Psychological correlates of self-reported functional limitation in patients with ankylosing spondylitis

Introduction  

Functional status is an integral component of health-related quality of life in patients with ankylosing spondylitis (AS). The purpose of this study was to investigate the role of psychological variables in self-reported functional limitation in patients with AS, while controlling for demographic and medical variables.     

Axis development: the mouse becomes a dachshund.

Targeted deletion of the gene for GDF11, a novel member of the TGFbeta family, has been found to cause an increase in the number of thoracic and lumbar vertebrae in the mouse. This is the first hint that a secreted factor may influence the specification of segment identity.     

SUSTAINED DRUG-INDUCED ELEVATION OF BRAIN GABA IN THE RAT1

Abstract— The contents of GABA, homocarnosine, and β-alanine can be raised in rat brain for long periods of time by the continued administration of phenelzine, aminooxyacetic acid (AOAA), or isonicotinic acid hydrazide (INH). These 3 compounds apparently act by preferential inhibition of the enzyme GABA aminotransferase (GABA-T). Oral administration of phenelzine (20 mg/kg per day) caused a 25–50 per cent increase in GABA levels in rat brain, but produced appreciable toxic side effects. A similar increase in GABA levels in brain resulted from oral administration to rats of INH in a dosage of 60 mg/kg per day, without production of any obvious toxic effects. Simultaneous administration of large doses of pyridoxine did not abolish the GABA-elevating effect of INH. Brain GABA levels in the rat were increased by approx. 50 per cent by daily injections of AOAA (2.5 mg/kg per day). At this low dosage, AOAA injections in rats could be continued for at least 6 weeks without producing evident toxic effects. Oral administration of large amounts of GABA, on the other hand, failed to increase the content of GABA in the brains of rats not treated with GABA-T inhibitors, and failed to produce any further increase of brain GABA levels in rats treated with AOAA.     

Comparison of the biochemical and kinetic properties of the type 1 receptor tyrosine kinase intracellular domains. Demonstration of differential sensitivity to kinase inhibitors.

Epidermal growth factor receptor (EGFR), ErbB-2, and ErbB-4 are members of the type 1 receptor tyrosine kinase family. Overexpression of these receptors, especially ErbB-2 and EGFR, has been implicated in multiple forms of cancer. Inhibitors of EGFR tyrosine kinase activity are being evaluated clinically for cancer therapy. The potency and selectivity of these inhibitors may affect the efficacy and toxicity of therapy. Here we describe the expression, purification, and biochemical comparison of EGFR, ErbB-2, and ErbB-4 intracellular domains. Despite their high degree of sequence homology, the three enzymes have significantly different catalytic properties and substrate kinetics. For example, the catalytic activity of ErbB-2 is less stable than that of EGFR. ErbB-2 uses ATP-Mg as a substrate inefficiently compared with EGFR and ErbB-4. The three enzymes have very similar substrate preferences for three optimized peptide substrates, but differences in substrate synergies were observed. We have used the biochemical and kinetic parameters determined from these studies to develop an assay system that accurately measures inhibitor potency and selectivity between the type 1 receptor family. We report that the selectivity profile of molecules in the 4-anilinoquinazoline series can be modified through specific aniline substitutions. Moreover, these compounds have activity in whole cells that reflect the potency and selectivity of target inhibition determined with this assay system.     

Antiviral Activity of a Small Molecule Deubiquitinase Inhibitor Occurs via Induction of the Unfolded Protein Response

Ubiquitin (Ub) is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub) cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs). However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA-mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1), a critical mediator of the unfolded protein response (UPR). WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1) through an IRE1-dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.