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Mao X.R.,University of Washington | Crowder C.M.,University of Washington | Crowder C.M.,Washington University
Molecular and Cellular Biology | Year: 2010

Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe hypoxia can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein response pathway (UPR) has been known for some time to respond to hypoxia and regulate hypoxic sensitivity; however, the role of the UPR, if any, in HP essentially has been unexplored. We have shown previously that a sublethal hypoxic exposure of the nematode Caenorhabditis elegans induces a protein chaperone component of the UPR (L. L. Anderson, X. Mao, B. A. Scott, and C. M. Crowder, Science 323:630-633, 2009). Here, we show that HP induces the UPR and that the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6. HP also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP. The phosphorylation of the translation factor eIF2α, an established mechanism of GCN-2-mediated translational suppression, was not necessary for HP. These data suggest a model where hypoxia-induced misfolded proteins trigger the activation of IRE-1, which along with GCN-2 controls an adaptive response that is essential to HP. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source


Sithinamsuwan P.,Phramongkutkloa Hospital | Letendre S.,University of California at San Diego | Ances B.,Washington University
Current HIV/AIDS Reports | Year: 2011

HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings. © 2010 The Author(s). Source


Nelson S.M.,Washington University
Brain structure & function | Year: 2010

In humans, the anterior insula (aI) has been the topic of considerable research and ascribed a vast number of functional properties by way of neuroimaging and lesion studies. Here, we argue that the aI, at least in part, plays a role in domain-general attentional control and highlight studies (Dosenbach et al. 2006; Dosenbach et al. 2007) supporting this view. Additionally, we discuss a study (Ploran et al. 2007) that implicates aI in processes related to the capture of focal attention. Task-level control and focal attention may or may not reflect information processing supported by a single functional area (within the aI). Therefore, we apply a novel technique (Cohen et al. 2008) that utilizes resting state functional connectivity MRI (rs-fcMRI) to determine whether separable regions exist within the aI. rs-fcMRI mapping suggests that the ventral portion of the aI is distinguishable from more dorsal/anterior regions, which are themselves distinct from more posterior parts of the aI. When these regions are applied to functional MRI (fMRI) data, the ventral and dorsal/anterior regions support processes potentially related to both task-level control and focal attention, whereas the more posterior aI regions did not. These findings suggest that there exists some functional heterogeneity within aI that may subserve related but distinct types of higher-order cognitive processing. Source


Tautenhahn R.,Scripps Research Institute | Patti G.J.,Washington University | Rinehart D.,Scripps Research Institute | Siuzdak G.,Scripps Research Institute
Analytical Chemistry | Year: 2012

Recently, interest in untargeted metabolomics has become prevalent in the general scientific community among an increasing number of investigators. The majority of these investigators, however, do not have the bioinformatic expertise that has been required to process metabolomic data by using command-line driven software programs. Here we introduce a novel platform to process untargeted metabolomic data that uses an intuitive graphical interface and does not require installation or technical expertise. This platform, called XCMS Online, is a web-based version of the widely used XCMS software that allows users to easily upload and process liquid chromatography/mass spectrometry data with only a few mouse clicks. XCMS Online provides a solution for the complete untargeted metabolomic workflow including feature detection, retention time correction, alignment, annotation, statistical analysis, and data visualization. Results can be browsed online in an interactive, customizable table showing statistics, chromatograms, and putative METLIN identities for each metabolite. Additionally, all results and images can be downloaded as zip files for offline analysis and publication. XCMS Online is available at https://xcmsonline. scripps.edu. © 2012 American Chemical Society. Source


Accumulations of aggregated proteins are a key feature of the pathology of all of the major neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) was brought into this fold quite recently with the discovery of TDP-43 (TAR DNA binding protein, 43 kDa) inclusions in nearly all ALS cases. In part this discovery was fueled by the recognition of the clinical overlap between ALS and frontotemporal lobar degeneration, where ubiquitinated TDP-43 inclusions were first identified. Later the identification of TDP-43 mutations in rare familial forms of ALS confirmed that altered TDP-43 function can be a primary cause of the disease. However, the simple concept that TDP-43 is an aggregation-prone protein that forms toxic inclusions capable of promoting neurodegeneration has not been upheld by initial investigations. This review discusses observations from human pathology, cell culture and animal model systems, to highlight our somewhat murky understanding of the relationship between TDP-43 aggregation and neurodegeneration. Aggregated proteins are a key pathologic feature of the major neurodegenerative diseases. TDP-43 aggregates are present in amyotrophic lateral sclerosis (ALS), and mutations in TDP-43 cause rare familial forms of ALS. This review discusses observations from human pathology, cell culture, and animal model systems, to explore our understanding of the relationship between TDP-43 aggregation and neurodegeneration. © 2011 FEBS. Source

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