Dual role of the exocyst in AMPA receptor targeting and insertion into the postsynaptic membrane

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102104/1/emboj7601065.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102104/2/emboj7601065-sup-0001.pd

Understanding Russia's return to the Middle East

Over recent years, there has been a significant resurgence of Russian power and influence in the Middle East, which has been evident in the diplomatic and military intervention into Syria. This article identifies the principal factors behind Russia’s return to the region. First, there are domestic political influences with the coincidence of the uprisings in the Middle East, the so-called ‘Arab Spring,’ with large-scale domestic opposition protests within Russia during the elections in 2011–2012. Second, there is the role of ideas, most notably the growing anti-Westernism in Putin’s third presidential term, along with Russia’s own struggle against Islamist terrorism. These ideational factors contributed to Russia’s resolve to support the Assad government against both Western intervention and its domestic Islamist opposition. Third, Russia has benefited from a pragmatic and flexible approach in its engagement with the region. Moscow seeks to ensure that it is a critical actor for all the various states and political movements in the Middle East

Broadly neutralizing antibodies abrogate established hepatitis C virus infection

In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs—AR3A, AR3B, and AR4A—delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection

Statistical evaluation of a new resistance model for cold-formed stainless steel cross-sections subjected to web crippling

This paper presents a statistical evaluation according to Annex D of EN 1990 (2002) of a new resistance function for web crippling design of cold-formed stainless steel cross-sections. This resistance function was derived by Bock et al. (2013) through the use of carefully validated numerical models with the aim to propose a design expression for stainless steel sections, which are currently designed following the provisions for cold-formed carbon steel sections given in EN 1993-1-3 (2006). Although it was shown that the proposed design equation is appropriate for application to various stainless steels, the statistical uncertainties in material properties that the different types of stainless steels exhibit require an assessment of various partial safety factors. The statistical assessment showed that the proposed resistance function by Bock et al. (2013) requires adjustment to satisfy the safety level set out in EN 1993-1-4 (2006); A recalibration is performed herein. The web crippling design provisions given in EN 1993-1-3 (2006) and SEI/ASCE 8-02 (2002) American standard for application to stainless steel are also statistically evaluated herein. Comparison with test and numerical data showed that the predictions of the recalibrated resistance function are better suited and consistent than existing design provisionsResearch Fund for Coal and Stee

Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells

Decreased left ventricle (LV) function caused by genetic mutations or injury often leads to debilitating and fatal cardiovascular disease. LV cardiomyocytes are, therefore, a potentially valuable therapeutical target. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are neither homogeneous nor functionally mature, which reduces their utility. Here, we exploit cardiac development knowledge to instruct differentiation of hPSCs specifically toward LV cardiomyocytes. Correct mesoderm patterning and retinoic acid pathway blocking are essential to generate near-homogenous LV-specific hPSC-CMs (hPSC-LV-CMs). These cells transit via first heart field progenitors and display typical ventricular action potentials. Importantly, hPSC-LV-CMs exhibit increased metabolism, reduced proliferation, and improved cytoarchitecture and functional maturity compared with age-matched cardiomyocytes generated using the standard WNT-ON/WNT-OFF protocol. Similarly, engineered heart tissues made from hPSC-LV-CMs are better organized, produce higher force, and beat more slowly but can be paced to physiological levels. Together, we show that functionally matured hPSC-LV-CMs can be obtained rapidly without exposure to current maturation regimes

Changing foreign policy: the Obama Administration’s decision to oust Mubarak

This paper analyses the decision of the Obama administration to redirect its foreign policy towards Egypt in the wake of the Arab Spring. It attempts to highlight the issue of how governments deal with decision-making at times of crisis, and under which circumstances they take critical decisions that lead to major shifts in their foreign policy track record. It focuses on the process that led to a reassessment of US (United States) foreign policy, shifting from decades of support to the autocratic regime of Hosni Mubarak, towards backing his ouster. Specifically, the paper attempts to assess to what extent the decision to withdraw US support from a longstanding state-leader and ally in the Middle East can be seen as a foreign policy change (FPC). A relevant research question this paper pursues is: how can the withdrawal of US support to a regime considered as an ally be considered, in itself, as a radical FPC

Identification of a Novel Signaling Pathway and Its Relevance for GluA1 Recycling

We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P2. In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P2 in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory