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1.  Identification of Molecular Markers Associated with Verticillium Wilt Resistance in Alfalfa (Medicago Sativa L.) Using High-Resolution Melting 
PLoS ONE  2014;9(12):e115953.
Verticillium wilt, caused by the soilborne fungus, Verticillium alfalfae, is one of the most serious diseases of alfalfa (Medicago sativa L.) worldwide. To identify loci associated with resistance to Verticillium wilt, a bulk segregant analysis was conducted in susceptible or resistant pools constructed from 13 synthetic alfalfa populations, followed by association mapping in two F1 populations consisted of 352 individuals. Simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers were used for genotyping. Phenotyping was done by manual inoculation of the pathogen to replicated cloned plants of each individual and disease severity was scored using a standard scale. Marker-trait association was analyzed by TASSEL. Seventeen SNP markers significantly associated with Verticillium wilt resistance were identified and they were located on chromosomes 1, 2, 4, 7 and 8. SNP markers identified on chromosomes 2, 4 and 7 co-locate with regions of Verticillium wilt resistance loci reported in M. truncatula. Additional markers identified on chromosomes 1 and 8 located the regions where no Verticillium resistance locus has been reported. This study highlights the value of SNP genotyping by high resolution melting to identify the disease resistance loci in tetraploid alfalfa. With further validation, the markers identified in this study could be used for improving resistance to Verticillium wilt in alfalfa breeding programs.
PMCID: PMC4275272  PMID: 25536106
2.  The Association between Body Mass Index and Mortality in Incident Dialysis Patients 
PLoS ONE  2014;9(12):e114897.
To study the body mass index (BMI) trajectory in patients with incident end-stage kidney disease and its association with all-cause mortality.
This longitudinal cohort study included 17022 adult patients commencing hemodialysis [HD] (n = 10860) or peritoneal dialysis [PD] (n = 6162) between 2001 and 2008 and had ≥6-month follow-up and ≥2 weight measurements, using the Australia and New Zealand Dialysis and Transplant Registry data. The association of time-varying BMI with all-cause mortality was explored using multivariate Cox regression models.
The median follow-up was 2.3 years. There was a non-linear change in the mean BMI (kg/m2) over time, with an initial decrease from 27.6 (95% confidence interval [CI]: 27.5, 27.7) to 26.7 (95% CI: 26.6, 26.9) at 3-month, followed by increments to 27.1 (95% CI: 27, 27.2) at 1-year and 27.2 (95% CI: 26.8, 27.1) at 3-year, and a gradual decrease subsequently. The BMI trajectory was significantly lower in HD patients who died than those who survived, although this pattern was not observed in PD patients. Compared to the reference time-varying BMI category of 25.1–28 kg/m2, the mortality risks of both HD and PD patients were greater in all categories of time-varying BMI <25 kg/m2. The mortality risks were significantly lower in all categories of time-varying BMI >28.1 kg/m2 among HD patients, but only in the category 28.1–31 kg/m2 among PD patients.
BMI changed over time in a non-linear fashion in incident dialysis patients. Time-varying measures of BMI were significantly associated with mortality risk in both HD and PD patients.
PMCID: PMC4267775  PMID: 25513810
3.  Does Histology Predict Survival of Advanced Non-Small Cell Lung Cancer Patients Treated with Platin-Based Chemotherapy? An Analysis of the Eastern Cooperative Oncology Group Study E1594 
We conducted this analysis to determine whether survival of advanced NSCLC patients treated with platin-based chemotherapy doublets involving paclitaxel, docetaxel or gemcitabine was dependent on histological subtypes and treatment regimen.
We retrospectively analyzed data from E1594, a front-line phase III study in which advanced NSCLC patients were randomized to receive one of four regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, and carboplatin-paclitaxel. Patients were classified into four histology groups: squamous cell (SCC), adeno- (AC), large cell (LCC) and others including not otherwise specified (O/NOS) carcinoma. Logrank test was performed to compare overall survival (OS) and progression free survival (PFS) distributions according to histology as well as treatment.
Of 1,139 patients including 716 men and 423 women, AC was the most common subtype (56.8%), followed by SCC (19.7%), O/NOS (17.0%) and LCC (6.5%). Men were more likely to have SCC and women were more likely to have AC (p=0.002). Among the four histology groups, there was no imbalance in regard to race, performance status, weight loss, brain metastasis or treatment. In each histology group, we found no significant difference in OS and PFS between the four chemotherapy regimens. Conversely, in each treatment arm, the survival outcome was similar between the four histology subtypes.
