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31.
Omid Haji-Ghassemi Sven Müller-Loennies Teresa Rodriguez Lore Brade Paul Kosma Helmut Brade Stephen V. Evans 《The Journal of biological chemistry》2015,290(32):19629-19640
Septic shock is a leading cause of death, and it results from an inflammatory cascade triggered by the presence of microbial products in the blood. Certain LPS from Gram-negative bacteria are very potent inducers and are responsible for a high percentage of septic shock cases. Despite decades of research, mAbs specific for lipid A (the endotoxic principle of LPS) have not been successfully developed into a clinical treatment for sepsis. To understand the molecular basis for the observed inability to translate in vitro specificity for lipid A into clinical potential, the structures of antigen-binding fragments of mAbs S1–15 and A6 have been determined both in complex with lipid A carbohydrate backbone and in the unliganded form. The two antibodies have separate germ line origins that generate two markedly different combining-site pockets that are complementary both in shape and charge to the antigen. mAb A6 binds lipid A through both variable light and heavy chain residues, whereas S1–15 utilizes exclusively the variable heavy chain. Both antibodies bind lipid A such that the GlcN-O6 attachment point for the core oligosaccharide is buried in the combining site, which explains the lack of LPS recognition. Longstanding reports of polyspecificity of anti-lipid A antibodies toward single-stranded DNA combined with observed homology of S1–15 and A6 and the reports of several single-stranded DNA-specific mAbs prompted the determination of the structure of S1–15 in complex with single-stranded DNA fragments, which may provide clues about the genesis of autoimmune diseases such as systemic lupus erythematosus, thyroiditis, and rheumatic autoimmune diseases. 相似文献
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Dupuytren's disease (DD) is an ill-defined fibroproliferative disorder of the palm of the hands leading to digital contracture.
DD commonly occurs in individuals of northern European extraction. Cellular components and processes associated with DD pathogenesis
include altered gene and protein expression of cytokines, growth factors, adhesion molecules, and extracellular matrix components.
Histology has shown increased but varying levels of particular types of collagen, myofibroblasts and myoglobin proteins in
DD tissue. Free radicals and localised ischaemia have been suggested to trigger the proliferation of DD tissue. Although the
existing available biological information on DD may contain potentially valuable (though largely uninterpreted) information,
the precise aetiology of DD remains unknown. Systems biology combines mechanistic modelling with quantitative experimentation
in studies of networks and better understanding of the interaction of multiple components in disease processes. Adopting systems
biology may be the ideal approach for future research in order to improve understanding of complex diseases of multifactorial
origin. In this review, we propose that DD is a disease of several networks rather than of a single gene, and show that this
accounts for the experimental observations obtained to date from a variety of sources. We outline how DD may be investigated
more effectively by employing a systems biology approach that considers the disease network as a whole rather than focusing
on any specific single molecule. 相似文献
35.
Barjaktarovic Z Schmaltz D Shyla A Azimzadeh O Schulz S Haagen J Dörr W Sarioglu H Schäfer A Atkinson MJ Zischka H Tapio S 《PloS one》2011,6(12):e27811
BACKROUND: Radiation therapy treatment of breast cancer, Hodgkin's disease or childhood cancers expose the heart to high local radiation doses, causing an increased risk of cardiovascular disease in the survivors decades after the treatment. The mechanisms that underlie the radiation damage remain poorly understood so far. Previous data show that impairment of mitochondrial oxidative metabolism is directly linked to the development of cardiovascular disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the radiation-induced in vivo effects on cardiac mitochondrial proteome and function were investigated. C57BL/6N mice were exposed to local irradiation of the heart with doses of 0.2 Gy or 2 Gy (X-ray, 200 kV) at the age of eight weeks, the control mice were sham-irradiated. After four weeks the cardiac mitochondria were isolated and tested for proteomic and functional alterations. Two complementary proteomics approaches using both peptide and protein quantification strategies showed radiation-induced deregulation of 25 proteins in total. Three main biological categories were affected: the oxidative phophorylation, the pyruvate metabolism, and the cytoskeletal structure. The mitochondria exposed to high-dose irradiation showed functional impairment reflected as partial deactivation of Complex I (32%) and Complex III (11%), decreased succinate-driven respiratory capacity (13%), increased level of reactive oxygen species and enhanced oxidation of mitochondrial proteins. The changes in the pyruvate metabolism and structural proteins were seen with both low and high radiation doses. CONCLUSION/SIGNIFICANCE: This is the first study showing the biological alterations in the murine heart mitochondria several weeks after the exposure to low- and high-dose of ionizing radiation. Our results show that doses, equivalent to a single dose in radiotherapy, cause long-lasting changes in mitochondrial oxidative metabolism and mitochondria-associated cytoskeleton. This prompts us to propose that these first pathological changes lead to an increased risk of cardiovascular disease after radiation exposure. 相似文献
36.
Hekmat O Kim YW Williams SJ He S Withers SG 《The Journal of biological chemistry》2005,280(42):35126-35135
New proteomics methods are required for targeting and identification of subsets of a proteome in an activity-based fashion. Here, we report the first gel-free, mass spectrometry-based strategy for mechanism-based profiling of retaining beta-endoglycosidases in complex proteomes. Using a biotinylated, cleavable 2-deoxy-2-fluoroxylobioside inactivator, we have isolated and identified the active-site peptides of target retaining beta-1,4-glycanases in systems of increasing complexity: pure enzymes, artificial proteomes, and the secreted proteome of the aerobic mesophilic soil bacterium Cellulomonas fimi. The active-site peptide of a new C. fimi beta-1,4-glycanase was identified in this manner, and the peptide sequence, which includes the catalytic nucleophile, is highly conserved among glycosidase family 10 members. The glycanase gene (GenBank accession number DQ146941) was cloned using inverse PCR techniques, and the protein was found to comprise a catalytic domain that shares approximately 70% sequence identity with those of xylanases from Streptomyces sp. and a family 2b carbohydrate-binding module. The new glycanase hydrolyzes natural and artificial xylo-configured substrates more efficiently than their cello-configured counterparts. It has a pH dependence very similar to that of known C. fimi retaining glycanases. 相似文献
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Shahabi V Whitney G Hamid O Schmidt H Chasalow SD Alaparthy S Jackson JR 《Cancer immunology, immunotherapy : CII》2012,61(5):733-737
Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement
in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78%
objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation.
As an immune potentiator, the mechanism of action of ipilimumab may not be dependent of the activity of the BRAF pathway.
To test this, we investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status
of the tumors. Thus, this retrospective analysis was carried using a set of tumor biopsies from a completed phase II clinical
trial. CA184004 was a randomized, double-blind, multicenter trial of 82 previously treated or untreated patients with unresectable
stage III/IV melanoma. Patients received ipilimumab 3 or 10 mg/kg every 3 weeks for four doses followed by maintenance dosing
in eligible patients. The BRAF-V600E mutation status for 80 patients was determined in tumor biopsies by PCR-based assays.
Data on disease control were available for 69 patients with evaluated BRAF-V600E mutation status. Rates of objective responses
and stable disease in patients with BRAF-V600E mutation positive tumors (30%) were comparable to those in patients with the
wild-type gene (~33%). Eleven patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive
tumors and 45% did not. In the 48 patients showing no DDC, the mutation frequency was 50%. In this study, no association between
BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected. 相似文献
40.
Nakhjavani M Morteza A Asgarani F Khalilzadeh O Ghazizadeh Z Bathaie SZ Esteghamati A 《Gene》2012,498(1):107-111