Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Interaction of plant growth regulators and reactive oxygen species to regulate petal senescence in wallflowers (Erysimum linifolium)

Background In many species floral senescence is coordinated by ethylene. Endogenous levels rise, and exogenous application accelerates senescence. Furthermore, floral senescence is often associated with increased reactive oxygen species, and is delayed by exogenously applied cytokinin. However, how these processes are linked remains largely unresolved. Erysimum linifolium (wallflower) provides an excellent model for understanding these interactions due to its easily staged flowers and close taxonomic relationship to Arabidopsis. This has facilitated microarray analysis of gene expression during petal senescence and provided gene markers for following the effects of treatments on different regulatory pathways. Results In detached Erysimum linifolium (wallflower) flowers ethylene production peaks in open flowers. Furthermore senescence is delayed by treatments with the ethylene signalling inhibitor silver thiosulphate, and accelerated with ethylene released by 2-chloroethylphosphonic acid. Both treatments with exogenous cytokinin, or 6-methyl purine (which is an inhibitor of cytokinin oxidase), delay petal senescence. However, treatment with cytokinin also increases ethylene biosynthesis. Despite the similar effects on senescence, transcript abundance of gene markers is affected differentially by the treatments. A significant rise in transcript abundance of WLS73 (a putative aminocyclopropanecarboxylate oxidase) was abolished by cytokinin or 6-methyl purine treatments. In contrast, WFSAG12 transcript (a senescence marker) continued to accumulate significantly, albeit at a reduced rate. Silver thiosulphate suppressed the increase in transcript abundance both of WFSAG12 and WLS73. Activity of reactive oxygen species scavenging enzymes changed during senescence. Treatments that increased cytokinin levels, or inhibited ethylene action, reduced accumulation of hydrogen peroxide. Furthermore, although auxin levels rose with senescence, treatments that delayed early senescence did not affect transcript abundance of WPS46, an auxin-induced gene. Conclusions A model for the interaction between cytokinins, ethylene, reactive oxygen species and auxin in the regulation of floral senescence in wallflowers is proposed. The combined increase in ethylene and reduction in cytokinin triggers the initiation of senescence and these two plant growth regulators directly or indirectly result in increased reactive oxygen species levels. A fall in conjugated auxin and/or the total auxin pool eventually triggers abscission

The distribution and re-distribution of income of selfemployed as freelancers and entrepreneurs in Europe

The economic transformations of modern industrial societies have changed the labor markets in terms of industrial relations and occupational structure. The transformation of the traditional welfare state, the deregulation of the labor markets, the technological change and the reorganization of industrial structures influenced strongly the attitude of individuals towards their preferred labor contract. The structural change of the occupational structure was one of the results of this tendency. In particular the self-employed and freelancers have been affected and are a driving factor of labor market changings. On the one side the value of autonomy regarding industrial relations is becoming more important for employees. On the other side employers want to get rid of social security contributions. As a result the multitudinousness of these professions increased. The increasing varieties of occupations among the self-employed and freelancers influenced strongly their income distribution. Recent studies for Germany have shown a great dispersion and a heterogeneous structure of earnings in particular of freelancers (liberal professions) and self-employed. Though there are a variety of international income distribution studies, but – as to the best to our knowledge – no study focusing on the selfemployed and freelancers within the total labor force. In our study we concentrate on the income distribution of self-employed and freelancers in different European countries. Based on the Luxembourg Income Study (LIS) we analyze five different European countries and the United States structured by different types of welfare states according to Esping Anderson. We analyze income distributional aspects, an occupational decomposition à la Shorrocks, and re-distributional effects of the tax and transfer systems

Start-up success of freelancers New microeconometric evidence from the German Socio-Economic Panel

If certain start-up characteristics will indicate a business success, knowing such characteristics could generate more successful start-ups and more efficient start-up counseling. Our study will contribut e to this by quantifying individual success determinants of freelance start-ups. The data base for the microeconometric analyses of the survival of the first three years is a revised German Socio-Economic Panel (SOEP) for 1992 until 2002, which allows to incorporate institutional, personal and family/household socio-economic variables. We describe and discuss the datawork to achieve compatible information over time within a revised GSOEP and present microeconometric rare events logit, logit and probit results. The start-up success measured as the probability to survive the first three years is first of all influenced by an active labour force participation with its acquired skills and working experiences just before the start-up period (rank 1), followed by a non-university degree as the highest general human capital indicator (rank 2), a general (non-linear) experience indicated by age (rank 3) and the business related background (rank 4) as the type of liberal profession in the group of the liberal medical professions and the liberal technical and scientific professions

Timing, Fragmentation of Work and Income Inequality - An Earnings Treatment Effects Approach

