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1.  KPP: KEGG Pathway Painter 
BMC Systems Biology  2015;9(Suppl 2):S3.
Background
High-throughput technologies became common tools to decipher genome-wide changes of gene expression (GE) patterns. Functional analysis of GE patterns is a daunting task as it requires often recourse to the public repositories of biological knowledge. On the other hand, in many cases researcher's inquiry can be served by a comprehensive glimpse. The KEGG PATHWAY database is a compilation of manually verified maps of biological interactions represented by the complete set of pathways related to signal transduction and other cellular processes. Rapid mapping of the differentially expressed genes to the KEGG pathways may provide an idea about the functional relevance of the gene lists corresponding to the high-throughput expression data.
Results
Here we present a web based graphic tool KEGG Pathway Painter (KPP). KPP paints pathways from the KEGG database using large sets of the candidate genes accompanied by "overexpressed" or "underexpressed" marks, for example, those generated by microarrays or miRNA profilings.
Conclusion
KPP provides fast and comprehensive visualization of the global GE changes by consolidating a list of the color-coded candidate genes into the KEGG pathways. KPP is freely available and can be accessed at http://web.cos.gmu.edu/~gmanyam/kegg/
doi:10.1186/1752-0509-9-S2-S3
PMCID: PMC4407080  PMID: 25879163
Data analysis; Data mining; Gene expression; Gene regulation; Visualization; Knowledge-based algorithms
2.  Anti-aging dilemma: to restore the hardware or to reinstall the software? 
Frontiers in Genetics  2015;6:129.
doi:10.3389/fgene.2015.00129
PMCID: PMC4396409  PMID: 25926845
metabolome; SEUs; mutations; Turing machines; hypercomputation
4.  Toward More Transparent and Reproducible Omics Studies Through a Common Metadata Checklist and Data Publications 
Abstract
Biological processes are fundamentally driven by complex interactions between biomolecules. Integrated high-throughput omics studies enable multifaceted views of cells, organisms, or their communities. With the advent of new post-genomics technologies, omics studies are becoming increasingly prevalent; yet the full impact of these studies can only be realized through data harmonization, sharing, meta-analysis, and integrated research. These essential steps require consistent generation, capture, and distribution of metadata. To ensure transparency, facilitate data harmonization, and maximize reproducibility and usability of life sciences studies, we propose a simple common omics metadata checklist. The proposed checklist is built on the rich ontologies and standards already in use by the life sciences community. The checklist will serve as a common denominator to guide experimental design, capture important parameters, and be used as a standard format for stand-alone data publications. The omics metadata checklist and data publications will create efficient linkages between omics data and knowledge-based life sciences innovation and, importantly, allow for appropriate attribution to data generators and infrastructure science builders in the post-genomics era. We ask that the life sciences community test the proposed omics metadata checklist and data publications and provide feedback for their use and improvement.
doi:10.1089/omi.2013.0149
PMCID: PMC3903324  PMID: 24456465
5.  Age-independent rise of inflammatory scores may contribute to accelerated aging in multi-morbidity 
Oncotarget  2015;6(3):1414-1421.
Aging is associated with an increase in a chronic, low-grade inflammation. This phenomenon, termed “inflammaging” is also a risk factor for both morbidity and mortality in the elderly. Frequent co-occurrence of chronic diseases, known as multi-morbidity, may be explained by interconnected pathophysiology of these conditions, most of which depend on its inflammatory component. Here we present an analysis of the U.S. National Health and Nutrition Examination Survey data collected between 1999 and 2008, for the presence, and the number, of chronic diseases along with HDL-cholesterol, C-reactive protein, white blood cell count, lymphocyte percent, monocyte percent, segmented neutrophils percent, eosinophils percent, basophils percent, and glycohemoglobin levels. Importantly, even after adjustment for age and BMI, many inflammatory markers continued to be associated to multi-morbidity. C-reactive protein (CRP) levels and Glasgow Prognostic Score (GPS) were most dramatically increased in parallel with an accumulation of chronic diseases, and may be utilized as multi-morbidity predictors. These observations point at background inflammation as direct, age-independent contributor to an accumulation of the disease burden. Our findings also suggest a possibility that systemic inflammation associated with chronic diseases may explain accelerated aging phenomenon previously observed among the patients with heavy disease burden.
