Publications by authors named "Eric Reed"

22 Publications

  • Page 1 of 1

A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify White and Brite Adipogens.

Environ Health Perspect 2021 Jul 29;129(7):77006. Epub 2021 Jul 29.

Boston University Superfund Research Program, Boston University, Massachusetts, USA.

Background: Chemicals in disparate structural classes activate specific subsets of the transcriptional programs of peroxisome proliferator-activated receptor- () to generate adipocytes with distinct phenotypes.

Objectives: Our objectives were to ) establish a novel classification method to predict ligands and modifying chemicals; and ) create a taxonomy to group chemicals on the basis of their effects on transcriptome and downstream metabolic functions. We tested the hypothesis that environmental adipogens highly ranked by the taxonomy, but segregated from therapeutic ligands, would induce white but not brite adipogenesis.

Methods: 3T3-L1 cells were differentiated in the presence of 76 chemicals (negative controls, nuclear receptor ligands known to influence adipocyte biology, potential environmental ligands). Differentiation was assessed by measuring lipid accumulation. mRNA expression was determined by RNA-sequencing (RNA-Seq) and validated by reverse transcription-quantitative polymerase chain reaction. A novel classification model was developed using an amended random forest procedure. A subset of environmental contaminants identified as strong agonists were analyzed by their effects on lipid handling, mitochondrial biogenesis, and cellular respiration in 3T3-L1 cells and human preadipocytes.

Results: We used lipid accumulation and RNA-Seq data to develop a classification system that ) identified agonists; and ) sorted chemicals into likely white or brite adipogens. Expression of was the most efficacious indicator of strong activation. 3T3-L1 cells treated with two known environmental ligands, tetrabromobisphenol A and triphenyl phosphate, which sorted distinctly from therapeutic ligands, had higher expression of white adipocyte genes but no difference in and expression, and higher fatty acid uptake but not mitochondrial biogenesis. Moreover, cells treated with two chemicals identified as highly ranked agonists, tonalide and quinoxyfen, induced white adipogenesis without the concomitant health-promoting characteristics of brite adipocytes in mouse and human preadipocytes.

Discussion: A novel classification procedure accurately identified environmental chemicals as ligands distinct from known -activating therapeutics.

Conclusion: The computational and experimental framework has general applicability to the classification of as-yet uncharacterized chemicals. https://doi.org/10.1289/EHP6886.
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http://dx.doi.org/10.1289/EHP6886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320370PMC
July 2021

Multi-resolution characterization of molecular taxonomies in bulk and single-cell transcriptomics data.

Nucleic Acids Res 2021 Jul 6. Epub 2021 Jul 6.

Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA 02118, USA.

As high-throughput genomics assays become more efficient and cost effective, their utilization has become standard in large-scale biomedical projects. These studies are often explorative, in that relationships between samples are not explicitly defined a priori, but rather emerge from data-driven discovery and annotation of molecular subtypes, thereby informing hypotheses and independent evaluation. Here, we present K2Taxonomer, a novel unsupervised recursive partitioning algorithm and associated R package that utilize ensemble learning to identify robust subgroups in a 'taxonomy-like' structure. K2Taxonomer was devised to accommodate different data paradigms, and is suitable for the analysis of both bulk and single-cell transcriptomics, and other '-omics', data. For each of these data types, we demonstrate the power of K2Taxonomer to discover known relationships in both simulated and human tissue data. We conclude with a practical application on breast cancer tumor infiltrating lymphocyte (TIL) single-cell profiles, in which we identified co-expression of translational machinery genes as a dominant transcriptional program shared by T cells subtypes, associated with better prognosis in breast cancer tissue bulk expression data.
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http://dx.doi.org/10.1093/nar/gkab552DOI Listing
July 2021

Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington's disease.

Am J Physiol Cell Physiol 2020 07 20;319(1):C218-C232. Epub 2020 May 20.

