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1.  Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse 
Journal of autoimmunity  2013;41:168-174.
Genetic polymorphism in MECP2/IRAK1 on chromosome Xq28 is a confirmed and replicated susceptibility locus for lupus. High linkage disequilibrium in this locus suggests that both MECP2 and IRAK1 are candidate genes for the disease. DNA methylation changes in lupus T cells play a central role in the pathogenesis of lupus, and MeCp-2 (encoded by MECP2) is a master regulator of gene expression and is also known to recruit DNA methyltransferase 1 (DNMT1) during DNA synthesis. Using human T cells from normal individuals with either the lupus risk or the lupus protective haplotype in MECP2/IRAK1, we demonstrate that polymorphism in this locus increases MECP2 isoform 2 mRNA expression in stimulated but not unstimulated T cells. By assessing DNA methylation levels across over 485,000 methylation sites across the entire genome, we further demonstrate that the lupus risk variant in this locus is associated with significant DNA methylation changes, including in the HLA-DR and HLA-DQ loci, as well as interferon-related genes such as IFI6, IRF6, and BST2. Further, using a human MECP2 transgenic mouse, we show that overexpression of MECP2 alters gene expression in stimulated T cells. This includes overexpression of Eif2c2 that regulates the expression of multiple microRNAs (such as miR-21), and the histone demethylase Jhdm1d. In addition, we show that MECP2 transgenic mice develop antinuclear antibodies. Our data suggest that the lupus associated variant in the MECP2/IRAK1 locus has the potential to affect all 3 epigenetic mechanisms: DNA methylation, microRNA expression, and histone modification. Importantly, these data support the notion that variants within the MECP2 gene can alter DNA methylation in other genetic loci including the HLA and interferon-regulated genes, thereby providing evidence for genetic-epigenetic interaction in lupus.
doi:10.1016/j.jaut.2012.12.012
PMCID: PMC3622940  PMID: 23428850
MECP2; IRAK1; lupus; epigenetics; polymorphism; DNA methylation; T cells; transgenic mouse
2.  The Impact of Problem-Solving Feedback on Team-Based Learning Case Responses 
Objective. To determine the amount and type of feedback needed to improve pharmacy students’ problem-solving skills using team-based learning (TBL) and a problem-solving rubric.
Methods. A problem-solving rubric was developed to assess the ability of pharmacy students’ to prioritize, organize, and defend the best and alternative options on TBL cases The study involved 3 groups of pharmacy students: second-year students in a cardiology class who received no feedback (control group), third-year students in an endocrinology class who received written feedback only, and third-year students in an endocrinology class who received written and verbal feedback. Students worked in groups on all TBL cases except the first and last one (beginning and end of course), which students completed independently as it served as a pretest and posttest.
Results. Significant improvements were seen in the ability of the third-year students who received verbal and written feedback to prioritize the information presented in the case and in their total score on the problem-solving rubric.
Conclusion. Providing pharmacy students with written and verbal explanations may help them improve their problem-solving skills overall. During verbal feedback, faculty members can provide more examples of how to improve and can field questions if needed.
doi:10.5688/ajpe779189
PMCID: PMC3831400  PMID: 24249851
team-based learning; problem-solving; rubrics; assessment; feedback
3.  Acute Lung Injury and Acute Kidney Injury Are Established by Four Hours in Experimental Sepsis and Are Improved with Pre, but Not Post, Sepsis Administration of TNF-α Antibodies 
PLoS ONE  2013;8(11):e79037.
Introduction
Acute kidney injury (AKI) and acute lung injury (ALI) are serious complications of sepsis. AKI is often viewed as a late complication of sepsis. Notably, the onset of AKI relative to ALI is unclear as routine measures of kidney function (BUN and creatinine) are insensitive and increase late. In this study, we hypothesized that AKI and ALI would occur simultaneously due to a shared pathophysiology (i.e., TNF-α mediated systemic inflammatory response syndrome [SIRS]), but that sensitive markers of kidney function would be required to identify AKI.
