Suchergebnisse

Argues that the Israel Lobby negatively impacts academic freedom, using case examples of the U of Michigan, DePaul U, & St. Thomas U. Adapted from the source document.

Protein folding homeostasis in the lumen of the endoplasmic reticulum is defended by signal transduction pathways that are activated by an imbalance between unfolded proteins and chaperones (so called ER stress). Collectively referred to as the unfolded protein response (UPR) this homeostatic response is initiated by three known ER stress transducers: IRE1, PERK and ATF6. These ER-localised transmembrane (TM) proteins posses lumenal stress sensing domains and cytosolic effector domains that collectively activate a gene expression programme regulating the production of proteins involved in the processing and maturation of secreted proteins that enter the ER. However, beyond limiting unfolded protein stress in the ER the UPR has important connections to lipid metabolism that are the subject of this review. ; This work was supported by a Wellcome Trust Intermediate Clinical Fellowship (to R.V.), a Wellcome Trust Principal Research Fellowship (to D.R.), and European Union Seventh Framework Programme Grant (Beta Bat, 277713). ; This is the final published version. It first appeared at: http://www.sciencedirect.com/science/article/pii/S0955067414001434#.

RIG-I-like receptors detect viral RNA in infected cells and promote oligomerization of the outer mitochondrial membrane protein MAVS to induce innate immunity to viral infection through type I interferon production. Mitochondrial reactive oxygen species (mROS) have been shown to enhance anti-viral MAVS signalling, but the mechanisms have remained obscure. Using a biochemical oligomerization-reporter fused to the transmembrane domain of MAVS, we found that mROS inducers promoted lipid-dependent MAVS transmembrane domain oligomerization in the plane of the outer mitochondrial membrane. These events were mirrored by Sendai virus infection, which similarly induced lipid peroxidation and promoted lipid-dependent MAVS transmembrane domain oligomerization. Our observations point to a role for mROS-induced changes in lipid bilayer properties in modulating antiviral innate signalling by favouring the oligomerization of MAVS transmembrane domain in the outer-mitochondrial membrane. ; This work was supported by a Wellcome Trust Intermediate Clinical Fellowship (093764 o RV), a Wellcome Trust Principal Research Fellowship (084812 to DR), a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (100140) and European Union Seventh Framework Programme Grant (Beta Bat, 277713). T

Lung cancer is the deadliest cancer worldwide and is of particular concern for Latin America. Its rising incidence in this area of the world poses myriad challenges for the region's economies, which are already struggling with limited resources to meet the health care needs of low- and middle-income populations. In this environment, we are concerned that regional governments are relatively unaware of the pressing need to implement effective strategies for the near future. Low-dose chest computed tomography (LDCT) for screening, and routine use of minimally invasive techniques for diagnosis and staging remain uncommon. According to results of the National Lung Screening Trial, LDCT lung cancer screening provided a 20% relative reduction in mortality rates among at-risk individuals. Nevertheless, this issue is still a matter of debate, particularly in developing countries, and it is not fully embraced in developing countries. The aim of this article is to provide an overview of what the standard of care is for lung cancer computed tomography screening around the world and to aid understanding of the challenges and potential solutions that can help with the implementation of LDCT in Latin America.

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins. ; Supported by Canadian Institutes of Health Research (PEF, PStGH), Alzheimer Society of Ontario (PEF, PStGH), Wellcome Trust (PStGH, MEV, CFK, GSK, DR, CEH), Medical Research Council (PStGH, MEV, CFK, GSK), National Institutes of Health Research, Alzheimer Research UK (CFK, GSK), Gates Cambridge Scholarship (JQL), Engineering and Physical Sciences Research Council (CFK, GSK), European Research Council Starting Grant RIBOMYLOME_309545 (GGT), European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement no. 322817 (CEH), and National Institute of Neurological Disorders and Stroke R01 NS07377 (NAS). The authors thank Tom Cech and Roy Parker for helpful discussions. ; This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.neuron.2015.10.030