PMCID: PMC4359303  PMID: 25638154
multi-morbidity; C-reactive protein; systemic inflammation; Glasgow Prognostic Score; aging
6.  Distance-based classifiers as potential diagnostic and prediction tools for human diseases 
BMC Genomics  2014;15(Suppl 12):S10.
Typically, gene expression biomarkers are being discovered in course of high-throughput experiments, for example, RNAseq or microarray profiling. Analytic pipelines that extract so-called signatures suffer from the "Dimensionality curse": the number of genes expressed exceeds the number of patients we can enroll in the study and use to train the discriminator algorithm. Hence, problems with the reproducibility of gene signatures are more common than not; when the algorithm is executed using a different training set, the resulting diagnostic signature may turn out to be completely different.
In this paper we propose an alternative novel approach which takes into account quantifiable expression levels of all genes assayed. In our analysis, the cumulative gene expression pattern of an individual patient is represented as a point in the multidimensional space formed by all gene expression profiles assayed in given system, where the clusters of "normal samples" and "affected samples" and defined. The degree of separation of the given sample from the space occupied by "normal samples" reflects the drift of the sample away from homeostasis in the course of development of the pathophysiological process that underly the disease. The outlined approach was validated using the publicly available glioma dataset deposited in Rembrandt and associated with survival data. Additionally, the applicability of the distance analysis to the classification of non-malignant sampled was tested using psoriatic lesions and non-lesional matched controls as a model.
Keywords: biomarkers; clustering; human diseases; RNA
doi:10.1186/1471-2164-15-S12-S10
PMCID: PMC4303935  PMID: 25563076
7.  Analysis of discordant Affymetrix probesets casts serious doubt on idea of microarray data reutilization 
BMC Genomics  2014;15(Suppl 12):S8.
Background
Affymetrix microarray technology allows one to investigate expression of thousands of genes simultaneously upon a variety of conditions. In a popular U133A microarray platform, the expression of 37% of genes is measured by more than one probeset. The discordant expression observed for two different probesets that match the same gene is a widespread phenomenon which is usually underestimated, ignored or disregarded.
Results
Here we evaluate the prevalence of discordant expression in data collected using Affymetrix HG-U133A microarray platform. In U133A, about 30% of genes annotated by two different probesets demonstrate a substantial correlation between independently measured expression values. To our surprise, sorting the probesets according to the nature of the discrepancy in their expression levels allowed the classification of the respective genes according to their fundamental functional properties, including observed enrichment by tissue-specific transcripts and alternatively spliced variants. On another hand, an absence of discrepancies in probesets that simultaneously match several different genes allowed us to pinpoint non-expressed pseudogenes and gene groups with highly correlated expression patterns. Nevertheless, in many cases, the nature of discordant expression of two probesets that match the same transcript remains unexplained. It is possible that these probesets report differently regulated sets of transcripts, or, in best case scenario, two different sets of transcripts that represent the same gene.
Conclusion
The majority of absolute gene expression values collected using Affymetrix microarrays may not be suitable for typical interpretative downstream analysis.
doi:10.1186/1471-2164-15-S12-S8
PMCID: PMC4303952  PMID: 25563078
8.  Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects 
BMC Gastroenterology  2014;14:208.
Background
Visceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH).
Methods
We analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1β (Interleukin- 1Beta) in obese subjects (BMI ≥ 35) with biopsy proven NAFLD.
Results
In adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1β were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis.
Conclusion
Our observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-014-0208-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-014-0208-8
PMCID: PMC4279907  PMID: 25512222
Obesity; NAFLD; Inflammasomes; Cytokines; Fibrosis
9.  Expression of energy metabolism related genes in the gastric tissue of obese individuals with non-alcoholic fatty liver disease 
BMC Gastroenterology  2014;14:72.
Background
Stomach is an integral part of the energy balance regulating circuit. Studies exploring the effects of cross-system changes in the energy homeostasis in stomach tissue are scarce. The proximity of the stomach to liver - the most common secondary target affected by obesity – suggests that these two organs are exposed to each other’s local secretion. Therefore, we aimed at expression profiling of energy metabolism associated genes in the gastric tissue of obese non-alcoholic fatty liver disease (NAFLD) patients.