Methods
Sepsis was induced in adult male C57B/6 mice with 5 different one time doses of intraperitoneal (IP) endotoxin (LPS) (0.00001, 0.0001, 0.001, 0.01, or 0.25 mg) or cecal ligation and puncture (CLP). SIRS was assessed by serum proinflammatory cytokines (TNF-α, IL-1β, CXCL1, IL-6), ALI was assessed by lung inflammation (lung myeloperoxidase [MPO] activity), and AKI was assessed by serum creatinine, BUN, and glomerular filtration rate (GFR) (by FITC-labeled inulin clearance) at 4 hours. 20 µgs of TNF-α antibody (Ab) or vehicle were injected IP 2 hours before or 2 hours after IP LPS.
Results
Serum cytokines increased with all 5 doses of LPS; AKI and ALI were detected within 4 hours of IP LPS or CLP, using sensitive markers of GFR and lung inflammation, respectively. Notably, creatinine did not increase with any dose; BUN increased with 0.01 and 0.25 mg. Remarkably, GFR was reduced 50% in the 0.001 mg LPS dose, demonstrating that dramatic loss of kidney function can occur in sepsis without a change in BUN or creatinine. Prophylactic TNF-α Ab reduced serum cytokines, lung MPO activity, and BUN; however, post-sepsis administration had no effect.
Conclusions
ALI and AKI occur together early in the course of sepsis and TNF-α plays a role in the early pathogenesis of both.
doi:10.1371/journal.pone.0079037
PMCID: PMC3827109  PMID: 24265742
4.  Environmental Exposure, Estrogen and Two X Chromosomes are Required for Disease Development in an Epigenetic Model of Lupus 
Journal of Autoimmunity  2011;38(2-3):J135-J143.
Systemic lupus erythematosus (SLE) is an autoimmune disease primarily afflicting women. The reason for the gender bias is unclear, but genetic susceptibility, estrogen and environmental agents appear to play significant roles in SLE pathogenesis. Environmental agents can contribute to lupus susceptibility through epigenetic mechanisms. We used (C57BL/6 × SJL)F1 mice transgenic for a dominant-negative MEK (dnMEK) that was previously shown to be inducibly and selectively expressed in T cells. In this model, induction of the dnMEK by doxycycline treatment suppresses T cell ERK signaling, decreasing DNA methyltransferase expression and resulting in DNA demethylation, overexpression of immune genes Itgal (CD11a) and Tnfsf7 (CD70), and anti-dsDNA antibody. To examine the role of gender and estrogen in this model, male and female transgenic mice were neutered and implanted with time-release pellets delivering placebo or estrogen. Doxycycline induced IgG anti-dsDNA antibodies in intact and neutered, placebo-treated control female but not male transgenic mice. Glomerular IgG deposits were also found in the kidneys of female but not male transgenic mice, and not in the absence of doxycycline. Estrogen enhanced anti-dsDNA IgG antibodies only in transgenic, ERK-impaired female mice. Decreased ERK activation also resulted in overexpression and demethylation of the X-linked methylation-sensitive gene CD40lg in female but not male mice, consistent with demethylation of the second X chromosome in the females. The results show that both estrogen and female gender contribute to the female predisposition in lupus susceptibility through hormonal and epigenetic X chromosome effects and through suppression of ERK signaling by environmental agents.
doi:10.1016/j.jaut.2011.11.001
PMCID: PMC3312994  PMID: 22142890
Extracellular Receptor Kinase (ERK); Systemic Lupus erythematosus (SLE); Mouse
5.  Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients 
Annals of the rheumatic diseases  2010;70(1):151-156.
Background
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities.
Objectives
To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE.
Methods
The relationship between the age at disease onset and SLE manifestations were explored in a multiracial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset.
Results
Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values <0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients.
Conclusions
The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
doi:10.1136/ard.2010.141697
PMCID: PMC3034281  PMID: 20881011
6.  Sig2BioPAX: Java tool for converting flat files to BioPAX Level 3 format 
Background
The World Wide Web plays a critical role in enabling molecular, cell, systems and computational biologists to exchange, search, visualize, integrate, and analyze experimental data. Such efforts can be further enhanced through the development of semantic web concepts. The semantic web idea is to enable machines to understand data through the development of protocol free data exchange formats such as Resource Description Framework (RDF) and the Web Ontology Language (OWL). These standards provide formal descriptors of objects, object properties and their relationships within a specific knowledge domain. However, the overhead of converting datasets typically stored in data tables such as Excel, text or PDF into RDF or OWL formats is not trivial for non-specialists and as such produces a barrier to seamless data exchange between researchers, databases and analysis tools. This problem is particularly of importance in the field of network systems biology where biochemical interactions between genes and their protein products are abstracted to networks.