Department of Biological Sciences, Wright State University, Dayton, Ohio.

Huntington's disease (HD) patients suffer from progressive and debilitating motor dysfunction for which only palliative treatment is currently available. Previously, we discovered reduced skeletal muscle Cl channel (ClC-1) and inwardly rectifying K channel (Kir) currents in R6/2 HD transgenic mice. To further investigate the role of ClC-1 and Kir currents in HD skeletal muscle pathology, we measured the effect of reduced ClC-1 and Kir currents on action potential (AP) repetitive firing in R6/2 mice using a two-electrode current clamp. We found that R6/2 APs had a significantly lower peak amplitude, depolarized maximum repolarization, and prolonged decay time compared with wild type (WT). Of these differences, only the maximum repolarization was accounted for by the reduction in ClC-1 and Kir currents, indicating the presence of additional ion channel defects. We found that both K1.5 and K3.4 mRNA levels were significantly reduced in R6/2 skeletal muscle compared with WT, which explains the prolonged decay time of R6/2 APs. Overall, we found that APs in WT and R6/2 muscle significantly and progressively change during activity to maintain peak amplitude despite buildup of Na channel inactivation. Even with this resilience, the persistently reduced peak amplitude of R6/2 APs is expected to result in earlier fatigue and may help explain the motor impersistence experienced by HD patients. This work lays the foundation to link electrical changes to force generation defects in R6/2 HD mice and to examine the regulatory events controlling APs in WT muscle.
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http://dx.doi.org/10.1152/ajpcell.00153.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468886PMC
July 2020

5' UTR variants in the quantitative trait gene Hnrnph1 support reduced 5' UTR usage and hnRNP H protein as a molecular mechanism underlying reduced methamphetamine sensitivity.

FASEB J 2020 07 13;34(7):9223-9244. Epub 2020 May 13.

Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA.

We previously identified a 210 kb region on chromosome 11 (50.37-50.58 Mb, mm10) containing two protein-coding genes (Hnrnph1, Rufy1) that was necessary for reduced methamphetamine-induced locomotor activity in C57BL/6J congenic mice harboring DBA/2J polymorphisms. Gene editing of a small deletion in the first coding exon supported Hnrnph1 as a quantitative trait gene. We have since shown that Hnrnph1 mutants also exhibit reduced methamphetamine-induced reward, reinforcement, and dopamine release. However, the quantitative trait variants (QTVs) that modulate Hnrnph1 function at the molecular level are not known. Nine single nucleotide polymorphisms and seven indels distinguish C57BL/6J from DBA/2J within Hnrnph1, including four variants within the 5' untranslated region (UTR). Here, we show that a 114 kb introgressed region containing Hnrnph1 and Rufy1 was sufficient to cause a decrease in MA-induced locomotor activity. Gene-level transcriptome analysis of striatal tissue from 114 kb congenics vs Hnrnph1 mutants identified a nearly perfect correlation of fold-change in expression for those differentially expressed genes that were common to both mouse lines, indicating functionally similar effects on the transcriptome and behavior. Exon-level analysis (including noncoding exons) revealed decreased 5' UTR usage of Hnrnph1 and immunoblot analysis identified a corresponding decrease in hnRNP H protein in 114 kb congenic mice. Molecular cloning of the Hnrnph1 5' UTR containing all four variants (but none of them individually) upstream of a reporter induced a decrease in reporter signal in both HEK293 and N2a cells, thus, identifying a set of QTVs underlying molecular regulation of Hnrnph1.
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http://dx.doi.org/10.1096/fj.202000092RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006537PMC
July 2020

Assessment of a Highly Multiplexed RNA Sequencing Platform and Comparison to Existing High-Throughput Gene Expression Profiling Techniques.

Front Genet 2019 5;10:150. Epub 2019 Mar 5.

Bioinformatics Program, Boston University, Boston, MA, United States.