Methods
A total of 24 patients with histologically-proven NAFLD were included. In the gastric tissue, gene expression profiling of 84 energy metabolism associated genes was carried out.
Results
The accumulation of the fat in the liver parenchyma is accompanied by downregulation of genes encoding for carboxypeptidase E (CPE) and Interleukin 1B (IL1B) in the gastric mucosa of same patient. In patients with high grade hepatic steatosis, Interleukin 1 beta encoding gene with anorexigenic function, IL1B was downregulated. The levels expression of 21 genes, including ADRA2B, CNR1 and LEP were significantly altered in the gastric tissue of NAFLD patients with hepatic inflammation. There were also indications of an increase in the opioid signaling within gastric mucosa that may results in a shift to proinflammatory environment within this organ and contribute to systemic inflammation and the pathogenic processes in hepatic parenchyma.
Conclusions
We have shown differential expression of energy metabolism associated genes in the gastric tissue of obese NAFLD patients. Importantly, these gene expression profiles are associated with changes in the hepatic parenchyma as reflected in increased scores for hepatic steatosis, inflammation, fibrosis and NASH. This study suggests the complex interplay of multiple organs in the pathogenesis of obesity-related complications such as NAFLD and provides further evidence supporting an important role for gastric tissue in promoting obesity-related complications.
doi:10.1186/1471-230X-14-72
PMCID: PMC4021272  PMID: 24716593
10.  Extracting Evolutionary Insights Using Bioinformatics 
doi:10.1155/2013/376235
PMCID: PMC3845244  PMID: 24324950
11.  Knowledge-based compact disease models identify new molecular players contributing to early-stage Alzheimer’s disease 
BMC Systems Biology  2013;7:121.
Background
High-throughput profiling of human tissues typically yield as results the gene lists comprised of a mix of relevant molecular entities with multiple false positives that obstruct the translation of such results into mechanistic hypotheses. From general probabilistic considerations, gene lists distilled for the mechanistically relevant components can be far more useful for subsequent experimental design or data interpretation.
Results
The input candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subsets of the same experiments and across different experiments and platforms. The cut-offs were established empirically through ontological and semantic enrichment; resultant shortened gene list was re-expanded by Ingenuity Pathway Assistant tool. The resulting sub-networks provided the basis for generating mechanistic hypotheses that were partially validated by literature search. This approach differs from previous consistency-based studies in that the cut-off on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The gene list distilled by this analytic technique and its network representation were termed Compact Disease Model (CDM). Here we present the CDM signature for the study of early-stage Alzheimer’s disease. The integrated analysis of this gene signature allowed us to identify the protein traffic vesicles as prominent players in the pathogenesis of Alzheimer’s. Considering the distances and complexity of protein trafficking in neurons, it is plausible that spontaneous protein misfolding along with a shortage of growth stimulation result in neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis have been discussed, with an emphasis on the protective effects of AT-1 mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Alignment with emerging literature confirmed many predictions derived from early-stage Alzheimer’s disease’ CDM.
Conclusions
A flexible approach for high-throughput data analysis, the Compact Disease Model generation, allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses.
doi:10.1186/1752-0509-7-121
PMCID: PMC3827844  PMID: 24196233
Signature; Network; Knowledge-based algorithms; Alzheimer’s; Protein traffic vesicles; Affymetrix; Illumina; Antihypertensive drugs
12.  An Exposure to the Oxidized DNA Enhances Both Instability of Genome and Survival in Cancer Cells 
PLoS ONE  2013;8(10):e77469.
Background
Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases and acts upon the cells. Response to cfDNA depends on concentrations and levels of the damage within cfDNA. Oxidized extracellular DNA acts as a stress signal and elicits an adaptive response.
Principal Findings
Here we show that oxidized extracellular DNA stimulates the survival of MCF-7 tumor cells. Importantly, in cells exposed to oxidized DNA, the suppression of cell death is accompanied by an increase in the markers of genome instability. Short-term exposure to oxidized DNA results in both single- and double strand DNA breaks. Longer treatments evoke a compensatory response that leads to a decrease in the levels of chromatin fragmentations across cell populations. Exposure to oxidized DNA leads to a decrease in the activity of NRF2 and an increase in the activity of NF-kB and STAT3. A model that describes the role of oxidized DNA released from apoptotic cells in tumor biology is proposed.
