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Molecular Medicine Volume 9

Articles from this Volume

Kevin K Kim, Kevin R Flaherty, Qi Long, Noboru Hattori, Thomas H. Sisson, Thomas V Colby, William D Travis, Fernando J Martinez, Susan Murray, and Richard H Simon

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Posted by Leah Caracappa on Jan 8, 2003 12:00 AM CST
Ming Yan and R John Collier

Certain mutations within the protective antigen (PA) moiety of anthrax toxin endow the protein with a dominant-negative (DN) phenotype, converting it into a potent antitoxin. Proteolytically activated PA oligomerizes to form ring-shaped heptameric complexes that insert into the membrane of an acidic intracellular compartment and promote translocation of bound edema factor and/or lethal factor to the cytosol. DN forms of PA co-oligomerize with the wild-type protein and block the translocation process. We prepared and characterized 4 DN forms: a single, a double, a triple, and a quadruple mutant. The mutants were made by site-directed mutation of the cloned form of PA in Escherichia coli and tested by various assays conducted on CHO cells or in solution. All 4 mutant PAs were competent for heptamerization and ligand binding but were defective in the pH-dependent functions: pore formation, ability to convert to the SDS-resistant heptamer, and ability to translocate bound ligand. The single mutant (F427K) showed less attenuation than the others in the pH-dependent functions and lower DN activity in a CHO cell assay. The quadruple (K397D + D425K + F427A + 2β2-2β3) deletion showed the most potent DN activity at low concentrations but also gave indications of low stability in a urea-mediated unfolding assay. The double mutant (K397D + D425K) and the triple (K397D + D425K + F427A) showed strong DN activity and slight reduction in stability relative to the wild-type protein. The properties of the double and the triple mutants make these forms worthy of testing in vivo as a new type of antitoxic agent for treatment of anthrax. 

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Posted by Leah Caracappa on Jan 7, 2003 12:00 AM CST
Jianhua Li, Riikka Kokkola, Siamak Tabibzadeh, Runkuan Yang, Mahendar Ochani, Xiaoling Qiang, Helena E Harris, Christopher J Czura, Haichao Wang, Luis Ulloa, Hong Wang, H Shaw Warren, Lyle L Moldawer, Mitchell P Fink, Ulf Andersson, Kevin J Tracey, and Huan Yang

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Posted by Leah Caracappa on Jan 6, 2003 12:00 AM CST
Arnab Roy Chowdhury, Suparna Mandal, Anindya Goswami, Monidipa Ghosh, Labanya Mandal, Debabani Chakraborty, Agneyo Ganguly, Gayatri Tripathi, Sibabrata Mukhopadhyay, Santu Bandyopadhyay, and Hemanta K Majumder

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Posted by Leah Caracappa on Jan 5, 2003 12:00 AM CST
Mei Zhang, Akiko Kimura, and Alan R Saltiel

Cbl-associated protein (CAP) is an adaptor protein that plays important roles in both signal transduction and cytoskeleton rearrangement. Alternative splicing of the gene SORBS1 results in multiple isoforms of CAP protein. We report here the cloning of 3 new CAP isoforms, CAP2, CAP3, and CAP4, from mouse adipose tissue. RT-PCR analyses reveal that the isoform mRNAs are differentially expressed. CAP2, CAP3, and CAP4 contain a coiled-coil domain. In addition, CAP4 contains a proline-rich region, part of which exists in CAP3. Coimmunoprecipitation experiments show that CAP4 forms a homodimeric complex. While these new isoforms similarly interact with Cbl, they exhibit varied binding specificity toward vinculin. In contrast to CAP1 and CAP2, CAP4 does not interact with vinculin, and CAP3 binds with low affinity. Immunofluorescence analysis demonstrates differential subcellular localization of Myc-tagged CAP isoforms in 3T3-L1 adipocytes. These results suggest that these new isoforms of CAP might play different signaling roles. 

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Posted by Leah Caracappa on Jan 4, 2003 12:00 AM CST
Giuseppina Caligiuri, Mats Rudling, Véronique Ollivier, Marie-Paule Jacob, Jean-Baptiste Michel, Göran K Hansson, and Antonino Nicoletti

Interleukin (IL)-10 is an anti-inflammatory cytokine that may play a protective role in atherosclerosis. The aim of this study was to assess the effect of IL-10 deficiency in the apolipoprotein E knockout mouse. Apolipoprotein E deficient (E–/–) and IL-10 deficient (–/–) mice were crossed to generate E–/–  IL-10–/– double knockout mice. By 16 wk, cholesterol and triglycerides were similar in double and single knockouts but the lack of IL-10 led to increased low-density lipoprotein cholesterol whereas very-low-density lipoprotein was reduced. In parallel, T-helper 1 responses and lesion size were dramatically increased in double knockout compared with E–/– controls. At 48 wk, matrix metalloproteinases and tissue factor activities were increased in lesions of double-knockout mice. Furthermore, markers of systemic coagulation were increased, and vascular thrombosis in response to i.v. thrombin occurred more frequently in E–/–  IL-10–/– than in E–/– mice. Our findings suggest that IL-10 deficiency plays a deleterious role in atherosclerosis. The early phase of lesion development was increased, and the proteolytic and procoagulant activity was elevated in advanced lesions. These data show that IL-10 may reduce atherogenesis and improve the stability of plaques. 

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Posted by Leah Caracappa on Jan 3, 2003 12:00 AM CST
Akira Sawa and Solomon H Snyder

Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated “negative” symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-D-aspartate receptors, especially the cotransmitter D-serine, are promising. Stimulation of the α7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin. 

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Posted by Leah Caracappa on Jan 2, 2003 12:00 AM CST
Stephen J Weiss

Molecular Medicine continues to provide a forum for disseminating new insights into the genetic, molecular, and cellular bases of disease that have been gleaned from the study of mammalian systems or model organisms. While the mission of the journal remains the same, beginning with this issue of Molecular Medicine, a changing of the editorial guard takes effect, and with it arrives changes in journal policy, new layouts, new formats for the print and electronic versions of the journal, a new publisher, and new online systems ( If change is good, so be it, as we are certainly on the right track. But to what end? Doesn’t the literature already abound in journals trumpeting new advances in the biomedical sciences? Even if convincing arguments could be forwarded that real needs exist for further modifying the standards of existing journals, how do we, as editors, persuade readers and authors alike that this will not be “business as usual” and that we want to help initiate change for the betterment of science? 

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Posted by Leah Caracappa on Jan 1, 2003 12:00 AM CST
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