The need to reduce per sample cost of RNA-seq profiling for scalable data generation has led to the emergence of highly multiplexed RNA-seq. These technologies utilize barcoding of cDNA sequences in order to combine multiple samples into a single sequencing lane to be separated during data processing. In this study, we report the performance of one such technique denoted as sparse full length sequencing (SFL), a ribosomal RNA depletion-based RNA sequencing approach that allows for the simultaneous sequencing of 96 samples and higher. We offer comparisons to well established single-sample techniques, including: full coverage Poly-A capture RNA-seq, microarrays, as well as another low-cost highly multiplexed technique known as 3' digital gene expression (3'DGE). Data was generated for a set of exposure experiments on immortalized human lung epithelial (AALE) cells in a two-by-two study design, in which samples received both genetic and chemical perturbations of known oncogenes/tumor suppressors and lung carcinogens. SFL demonstrated improved performance over 3'DGE in terms of coverage, power to detect differential gene expression, and biological recapitulation of patterns of differential gene expression from lung cancer mutation signatures.
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http://dx.doi.org/10.3389/fgene.2019.00150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411637PMC
March 2019

C57BL/6 substrain differences in inflammatory and neuropathic nociception and genetic mapping of a major quantitative trait locus underlying acute thermal nociception.

Mol Pain 2019 Jan-Dec;15:1744806918825046

3 Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.

Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund's Adjuvant model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic constrictive nerve injury, a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-chronic constrictive nerve injury. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J × B6N-F2 cross (N = 164), we mapped a major quantitative trait locus underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (log of the odds [LOD] = 3.81, p < 0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression quantitative trait loci associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (false discovery rate < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.
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http://dx.doi.org/10.1177/1744806918825046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365993PMC
May 2019

Levator Auris Longus Preparation for Examination of Mammalian Neuromuscular Transmission Under Voltage Clamp Conditions.

J Vis Exp 2018 05 5(135). Epub 2018 May 5.

Department of Biological Sciences, Wright State University;

This protocol describes a technique to record synaptic transmission from the neuromuscular junction under current-clamp and voltage-clamp conditions. An ex vivo preparation of the levator auris longus (LAL) is used because it is a thin muscle that provides easy visualization of the neuromuscular junction for microelectrode impalement at the motor endplate. This method allows for the recording of spontaneous miniature endplate potentials and currents (mEPPs and mEPCs), nerve-evoked endplate potentials and currents (EPPs and EPCs), as well as the membrane properties of the motor endplate. Results obtained from this method include the quantal content (QC), number of vesicle release sites (n), probability of vesicle release (prel), synaptic facilitation and depression, as well as the muscle membrane time constant (τm) and input resistance. Application of this technique to mouse models of human disease can highlight key pathologies in disease states and help identify novel treatment strategies. By fully voltage-clamping a single synapse, this method provides one of the most detailed analyses of synaptic transmission currently available.
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http://dx.doi.org/10.3791/57482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101114PMC
May 2018

MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study.

Neurology 2018 01 27;90(4):e264-e272. Epub 2017 Dec 27.

From the Bioinformatics Program (E.R.R., R.H.M.), Boston University; Department of Neurology (J.C.L., J.B., R.H.M.), Boston University School of Medicine, MA; and Departments of Neurology and Psychiatry (J.H.B., J.S.P.) and Internal Medicine (J.S.), Carver College of Medicine, University of Iowa, Iowa City.

Objective: To investigate the feasibility of microRNA (miRNA) levels in CSF as biomarkers for prodromal Huntington disease (HD).

Methods: miRNA levels were measured in CSF from 60 PREDICT-HD study participants using the HTG protocol. Using a CAG-Age Product score, 30 prodromal HD participants were selected based on estimated probability of imminent clinical diagnosis of HD (i.e., low, medium, high; n = 10/group). For comparison, participants already diagnosed (n = 15) and healthy controls (n = 15) were also selected.