Our analysis suggests that histology does not predict survival benefit in advanced NSCLC patients treated with first-line platin-based doublets involving paclitaxel, docetaxel or gemcitabine.
PMCID: PMC4264629  PMID: 23611404
NSCLC; Histology; Prognostic; Survival; First-line Chemotherapy
4.  Intellectual Disabilities and Neglectful Parenting: Preliminary Findings on the Role of Cognition in Parenting Risk 
Parents with intellectual disabilities (PID) are over-represented in the child protective services (CPS) system. This study examined a more nuanced view of the role of cognition in parenting risk. Its goal was to validate a social information processing (SIP) model of child neglect that draws on social cognition research and advances in neuroscience. Mothers who had CPS child neglect cases were compared with mothers with no CPS involvement on a set of SIP factors. Mothers with low IQs were oversampled. As predicted, the Neglect group had significantly greater SIP problems than the Comparison mothers. SIP problems were associated with direct measures of neglect (e.g., cognitive stimulation provided children, home hygiene, belief regarding causes of child injuries). Further, for the direct measures that were most closely linked to CPS Neglect Status, IQ did not add significant predictive capacity beyond SIP factors in preliminary model testing. Implications for intervention with PID discussed.
PMCID: PMC4264989  PMID: 25506405
5.  Fertility Intentions, Career Considerations and Subsequent Births: The Moderating Effects of Women’s Work Hours 
Prior research indicates a negative relationship between women’s labor force participation and fertility at the individual level in the United States, but little is known about the reasons for this relationship beyond work hours. We employed discrete event history models using panel data from the National Survey of Families and Households (N = 2,411) and found that the importance of career considerations mediates the work hours/fertility relationship. Further, fertility intentions and the importance of career considerations were more predictive of birth outcomes as women’s work hours increase. Ultimately, our findings challenge the assumption that working more hours is the direct cause for employed women having fewer children and highlight the importance of career and fertility preferences in fertility outcomes.
PMCID: PMC4264994  PMID: 25506189
Fertility; Work; Childbearing; Intentions; Career importance; Event history analysis
6.  Semantically Linking In Silico Cancer Models 
Cancer Informatics  2014;13(Suppl 1):133-143.
Multiscale models are commonplace in cancer modeling, where individual models acting on different biological scales are combined within a single, cohesive modeling framework. However, model composition gives rise to challenges in understanding interfaces and interactions between them. Based on specific domain expertise, typically these computational models are developed by separate research groups using different methodologies, programming languages, and parameters. This paper introduces a graph-based model for semantically linking computational cancer models via domain graphs that can help us better understand and explore combinations of models spanning multiple biological scales. We take the data model encoded by TumorML, an XML-based markup language for storing cancer models in online repositories, and transpose its model description elements into a graph-based representation. By taking such an approach, we can link domain models, such as controlled vocabularies, taxonomic schemes, and ontologies, with cancer model descriptions to better understand and explore relationships between models. The union of these graphs creates a connected property graph that links cancer models by categorizations, by computational compatibility, and by semantic interoperability, yielding a framework in which opportunities for exploration and discovery of combinations of models become possible.
PMCID: PMC4260769  PMID: 25520553
tumor modeling; in silico oncology; model exploration; property graphs; neo4j
7.  Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease 
Neurology  2013;81(23):2015-2023.
To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD).
This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2.
Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months.
This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials.
Classification of evidence:
This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months.
PMCID: PMC4211922  PMID: 24122181
8.  Heterologous Expression of Xylanase Enzymes in Lipogenic Yeast Yarrowia lipolytica 
PLoS ONE  2014;9(12):e111443.
To develop a direct microbial sugar conversion platform for the production of lipids, drop-in fuels and chemicals from cellulosic biomass substrate, we chose Yarrowia lipolytica as a viable demonstration strain. Y. lipolytica is known to accumulate lipids intracellularly and is capable of metabolizing sugars to produce lipids; however, it lacks the lignocellulose-degrading enzymes needed to break down biomass directly. While research is continuing on the development of a Y. lipolytica strain able to degrade cellulose, in this study, we present successful expression of several xylanases in Y. lipolytica. The XynII and XlnD expressing Yarrowia strains exhibited an ability to grow on xylan mineral plates. This was shown by Congo Red staining of halo zones on xylan mineral plates. Enzymatic activity tests further demonstrated active expression of XynII and XlnD in Y. lipolytica. Furthermore, synergistic action in converting xylan to xylose was observed when XlnD acted in concert with XynII. The successful expression of these xylanases in Yarrowia further advances us toward our goal to develop a direct microbial conversion process using this organism.
