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91.
Chien-Sheng Chen Sean Sullivan Troy Anderson Aik Choon Tan Philip J. Alex Steven R. Brant Carmen Cuffari Theodore M. Bayless Monica V. Talor C. Lynne Burek Huan Wang Richard Li Lisa Wu Datta Yuqiong Wu Raimond L. Winslow Heng Zhu Xuhang Li 《Molecular & cellular proteomics : MCP》2009,8(8):1765-1776
Specific antimicrobial antibodies present in the sera of patients with inflammatory bowel disease (IBD) have been proven to be valuable serological biomarkers for diagnosis/prognosis of the disease. Herein we describe the use of a whole Escherichia coli proteome microarray as a novel high throughput proteomics approach to screen and identify new serological biomarkers for IBD. Each protein array, which contains 4,256 E. coli K12 proteins, was screened using individual serum from healthy controls (n = 39) and clinically well characterized patients with IBD (66 Crohn disease (CD) and 29 ulcerative colitis (UC)). Proteins that could be recognized by serum antibodies were visualized and quantified using Cy3-labeled goat anti-human antibodies. Surprisingly significance analysis of microarrays identified a total of 417 E. coli proteins that were differentially recognized by serum antibodies between healthy controls and CD or UC. Among those, 169 proteins were identified as highly immunogenic in healthy controls, 186 proteins were identified as highly immunogenic in CD, and only 19 were identified as highly immunogenic in UC. Using a supervised learning algorithm (k-top scoring pairs), we identified two sets of serum antibodies that were novel biomarkers for specifically distinguishing CD from healthy controls (accuracy, 86 ± 4%; p < 0.01) and CD from UC (accuracy, 80 ± 2%; p < 0.01), respectively. The Set 1 antibodies recognized three pairs of E. coli proteins: Era versus YbaN, YhgN versus FocA, and GabT versus YcdG, and the Set 2 antibodies recognized YidX versus FrvX. The specificity and sensitivity of Set 1 antibodies were 81 ± 5 and 89 ± 3%, respectively, whereas those of Set 2 antibodies were 84 ± 1 and 70 ± 6%, respectively. Serum antibodies identified for distinguishing healthy controls versus UC were only marginal because their accuracy, specificity, and sensitivity were 66 ± 5, 69 ± 5, and 61 ± 7%, respectively (p < 0.04). Taken together, we identified novel sets of serological biomarkers for diagnosis of CD versus healthy control and CD versus UC.Crohn disease (CD)1 and ulcerative colitis (UC) are chronic, idiopathic, and clinically heterogeneous intestinal disorders collectively known as inflammatory bowel disease (IBD) (1, 2). Although the distinction between UC and CD would seem clear based on the combination of clinical, endoscopic, and radiological criteria, indeterminate colitis is present in up to 10 and 20% of adult and pediatric patients with isolated colitis, respectively (3, 4).Serological testing is a non-invasive method for diagnosing IBD and differentiating UC from CD (5–7). Several serological IBD biomarkers have been identified in the past decade, and some have been used in IBD clinics (5–7) (see the list below). Many of these antibodies are produced on intestinal exposure to normal commensal bacteria in genetically susceptible individuals. Although it is not known whether these antibodies are pathogenic or not, they are specific to patients with either CD or UC and may reflect a dysregulated immune inflammatory response to intestinal bacterial antigens (2, 8–10). Several experimental animal models of IBD have led to the theory that the pathogenesis of IBD is the result of an aberrant immune response to normal commensal bacteria in genetically susceptible individuals (11, 12). In fact, most of the major serological biomarkers being used in IBD clinics are antibodies to microbial antigens, including yeast oligomannose (anti-Saccharomyces cerevisiae (ASCA)), bacterial outer membrane porin C (OmpC), Pseudomonas fluorescens bacterial sequence I2 (anti-I2), and most recently bacterial flagellin (CBir 1) (5–7, 13). All of these antimicrobial antibodies show a preponderance in patients with CD. However, ASCA has been identified in up to 5% of patients with UC (13, 14).In comparison, perinuclear anti-neutrophil cytoplasmic antibody (pANCA) with perinuclear highlighting was first described in 