Results: A total of 2,081 miRNAs were detected and 6 were significantly increased in the prodromal HD gene expansion carriers vs controls at false discovery rate q < 0.05 (miR-520f-3p, miR-135b-3p, miR-4317, miR-3928-5p, miR-8082, miR-140-5p). Evaluating the miRNA levels in each of the HD risk categories, all 6 revealed a pattern of increasing abundance from control to low risk, and from low risk to medium risk, which then leveled off from the medium to high risk and HD diagnosed groups.

Conclusions: This study reports miRNAs as CSF biomarkers of prodromal and diagnosed HD. Importantly, miRNAs were detected in the prodromal HD groups furthest from diagnosis where treatments are likely to be most consequential and meaningful. The identification of potential biomarkers in the disease prodrome may prove useful in evaluating treatments that may postpone disease onset.

Clinicaltrialsgov Identifier: NCT00051324.
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http://dx.doi.org/10.1212/WNL.0000000000004844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798654PMC
January 2018

Depressed Synaptic Transmission and Reduced Vesicle Release Sites in Huntington's Disease Neuromuscular Junctions.

J Neurosci 2017 08 19;37(34):8077-8091. Epub 2017 Jul 19.

Departments of Biological Sciences and

Huntington's disease (HD) is a progressive and fatal degenerative disorder that results in debilitating cognitive and motor dysfunction. Most HD studies have focused on degeneration of the CNS. We previously discovered that skeletal muscle from transgenic R6/2 HD mice is hyperexcitable due to decreased chloride and potassium conductances. The progressive and early onset of these defects suggest a primary myopathy in HD. In this study, we examined the relationship between neuromuscular transmission and skeletal muscle hyperexcitability. We used an preparation of the levator auris longus muscle from male and female late-stage R6/2 mice and age-matched wild-type controls. Immunostaining of the synapses and molecular analyses revealed no evidence of denervation. Physiologically, we recorded spontaneous miniature endplate currents (mEPCs) and nerve-evoked EPCs (eEPCs) under voltage-clamp, which, unlike current-clamp records, were independent of the changes in muscle membrane properties. We found a reduction in the number of vesicles released per action potential (quantal content) in R6/2 muscle, which analysis of eEPC variance and morphology indicate is caused by a reduction in the number of vesicle release sites () rather than a change in the probability of release (). Furthermore, analysis of high-frequency stimulation trains suggests an impairment in vesicle mobilization. The depressed neuromuscular transmission in R6/2 muscle may help compensate for the muscle hyperexcitability and contribute to motor impersistence. Recent evidence indicates that Huntington's disease (HD) is a multisystem disorder. Our examination of neuromuscular transmission in this study reveals defects in the motor nerve terminal that may compensate for the muscle hyperexcitability in HD. The technique we used eliminates the effects of the altered muscle membrane properties on synaptic currents and thus provides hitherto the most detailed analysis of synaptic transmission in HD. Clinically, the striking depression of neurotransmission we found may help explain the motor impersistence in HD patients. Therapies that target the highly accessible peripheral nerve and muscle system provide a promising new avenue to lessen the debilitating motor symptoms of HD.
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http://dx.doi.org/10.1523/JNEUROSCI.0313-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566863PMC
August 2017

The greater snow goose Anser caerulescens atlanticus: Managing an overabundant population.

Ambio 2017 Mar;46(Suppl 2):262-274

Canadian Wildlife Service, Environment and Climate Change Canada, 801-1550 Avenue d'Estimauville, Québec, QC, G1J 0C3, Canada.

