Molecular recognition of angiogenesis inhibitors fumagillin and ovalicin by methionine aminopeptidase 2

Angiogenesis inhibitors are a novel class of promising therapeutic agents for treating cancer and other human diseases. Fumagillin and ovalicin compose a class of structurally related natural products that potently inhibit angiogenesis by blocking endothelial cell proliferation. A synthetic analog of fumagillin, TNP-470, is currently undergoing clinical trials for treatment of a variety of cancers. A common target for fumagillin and ovalicin recently was identified as the type 2 methionine aminopeptidase (MetAP2). These natural products bind MetAP2 covalently, inhibiting its enzymatic activity. The specificity of this binding is underscored by the lack of inhibition of the closely related type 1 enzyme, MetAP1. The molecular basis of the high affinity and specificity of these inhibitors for MetAP2 has remained undiscovered. To determine the structural elements of these inhibitors and MetAP2 that are involved in this interaction, we synthesized fumagillin analogs in which each of the potentially reactive epoxide groups was removed either individually or in combination. We found that the ring epoxide in fumagillin is involved in the covalent modification of MetAP2, whereas the side chain epoxide group is dispensable. By using a fumagillin analog tagged with fluorescein, His-231 in MetAP2 was identified as the residue that is covalently modified by fumagillin. Site-directed mutagenesis of His-231 demonstrated its importance for the catalytic activity of MetAP2 and confirmed that the same residue is covalently modified by fumagillin. These results, in agreement with a recent structural study, suggest that fumagillin and ovalicin inhibit MetAP2 by irreversible blockage of the active site.     

Surgery for peptic strictures

Benign peptic stricture of the esophagus is a complex disorder which results from persistent gastroesophageal reflux. Its successful management depends on an accurate preoperative evaluation of the stricture and the patient. Surgical management of peptic strictures can be quite effective in relieving the symptoms and halting the pathologic gastroesophageal reflux that accompanies this disorder. This article reviews the general principles of evaluation and surgical treatment of benign peptic esophageal strictures.     

The arabidopsis ACT7 actin gene is expressed in rapidly developing tissues and responds to several external stimuli

ACT7 encodes one of the six distinct and ancient subclasses of actin protein in the complex Arabidopsis actin gene family. We determined the sequence and structure of the Arabidopsis thaliana ACT7 actin gene and investigated its tissue-specific expression and regulation. The ACT7 mRNA levels varied by 128-fold among several different tissues and organs. The highest levels of aCT7 mRNA were found in rapidly expanding vegetative organs, the lowest in pollen. A translational fusion with the 5' end of ACT 7 (1.9 kb) joined to the beta-glucuronidase reporter gene was strongly and preferentially expressed in all young, developing vegetative tissues of transgenic Arabidopsis plants. ACT7 was the only Arabidopsis actin gene strongly expressed in the hypocotyl and seed coat. Although no beta-glucuronidase expression was seen in developing ovules or immature seeds, strong expression was seen in dry seeds and immediately after imbibition in the entire seedling. ACT7 was the only Arabidopsis actin gene to respond strongly to auxin, other hormone treatments, light regime, and wounding, and may be the primary actin gene responding to external stimuli. The ACT7 promoter sequence contains a remarkable number of motifs with sequence similarity to putative phytohormone response elements.     

A framework for analysis of data quality research

Organizational databases are pervaded with data of poor quality. However, there has not been an analysis of the data quality literature that provides an overall understanding of the state-of-art research in this area. Using an analogy between product manufacturing and data manufacturing, this paper develops a framework for analyzing data quality research, and uses it as the basis for organizing the data quality literature. This framework consists of seven elements: management responsibilities, operation and assurance costs, research and development, production, distribution, personnel management, and legal function. The analysis reveals that most research efforts focus on operation and assurance costs, research and development, and production of data products. Unexplored research topics and unresolved issues are identified and directions for future research provided     

The effect of photomirex on the in vitro perfused ovary of the rat

We describe the cloning of p63, a gene at chromosome 3q27-29 that bears strong homology to the tumor suppressor p53 and to the related gene, p73. p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. We demonstrate that these truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63, and we suggest the possibility of physiological interactions among members of the p53 family.     

Distribution of bacteria with the arylsulfate sulfotransferase activity

We herein report a simple method using intestinal clamps to prevent intraoperative contamination during an immediate mucocutaneous suture of the intestinal stoma. Using this technique, a protruded intestinal stoma can be constructed reliably without soiling. The technique can be used both for constructing an end as well as a loop intestinal stoma.     

Signal decay through a reverse phosphorelay in the Arc two-component signal transduction system

Escherichia coli senses and signals anoxic or low redox conditions in its growth environment by the Arc two-component system. Under those conditions, the tripartite sensor kinase ArcB undergoes autophosphorylation at the expense of ATP and subsequently transphosphorylates its cognate response regulator ArcA through a His --> Asp --> His --> Asp phosphorelay pathway. In this study we used various combinations of wild-type and mutant ArcB domains to analyze in vitro the pathway for signal decay. The results indicate that ArcA-P dephosphorylation does not occur by direct hydrolysis but by transfer of the phosphoryl group to the secondary transmitter and subsequently to the receiver domain of ArcB. This reverse phosphorelay involves both the conserved His-717 of the secondary transmitter domain and the conserved Asp-576 of the receiver domain of ArcB but not the conserved His-292 of its primary transmitter domain. This novel pathway for signal decay may generally apply to signal transduction systems with tripartite sensor kinases.     

Sustained transmission of mumps in a highly vaccinated population: assessment of primary vaccine failure and waning vaccine-induced immunity

Electrolyte addition to nonionic contrast media has been suggested to further reduce the incidence of ventricular fibrillation during coronary arteriography. The present study was designed to investigate the effects of adding 30 mM NaCl, 0.9 mM KCl, 0.15 mM CaCl2 and 0.1 mM MgCl2 to iohexol on cardiac electrophysiology and hemodynamics (iohexol+electrolytes = IPE). Contrast media were injected into the left main coronary artery in 9 open-chest, anesthetized dogs before and after induction of acute ischemic heart failure. IPE increased left ventricular inotropy (LV dP/dtmax) with no initial decrease, even during heart failure. During heart failure IPE induced the same hemodynamic effects as iohexol without electrolyte addition. IPE slightly lengthened epicardial monophasic action potential duration before heart failure. We conclude that IPE appears to be well tolerated hemodynamically. The electrophysiologic differences between IPE and iohexol are small when the injection time is not longer than 5 s.