PI3K mediated activation of GSK‑3β reduces at‑level primary afferent growth responses associated with excitotoxic spinal cord injury dysesthesias

Background Neuropathic pain and sensory abnormalities are a debilitating secondary consequence of spinal cord injury (SCI). Maladaptive structural plasticity is gaining recognition for its role in contributing to the development of post SCI pain syndromes. We previously demonstrated that excitotoxic induced SCI dysesthesias are associated with enhanced dorsal root ganglia (DRG) neuronal outgrowth. Although glycogen synthase kinase-3β (GSK-3β) is a known intracellular regulator neuronal growth, the potential contribution to primary afferent growth responses following SCI are undefined. We hypothesized that SCI triggers inhibition of GSK-3β signaling resulting in enhanced DRG growth responses, and that PI3K mediated activation of GSK-3β can prevent this growth and the development of at-level pain syndromes. Results Excitotoxic SCI using intraspinal quisqualic acid (QUIS) resulted in inhibition of GSK-3β in the superficial spinal cord dorsal horn and adjacent DRG. Double immunofluorescent staining showed that GSK-3βP was expressed in DRG neurons, especially small nociceptive, CGRP and IB4-positive neurons. Intrathecal administration of a potent PI3-kinase inhibitor (LY294002), a known GSK-3β activator, significantly decreased GSK-3βP expression levels in the dorsal horn. QUIS injection resulted in early (3 days) and sustained (14 days) DRG neurite outgrowth of small and subsequently large fibers that was reduced with short term (3 days) administration of LY294002. Furthermore, LY294002 treatment initiated on the date of injury, prevented the development of overgrooming, a spontaneous at-level pain related dysesthesia. Conclusions QUIS induced SCI resulted in inhibition of GSK-3β in primary afferents and enhanced at-level DRG intrinsic growth (neurite elongation and initiation). Early PI3K mediated activation of GSK-3β attenuated QUIS-induced DRG neurite outgrowth and prevented the development of at-level dysesthesias.ECU Open Access Publishing Support Fun

Cross-Country Heterogeneity and Endogeneity Bias in Life Satisfaction Estimations - Macro- and Micro-Level Evidence for Advanced, Developing and Transition Countries

The past literature found evidence for the presence of endogeneity issues due to individuals' heterogeneity and omitted time-varying variables in the relationship between income and life satisfaction on the micro-level for the UK (Powdthavee (2010)). The aim of the present contribution is to put these results in a broader context and to investigate the role of cross-country heterogeneity and income endogeneity in estimations on life satisfaction for sub-samples of advanced, developing and transition countries. The paper is innovative in merging this methodology with a multi-country setting, particularly considering transition and developing countries. Instrumenting for income, we find that cross-country heterogeneity is associated with a significantly lower estimate for the income effect, whereas controlling for endogeneity bias delivers significantly higher estimates. This points to a negative bias in the OLS estimate, and thus approves previous literature's findings. Capturing endogeneity appears to be essential in studies on life satisfaction. The negative bias apparently is highest for the sub-sample of transition countries and lowest for advanced countries. Most of the macro- and micro-level impacts are in line with the previous literature

Services Sectors' Concentration: The European Union, Greece, and the New Economic Geography

The aim of this article is to investigate services sectors' concentration in the European Union based on employment data and to disentangle the sector-specific developments and influential factors over time. We find that only the financial intermediation, retail trade and water transport sectors are subject to an increasing level of concentration over time. Moreover, we can detect a strong specialization tendency in the sectors of tourism and public administration for the Greek economy. Implementing a two-way fixed effects model, we find that knowledge spillovers as well as externalities arising from technological similarities appear to be highly significant in explaining services' concentration patterns for the European Union. Technological differences as a reason for services' concentration only appear to have been important in the period prior to the Single European Market Enactment. Further evidence is found for the relevance of factor intensity in explaining concentration of non-market services

Identification of functional differences between recombinant human α and β cardiac myosin motors

The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is >ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding

Modeling Services Sectors’ Agglomeration within a New Economic Geography Model

This study investigates whether services sectors' agglomeration can be explained within a common New Economic Geography model by Krugman and Venables (1996). Special feature of this modeling is to account for the lower importance of intermediate goods received for the services sector, a fact that has been shown in Empirics for the European Union (Krenz (2010)). The results show different strengths of agglomeration for both the industrial and services sector depending on initial values of strength of intra-sectoral and inter-sectoral inputs, consumers' preferences, scale economies and transport costs. The lower extent of services sectors' agglomeration seen in Empirics can be explained within the model

A Panel Co-Integration Analysis of Industrial and Services Sectors' Agglomeration in the European Union

This study empirically investigates the relevance of Traditional Trade Theory, New Trade Theory and New Economic Geography in explaining industrial and services sectors' agglomeration in the European Union. Therefore, new dynamic panel data estimation techniques will be employed. Static panel data analysis reveals that assumptions of New Trade Theory and New Economic Geography can explain industrial concentration in the EU best. Results from dynamic panel OLS show that intermediate goods' intensity and therewith New Economic Geography's assumptions are important in explaining both industrial and services sectors' agglomeration. Several non-stationarity and co-integration relationships can be detected. Further, decomposition of effects across and within sectors is provided. Scale economies are only important for across industries' variation in agglomeration, not within. For services sectors' agglomeration results show that intermediate goods intensity matters only for within and not across industries' variation in agglomeration. Further evidence for intrasectoral trade explaining equalizing economic structures for services sectors is given