removed reduced care activities, but partial embryo removal did not affect caregiving, evidence of 'unshared' parental care. In the long-term, females with all embryos removed ceased care. Thus, females have a maternal state that is maintained by stimuli from offspring. Transplantation of early/late stage embryos among females originally carrying early/late stage embryos revealed that stimuli from embryos indicate their age-dependent needs, but only modify caregiving within the constraints of a changing endogenous maternal state. Thus, we demonstrate that mothers and offspring share motivational control of care. However, we highlight the inappropriate use of motivational data in reaching conclusions about the resolution of parent - offspring conflict.

Secretory products of the haptoral reservoirs and peduncular glands in two species of Bravohollisia (Monogenea : Ancyrocephalidae)

Light and electron microscopy were used to characterize the structure of secretory cells and their products involved in attachment of two monogenean parasites of fish, in order to understand their role in the attachment process. In Bravohollisia rosetta and Bravohollisia gussevi, peduncular gland cells with two nuclei, granular endoplasmic reticulum, and Golgi bodies produce dual electron-dense (DED) secretory bodies with a homogenous electron-dense rind and a less electron-dense fibrillar core (oval and concave in B. rosetta and oval in B. gussevi). The DED secretory bodies are altered as they migrate from the gland cell to the haptoral reservoir, the superficial anchor grooves, and into the gill tissues. The contents of the DED secretory bodies are exocytosed into the reservoirs, fibrillar cores persisting in the matrix, some of which condense, forming highly electron-dense spherical bodies. Small, oval, electron-dense bodies occur in the grooves, while no inclusions are visible in the homogenous exudate within the gill tissues. The single tubular extension of the reservoir enters a bifurcate channel within the anchor via a concealed, crevice-like opening on one side of the anchor. The channel directs secretions into the left and the right grooves via concealed apertures. The secretions, introduced into the tissues by the anchors, probably assist in attachment. The secretions are manifested externally as net-like structures and observed in some cases to be still attached to the point of exudation, on anchors detached from the gill tissues. This suggests that despite having the anchors detached, the worms can still remain anchored to the gill tissues via these net-like structures. Based on this, it is postulated that the net-like secretions probably function as a safety line to anchor the worm during the onset of locomotion and in doing so reduce the risk of tearing host tissues.