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Search Results: 1 - 10 of 5734 matches for " Igor Dozmorov "
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Immune System as a Sensory System
Igor M. Dozmorov,D. Dresser
International Journal of Biomedical Science , 2011,
Abstract: As suggested by the well-known gestalt concept the immune system can be regarded as an integrated complex system, the functioning of which cannot be fully characterized by the behavior of its constituent elements. Similar approaches to the immune system in particular and sensory systems in general allows one to discern similarities and differences in the process of distinguishing informative patterns in an otherwise random background, thus initiating an appropriate and adequate response. This may lead to a new interpretation of difficulties in the comprehension of some immunological phenomena.
A Comprehensive and Universal Method for Assessing the Performance of Differential Gene Expression Analyses
Mikhail G. Dozmorov,Joel M. Guthridge,Robert E. Hurst,Igor M. Dozmorov
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012657
Abstract: The number of methods for pre-processing and analysis of gene expression data continues to increase, often making it difficult to select the most appropriate approach. We present a simple procedure for comparative estimation of a variety of methods for microarray data pre-processing and analysis. Our approach is based on the use of real microarray data in which controlled fold changes are introduced into 20% of the data to provide a metric for comparison with the unmodified data. The data modifications can be easily applied to raw data measured with any technological platform and retains all the complex structures and statistical characteristics of the real-world data. The power of the method is illustrated by its application to the quantitative comparison of different methods of normalization and analysis of microarray data. Our results demonstrate that the method of controlled modifications of real experimental data provides a simple tool for assessing the performance of data preprocessing and analysis methods.
Statistical monitoring of weak spots for improvement of normalization and ratio estimates in microarrays
Igor Dozmorov, Nicholas Knowlton, Yuhong Tang, Michael Centola
BMC Bioinformatics , 2004, DOI: 10.1186/1471-2105-5-53
Abstract: We developed a multistep procedure for analysis of mRNA expression data that robustly identifies the additive noise in a microarray experiment. This analysis is predicated on the fact that additive noise signals can be accurately identified by both distribution and statistical analysis.Identification of additive noise in this manner allows exclusion of noncorrelated weak signals from regression-based normalization of compared profiles thus maximizing the accuracy of these methods. Moreover, genes expressed at very low levels can be clearly identified due to the fact that their expression distribution is stable and distinguishable from the random pattern of additive noise.Microarrays are powerful and cost-effective tools for large-scale analysis of gene expression. While the utility of this technology has been established [1,2], analytical methods are evolving and a matter of contention. Key among the more controversial aspects is the treatment of data from weak spots, which significantly influences outcomes. For example, ratio analysis is commonly employed to determine expression differences between two samples. However any procedure that uses raw intensities to infer relative expression is limited due to the fact that accuracy is signal level dependent, with variation increasing dramatically for low intensity signals [1,3]. Several methods have been developed to diminish the influence of additive noise. One solution is to ignore any genes whose transcripts are present at a low total abundance, to exclude weak spots – arbitrarily (in Kooperberg etal., [3] an intensity cutoff was used such that the relative error in ratios was less than 25%) or with some statistical procedures [4,5]. Other methods proposed for discriminating expressed genes from those not expressed, such as the method of Greller and Tobin [6], are suitable only for bimodal distributions in which the distribution of intensities for these two subsets are non-overlapping, unlike many empirical data sets
Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells
Mikhail G Dozmorov, Kimberly D Kyker, Ricardo Saban, Nicholas Knowlton, Igor Dozmorov, Michael B Centola, Robert E Hurst
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-12
