Intermittent Hypoxia-Induced Cognitive Deficits Are Mediated by NADPH Oxidase Activity in a Murine Model of Sleep Apnea

Background: In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Excessive NADPH oxidase activity may play a role in IH-induced CNS dysfunction. Methods and Findings: The effect of IH during light period on two forms of spatial learning in the water maze and well as markers of oxidative stress was assessed in mice lacking NADPH oxidase activity (gp91phox _/Y) and wild-type littermates. On a standard place training task, gp91phox _/Y displayed normal learning, and were protected from the spatial learning deficits observed in wild-type littermates exposed to IH. Moreover, anxiety levels were increased in wild-type mice exposed to IH as compared to room air (RA) controls, while no changes emerged in gp91phox _/Y mice. Additionally, wild-type mice, but not gp91phox _/Y mice had significantly elevated levels of NADPH oxidase expression and activity, as well as MDA and 8-OHDG in cortical and hippocampal lysates following IH exposures. Conclusions: The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by excessive NADPH oxidase activity, and thus pharmacological agents targeting NADPH oxidase may provid

Reactive oxygen species in phagocytic leukocytes

Phagocytic leukocytes consume oxygen and generate reactive oxygen species in response to appropriate stimuli. The phagocyte NADPH oxidase, a multiprotein complex, existing in the dissociated state in resting cells becomes assembled into the functional oxidase complex upon stimulation and then generates superoxide anions. Biochemical aspects of the NADPH oxidase are briefly discussed in this review; however, the major focus relates to the contributions of various modes of microscopy to our understanding of the NADPH oxidase and the cell biology of phagocytic leukocytes

Robust sequence alignment using evolutionary rates coupled with an amino acid substitution matrix

BACKGROUND: Selective pressures at the DNA level shape genes into profiles consisting of patterns of rapidly evolving sites and sites withstanding change. These profiles remain detectable even when protein sequences become extensively diverged. A common task in molecular biology is to infer functional, structural or evolutionary relationships by querying a database using an algorithm. However, problems arise when sequence similarity is low. This study presents an algorithm that uses the evolutionary rate at codon sites, the dN/dS (ω) parameter, coupled to a substitution matrix as an alignment metric for detecting distantly related proteins. The algorithm, called BLOSUM-FIRE couples a newer and improved version of the original FIRE (Functional Inference using Rates of Evolution) algorithm with an amino acid substitution matrix in a dynamic scoring function. The enigmatic hepatitis B virus X protein was used as a test case for BLOSUM-FIRE and its associated database EvoDB. RESULTS: The evolutionary rate based approach was coupled with a conventional BLOSUM substitution matrix. The two approaches are combined in a dynamic scoring function, which uses the selective pressure to score aligned residues. The dynamic scoring function is based on a coupled additive approach that scores aligned sites based on the level of conservation inferred from the ω values. Evaluation of the accuracy of this new implementation, BLOSUM-FIRE, using MAFFT alignment as reference alignments has shown that it is more accurate than its predecessor FIRE. Comparison of the alignment quality with widely used algorithms (MUSCLE, T-COFFEE, and CLUSTAL Omega) revealed that the BLOSUM-FIRE algorithm performs as well as conventional algorithms. Its main strength lies in that it provides greater potential for aligning divergent sequences and addresses the problem of low specificity inherent in the original FIRE algorithm. The utility of this algorithm is demonstrated using the Hepatitis B virus X (HBx) protein, a protein of unknown function, as a test case. CONCLUSION: This study describes the utility of an evolutionary rate based approach coupled to the BLOSUM62 amino acid substitution matrix in inferring protein domain function. We demonstrate that such an approach is robust and performs as well as an array of conventional algorithms.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

The Academic Dispositif: Towards a Context-Centred Discourse Analysis

This contribution outlines the dispositif approach, which combines a linguistic discourse analysis of texts with a sociological study of the social context (i.e. the dispositif understood as an institutional arrangement of practices and structures). The authors use the discourse of academic researchers to exemplify this approach. By articulating correspondence analysis of self-representations on researchers’ homepages with institutional data of sociology professors in the United Kingdom, they outline a research design that consists of three components: a linguistic analysis of texts, a sociological analysis of institutional contexts, and a theoretical account of how the two are related in the academic dispositif. The dispositif perspective on discourse aims to respond to a demand for systematic discourse research on the social and institutional contexts of discursive practices

Bedeutung festlegen. Die vielen Stimmen der postliberalen Hegemonie in Russland

Dieser Beitrag untersucht eine Rede des russischen Präsidenten Wladimir Putin nach der Geiselnahme in einer Mittelschule in der nordossetischen Stadt Beslan durch nordkaukasische Terroristen im September 2004. Nach gängiger Meinung kennzeichnet dieses Ereignis das Ende der liberalen Hegemonie im postsowjetischen Russland. Ein genauerer Blick zeigt jedoch, dass die Rede auf ganz unterschiedliche Weise gelesen und verstanden werden kann. Folgt man den Reaktionen, die sich in einem Korpus von Presseartikeln finden ließen, aktiviert die Rede sowohl „internationalistische“ als auch „souveränistische“ Lesarten im Mediendiskurs. Ich hebe die polyphone Organisation des Diskurses hervor und argumentiere so für einen produktiven Austausch zwischen der französischen Tradition der Diskursanalyse, dem Interaktionismus und der Kritischen Diskursanalyse. In Anbetracht dessen werden sich die Leserinnen und Leser mit den vielen unterschiedlichen Stimmen beschäftigen müssen, die den politischen Diskurs kreuz und quer durchlaufen. Begreift man die Organisation des Diskurses als polyphon, lässt sich jedoch schlussfolgern, dass seine Bedeutung von den Teilnehmern des politischen Diskurses „festgelegt“ werden muss

Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes.

AIMS/HYPOTHESIS: More than 40 regions of the human genome confer susceptibility for type 1 diabetes and could be used to establish population screening strategies. The aim of our study was to identify weighted sets of SNP combinations for type 1 diabetes prediction. METHODS: We applied multivariable logistic regression and Bayesian feature selection to the Type 1 Diabetes Genetics Consortium (T1DGC) dataset with genotyping of HLA plus 40 SNPs within other type 1 diabetes-associated gene regions in 4,574 cases and 1,207 controls. We tested the weighted models in an independent validation set (765 cases, 423 controls), and assessed their performance in 1,772 prospectively followed children. RESULTS: The inclusion of 40 non-HLA gene SNPs significantly improved the prediction of type 1 diabetes over that provided by HLA alone (p = 3.1 × 10(-25)), with a receiver operating characteristic AUC of 0.87 in the T1DGC set, and 0.84 in the validation set. Feature selection identified HLA plus nine SNPs from the PTPN22, INS, IL2RA, ERBB3, ORMDL3, BACH2, IL27, GLIS3 and RNLS genes that could achieve similar prediction accuracy as the total SNP set. Application of this ten SNP model to prospectively followed children was able to improve risk stratification over that achieved by HLA genotype alone. CONCLUSIONS: We provided a weighted risk model with selected SNPs that could be considered for recruitment of infants into studies of early type 1 diabetes natural history or appropriately safe prevention

CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca²⁺ signaling

A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can down-modulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in α2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca2+ signaling by controling the CD22 assocation to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrsoine-based inhibition motifs have increased B-cell Ca2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity