Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase

Introduction: Tuberous sclerosis complex (TSC) is a genetic disease resulting from mutation in TSC1 or TSC2 and subsequent hyperactivation of mammalian Target of Rapamycin (mTOR). Common TSC features include brain lesions, such as cortical tubers and subependymal giant cell astrocytomas (SEGAs). However, the current treatment with mTOR inhibitors has critical limitations. We aimed to identify new targets for TSC pharmacotherapy. Results: The results of our shRNA screen point to glutamate-cysteine ligase catalytic subunit (GCLC), a key enzyme in glutathione synthesis, as a contributor to TSC-related phenotype. GCLC inhibition increased cellular stress and reduced mTOR hyperactivity in TSC2-depleted neurons and SEGA-derived cells. Moreover, patients’ brain tubers showed elevated GCLC and stress markers expression. Finally, GCLC inhibition led to growth arrest and death of SEGA-derived cells. Conclusions: We describe GCLC as a part of redox adaptation in TSC, needed for overgrowth and survival of mutant cells, and provide a potential novel target for SEGA treatment. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0225-z) contains supplementary material, which is available to authorized users

Climate scenario development and applications for local/regional climate change impact assessments: An overview for the non-climate scientist. Geography Compass 5: 301–28

Abstract Although downscaling methods for deriving local ⁄ regional climate change scenarios have been extensively studied, little guidance exists on how to use the downscaled scenarios in applications such as impact assessments. In this second part of a two-part communication, we review for nonclimate scientists a number of practical considerations when utilizing climate change scenarios. The issues discussed are drawn from questions frequently asked by our colleagues on assessment teams and include sources of observational data for scenario evaluation, the advantages of scenario ensembles, adjusting for scenario biases, and the availability of archived downscaled scenarios. Together with Part I, which reviews various downscaling methods, Part II is intended to improve the communication between suppliers and users of local ⁄ regional climate change scenarios, with the overall goal of improving the utility of climate impact assessments through a better understanding by all assessment team members of the strengths and limitations of local ⁄ regional climate change scenarios

Climate scenario development and applications for local / regional climate change impact assessments : anoverview for the non-climate scientist

Abstract The majority of climate change impact assessments focus on potential impacts at the local ⁄ regional scale. Climate change scenarios with a fine spatial resolution are essential components of these assessments. Scenarios must be designed with the goals of the assessment in mind. Often the scientists and stakeholders leading, or participating in, impact assessments are unaware of the challenging and time-consuming nature of climate scenario development. The intent of this review, presented in two parts, is to strengthen the communication between the developers and users of climate scenarios and ultimately to improve the utility of climate impact assessments. In Part I, approaches to climate downscaling are grouped into three broad categoriesdynamic downscaling, empirical-dynamic downscaling and disaggregation downscaling methods -and the fundamental considerations of the different methods are highlighted and explained for non-climatologists. Part II focuses on the application of climate change scenarios

Climate scenario development and applications for local/regional climate change impact assessments: An overview for the non-climate scientist. Geography Compass 5: 301–28

Abstract The majority of climate change impact assessments focus on potential impacts at the local ⁄ regional scale. Climate change scenarios with a fine spatial resolution are essential components of these assessments. Scenarios must be designed with the goals of the assessment in mind. Often the scientists and stakeholders leading, or participating in, impact assessments are unaware of the challenging and time-consuming nature of climate scenario development. The intent of this review, presented in two parts, is to strengthen the communication between the developers and users of climate scenarios and ultimately to improve the utility of climate impact assessments. In Part I, approaches to climate downscaling are grouped into three broad categoriesdynamic downscaling, empirical-dynamic downscaling and disaggregation downscaling methods -and the fundamental considerations of the different methods are highlighted and explained for non-climatologists. Part II focuses on the application of climate change scenarios

GSK3 beta Controls mTOR and Prosurvival Signaling in Neurons

Glycogen synthase kinases-3β (GSK3β) is a key regulator of cell homeostasis. In neurons, GSK3β contributes to control of neuronal transmission and plasticity. Despite extensive studies in non-neuronal cells, crosstalk between GSK3β and other signaling pathways remains not well defined in neurons. In the present study, we report that GSK3β positively affected the activity of effectors of mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2), in mature neurons in vitro and in vivo. GSK3β also promoted prosurvival signaling and attenuated kainic acid-induced apoptosis. Our study identified GSK3β as a positive regulator of prosurvival signaling, including the mTOR pathway, and indicates the possible neuroprotective role of GSK3β in models of pharmacologically induced excitotoxicity.status: publishe

A Conceptual Framework for Multi-Regional Climate Change Assessments for International Market Systems with Long-Term Investments

A conceptual framework for climate change assessments of international market systems that involve long-term investments is proposed. The framework is a hybrid of dynamic and static modeling. Dynamic modeling is used for those system components for which temporally continuous modeling is possible, while fixed time slices are used for other system components where it can be assumed that underlying assumptions are held constant within the time slices but allowed to vary between slices. An important component of the framework is the assessment of the “metauncertainty” arising from the structural uncertainties of a linked sequence of climate, production, trade and decision-making models. The impetus for proposing the framework is the paucity of industry-wide assessments for market systems with multiple production regions and long-term capital investments that are vulnerable to climate variations and change, especially climate extremes. The proposed framework is pragmatic, eschewing the ideal for the tractable. Even so, numerous implementation challenges are expected, which are illustrated using an example industry. The conceptual framework is offered as a starting point for further discussions of strategies and approaches for climate change impact, vulnerability and adaptation assessments for international market systems