Between the early 1900s and the 1990s, the greater snow goose Anser caerulescens atlanticus population grew from 3000 individuals to more than 700 000. Because of concerns about Arctic degradation of natural habitats through overgrazing, a working group recommended the stabilization of the population. Declared overabundant in 1998, special management actions were then implemented in Canada and the United States. Meanwhile, a cost-benefit socioeconomic analysis was performed to set a target population size. Discussions aiming towards attaining a common vision were undertaken with stakeholders at multiple levels. The implemented measures have had varying success; but population size has been generally stable since 1999. To be effective and meet social acceptance, management actions must have a scientific basis, result from a consensus among stakeholders, and include an efficient monitoring programme. In this paper, historical changes in population size and management decisions along with past and current challenges encountered are discussed.
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http://dx.doi.org/10.1007/s13280-016-0887-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316327PMC
March 2017

Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating.

Biol Psychiatry 2017 05 25;81(9):757-769. Epub 2016 Oct 25.

Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University, Boston, Massachusetts. Electronic address:

Background: Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions.

Methods: We assessed binge eating in closely related C57BL/6 mouse substrains and in an F cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment.

Results: C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression.

Conclusions: We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.
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http://dx.doi.org/10.1016/j.biopsych.2016.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386810PMC
May 2017

A population model of the impact of a rodenticide containing strychnine on Great Basin Gophersnakes (Pituophis catenifer deserticola).

Ecotoxicology 2016 Sep 20;25(7):1390-405. Epub 2016 Jul 20.

Environment and Climate Change Canada, Science and Technology Branch, 5421 Robertson Road, Delta, BC, V4K3N2, Canada.

Strychnine is a neurotoxin and an active ingredient in some rodenticides which are placed in burrows to suppress pocket gopher (Thomomys talpoides) populations in range and crop land in western North America. The population level impact was modelled of the use of strychnine-based rodenticides on a non-target snake species, the Great Basin Gophersnake (Pituophis catenifer deserticola), which is a predator of pocket gopher and a Species at Risk in Canada. Using information on population density, demographics, and movement and habitat suitability for the Gophersnake living in an agricultural valley in BC, Canada, we estimated the impact of the poisoning of adult snakes on the long-term population size. To determine the area where Gophersnakes could be exposed to strychnine, we used vendor records of a rodenticide, and quantified the landcover areas of orchards and vineyards where the compound was most commonly applied. GIS analysis determined the areas of overlap between those agricultural lands and suitable habitats used by Gophersnakes. Stage-based population matrix models revealed that in a low density (0.1/ha) population scenario, a diet of one pocket gopher per year wherein 10 % of them carried enough strychnine to kill an adult snake could cause the loss of 2 females annually from the population and this would reduce the population by 35.3 % in 25 years. Under the same dietary exposure, up to 35 females could die per year in a high density (0.4/ha) population which would result in a loss of 50 % of adults in 25 years.
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http://dx.doi.org/10.1007/s10646-016-1690-2DOI Listing
September 2016

Genome-wide interrogation reveals hundreds of long intergenic noncoding RNAs that associate with cardiometabolic traits.

Hum Mol Genet 2016 07 10;25(14):3125-3141. Epub 2016 Jun 10.

Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, NY 10032, USA

Long intergenic noncoding RNAs (lincRNAs) play important roles in disease, but the vast majority of these transcripts remain uncharacterized. We defined a set of 54 944 human lincRNAs by drawing on four publicly available lincRNA datasets, and annotated ∼2.5 million single nucleotide polymorphisms (SNPs) from each of 15 cardiometabolic genome-wide association study datasets into these lincRNAs. We identified hundreds of lincRNAs with at least one trait-associated SNP: 898 SNPs in 343 unique lincRNAs at 5% false discovery rate, and 469 SNPs in 146 unique lincRNAs meeting Bonferroni-corrected P < 0.05. An additional 64 trait-associated lincRNAs were identified using a class-level testing strategy at Bonferroni-corrected P < 0.05. To better understand the genomic context and prioritize trait-associated lincRNAs, we examined the pattern of linkage disequilibrium between SNPs in the lincRNAs and SNPs that met genome-wide-significance in the region (±500 kb of lincRNAs). A subset of the lincRNA-trait association findings was replicated in independent Genome-wide association studies data from the Pakistan Risk of Myocardial Infarction Study study. For trait-associated lincRNAs, we also investigated synteny and conservation relative to mouse, expression patterns in five cardiometabolic-relevant tissues, and allele-specific expression in RNA sequencing data for adipose tissue and leukocytes. Finally, we revealed a functional role in human adipocytes for linc-NFE2L3-1, which is expressed in adipose and is associated with waist-hip ratio adjusted for BMI. This comprehensive profile of trait-associated lincRNAs provides novel insights into disease mechanism and serves as a launching point for interrogation of the biology of specific lincRNAs in cardiometabolic disease.
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http://dx.doi.org/10.1093/hmg/ddw154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181595PMC
July 2016