Conclusions/Significance
Survival of cells with an unstable genome may substantially augment progression of malignancy. Further studies of the effects of extracellular DNA on malignant and normal cells are warranted.
doi:10.1371/journal.pone.0077469
PMCID: PMC3798467  PMID: 24147001
13.  Molecular signature of adipose tissue in patients with both Non-Alcoholic Fatty Liver Disease (NAFLD) and Polycystic Ovarian Syndrome (PCOS) 
Background
Polycystic ovarian syndrome (PCOS) is one of the most common reproductive disorders with strong association with both insulin resistance and non-alcoholic fatty liver disease (NAFLD). To untangle the complex relationship between PCOS and NAFLD, we analyzed serum biomarkers of apoptosis, some adipokines and mRNA profiles in the visceral adipose tissue of obese patients with NAFLD who were also diagnosed with PCOS and compared to a group with NAFLD only.
Methods
We included patients with biopsy-proven NAFLD and PCOS (N = 12) and BMI-matched biopsy-proven NAFLD patients without PCOS (N = 12). Expression levels of individual mRNAs and soluble serum biomarkers were compared by non-parametric Mann–Whitney test. The analysis also included Spearman rank correlation tests and multiple regression analysis. For co-correlated genes, the factor analysis was performed.
Results
The total serum levels of apoptotic biomarker M30 were significantly elevated in PCOS patients with liver steatosis as compared to non-PCOS NAFLD controls (P < 0.02), pointing that androgen-dependent proapoptotic PCOS environment that may directly contribute to NAFLD progression in these patients. Similarly, hyperandrogenism may explain the observed PCOS-specific decrease (P < 0.04) in adipose LDLR mRNA expression that may be connected to the proneness of PCOS patients to NAFLD. The levels of mRNA encoding angiogenesis-associated GSK-3B interacting protein ninein were also significantly increased in the adipose tissue of NAFLD patients with PCOS (P < 0.007). Furthermore, the levels of resistin positively correlated with expression levels of LDLR and prothrombin time (PT).
Conclusion
An androgen-dependent proapoptotic PCOS environment may directly contribute to NAFLD progression in these patients. Hyperandrogenism may explain an observed decrease in adipose LDLR mRNA expression. An inflammation-associated increase in the release of resistin into circulation might contribute to the prothrombotic state observed under conditions associated with insulin resistance, including PCOS. The studies of larger cohorts of NAFLD with and without PCOS patients are needed to further assess these potential interactions.
doi:10.1186/1479-5876-11-133
PMCID: PMC3681627  PMID: 23721173
NAFLD; PCOS; LDLR; M30; Apoptosis; Ninein; Resistin
15.  Oxidized Extracellular DNA as a Stress Signal in Human Cells 
The term “cell-free DNA” (cfDNA) was recently coined for DNA fragments from plasma/serum, while DNA present in in vitro cell culture media is known as extracellular DNA (ecDNA). Under oxidative stress conditions, the levels of oxidative modification of cellular DNA and the rate of cell death increase. Dying cells release their damaged DNA, thus, contributing oxidized DNA fragments to the pool of cfDNA/ecDNA. Oxidized cell-free DNA could serve as a stress signal that promotes irradiation-induced bystander effect. Evidence points to TLR9 as a possible candidate for oxidized DNA sensor. An exposure to oxidized ecDNA stimulates a synthesis of reactive oxygen species (ROS) that evokes an adaptive response that includes transposition of the homologous loci within the nucleus, polymerization and the formation of the stress fibers of the actin, as well as activation of the ribosomal gene expression, and nuclear translocation of NF-E2 related factor-2 (NRF2) that, in turn, mediates induction of phase II detoxifying and antioxidant enzymes. In conclusion, the oxidized DNA is a stress signal released in response to oxidative stress in the cultured cells and, possibly, in the human body; in particular, it might contribute to systemic abscopal effects of localized irradiation treatments.
doi:10.1155/2013/649747
PMCID: PMC3606786  PMID: 23533696
16.  Knowledge-Based Identification of Soluble Biomarkers: Hepatic Fibrosis in NAFLD as an Example 
PLoS ONE  2013;8(2):e56009.