Results
For the purpose of converting biochemical interactions into the BioPAX format, which is the leading standard developed by the computational systems biology community, we developed an open-source command line tool that takes as input tabular data describing different types of molecular biochemical interactions. The tool converts such interactions into the BioPAX level 3 OWL format. We used the tool to convert several existing and new mammalian networks of protein interactions, signalling pathways, and transcriptional regulatory networks into BioPAX. Some of these networks were deposited into PathwayCommons, a repository for consolidating and organizing biochemical networks.
Conclusions
The software tool Sig2BioPAX is a resource that enables experimental and computational systems biologists to contribute their identified networks and pathways of molecular interactions for integration and reuse with the rest of the research community.
doi:10.1186/1751-0473-6-5
PMCID: PMC3071313  PMID: 21418653
7.  A polymorphism within interleukin-21 receptor (IL21R) confers risk for systemic lupus erythematosus 
Arthritis and rheumatism  2009;60(8):2402-2407.
Objective
Interleukin (IL) 21 is a member of the type I cytokine superfamily that exerts a variety of effects on the immune system including B cell activation, plasma cell differentiation, and immunoglobulin production. The expression of IL21R is reduced in B cells from lupus patients, while IL21 serum levels are increased in both lupus patients and some lupus-murine models. We recently reported that polymorphisms within the IL21 gene are associated with increased susceptibility to lupus. Herein, we examined the genetic association between SNPs within IL21R and lupus.
Methods
We genotyped 17 SNPs in the IL21R gene in two large cohorts of lupus patients and ethnically-matched healthy controls. Genotyping was performed with the Illumina BeadStation 500GX instrument using Illumina Infinum II genotyping assays.
Results
We identified and confirmed the association between rs3093301 within the IL21R gene and lupus in two independent European-derived and Hispanic cohorts (meta analysis odds ratio= 1.16, 95% CI= 1.08-1.25, meta analysis p=1.0×10-4).
Conclusion
We identified IL21R as a novel susceptibility gene for lupus.
doi:10.1002/art.24658
PMCID: PMC2782592  PMID: 19644854
8.  Variants within MECP2, a key transcriptional regulator, are associated with increased susceptibility to lupus and differential gene expression in lupus patients 
Arthritis and rheumatism  2009;60(4):1076-1084.
Objective
Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. Herein, we study methyl-CpG-binding protein 2 (MECP2) polymorphism in a large cohort of lupus patients and controls, and determine functional consequences of the lupus-associated MECP2 haplotype.
Methods
We genotyped 18 SNPs within MECP2, located on chromosome Xq28, in a large cohort of European-derived lupus patients and controls. We studied the functional effects of the lupus-associated MECP2 haplotype by determining gene expression profiles in B cell lines from female lupus patients with and without the lupus-associated MECP2 risk haplotype.
Results
We confirm, replicate, and extend the genetic association between lupus and genetic markers within MECP2 in a large independent cohort of European-derived lupus patients and controls (OR= 1.35, p= 6.65×10−11). MECP2 is a dichotomous transcriptional regulator that either activates or represses gene expression. We identified 128 genes that are differentially expressed in lupus patients with the disease-associated MECP2 haplotype; most (~81%) are upregulated. Genes that were upregulated have significantly more CpG islands in their promoter regions compared to downregulated genes. Gene ontology analysis using the differentially expressed genes revealed significant association with epigenetic regulatory mechanisms suggesting that these genes are targets for MECP2 regulation in B cells. Further, at least 13 of the 104 upregulated genes are interferon-regulated genes. The disease-risk MECP2 haplotype is associated with increased expression of the MECP2 transcriptional co-activator CREB1, and decreased expression of the co-repressor HDAC1.
Conclusion
Polymorphism in the MECP2 locus is associated with lupus and, at least in part, contributes to the interferon signature observed in lupus patients.
doi:10.1002/art.24360
PMCID: PMC2734382  PMID: 19333917
9.  Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study 
Introduction
Behçet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behçet's disease.
Methods
Using DNA pooling technology and the Affymetrix 500K arrays, we identified possible candidate gene associations with Behçet's disease in a cohort of 152 Behçet's disease patients and 172 healthy ethnically matched controls. Genetic loci that were identified in the pooling study were genotyped in patients and controls using TaqMan genotyping technology.