Abstract: Five bladder cancer cell lines and one immortalized, but non-tumorigenic, urothelial line were grown on Matrigel, a cancer-derived ECM, on SISgel, a normal-derived ECM, and on plastic, where the only ECM is derived from the cells themselves. The transcriptomes were analyzed on an array of 1186 well-annotated cancer derived cDNAs containing most of the major pathways for malignancy. Hypervariable genes expressing more variability across cell lines than a set expressing technical variability were analyzed further. Expression values were clustered, and to identify genes most likely to represent biological factors, statistically over-represented ontologies and transcriptional regulatory elements were identified.Approximately 400 of the 1186 total genes were expressed 2 SD above background. Approximately 100 genes were hypervariable in cells grown on each ECM, but the pattern was different in each case. A core of 20 were identified as hypervariable under all 3 growth conditions, and 33 were hypervariable on both SISgel and Matrigel, but not on plastic. Clustering of the hypervariable genes showed very different patterns for the same 6 cell types on the different ECM. Even when loss of cell cycle regulation was identified, different genes were involved, depending on the ECM. Under the most permissive conditions of growth where the malignant phenotype was fully expressed, activation of AKT was noted. TGFβ1 signaling played a major role in the response of bladder cancer cells to ECM. Identification of TREs on genes that clustered together suggested some clustering was driven by specific transcription factors.The extracellular matrix on which cancer cells are grown has a major effect on gene expression. A core of 20 malignancy-related genes were not affected by matrix, and 33 were differentially expressed on 3-dimensional culture as opposed to plastic. Other than these genes, the patterns of expression were very different in cells grown on SISgel than on Matrigel or even pla
Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis
James N Jarvis, Igor Dozmorov, Kaiyu Jiang, Mark Frank, Peter Szodoray, Philip Alex, Michael Centola
Arthritis Research & Therapy , 2004, DOI: 10.1186/ar1018
Abstract: 'Juvenile rheumatoid arthritis' (JRA), a term for the most prevalent form of arthritis in children, is applied to a family of illnesses characterized by chronic inflammation and hypertrophy of the synovial membranes. The term overlaps, but is not completely synonymous, with the family of illnesses referred to as juvenile chronic arthritis and/or juvenile idiopathic arthritis in Europe. We [1] and others [2] have proposed that the pathogenesis of rheumatoid disease in adults and children involves complex interactions between innate and adaptive immunity. This complexity lies at the core of the difficulty of unraveling disease pathogenesis. Both innate and adaptive immune systems use multiple cell types, a vast array of cell-surface and secreted proteins, and interconnected networks of positive and negative feedback [3]. Furthermore, while separable in thought, the innate and adaptive wings of the immune system are functionally intersected [4], and pathologic events occurring at these intersecting points are likely to be highly relevant to our understanding of pathogenesis of adult and childhood forms of chronic arthritis [5].Polyarticular JRA is a distinct clinical subtype characterized by inflammation and synovial proliferation in multiple joints (four or more), including the small joints of the hands [6]. This subtype of JRA may be severe, because of both its multiple joint involvement and its capacity to progress rapidly over time. Although clinically distinct, polyarticular JRA is not homogeneous, and patients vary in disease manifestations, age of onset, prognosis, and therapeutic response. These differences very likely reflect a spectrum of variation in the nature of the immune and inflammatory attack that can occur in this disease [1].Gene expression profiling using microarrays provides a highly parallel assay for assessing molecular pathophysiology in a comprehensive manner. It holds the potential to refine our understanding of complex disease states. However
Bladder inflammatory transcriptome in response to tachykinins: Neurokinin 1 receptor-dependent genes and transcription regulatory elements
Ricardo Saban, Cindy Simpson, Rajanikanth Vadigepalli, Sylvie Memet, Igor Dozmorov, Marcia R Saban
BMC Urology , 2007, DOI: 10.1186/1471-2490-7-7