1990. Although generally considered an autoantibody, the specific antigenic stimulation for pANCA production remains unclear. This autoantibody is present in up to 70% of patients with UC and in up to 20% of patients with CD (6, 10). Recently a panel of five new anti-glycan antibodies have been identified, including anti-chitobioside IgA, anti-laminaribioside IgG, anti-mannobioside IgG, and antibodies against two major chemically synthesized (Σ) oligomannose epitopes, Man α-1,3 Man α-1,2 Man (ΣMan3) and Man α-1,3 Man α-1,2 Man α-1,2 Man (ΣMan4) (5, 13, 15). These new biomarkers serve as valuable complimentary tools to the available serological biomarkers mentioned above. Collectively these antibodies are not generally present in either children or adults with non-IBD disease and may represent serological markers of intestinal inflammation specific to UC or CD.Although encouraging, none of the current commercially available biomarker tests/assays, including all of those mentioned above, can be used as stand alone tools in clinics and therefore are only recommended as an adjunct to endoscopy in diagnosis and prognosis of the disease (5, 7, 16). Therefore, additional specific and sensitive IBD biomarkers are needed as are prospective studies to assess the utility of current and newly identified biomarkers (5, 13). Proteomics technologies such as two-dimensional gel electrophoresis, various variations of mass spectrometry, and protein chip (array) technology are now proving to be powerful tools in biomarker discovery and are beginning to be utilized in IBD biomarker discovery (5, 17). These technologies enable robust and/or large scale and high throughput identification and analysis of differential protein expression when comparing disease with control. Blood-based (serum- or plasma-based) proteomics holds particular promises for biomarker discovery of various human diseases such as neurodegenerative diseases and cancers (18–20). Antigen microarrays are also powerful tools that allow high throughput serum analysis of aberrant immune responses in autoimmune diseases (21–23) as well as efficient discovery of biomarkers for infectious pathogens (24). Herein we describe the use of an Escherichia coli proteome microarray to characterize the differential immune response (serum anti-E. coli antibodies) among patients clinically classified as CD, UC, and healthy controls. We hypothesized that novel IBD-specific antimicrobial antibodies, particularly anti-E. coli antibodies, are present in IBD patients and are likely to be identified by screening the sera with E. coli protein arrays. 相似文献
92.
Xin He Moushumi Sen Sarma Xu Ling Brant Chee Chengxiang Zhai Bruce Schatz 《BMC bioinformatics》2010,11(1):272
Background
Large-scale genomic studies often identify large gene lists, for example, the genes sharing the same expression patterns. The interpretation of these gene lists is generally achieved by extracting concepts overrepresented in the gene lists. This analysis often depends on manual annotation of genes based on controlled vocabularies, in particular, Gene Ontology (GO). However, the annotation of genes is a labor-intensive process; and the vocabularies are generally incomplete, leaving some important biological domains inadequately covered. 相似文献93.
Mavel S Dikic B Palakas S Emond P Greguric I de Gracia AG Mattner F Garrigos M Guilloteau D Katsifis A 《Bioorganic & medicinal chemistry》2006,14(5):1599-1607
Multidrug resistance (MDR) is one of the major problems affecting the treatment of cancer. In vivo visualization and quantification of MDR proteins would be of great value to better select the therapeutic strategy. Six flavone-based compounds were synthesized and evaluated for their cytotoxic activity and MDR-reversing capacity using hMRP1 or hMDR1 overexpressing cell lines for in vitro assays. All the flavone derivatives were highly selective for hMRP1-expressing cell lines. These derivatives each used at 4muM (a non-cytotoxic concentration) enhance significantly the sensitivity of hMRP1-mediated MDR cell line toward doxorubicin toxicity. Their MDR-reversing capacity suggests that, in particular, the 4'-fluoroalkyloxy and 4'-iodo apigenin derivatives are potential new radiopharmaceuticals to visualize in vivo MRP1-mediated MDR phenomenon by PET or SPECT. 相似文献
94.