PMCID: PMC4251831  PMID: 25462572
9.  Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597 
Journal of Clinical Oncology  2013;31(33):4179-4187.
Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non–small-cell lung cancer (NSCLC) receiving selenium supplementation.
Patients and Methods
Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence.
The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected.
Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC.
PMCID: PMC3821010  PMID: 24002495
10.  High dimensional biological data retrieval optimization with NoSQL technology 
BMC Genomics  2014;15(Suppl 8):S3.
High-throughput transcriptomic data generated by microarray experiments is the most abundant and frequently stored kind of data currently used in translational medicine studies. Although microarray data is supported in data warehouses such as tranSMART, when querying relational databases for hundreds of different patient gene expression records queries are slow due to poor performance. Non-relational data models, such as the key-value model implemented in NoSQL databases, hold promise to be more performant solutions. Our motivation is to improve the performance of the tranSMART data warehouse with a view to supporting Next Generation Sequencing data.
In this paper we introduce a new data model better suited for high-dimensional data storage and querying, optimized for database scalability and performance. We have designed a key-value pair data model to support faster queries over large-scale microarray data and implemented the model using HBase, an implementation of Google's BigTable storage system. An experimental performance comparison was carried out against the traditional relational data model implemented in both MySQL Cluster and MongoDB, using a large publicly available transcriptomic data set taken from NCBI GEO concerning Multiple Myeloma. Our new key-value data model implemented on HBase exhibits an average 5.24-fold increase in high-dimensional biological data query performance compared to the relational model implemented on MySQL Cluster, and an average 6.47-fold increase on query performance on MongoDB.
The performance evaluation found that the new key-value data model, in particular its implementation in HBase, outperforms the relational model currently implemented in tranSMART. We propose that NoSQL technology holds great promise for large-scale data management, in particular for high-dimensional biological data such as that demonstrated in the performance evaluation described in this paper. We aim to use this new data model as a basis for migrating tranSMART's implementation to a more scalable solution for Big Data.
PMCID: PMC4248814  PMID: 25435347
11.  Activity of dalotuzumab, a selective anti-IGF1R antibody, in combination with erlotinib in unselected patients with Non-small-cell lung cancer: a phase I/II randomized trial 
We investigated the safety and antitumor activity of dalotuzumab, a selective anti-insulin growth factor 1 receptor monoclonal antibody (IGF1R MoAb), plus erlotinib in a sequential phase I/II trial in unselected patients with refractory advanced non-small-cell lung cancer (NSCLC).The phase I trial determined the recommended dose and safety of erlotinib plus dalotuzumab at 5 mg/kg or 10 mg/kg weekly in 20 patients. The phase II trial compared outcomes to erlotinib alone and erlotinib plus dalotuzumab at the mg/kg established in the phase I trial.
Erlotinib at 150 mg plus dalotuzumab at 10 mg/kg was safe. The phase II trial included 37 patients in the erlotinib arm and 38 patients in the erlotinib plus dalotuzumab arm. Progression-free survival was 1.6 versus 2.5 months, overall survival was 10.2 and 6.6 months, and the objective response rate was 7.9% and 2.7%, respectively, with no significant differences between the two arms. Grade 3-5 adverse events occurred in 11 (28.9%) versus 13 (35.1%) patients, respectively. The most frequent adverse events were asthenia (36.8% vs. 37.8%), dehydration (5.3% vs. 2.7%), diarrhea (71% vs. 81.1%), hyperglycemia (13.1% vs.18.9%), and skin-related toxicities (92.1% vs. 86.4%).
The addition of dalotuzumab to erlotinib did not improve efficacy outcome in patients with refractory advanced NSCLC.
