On the self-association potential of transmembrane tight junction proteins

Tight junctions seal intercellular clefts via membrane-related strands, hence, maintaining important organ functions. We investigated the self-association of strand-forming transmembrane tight junction proteins. The regulatory tight junction protein occludin was differently tagged and cotransfected in eucaryotic cells. These occludins colocalized within the plasma membrane of the same cell, coprecipitated and exhibited fluorescence resonance energy transfer. Differently tagged strand-forming claudin-5 also colocalized in the plasma membrane of the same cell and showed fluorescence resonance energy transfer. This demonstrates self-association in intact cells both of occludin and claudin-5 in one plasma membrane. In search of dimerizing regions of occludin, dimerization of its cytosolic C-terminal coiledcoil domain was identified. In claudin-5, the second extracellular loop was detected as a dimer. Since the transmembrane junctional adhesion molecule also is known to dimerize, the assumption that homodimerization of transmembrane tight junction proteins may serve as a common structural feature in tight junction assembly is supported. Received 6 October 2005; received after revision 14 December 2005; accepted 27 December 2005 †These authors contributed equally to this work.     

Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies

Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to new therapeutic approaches. Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006     

The neurotrophic receptor TrkB: a drug target in anti-cancer therapy?

Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target, and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer. Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006     

Optimal maintenance and replacement of extraction machinery

This paper considers a problem of optimal preventive maintenance and replacement schedule of equipment devoted to extracting resources from known deposits. Typical examples are oil drills, mine shovels, etc. At most one replacement of the existing machinery by a new one is allowed. The problem is formulated as an optimal control problem subject to the state constraint that the remaining deposit at any given time is nonnegative. We show that the optimal preventive maintenance, production rates, and the replacement and salvage times of the existing machinery and the new one, if required, can be obtained by solving sequentially a series of free-end-point optimal control problems. Moreover, an algorithm based on this result is developed and used to solve two illustrative examples.     

从人工生命到人工社会--复杂社会系统研究的现状和展望

介绍了人工社会研究工作的内容、方法及其思想基础，并对其应用和未来趋势进行展望。文中简述了社会学研究的历史阶段、主要问题和困难，人工生命和人工社会方法的有效性，并着重描述了Epstein和Axtell的工作，以及相应的涌现方法在复杂社会系统研究中的中心作用。本文还讨论了目前对人工社会方法的各种批判意见及其回应。     

Immigration, emigration and the ageing of the overseas-born population in the United Kingdom

This article uses data from the 1971 and 2001 Censuses, the 1999-2003 Labour Force Survey and the 1977 to 2002 International Passenger Survey to investigate the migration processes contributing to the age structure and ageing of the UK's overseas-born population. Overall almost half of recent decades' immigrants to the UK emigrate again within five years of arrival, but with large variation by overseas country of birth. Between half and two thirds of the immigrants born in the continental European Union, North America and Oceania emigrate again within five years, while 15 per cent of those born in the Indian subcontinent do so. Significant cumulative emigration more than five years after arrival is seen among earlier immigrants from the Indian subcontinent, the Caribbean Commonwealth and Europe. Large country-of-origin variations in the ratio of pension-age population to working-age population primarily reflect the country composition of immigration streams 30 or more years before.     

Simultaneous care for parents and care for children among mid-life British women and men

This article investigates care provided to parents and parents-in-law by mid-life adults with dependent children at home. Data from the General Household Survey are used first to estimate the prevalence of this 'two-way' care over the past decade, and second to develop forecasts of two-way care for a generation of women who have just finished their childbearing years. Having a higher education qualification is associated with later ages both of caring for parents and of having children at home. Increasingly late first childbearing, however, points towards a potentially greater caring 'squeeze' for higher-qualified women, with a little over 1 in 10 at age 45 projected to be caring for a parent while still having a child under 18 in the household.     

Which authorities are alike?

This article describes the first results from the recent revision to The ONS classification of local and health authorities of Great Britain to allow for boundary changes. For each local and health authority of Great Britain as at April 1999 it presents 'most similar' authorities as measured by a selection of 37 socioeconomic and demographic variables from the 1991 Census. These results will assist local and health authorities in identifying other appropriate authorities for comparative studies. A second article, to be published in Population Trends 99, will present the results of the analysis to identify groups of authorities in a hierarchy of new Clusters, Groups and Families for the revised classification.     

Best weight pattern evaluation based security constrained power dispatch algorithm

This paper presents a methodology which determines the allocation of power demand among the committed generating units while minimizes number of objectives as well as meets physical and technological system constraints. The procedure considers two decoupled problems based upon the dependency of their goals on either active power or reactive power generation. Both the problems have been solved sequentially to achieve optimal allocation of active and reactive power generation while minimizes operating cost, gaseous pollutants emission objectives and active power transmission loss with consideration of system operating constraints along with generators prohibited operating zones and transmission line flow limits. The active and reactive power line flows are obtained with the help of generalized generation shift distribution factors （GGDF） and generalized Z-bus distribution factors （GZBDF）, respectively. First problem is solved in multi-objective framework in which the best weights assigned to objectives are determined while employing weighting method and in second problem, active power loss of the system is minimized subject to system constraints. The validity of the proposed method is demonstrated on 30-bus IEEE power system.