Arginyltransferase, Its Specificity, Putative Substrates, Bidirectional Promoter, and Splicing-derived Isoforms

Substrates of the N-end rule pathway include proteins with destabilizing N-terminal residues. Three of them, Asp, Glu, and (oxidized) Cys, function through their conjugation to Arg, one of destabilizing N-terminal residues that are recognized directly by the pathway's ubiquitin ligases. The conjugation of Arg is mediated by arginyltransferase, encoded by ATE1. Through its regulated degradation of specific proteins, the arginylation branch of the N-end rule pathway mediates, in particular, the cardiovascular development, the fidelity of chromosome segregation, and the control of signaling by nitric oxide. We show that mouse ATE1 specifies at least six mRNA isoforms, which are produced through alternative splicing, encode enzymatically active arginyltransferases, and are expressed at varying levels in mouse tissues. We also show that the ATE1 promoter is bidirectional, mediating the expression of both ATE1 and an oppositely oriented, previously uncharacterized gene. In addition, we identified GRP78 (glucose-regulated protein 78) and protein-disulfide isomerase as putative physiological substrates of arginyltransferase. Purified isoforms of arginyltransferase that contain the alternative first exons differentially arginylate these proteins in extract from ATE1-/- embryos, suggesting that specific isoforms may have distinct functions. Although the N-end rule pathway is apparently confined to the cytosol and the nucleus, and although GRP78 and protein-disulfide isomerase are located largely in the endoplasmic reticulum, recent evidence suggests that these proteins are also present in the cytosol and other compartments in vivo, where they may become N-end rule substrates

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Clinical characteristics of amyloidosis with isolated respiratory system involvement: A review of 13 cases

Background: Isolated pulmonary amyloidosis is a very rare disease. Methods: We retrospectively reviewed the records of patients with pathologically proven isolated pulmonary amyloidosis treated at our hospital from 1990 to 2011. Results: There were 9 males and 4 females with a mean age of 54.7 years (range, 45-72 years) and the mean course of disease was 46.5 months (range, 5 months-15 years). The most common symptoms were cough (10/13), expectoration (8/13), hemoptysis (4/13), chest tightness (12/13), dyspnea (10/13), chest pain (3/13), fever (5/13), and body weight loss (2/13). Radiological findings included tracheal stenosis (2/13), bronchial stenosis with atelectasis (5/13), pulmonary nodules (3/13), lung consolidation (1/13), and lymph node enlargement with pleural effusion (2/13). Treatments included endotracheal stenting, endoscopic resection of tracheal and bronchial lesions, lung resection, and drug therapy with glucocorticoids, antineoplastic agents, or antibiotics. Four patients died of the disease within 1 year of diagnosis, 2 died of pneumonia at 3-4 years after original treatment, and the remaining patients are alive with follow-up ranging from 3 to 15 years. Conclusions: Isolated pulmonary amyloidosis is a rare disease with a relatively high mortality and its various manifestations make diagnosis challenging. Surgical resection of lesions and chemotherapy tend to be effective treatments

Sulbactam-based therapy for Acinetobacter baumannii infection: a systematic review and meta-analysis

BACKGROUND: A number of studies have reported on the effectiveness of sulbactam-based therapies for Acinetobacter baumannii infection; however, there is little evidence that sulbactam-based therapies are more or less effective than alternative therapies. Unfortunately, there is a distinct lack of high quality data (i.e., from randomized controlled trials) available on this issue. Therefore, we conducted a systematic review and meta-analysis comparing the efficacy of sulbactam-based and non-sulbactam-based regimens in the treatment of A. baumannii infection. METHODS: We searched PubMed, MEDLINE, Biomedical Central, Google Scholar, the China National Knowledge Infrastructure, the Cochrane library, and the Directory of Open Access using the terms "sulbactam and baumannii" or "maxtam and baumannii". Randomized controlled trials, controlled clinical studies, and cohort studies were considered for inclusion. The primary outcome was the clinical response rate for sulbactam-based therapy vs comparator therapies. RESULTS: Four studies (1 prospective, 3 retrospective) were included in the metaanalysis. Sulbactam was given in combination with ampicillin, carbapenem, or cefoperazone (n = 112 participants). Comparator drugs included colistin, cephalosporins, anti-pseudomonas penicillins, fluoroquinolones, minocycline/doxycycline, aminoglycosides, tigecycline, polymyxin, imipenem/cilastatin, and combination therapy (n = 107 participants). The combined clinical response rate odds ratio did not significantly favor sulbactam-based therapy over comparator therapy (odds ratio = 1.054, 95% confidence interval = 0.550-2.019, p = 0.874), nor did any of the individual study odds ratios. CONCLUSIONS: The available evidence suggests that sulbactam-based therapy may be similarly efficacious to alternative antimicrobial therapies for the treatment of A. baumannii infection. Further research on this issue is warranted given the limited availability of data from high quality/randomized controlled trials