PMCID: PMC4237770  PMID: 25414803
Non-small-cell lung cancer; Epidermal growth factor receptor; Insulin growth factor receptor; Dalotuzumab; Phase I/II trial
12.  Evaluation of gastrointestinal bleeding: Update of current radiologic strategies 
Gastrointestinal bleeding (GIB) is a common presentation with significant associated morbidity and mortality, the prevalence of which continues to rise with the ever-increasing aging population. Initial evaluation includes an esophagoduodeonscopy and/or colonoscopy, which may fail to reveal a source. Such cases prove to be a dilemma and require collaboration between gastroenterology and radiology in deciding the most appropriate approach. Recently, there have been a number of radiologic advances in the approach to GIB. The purpose of this review is to provide an evidence-based update on the most current radiologic modalities available and an algorithmic approach to GIB.
PMCID: PMC4218949  PMID: 25374760
Gastrointestinal bleeding; Angiography; Scintigraphy; Enterography; Enteroscopy; Embolization
13.  Diagnostic Accuracy of MALDI Mass Spectrometric Analysis of Unfractionated Serum in Lung Cancer 
There is a critical need for improvements in the noninvasive diagnosis of lung cancer. We hypothesized that matrix-assisted laser desorption ionization mass spectrometry (MALDI MS) analysis of the most abundant peptides in the serum may distinguish lung cancer cases from matched controls.
Patients and Methods
We used MALDI MS to analyze unfractionated serum from a total of 288 cases and matched controls split into training (n = 182) and test sets (n = 106). We used a training–testing paradigm with application of the model profile defined in a training set to a blinded test cohort.
Reproducibility and lack of analytical bias was confirmed in quality-control studies. A serum proteomic signature of seven features in the training set reached an overall accuracy of 78%, a sensitivity of 67.4%, and a specificity of 88.9%. In the blinded test set, this signature reached an overall accuracy of 72.6 %, a sensitivity of 58%, and a specificity of 85.7%. The serum signature was associated with the diagnosis of lung cancer independently of gender, smoking status, smoking pack-years, and C-reactive protein levels. From this signature, we identified three discriminatory features as members of a cluster of truncated forms of serum amyloid A.
We found a serum proteomic profile that discriminates lung cancer from matched controls. Proteomic analysis of unfractionated serum may have a role in the noninvasive diagnosis of lung cancer and will require methodological refinements and prospective validation to achieve clinical utility.
PMCID: PMC4220686  PMID: 17909350
Mass spectrometry; Biomarker; Blood; Diagnosis
14.  Optimising parallel R correlation matrix calculations on gene expression data using MapReduce 
BMC Bioinformatics  2014;15(1):351.
High-throughput molecular profiling data has been used to improve clinical decision making by stratifying subjects based on their molecular profiles. Unsupervised clustering algorithms can be used for stratification purposes. However, the current speed of the clustering algorithms cannot meet the requirement of large-scale molecular data due to poor performance of the correlation matrix calculation. With high-throughput sequencing technologies promising to produce even larger datasets per subject, we expect the performance of the state-of-the-art statistical algorithms to be further impacted unless efforts towards optimisation are carried out. MapReduce is a widely used high performance parallel framework that can solve the problem.
In this paper, we evaluate the current parallel modes for correlation calculation methods and introduce an efficient data distribution and parallel calculation algorithm based on MapReduce to optimise the correlation calculation. We studied the performance of our algorithm using two gene expression benchmarks. In the micro-benchmark, our implementation using MapReduce, based on the R package RHIPE, demonstrates a 3.26-5.83 fold increase compared to the default Snowfall and 1.56-1.64 fold increase compared to the basic RHIPE in the Euclidean, Pearson and Spearman correlations. Though vanilla R and the optimised Snowfall outperforms our optimised RHIPE in the micro-benchmark, they do not scale well with the macro-benchmark. In the macro-benchmark the optimised RHIPE performs 2.03-16.56 times faster than vanilla R. Benefiting from the 3.30-5.13 times faster data preparation, the optimised RHIPE performs 1.22-1.71 times faster than the optimised Snowfall. Both the optimised RHIPE and the optimised Snowfall successfully performs the Kendall correlation with TCGA dataset within 7 hours. Both of them conduct more than 30 times faster than the estimated vanilla R.
The performance evaluation found that the new MapReduce algorithm and its implementation in RHIPE outperforms vanilla R and the conventional parallel algorithms implemented in R Snowfall. We propose that MapReduce framework holds great promise for large molecular data analysis, in particular for high-dimensional genomic data such as that demonstrated in the performance evaluation described in this paper. We aim to use this new algorithm as a basis for optimising high-throughput molecular data correlation calculation for Big Data.
