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( Y. Y. Wang ),( Z. B. Fu ),( K. L. Ng ),( C. C. Lam ),( A. K. N. Chan ),( K. F. Sze ),( W. K. R. Wong ) 한국미생물 · 생명공학회 2011 Journal of microbiology and biotechnology Vol.21 No.6
Production of recombinant proteins by excretory expression has many advantages over intracellular expression in Escherichia coli. Hyperexpression of a secretory exoglucanase, Exg, of Cellulomonas fimi was previously shown to saturate the SecYEG pathway and result in dramatic cell death of E. coli. In this study, we demonstrated that overexpression of the PspA in the JM101(pM1VegGcexL-pspA) strain enhanced excretion of Exg to 1.65 U/ml using shake-flask cultivation, which was 80% higher than the highest yield previously obtained from the optimized JM101(pM1VegGcexL) strain. A much higher excreted Exg activity of 4.5 U/ml was further achieved with high cell density cultivation using rich media. Furthermore, we showed that the PspA overexpression strain enjoyed an elevated critical value (CV), which was defined as the largest quotient between the intracellular unprocessed precursor and its secreted mature counterpart that was still tolerable by the host cells prior to the onset of cell death, improving from the previously determined CV of 20/80 to the currently achieved CV of 45/55 for Exg. The results suggested that the PspA overexpression strain might tolerate a higher level of precursor Exg making use of the SecYEG pathway for secretion. The reduced lethal effect might be attributable to the overexpressed PspA, which was postulated to be able to reduce membrane depolarization and damage. Our findings introduce a novel strategy of the combined application of metabolic engineering and construct optimization to the attainment of the best possible E. coli producers for secretory/excretory production of recombinant proteins, using Exg as the model protein.
Pejnovic, N.,Vratimos, A.,Lee, S.H.,Popadic, D.,Takeda, K.,Akira, S.,Chan, W.L. Pergamon Press 2009 Molecular immunology Vol.47 No.1
Recent reports show T helper 17 (Th17) cells are involved in the pathogenesis of various chronic inflammatory diseases formerly categorized as Th1-mediated disorders. Interleukin-18 (IL-18) induces Th1 cells to produce interferon-γ (IFN-γ) which is proatherogenic, while cholesterol causes atherosclerosis and stimulates intact rat aortae to produce prostaglandin E<SUB>2</SUB> (PGE<SUB>2</SUB>), a strong regulator of IL-23 that expands Th17. We wanted to test whether Th17 is proatherogenic and whether cholesterol can induce the alternative Th17 pathway in IL-18 deficient apolipoprotein E-knockout (ApoE<SUP>-/-</SUP>) mice that have reduced Th1 cells, if they are fed high-cholesterol diet. IL-18<SUP>+/+</SUP>ApoE<SUP>-/-</SUP> and IL-18<SUP>-/-</SUP>ApoE<SUP>-/-</SUP> mice aged 5 weeks were fed high-cholesterol diet (HCD) and control littermates of IL-18<SUP>-/-</SUP>ApoE<SUP>-/-</SUP> low-cholesterol diet (LCD) for 12 weeks. At termination, cryosectioned aortic arches were stained for lesion measurement and immunohistochemistry. We found that serum cholesterol and triglyceride levels were significantly higher in IL-18<SUP>-/-</SUP>ApoE<SUP>-/-</SUP> mice on HCD and they also had significantly increased atherosclerosis compared with 18<SUP>+/+</SUP>ApoE<SUP>-/-</SUP> mice or IL-18<SUP>-/-</SUP>ApoE<SUP>-/-</SUP> mice on LCD. Increased atherosclerosis correlates with enhanced Th17-cells, IL-23-producing vascular smooth muscle cells (VSMC) and macrophages, and thin fibrous cap in lesions, the morphology indicative of unstable plaques prone to rupture. In vitro, cholesterol significantly enhances VSMCs explanted from IL-18<SUP>-/-</SUP>ApoE<SUP>-/-</SUP> but not IL-18<SUP>+/+</SUP>ApoE<SUP>-/-</SUP> aorta to produce IL-23 and homocysteine mediates secretion. This study suggests that in IL-18 deficiency, cholesterol in HCD synergize mechanistically with homocysteine to accelerate atherosclerosis via the alternative IL-23/Th17 pathway, demonstrating a new role for Th17 in atherosclerosis.
Neuromyelitis optica and multiple sclerosis: Seeing differences through optical coherence tomography
Bennett, JL,de Seze, J,Lana-Peixoto, M,Palace, J,Waldman, A,Schippling, S,Tenembaum, S,Banwell, B,Greenberg, B,Levy, M,Fujihara, K,Chan, KH,Kim, HJ,Asgari, N,Sato, DK,Saiz, A,Wuerfel, J,Zimmermann, H SAGE Publications 2015 Multiple sclerosis journal: clinical and laborator Vol.21 No.6
<P>Neuromyelitis optica (NMO) is an inflammatory autoimmune disease of the central nervous system that preferentially targets the optic nerves and spinal cord. The clinical presentation may suggest multiple sclerosis (MS), but a highly specific serum autoantibody against the astrocytic water channel aquaporin-4 present in up to 80% of NMO patients enables distinction from MS. Optic neuritis may occur in either condition resulting in neuro-anatomical retinal changes. Optical coherence tomography (OCT) has become a useful tool for analyzing retinal damage both in MS and NMO. Numerous studies showed that optic neuritis in NMO typically results in more severe retinal nerve fiber layer (RNFL) and ganglion cell layer thinning and more frequent development of microcystic macular edema than in MS. Furthermore, while patients’ RNFL thinning also occurs in the absence of optic neuritis in MS, subclinical damage seems to be rare in NMO. Thus, OCT might be useful in differentiating NMO from MS and serve as an outcome parameter in clinical studies.</P>