The discovery of biomarkers is often performed using high-throughput proteomics-based platforms and is limited to the molecules recognized by a given set of purified and validated antigens or antibodies. Knowledge-based, or systems biology, approaches that involve the analysis of integrated data, predominantly molecular pathways and networks may infer quantitative changes in the levels of biomolecules not included by the given assay from the levels of the analytes profiled. In this study we attempted to use a knowledge-based approach to predict biomarkers reflecting the changes in underlying protein phosphorylation events using Nonalcoholic Fatty Liver Disease (NAFLD) as a model. Two soluble biomarkers, CCL-2 and FasL, were inferred in silico as relevant to NAFLD pathogenesis. Predictive performance of these biomarkers was studied using serum samples collected from patients with histologically proven NAFLD. Serum levels of both molecules, in combination with clinical and demographic data, were predictive of hepatic fibrosis in a cohort of NAFLD patients. Our study suggests that (1) NASH-specific disruption of the kinase-driven signaling cascades in visceral adipose tissue lead to detectable changes in the levels of soluble molecules released into the bloodstream, and (2) biomarkers discovered in silico could contribute to predictive models for non-malignant chronic diseases.
doi:10.1371/journal.pone.0056009
PMCID: PMC3566090  PMID: 23405244
17.  Gene expression profiles associated with depression in patients with chronic hepatitis C (CH-C) 
Brain and Behavior  2012;2(5):525-531.
The standard treatment for CH-C, pegylated interferon-α and ribavirin (PEG-IFN + RBV), is associated with depression. Recent studies have proposed a new role for cytokines in the pathogenesis of depression. We aimed to assess differential gene expression related to depression in CH-C patients treated with PEG-IFN + RBV. We included 67 CH-C patients being treated with PEG-IFN+RBV. Of the entire study cohort, 22% had pre-existing depression, while another 37% developed new depression in course of the treatment. Pretreatment blood samples were collected into PAXgene™ RNA tubes, the RNAs extracted from peripheral blood mononuclear cells (PBMCs) were used for one step RT-PCR to profile 160 mRNAs. Differentially expressed genes were separated into up- and down-regulated genes according to presence or absence of depression at baseline (pre-existing depression) or following the initiation of treatment (treatment-related depression). The mRNA expression profile associated with any depression and with treatment-related depression included four and six genes, respectively. Our data demonstrate a significant down-regulation of TGF-β1 and the shift of Th1-Th2 cytokine balance in the depression associated with IFN-based treatment of HCV infection. We propose that TGF-β1 plays an important role in the imbalance of Th1/Th2 in patients with CH-C and depression. With further validation, TGF-β1 and other components of Th1/Th2 regulation pathway may provide a future marker for CH-C patients predisposed to depression.
doi:10.1002/brb3.72
PMCID: PMC3489805  PMID: 23139898
Depression; hepatitis C; interferon; ribavirin; TGFβ1; Th1/Th2 cytokines; treatment
18.  The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin 
Background
Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.
Methods
Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.
Results
The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.
Conclusions
IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.
doi:10.1186/1479-5876-10-25
PMCID: PMC3296607  PMID: 22313623
HCV; Gene Expression; Pathway Analysis; IL28B; SOCS1; IRF2; chronic hepatitis C; HCV treatment
19.  Comparative Analysis of the lux Operons in Aliivibrio logei KCh1 (a Kamchatka Isolate) and Aliivibrio salmonicida ▿  
Journal of Bacteriology  2011;193(15):3998-4001.
Here we provide a molecular description of a new psychrophilic strain, KCh11, of marine luminescent bacteria classified as Aliivibrio logei. We sequenced the entire lux operon of A. logei KCh1 and showed that it is substantially similar to the lux operon of Aliivibrio salmonicida. It was demonstrated that the reduced production of bioluminescence in A. salmonicida is most likely defined by a specific defect in its luxD gene.
doi:10.1128/JB.05320-11
PMCID: PMC3147497  PMID: 21665974
20.  A Network-Based Approach to Prioritize Results from Genome-Wide Association Studies 
PLoS ONE  2011;6(9):e24220.