Abstract: An expression analysis was performed using urinary bladders isolated from sensitized wild type (WT) and NK1R-/- mice that were stimulated with saline, LPS, or antigen to provoke inflammation. Based on cDNA array results, NK1R-dependent genes were selected. PAINT software was used to query TRANSFAC database and to retrieve upstream TREs that were confirmed by electrophoretic mobility shift assays.The regulatory network of TREs driving NK1R-dependent genes presented cRel in a central position driving 22% of all genes, followed by AP-1, NF-kappaB, v-Myb, CRE-BP1/c-Jun, USF, Pax-6, Efr-1, Egr-3, and AREB6. A comparison between NK1R-dependent and NK1R-independent genes revealed Nkx-2.5 as a unique discriminator. In the presence of NK1R, Nkx2-5 _01 was significantly correlated with 36 transcripts which included several candidates for mediating bladder development (FGF) and inflammation (PAR-3, IL-1R, IL-6, α-NGF, TSP2). In the absence of NK1R, the matrix Nkx2-5_02 had a predominant participation driving 8 transcripts, which includes those involved in cancer (EYA1, Trail, HSF1, and ELK-1), smooth-to-skeletal muscle trans-differentiation, and Z01, a tight-junction protein, expression. Electrophoretic mobility shift assays confirmed that, in the mouse urinary bladder, activation of NK1R by substance P (SP) induces both NKx-2.5 and NF-kappaB translocations.This is the first report describing a role for Nkx2.5 in the urinary tract. As Nkx2.5 is the unique discriminator of NK1R-modulated inflammation, it can be imagined that in the near future, new based therapies selective for controlling Nkx2.5 activity in the urinary tract may be used in the treatment in a number of bladder disorders.Substance P belongs to the tachykinins (TKs) family of peptides involved in the peripheral and central regulation of urinary functions [1] through the stimulation of neurokinin (NK) NK1, NK2, and NK3 receptors [2,3]. At the urinary system level, TKs stimulate smooth muscle tone, ureteric perista
Evidence of Dynamically Dysregulated Gene Expression Pathways in Hyperresponsive B Cells from African American Lupus Patients
Igor Dozmorov, Nicolas Dominguez, Andrea L. Sestak, Julie M. Robertson, John B. Harley, Judith A. James, Joel M. Guthridge
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071397
Abstract: Recent application of gene expression profiling to the immune system has shown a great potential for characterization of complex regulatory processes. It is becoming increasingly important to characterize functional systems through multigene interactions to provide valuable insights into differences between healthy controls and autoimmune patients. Here we apply an original systematic approach to the analysis of changes in regulatory gene interconnections between in Epstein-Barr virus transformed hyperresponsive B cells from SLE patients and normal control B cells. Both traditional analysis of differential gene expression and analysis of the dynamics of gene expression variations were performed in combination to establish model networks of functional gene expression. This Pathway Dysregulation Analysis identified known transcription factors and transcriptional regulators activated uniquely in stimulated B cells from SLE patients.
Identification of Unique MicroRNA Signature Associated with Lupus Nephritis
Jeannie L. Te,Igor M. Dozmorov,Joel M. Guthridge,Kim L. Nguyen,Joshua W. Cavett,Jennifer A. Kelly,Gail R. Bruner,John B. Harley,Joshua O. Ojwang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010344
Abstract: MicroRNAs (miRNA) have emerged as an important new class of modulators of gene expression. In this study we investigated miRNA that are differentially expressed in lupus nephritis. Microarray technology was used to investigate differentially expressed miRNA in peripheral blood mononuclear cells (PBMCs) and Epstein-Barr Virus (EBV)-transformed cell lines obtained from lupus nephritis affected patients and unaffected controls. TaqMan-based stem-loop real-time polymerase chain reaction was used for validation. Microarray analysis of miRNA expressed in both African American (AA) and European American (EA) derived lupus nephritis samples revealed 29 and 50 differentially expressed miRNA, respectively, of 850 tested. There were 18 miRNA that were differentially expressed in both racial groups. When samples from both racial groups and different specimen types were considered, there were 5 primary miRNA that were differentially expressed. We have identified 5 miRNA; hsa-miR-371-5P, hsa-miR-423-5P, hsa-miR-638, hsa-miR-1224-3P and hsa-miR-663 that were differentially expressed in lupus nephritis across different racial groups and all specimen types tested. Hsa-miR-371-5P, hsa-miR-1224-3P and hsa-miR-423-5P, are reported here for the first time to be associated with lupus nephritis. Our work establishes EBV-transformed B cell lines as a useful model for the discovery of miRNA as biomarkers for SLE. Based on these findings, we postulate that these differentially expressed miRNA may be potential novel biomarkers for SLE as well as help elucidate pathogenic mechanisms of lupus nephritis. The investigation of miRNA profiles in SLE may lead to the discovery and development of novel methods to diagnosis, treat and prevent SLE.