Traditional welfare analyses based on money income needs to be broadened by its time dimension. In the course of time the traditional full-time work is diminishing and new labour arrangements are discussed (keyword: flexible labour markets). Our study is contributing to economic well-being by adding insights into particular work effort characteristics - the daily timing of work and its fragmentation - and its resulting income distribution. With our focus on ‘who is working when within a day with which earnings consequences’ we go beyond traditional labour market analyses with its working time division into aggregated full and part time work, working hours spread across a week and weekend, life time working etc. Whereas the first part of our study is describing the distribution of timing and fragmentation of daily work time and its resulting income based on more than 35.000 diaries of the recent German Time Budget Survey 2001/2002, the second part of our study quantifies determinants of arrangement specific earnings functions detecting significant explanatory pattern of what is behind. The economic theory behind is a human capital approach in a market and non-market context, extended by non-market time use, the partner’s working condition, social networking as well as household and regional characteristics. The econometrics use a treatment effects type interdependent estimation of endogenous participation (selection) in a daily working hour pattern (self-selection)and pattern specific earnings function explanation. The overall result: Individual earnings in Germany are dependent on and significant different with regard to the daily working hour arrangement capturing timing and fragmentation of work time. Market and non-market factors are important and significant in explaining earnings

The Timing of Daily Demand for Goods and Services – Multivariate Probit Estimates and Microsimulation Results for an Aged Population with German Time Use Diary Data

Though consumption research provides a broad spectrum of theoretical and empirical founded results, studies based on a daily focus are missing. Knowledge about the individual timing of daily demand for goods and services, opens – beyond a genuine contribution to consumption research – interesting societal and macro economic as well as individual personal and firm perspectives: it is important for an efficient timely coordination of supply and demand in the timing perspective as well as for a targeted economic, social and societal policy for a better support of the every day coordination of life. Last not least, the individual daily public and private living situations will be visible, which are of particular importance for the social togetherness in family and society. Our study contributes to the timing of daily consumption for goods and services with an empirical founded microanalysis on the basis of more than 37.000 individual time use diaries of the nationwide Time Budget Survey of the German Federal Statistical Office 2001/02. We describe the individual timing of daily demand for goods and services for important socio-demographic groups like for women and men, the economic situation with income poverty and daily working hour arrangements. The multivariate microeconometric explanation of the daily demand for goods and services is based on a latent utility maximizing approach over a day. We estimate an eight equation Multivariate/Simultaneous Probit Model, which allows the decision for multiple consumption activities in more than one time period a day. The estimates quantify effects on the timing of daily demand by individual socio-economic variables, which encompasses, personal, household, regional characteristics as well as daily working hour arrangements within a flexible labour market. The question about individual effects of an aged society on the timing of daily demand for goods and services is analyzed with our microsimulation model ServSim and a population forecast for 2020 by the German Federal Statistical Office. Main result: There are significant differences in explaining the timing of daily demand for goods compared to services on the one hand and in particular for different daily time periods. The conclusion: without the timing aspects an important and significant dimension for understanding individual consumption behaviour and their impacts on other individual living conditions would be missing

Genome Stability of Lyme Disease Spirochetes: Comparative Genomics of Borrelia burgdorferi Plasmids

Lyme disease is the most common tick-borne human illness in North America. In order to understand the molecular pathogenesis, natural diversity, population structure and epizootic spread of the North American Lyme agent, Borrelia burgdorferi sensu stricto, a much better understanding of the natural diversity of its genome will be required. Towards this end we present a comparative analysis of the nucleotide sequences of the numerous plasmids of B. burgdorferi isolates B31, N40, JD1 and 297. These strains were chosen because they include the three most commonly studied laboratory strains, and because they represent different major genetic lineages and so are informative regarding the genetic diversity and evolution of this organism. A unique feature of Borrelia genomes is that they carry a large number of linear and circular plasmids, and this work shows that strains N40, JD1, 297 and B31 carry related but non-identical sets of 16, 20, 19 and 21 plasmids, respectively, that comprise 33–40% of their genomes. We deduce that there are at least 28 plasmid compatibility types among the four strains. The B. burgdorferi ∼900 Kbp linear chromosomes are evolutionarily exceptionally stable, except for a short ≤20 Kbp plasmid-like section at the right end. A few of the plasmids, including the linear lp54 and circular cp26, are also very stable. We show here that the other plasmids, especially the linear ones, are considerably more variable. Nearly all of the linear plasmids have undergone one or more substantial inter-plasmid rearrangements since their last common ancestor. In spite of these rearrangements and differences in plasmid contents, the overall gene complement of the different isolates has remained relatively constant