PMCID: PMC4246436  PMID: 25371114
15.  Regulation of SIRT1 by Oxidative Stress-Responsive miRNAs and a Systematic Approach to Identify Its Role in the Endothelium 
Antioxidants & Redox Signaling  2013;19(13):1522-1538.
Significance: Oxidative stress is a common denominator of various risk factors contributing to endothelial dysfunction and vascular diseases. Accumulated evidence suggests that sirtuin 1 (SIRT1) expression and/or activity is impaired by supraphysiological levels of oxidative stress, which in turn disrupts endothelial homeostasis. Recent Advances: Several microRNAs (miRNAs) are induced by oxidative stress and termed as oxidative stress-responsive miRNAs. They may play a role linking the imbalanced redox state with dysregulated SIRT1. Critical Issues: This review summarizes recent findings on oxidative stress-responsive miRNAs and their involvement in SIRT1 regulation. Because of the unique characteristics of miRNAs, research in this new area requires an integrative approach that combines bioinformatics and experimental validation. Thus, a research strategy is discussed to identify the SIRT1-regulating miRNAs under oxidative stress and their functional outcomes in relation to endothelial dysfunction. Additionally, the miRNAs implicated in vascular diseases such as atherosclerosis and abdominal aortic aneurysms are discussed along with the translational potential and challenges of using miRNAs and its analogs as therapeutic agents. Future Directions: Although at its infancy, research on oxidative stress-responsive miRNAs and their regulation of SIRT1 may provide new insights in understanding vascular disorders. Moreover, systematic approaches integrating in silico, in vitro, and in vivo observations can be useful tools in revealing the pathways modulating endothelial biology. Antioxid. Redox Signal. 19, 1522–1538.
PMCID: PMC3797452  PMID: 23477488
16.  Quality indicators for the assessment and management of pain in the emergency department: A systematic review 
Appropriate and timely treatment of pain are very important, particularly in the emergency department, where pain continues to be undertreated. One of the ways in which the undertreatment of pain can be mitigated is the use of defined quality benchmarks. This systematic review of the literature was performed to identify such quality indicators. The resulting 20 quality indicators may be used to improve pain assessment and management protocols in the emergency department setting.
Evidence indicates that pain is undertreated in the emergency department (ED). The first step in improving the pain experience for ED patients is to accurately and systematically assess the actual care being provided. Identifying gaps in the assessment and treatment of pain and improving patient outcomes requires relevant, evidence-based performance measures.
To systematically review the literature and identify quality indicators specific to the assessment and management of pain in the ED.
Four major bibliographical databases were searched from January 1980 to December 2010, and relevant journals and conference proceedings were manually searched. Original research that described the development or collection of data on one or more quality indicators relevant to the assessment or management of pain in the ED was included.
The search identified 18,078 citations. Twenty-three articles were included: 15 observational (cohort) studies; three before-after studies; three audits; one quality indicator development study; and one survey. Methodological quality was moderate, with weaknesses in the reporting of study design and methodology. Twenty unique indicators were identified, with the majority (16 of 20) measuring care processes. Overall, 91% (21 of 23) of the studies reported indicators for the assessment or management of presenting pain, as opposed to procedural pain. Three of the studies included children; however, none of the indicators were developed specifically for a pediatric population.
Gaps in the existing literature include a lack of measures reflecting procedural pain, patient outcomes and the pediatric population. Future efforts should focus on developing indicators specific to these key areas.
PMCID: PMC4273718  PMID: 25337856
Emergency department; Pain assessment and management; Quality indicators; Systematic review
17.  Croup in children 
PMCID: PMC3796596  PMID: 23939212
18.  Using technology to revolutionize cooperative learning: an opinion 
Frontiers in Psychology  2014;5:1156.
PMCID: PMC4195269  PMID: 25352815
cooperative learning; technology; social interdependence; cooperation; promotive interaction
19.  Deep sequencing of HetR-bound DNA reveals novel HetR targets in Anabaena sp. strain PCC7120 
BMC Microbiology  2014;14(1):255.