Anthrax Lethal Toxin-Induced Gene Expression Changes in Mouse Lung
Eric K. Dumas,Philip M. Cox,Charles O’Connor Fullenwider,Melissa Nguyen,Michael Centola,Mark Barton Frank,Igor Dozmorov,Judith A. James,A. Darise Farris
Toxins , 2011, DOI: 10.3390/toxins3091111
Abstract: A major virulence factor of Bacillus anthracis is the anthrax Lethal Toxin (LeTx), a bipartite toxin composed of Protective Antigen and Lethal Factor. Systemic administration of LeTx to laboratory animals leads to death associated with vascular leakage and pulmonary edema. In this study, we investigated whether systemic exposure of mice to LeTx would induce gene expression changes associated with vascular/capillary leakage in lung tissue. We observed enhanced susceptibility of A/J mice to death by systemic LeTx administration compared to the C57BL/6 strain. LeTx-induced groups of both up- and down-regulated genes were observed in mouse lungs 6 h after systemic administration of wild type toxin compared to lungs of mice exposed to an inactive mutant form of the toxin. Lungs of the less susceptible C57BL/6 strain showed 80% fewer differentially expressed genes compared to lungs of the more sensitive A/J strain. Expression of genes known to regulate vascular permeability was modulated by LeTx in the lungs of the more susceptible A/J strain. Unexpectedly, the largest set of genes with altered expression was immune specific, characterized by the up-regulation of lymphoid genes and the down-regulation of myeloid genes. Transcripts encoding neutrophil chemoattractants, modulators of tumor regulation and angiogenesis were also differentially expressed in both mouse strains. These studies provide new directions for the investigation of vascular leakage and pulmonary edema induced by anthrax LeTx.
Regulatory network of inflammation downstream of proteinase-activated receptors
Ricardo Saban, Michael R D'Andrea, Patricia Andrade-Gordon, Claudia K Derian, Igor Dozmorov, Michael A Ihnat, Robert E Hurst, Cindy Simpson, Marcia R Saban
BMC Physiology , 2007, DOI: 10.1186/1472-6793-7-3
Abstract: We have shown that intravesical administration of PAR-activating peptides leads to an inflammatory reaction characterized by edema and granulocyte infiltration. Moreover, the inflammatory response to intravesical instillation of known pro-inflammatory stimuli such as E. coli lipopolysaccharide (LPS), substance P (SP), and antigen was strongly attenuated by PAR1- and to a lesser extent by PAR2-deficiency.Here, cDNA array experiments determined inflammatory genes whose expression is dependent on PAR1 activation. For this purpose, we compared the alteration in gene expression in wild type and PAR1-/- mice induced by classical pro-inflammatory stimuli (LPS, SP, and antigen). 75 transcripts were considered to be dependent on PAR-1 activation and further annotated in silico by Ingenuity Pathways Analysis (IPA) and gene ontology (GO). Selected transcripts were target validated by quantitative PCR (Q-PCR). Among PAR1-dependent transcripts, the following have been implicated in the inflammatory process: b2m, ccl7, cd200, cd63, cdbpd, cfl1, dusp1, fkbp1a, fth1, hspb1, marcksl1, mmp2, myo5a, nfkbia, pax1, plaur, ppia, ptpn1, ptprcap, s100a10, sim2, and tnfaip2. However, a balanced response to signals of injury requires a transient cellular activation of a panel of genes together with inhibitory systems that temper the overwhelming inflammation. In this context, the activation of genes such as dusp1 and nfkbia seems to counter-balance the inflammatory response to PAR activation by limiting prolonged activation of p38 MAPK and increased cytokine production. In contrast, transcripts such as arf6 and dcnt1 that are involved in the mechanism of PAR re-sensitization would tend to perpetuate the inflammatory reaction in response to common pro-inflammatory stimuli.The combination of cDNA array results and genomic networks reveals an overriding participation of PAR1 in bladder inflammation, provides a working model for the involvement of downstream signaling, and evokes testable hypoth
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