Genome-wide association studies (GWAS) are a valuable approach to understanding the genetic basis of complex traits. One of the challenges of GWAS is the translation of genetic association results into biological hypotheses suitable for further investigation in the laboratory. To address this challenge, we introduce Network Interface Miner for Multigenic Interactions (NIMMI), a network-based method that combines GWAS data with human protein-protein interaction data (PPI). NIMMI builds biological networks weighted by connectivity, which is estimated by use of a modification of the Google PageRank algorithm. These weights are then combined with genetic association p-values derived from GWAS, producing what we call ‘trait prioritized sub-networks.’ As a proof of principle, NIMMI was tested on three GWAS datasets previously analyzed for height, a classical polygenic trait. Despite differences in sample size and ancestry, NIMMI captured 95% of the known height associated genes within the top 20% of ranked sub-networks, far better than what could be achieved by a single-locus approach. The top 2% of NIMMI height-prioritized sub-networks were significantly enriched for genes involved in transcription, signal transduction, transport, and gene expression, as well as nucleic acid, phosphate, protein, and zinc metabolism. All of these sub-networks were ranked near the top across all three height GWAS datasets we tested. We also tested NIMMI on a categorical phenotype, Crohn’s disease. NIMMI prioritized sub-networks involved in B- and T-cell receptor, chemokine, interleukin, and other pathways consistent with the known autoimmune nature of Crohn’s disease. NIMMI is a simple, user-friendly, open-source software tool that efficiently combines genetic association data with biological networks, translating GWAS findings into biological hypotheses.
doi:10.1371/journal.pone.0024220
PMCID: PMC3168369  PMID: 21915301
21.  Non-Invasive markers for hepatic fibrosis 
BMC Gastroenterology  2011;11:91.
With great advancements in the therapeutic modalities used for the treatment of chronic liver diseases, the accurate assessment of liver fibrosis is a vital need for successful individualized management of disease activity in patients. The lack of accurate, reproducible and easily applied methods for fibrosis assessment has been the major limitation in both the clinical management and for research in liver diseases. However, the problem of the development of biomarkers capable of non-invasive staging of fibrosis in the liver is difficult due to the fact that the process of fibrogenesis is a component of the normal healing response to injury, invasion by pathogens, and many other etiologic factors. Current non-invasive methods range from serum biomarker assays to advanced imaging techniques such as transient elastography and magnetic resonance imaging (MRI). Among non-invasive methods that gain strongest clinical foothold are FibroScan elastometry and serum-based APRI and FibroTest. There are many other tests that are not yet widely validated, but are none the less, promising. The rate of adoption of non-invasive diagnostic tests for liver fibrosis differs from country to country, but remains limited. At the present time, use of non-invasive procedures could be recommended as pre-screening that may allow physicians to narrow down the patients' population before definitive testing of liver fibrosis by biopsy of the liver. This review provides a systematic overview of these techniques, as well as both direct and indirect biomarkers based approaches used to stage fibrosis and covers recent developments in this rapidly advancing area.
doi:10.1186/1471-230X-11-91
PMCID: PMC3176189  PMID: 21849046
22.  An efficient algorithm for systematic analysis of nucleotide strings suitable for siRNA design 
BMC Research Notes  2011;4:168.
Background
The "off-target" silencing effect hinders the development of siRNA-based therapeutic and research applications. Existing solutions for finding possible locations of siRNA seats within a large database of genes are either too slow, miss a portion of the targets, or are simply not designed to handle a very large number of queries. We propose a new approach that reduces the computational time as compared to existing techniques.
Findings
The proposed method employs tree-based storage in a form of a modified truncated suffix tree to sort all possible short string substrings within given set of strings (i.e. transcriptome). Using the new algorithm, we pre-computed a list of the best siRNA locations within each human gene ("siRNA seats"). siRNAs designed to reside within siRNA seats are less likely to hybridize off-target. These siRNA seats could be used as an input for the traditional "set-of-rules" type of siRNA designing software. The list of siRNA seats is available through a publicly available database located at http://web.cos.gmu.edu/~gmanyam/siRNA_db/search.php
Conclusions
In attempt to perform top-down prediction of the human siRNA with minimized off-target hybridization, we developed an efficient algorithm that employs suffix tree based storage of the substrings. Applications of this approach are not limited to optimal siRNA design, but can also be useful for other tasks involving selection of the characteristic strings specific to individual genes. These strings could then be used as siRNA seats, as specific probes for gene expression studies by oligonucleotide-based microarrays, for the design of molecular beacon probes for Real-Time PCR and, generally, any type of PCR primers.