Casas AM Djemel A Ciudad FJ Yahiaoui S Ponce LJ Contreras-Moreira B Gracia MP Lasa JM Igartua E 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2011,122(7):1293-1304
In barley, three genes are responsible for the vernalization requirement: VrnH1, VrnH2 and VrnH3. The winter growth habit of barley requires the presence of a recessive VrnH1 allele, together with an active VrnH2 allele. The candidate for VrnH3 (HvFT1) has been recently identified, with evidences pointing at a central role in the integration of the vernalization and photoperiod pathways. Functional polymorphisms have been proposed, but experimental evidence of their role on agronomic performance and adaptation is needed. We examined allelic variation at the promoter and intron 1 of the HvFT1 gene in a landrace collection of barley, finding a high diversity level, with its geographic distribution correlated with latitude. Focusing on genotypes with winter alleles in VrnH1 and VrnH2, an association analysis of the four main HvFT1 haplotypes found in the landrace collection detected differences in time to flowering. Landraces with the intron 1 TC allele, prevalent in the south, flowered 6?C7?days earlier than those with the AG allele, under natural conditions. These results were validated in an independent F2 population. In both data sets, the effect found was similar, but in opposite direction to that described in literature. The polymorphism reported at intron 1 contributes to variation in flowering time under field conditions. We have found that polymorphisms at the promoter also contribute to the effect of the gene on flowering time under field and controlled conditions. The variety of HvFT1 alleles described constitutes an allelic series that may have been a factor in agro-ecological adaptation of barley. 相似文献
95.
Woldt E Matz RL Terrand J Mlih M Gracia C Foppolo S Martin S Bruban V Ji J Velot E Herz J Boucher P 《The Journal of biological chemistry》2011,286(19):16775-16782
The low density lipoprotein receptor-related protein (LRP1) is a transmembrane receptor that integrates multiple signaling pathways. Its cytoplasmic domain serves as docking sites for several adaptor proteins such as the Src homology 2/α-collagen (ShcA), which also binds to several tyrosine kinase receptors such as the insulin-like growth factor 1 (IGF-1) receptor. However, the physiological significance of the physical interaction between LRP1 and ShcA, and whether this interaction modifies tyrosine kinase receptor signaling, are still unknown. Here we report that LRP1 forms a complex with the IGF-1 receptor, and that LRP1 is required for ShcA to become sensitive to IGF-1 stimulation. Upon IGF-1 treatment, ShcA is tyrosine phosphorylated and translocates to the plasma membrane only in the presence of LRP1. This leads to the recruitment of the growth factor receptor-bound protein 2 (Grb2) to ShcA, and activation of the Ras/MAP kinase pathway. Conversely, in the absence of ShcA, IGF-1 signaling bifurcates toward the Akt/mammalian target of rapamycin pathway and accelerates adipocyte differentiation when cells are stimulated for adipogenesis. These results establish the LRP1-ShcA complex as an essential component in the IGF-1-regulated pathway for MAP kinase and Akt/mammalian target of rapamycin activation, and may help to understand the IGF-1 signaling shift from clonal expansion to growth-arrested cells and differentiation during adipogenesis. 相似文献
96.
Casao MC Igartua E Karsai I Lasa JM Gracia MP Casas AM 《Journal of experimental botany》2011,62(6):1939-1949
The response to vernalization and the expression of genes associated with responses to vernalization (VRNH1, VRNH2, and VRNH3) and photoperiod (PPDH1 and PPDH2) were analysed in four barley (Hordeum vulgare L.) lines: 'Alexis' (spring), 'Plaisant' (winter), SBCC058, and SBCC106 (Spanish inbred lines), grown under conditions of vernalization and short days (VSD) or no vernalization and long days (NVLD). The four genotypes differ in VRNH1. Their growth habits and responses to vernalization correlated with the level of expression of VRNH1 and the length of intron 1. 'Alexis' and 'Plaisant' behaved as expected. SBCC058 and SBCC106 showed an intermediate growth habit and flowered relatively late in the absence of vernalization. VRNH1 expression was induced by cold for all genotypes. Under VSD, VRNH1 expression was detected in the SBCC genotypes later than in 'Alexis' but earlier than in 'Plaisant'. VRNH2 was repressed under short days while VRNH1 expression increased in parallel. VRNH3 was detected only in 'Alexis' under NVLD, whereas it was not expressed in plants with the active allele of VRNH2 (SBCC058 and 'Plaisant'). Under VSD, PPDH2 was expressed in 'Alexis', SBCC058, and SBCC106, but it was only expressed weakly in 'Alexis' under NVLD. Further analysis of PPDH2 expression in two barley doubled haploid populations revealed that, under long days, HvFT3 and VRNH2 expression levels were related inversely. The timing of VRNH2 expression under a long photoperiod suggests that this gene might be involved in repression of PPDH2 and, indirectly, in the regulation of flowering time through an interaction with the day-length pathway. 相似文献
97.