Anabaena (also Nostoc) sp. strain PCC7120, hereafter Anabaena, is a cyanobacterium that fixes atmospheric N2 in specialized cells called heterocysts. Heterocyst differentiation is regulated by a homodimeric transcription factor, HetR. HetR is expressed at a basal level in all cells but its expression increases in differentiating cells early after nitrogen deprivation. HetR is required for heterocyst development, and therefore nitrogen fixation and diazotrophic growth. Overexpression of HetR leads to multiple contiguous heterocysts (Mch phenotype). HetR binds in vitro to DNA fragments upstream of several genes upregulated in heterocysts, including hetZ, hetP, hepA, patS, pknE, and hetR itself. HetR binds an inverted repeat sequence upstream of a few of these genes; however, HetR binds to promoters that do not contain this sequence, such as the promoter regions for patS and pknE.
We employed chromatin pull-down and deep sequencing (ChIP-seq) to globally identify HetR DNA targets in vivo at six hours after fixed-nitrogen deprivation. We identified novel DNA binding targets of tagged HetR-6xHis and defined a consensus HetR binding site from these HetR target sequences. Promoter-gfp reporter fusions were used to determine the spatiotemporal expression of four potential HetR-target genes. The promoter region for asr1469 was expressed transiently in differentiating heterocysts, alr3758 was upregulated in heterocysts, asl2028 was expressed in vegetative cells, and alr2242 was derepressed in vegetative cells of a hetR mutant strain.
In addition to identifying known HetR target genes hetR and hetP, the ChIP-seq data were used to identify new potential HetR targets and to define a consensus HetR-binding site. The in vivo ChIP-seq analysis of HetR’s regulon suggests a possible role for HetR in vegetative cells in addition to its role in heterocyst development. The potential HetR target genes identified in this study provide new subjects for future work on the role of HetR in gene regulation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0255-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4192349  PMID: 25278209
Cyanobacteria; Heterocyst development; HetR; ChIP-seq
20.  Should we disclose amyloid imaging results to cognitively normal individuals? 
Demonstration of brain accumulation of fibrillar amyloid beta protein via positron emission tomography (PET) with amyloid specific ligands may support the diagnosis of Alzheimer's disease (AD). There is increasing recognition of the potential use of amyloid imaging to detect in vivo the pathology of AD in individuals with no ostensible cognitive impairment. Research use of amyloid PET in cognitively normal patients will be key to pursuit of therapies able to delay cognitive impairment and dementia due to AD. We review the pros and cons of disclosing amyloid imaging results to cognitively normal individuals in clinical and research settings and provide draft recommendations.
PMCID: PMC4184474  PMID: 25285157
ethics; disclosure; amyloid PET; Alzheimer's disease
21.  Paediatric pain management practice and policies across Alberta emergency departments 
Paediatrics & Child Health  2014;19(4):190-194.
Many children requiring acute care receive suboptimal analgesia.
To describe paediatric pain management practices and policies in emergency departments (EDs) in Alberta.
A descriptive survey was distributed to each of the EDs in Alberta.
A response rate of 67% (72 of 108) was obtained. Seventy-one percent (42 of 59) of EDs reported the use of a pain tool, 29.3% (17 of 58) reported mandatory pain documentation and 16.7% (10 of 60) had nurse-initiated pain protocols. Topical anesthetics were reported to be used for intravenous line insertion by 70.4% of respondents (38 of 54) and for lumbar puncture (LP) by 30.8% (12 of 39). According to respondents, infiltrated anesthetic was used for LP by 69.2% (27 of 39) of respondents, and oral sucrose was used infrequently for urinary catheterization (one of 46 [2.2%]), intravenous line insertion (zero of 54 [0%]) and LP (one of 39 [2.6%]).
Few Alberta EDs use policies and protocols to manage paediatric pain. Noninvasive methods to limit procedural pain are underutilized. Canadian paediatricians must advocate for improved analgesia to narrow this knowledge-to-practice gap.
PMCID: PMC4028644  PMID: 24855415
Analgesia; Emergency; Pain; Paediatrics; Survey
22.  Marital Name Changing Attitudes and Plans of College Students: Comparing Change Over Time and Across Regions 
Sex roles  2011;66(3-4):282-292.