doi:10.1186/1756-0500-4-168
PMCID: PMC3117723  PMID: 21619643
23.  The N-Terminal Domain of Aliivibrio fischeri LuxR Is a Target of the GroEL Chaperonin▿  
Journal of Bacteriology  2010;192(20):5549-5551.
Here we show that the C-terminal domain of LuxR activates the transcription of Aliivibrio fischeri luxICDABEG in Escherichia coli SKB178 gro+ and E. coli OFB1111 groEL673 strains to the same level. Using affinity chromatography, we showed that GroEL binds to the N-terminal domain of LuxR, pointing to a GroEL/GroES requirement for the folding of the N-terminal domain of LuxR.
doi:10.1128/JB.00754-10
PMCID: PMC2950498  PMID: 20729362
24.  Validation of endogenous reference genes for qRT-PCR analysis of human visceral adipose samples 
BMC Molecular Biology  2010;11:39.
Background
Given the epidemic proportions of obesity worldwide and the concurrent prevalence of metabolic syndrome, there is an urgent need for better understanding the underlying mechanisms of metabolic syndrome, in particular, the gene expression differences which may participate in obesity, insulin resistance and the associated series of chronic liver conditions. Real-time PCR (qRT-PCR) is the standard method for studying changes in relative gene expression in different tissues and experimental conditions. However, variations in amount of starting material, enzymatic efficiency and presence of inhibitors can lead to quantification errors. Hence the need for accurate data normalization is vital. Among several known strategies for data normalization, the use of reference genes as an internal control is the most common approach. Recent studies have shown that both obesity and presence of insulin resistance influence an expression of commonly used reference genes in omental fat. In this study we validated candidate reference genes suitable for qRT-PCR profiling experiments using visceral adipose samples from obese and lean individuals.
Results
Cross-validation of expression stability of eight selected reference genes using three popular algorithms, GeNorm, NormFinder and BestKeeper found ACTB and RPII as most stable reference genes.
Conclusions
We recommend ACTB and RPII as stable reference genes most suitable for gene expression studies of human visceral adipose tissue. The use of these genes as a reference pair may further enhance the robustness of qRT-PCR in this model system.
doi:10.1186/1471-2199-11-39
PMCID: PMC2886049  PMID: 20492695
25.  Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region 
Tumour Biology  2009;31(1):33-45.
Deletion of 13q14.3 and a candidate gene KCNRG (potassium channel regulating gene) is the most frequent chromosomal abnormality in B-cell chronic lymphocytic leukemia and is a common finding in multiple myeloma (MM). KCNRG protein may interfere with the normal assembly of the K+ channel proteins causing the suppression of Kv currents. We aimed to examine possible role of KCNRG haploinsufficiency in chronic lymphocytic leukemia (CLL) and MM cells. We performed detailed genomic analysis of the KCNRG locus; studied effects of the stable overexpression of KCNRG isoforms in RPMI-8226, HL-60, and LnCaP cells; and evaluated relative expression of its transcripts in various human lymphomas. Three MM cell lines and 35 CLL PBL samples were screened for KCNRG mutations. KCNRG exerts growth suppressive and pro-apoptotic effects in HL-60, LnCaP, and RPMI-8226 cells. Direct sequencing of KCNRG exons revealed point mutation delT in RPMI-8226 cell line. Levels of major isoform of KCNRG mRNA are lower in DLBL lymphomas compared to normal PBL samples, while levels of its minor mRNA are decreased across the broad range of the lymphoma types. The haploinsufficiency of KCNRG might be relevant to the progression of CLL and MM at least in a subset of patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s13277-009-0005-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s13277-009-0005-0
PMCID: PMC2803748  PMID: 20237900
Tumor suppressor candidate; Potassium channels; 13q14; Chronic lymphocytic leukemia; Multiple myeloma; KCNRG

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