Results
We identified genetic associations between Behçet's disease and single-nucleotide polymorphisms (SNPs) in KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 (odds ratio = 2.04, 2.26, 1.84, 1.71, and 1.61, respectively; P value = 4.2 × 10-5, 1.0 × 10-4, 3.0 × 10-4, 1.5 × 10-3, and 5.8 × 10-3, respectively). Among the associated SNPs, the Behçet's disease-risk allele in rs2061634 leads to substitution of serine to cysteine at amino acid position 995 (S995C) in the KIAA1529 protein.
Conclusions
Using an unbiased whole-genome genetic association approach, we identified novel candidate genetic loci that are associated with increased susceptibility for Behçet's disease. These findings will help to better understand the pathogenesis of Behçet's disease and identify novel targets for therapeutic intervention.
doi:10.1186/ar2695
PMCID: PMC2714112  PMID: 19442274
10.  SNAVI: Desktop application for analysis and visualization of large-scale signaling networks 
BMC Systems Biology  2009;3:10.
Background
Studies of cellular signaling indicate that signal transduction pathways combine to form large networks of interactions. Viewing protein-protein and ligand-protein interactions as graphs (networks), where biomolecules are represented as nodes and their interactions are represented as links, is a promising approach for integrating experimental results from different sources to achieve a systematic understanding of the molecular mechanisms driving cell phenotype. The emergence of large-scale signaling networks provides an opportunity for topological statistical analysis while visualization of such networks represents a challenge.
Results
SNAVI is Windows-based desktop application that implements standard network analysis methods to compute the clustering, connectivity distribution, and detection of network motifs, as well as provides means to visualize networks and network motifs. SNAVI is capable of generating linked web pages from network datasets loaded in text format. SNAVI can also create networks from lists of gene or protein names.
Conclusion
SNAVI is a useful tool for analyzing, visualizing and sharing cell signaling data. SNAVI is open source free software. The installation may be downloaded from: . The source code can be accessed from:
doi:10.1186/1752-0509-3-10
PMCID: PMC2637233  PMID: 19154595
11.  Modeling the Value of Strategic Actions in the Superior Colliculus 
In learning models of strategic game play, an agent constructs a valuation (action value) over possible future choices as a function of past actions and rewards. Choices are then stochastic functions of these action values. Our goal is to uncover a neural signal that correlates with the action value posited by behavioral learning models. We measured activity from neurons in the superior colliculus (SC), a midbrain region involved in planning saccadic eye movements, while monkeys performed two saccade tasks. In the strategic task, monkeys competed against a computer in a saccade version of the mixed-strategy game ”matching-pennies”. In the instructed task, saccades were elicited through explicit instruction rather than free choices. In both tasks neuronal activity and behavior were shaped by past actions and rewards with more recent events exerting a larger influence. Further, SC activity predicted upcoming choices during the strategic task and upcoming reaction times during the instructed task. Finally, we found that neuronal activity in both tasks correlated with an established learning model, the Experience Weighted Attraction model of action valuation (Camerer and Ho, 1999). Collectively, our results provide evidence that action values hypothesized by learning models are represented in the motor planning regions of the brain in a manner that could be used to select strategic actions.
doi:10.3389/neuro.08.057.2009
PMCID: PMC2821176  PMID: 20161807
decision; macaque; mixed strategy; motor intention; saccade; reinforcement; game theory; EWA
12.  Common Variants within MECP2 Confer Risk of Systemic Lupus Erythematosus 
PLoS ONE  2008;3(3):e1727.
Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that affects multiple organ systems. Herein, we report on an X-chromosome gene association with SLE. Methyl-CpG-binding protein 2 (MECP2) is located on chromosome Xq28 and encodes for a protein that plays a critical role in epigenetic transcriptional regulation of methylation-sensitive genes. Utilizing a candidate gene association approach, we genotyped 21 SNPs within and around MECP2 in SLE patients and controls. We identify and replicate association between SLE and the genomic element containing MECP2 in two independent SLE cohorts from two ethnically divergent populations. These findings are potentially related to the overexpression of methylation-sensitive genes in SLE.
doi:10.1371/journal.pone.0001727
PMCID: PMC2253825  PMID: 18320046

Results 1-12 (12)