This study examines time period and regional effects on U.S. college students’ attitudes and plans regarding marital naming. Data were gathered at a Midwestern college in 1990 and 2006 and at an Eastern university in 2006 (N=867). No time period effect was identified for marital name plans in the Midwest samples. Women were neither more nor less likely to plan to retain their birth name in 1990 as compared to 2006. A time period effect was found for attitudes: Midwest women in 2006 were more likely to say a woman was more committed to the marriage if she took her husband's last name as compared to Midwest women in 1990. This indicates that women in the Midwest may have become more conservative over time. We also found regional differences: women in the East were significantly more likely than women in the Midwest to plan to keep their birth surname upon marriage. Findings suggest a trend toward more conservative attitudes over time and location although plans, perhaps due to the rareness of maintaining a birth surname upon marriage, have not changed.
PMCID: PMC4170063  PMID: 25249711
Marital naming; Plans; Attitudes; Time; Region
23.  Uniform Spinning Sampling Gradient Electron Paramagnetic Resonance Imaging 
To improve the quality and speed of electron paramagnetic resonance imaging (EPRI) acquisition by combining a uniform sampling distribution with spinning gradient acquisition.
Theory and Methods
A uniform sampling distribution was derived for spinning gradient EPRI acquisition (Uniform Spinning Sampling, USS) and compared to the existing (Equilinear Spinning Sampling, ESS) acquisition strategy. Novel corrections were introduced to reduce artifacts in experimental data.
Simulations demonstrated that USS puts an equal number of projections near each axis whereas ESS puts excessive projections at one axis, wasting acquisition time. Artifact corrections added to the magnetic gradient waveforms reduced noise and correlation between projections. USS images had higher SNR (85.9±0.8 vs. 56.2±0.8) and lower mean-squared error than ESS images. The quality of the USS images did not vary with the magnetic gradient orientation, in contrast to ESS images. The quality of rat heart images was improved using USS compared to that with ESS or traditional fast-scan acquisitions.
A novel EPRI acquisition which combines spinning gradient acquisition with a uniform sampling distribution was developed. This USS spinning gradient acquisition offers superior SNR and reduced artifacts compared to prior methods enabling potential improvements in speed and quality of EPR imaging in biological applications.
PMCID: PMC4155028  PMID: 23475830
24.  Ethical Problems with Infertility Treatments: Attitudes and Explanations* 
The Social science journal  2010;47(4):731-746.
Although media coverage of infertility treatments has increased markedly over the past decade, there is a dearth of empirical information about public perceptions of the ethics of infertility procedures (e.g. artificial insemination, in-vitro fertilization, donor eggs, surrogate mothering, gestational carriers) and about the factors that shape them. Two representative telephone survey samples (930 adults in a Midwestern state, and 580 adult women aged 25 to 50 in the North Central region) are analyzed to gauge public views on the ethics of infertility treatments and estimate the effects of social structure and exposure on these views. Ethical concerns were viewed as more serious for techniques that could result in a child who may not be biologically related to the woman or her partner than for those yielding a child biologically related to both parents. Social structural factors such as age and education were the strongest predictors of attitudes towards the ethics of infertility treatments. Neither parenthood nor experiencing infertility was related to ethical concerns, although women reporting the use of infertility services had fewer ethical concerns than their counterparts.
PMCID: PMC4157571  PMID: 25210214
25.  Identification of prohibitin and prohibiton as novel factors binding to the p53 induced gene 3 (PIG3) promoter (TGYCC)15 motif 
The promoter of p53 induced gene 3 (PIG3) contains a variable number of tandem repeats (VNTRs) of pentanucleotides (TGYCC)n that is known as a p53 binding site. In this study, we investigated whether other potential molecules could bind to this PIG3 promoter (TGYCC)n motif. Ligand-chromatography combined with liquid chromatography–tandem mass spectrometry analyses indicated direct interactions of prohibitin and/or prohibiton with the (TGYCC)15 motif, which was confirmed by electrophoretic mobility shift assay and super-gel shift analysis with anti-prohibitin and anti-prohibiton antibodies. Using the chromatin immunopercipipation assay, we further demonstrated that prohibitin and prohibiton associated with the (TGYCC)15 motif in vivo regardless of the p53 status and apoptotic stress. We also found that prohibitin and prohibiton up-regulated PIG3 transcription independent of p53, although p53 obviously enhanced this process, and that the knock-down of prohibitin and prohibiton inhibited camptothecin-induced apoptosis. Taken together, our findings suggest that prohibitin and prohibiton contribute to PIG3-mediated apoptosis by binding to the PIG3 promoter (TGYCC)15 motif.
PMCID: PMC4155496  PMID: 24388982
PIG3; Prohibitin; Prohibiton; (TGYCC)n motif

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