98.
Hamel B Monaghan-Benson E Rojas RJ Temple BR Marston DJ Burridge K Sondek J 《The Journal of biological chemistry》2011,286(14):12141-12148
SmgGDS is an atypical guanine nucleotide exchange factor (GEF) that promotes both cell proliferation and migration and is up-regulated in several types of cancer. SmgGDS has been previously shown to activate a wide variety of small GTPases, including the Ras family members Rap1a, Rap1b, and K-Ras, as well as the Rho family members Cdc42, Rac1, Rac2, RhoA, and RhoB. In contrast, here we show that SmgGDS exclusively activates RhoA and RhoC among a large panel of purified GTPases. Consistent with the well known properties of GEFs, this activation is catalytic, and SmgGDS preferentially binds to nucleotide-depleted RhoA relative to either GDP- or GTPγS-bound forms. However, mutational analyses indicate that SmgGDS utilizes a distinct exchange mechanism compared with canonical GEFs and in contrast to known GEFs requires RhoA to retain a polybasic region for activation. A homology model of SmgGDS highlights an electronegative surface patch and a highly conserved binding groove. Mutation of either area ablates the ability of SmgGDS to activate RhoA. Finally, the in vitro specificity of SmgGDS for RhoA and RhoC is retained in cells. Together, these results indicate that SmgGDS is a bona fide GEF that specifically activates RhoA and RhoC through a unique mechanism not used by other Rho family exchange factors. 相似文献
99.
Juan F. Alcala-Diaz Javier Delgado-Lista Pablo Perez-Martinez Antonio Garcia-Rios Carmen Marin Gracia M. Quintana-Navarro Purificacion Gomez-Luna Antonio Camargo Yolanda Almaden Javier Caballero Francisco J. Tinahones Jose M. Ordovas Francisco Perez-Jimenez Jose Lopez-Miranda 《PloS one》2014,9(5)
Objective
To determine whether metabolic syndrome traits influence the postprandial lipemia response of coronary patients, and whether this influence depends on the number of MetS criteria.Materials and Methods
1002 coronary artery disease patients from the CORDIOPREV study were submitted to an oral fat load test meal with 0.7 g fat/kg body weight (12% saturated fatty acids, 10% polyunsaturated fatty acids, 43% monounsaturated fatty acids), 10% protein and 25% carbohydrates. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Total and incremental area under the curves of the different postprandial parameters were calculated following the trapezoid rule to assess the magnitude of change during the postprandial stateResults
Postprandial lipemia response was directly related to the presence of metabolic syndrome. We found a positive association between the number of metabolic syndrome criteria and the response of postprandial plasma triglycerides (p<0.001), area under the curve of triglycerides (p<0.001) and incremental area under the curve of triglycerides (p<0.001). However, the influence of them on postprandial triglycerides remained statistically significant only in those patients without basal hypertriglyceridemia. Interestingly, in stepwise multiple linear regression analysis with the AUC of triglycerides as the dependent variable, only fasting triglycerides, fasting glucose and waist circumference appeared as significant independent (P<0.05) contributors. The multiple lineal regression (R) was 0.77, and fasting triglycerides showed the greatest effect on AUC of triglycerides with a standardized coefficient of 0.75.Conclusions
Fasting triglycerides are the major contributors to the postprandial triglycerides levels. MetS influences the postprandial response of lipids in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients. 相似文献100.
J. L. Arsuaga C. Lorenzo I. Martínez A. Gracia J. M. Carretero N. García López-Polín 《Human Evolution》2000,15(1-2):75-82
After 20 years of research, the Atapuerca sites have provided a large amount of archaeological and palaeontological remains.
Human fossils have been found in three sites: Gran Dolina, galería and Sima de los Huesos. The Early Pleistocene human fossils
from Gran Dolina have been ascribed to a new species,Homo antecessor, that represent the last common ancestor of Neandertals and modern humans. The Sima de los Huesos fossils and all the European
Middle Pleistocene human fossils are the ancestors exclusively of the Neandertals, which evolved in Europe in conditions of
geographic and genetic isolation. 相似文献