Clinical training in the rural setting: using photovoice to understand student experiences.

Rural Remote Health 2016 Apr-Jun;16(2):3877. Epub 2016 May 14.

State University of New York - Upstate Medical University, Syracuse, New York, USA.

Introduction: Attracting and retaining healthcare providers in rural locations in the USA has been an issue for more than two decades. In response to this need, many health sciences education institutions in the USA have developed special programs to encourage students to become healthcare providers in rural locations. One approach is the use of community-based education experiences through rural track programs. Rural track programs seek to address the shortage of healthcare providers working in rural areas by nurturing and educating students interested in rural practice and primary care. Such programs serve both medical students and students of other health professions. Yet, little is known about student experiences in rural track programs. As such, this study aimed to generate discourse on student experiences in the rural training environment and gain insight into the impact of rural environments on student learning.

Methods: An exploratory qualitative analysis of medical and physician assistant student experiences in two rural medical education training programs was conducted using the photovoice methodology. Photovoice is a participatory research method combining photography with participant commentary and focus groups.

Results: Twenty-two third-year medical and six second-year physician assistant students participated in the study. Students noted that in their rural sites the learning environment extended beyond direct clinical teaching in four primary ways: (1) relationships with clinical faculty translated to a sense of meaningful participation in healthcare teams; (2) connections with community members outside of clinical settings led to increased awareness of healthcare concerns; (3) rural settings provided important space to reflect on their experiences; and (4) the importance of infrastructure was highlighted. Students also believed that diversity of occupation, education, attitude, and perception of medical care impact learning in rural environments.

Conclusions: The photovoice participatory research methodology allowed for a deeper understanding of the aspects of the rural training experience that resonated most among students in real time, using visual representations of students' lived experiences as defined by the students.
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January 2017

A Simple Test of Class-Level Genetic Association Can Reveal Novel Cardiometabolic Trait Loci.

PLoS One 2016 9;11(2):e0148218. Epub 2016 Feb 9.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA, United States of America.

Background: Characterizing the genetic determinants of complex diseases can be further augmented by incorporating knowledge of underlying structure or classifications of the genome, such as newly developed mappings of protein-coding genes, epigenetic marks, enhancer elements and non-coding RNAs.

Methods: We apply a simple class-level testing framework, termed Genetic Class Association Testing (GenCAT), to identify protein-coding gene association with 14 cardiometabolic (CMD) related traits across 6 publicly available genome wide association (GWA) meta-analysis data resources. GenCAT uses SNP-level meta-analysis test statistics across all SNPs within a class of elements, as well as the size of the class and its unique correlation structure, to determine if the class is statistically meaningful. The novelty of findings is evaluated through investigation of regional signals. A subset of findings are validated using recently updated, larger meta-analysis resources. A simulation study is presented to characterize overall performance with respect to power, control of family-wise error and computational efficiency. All analysis is performed using the GenCAT package, R version 3.2.1.

Results: We demonstrate that class-level testing complements the common first stage minP approach that involves individual SNP-level testing followed by post-hoc ascribing of statistically significant SNPs to genes and loci. GenCAT suggests 54 protein-coding genes at 41 distinct loci for the 13 CMD traits investigated in the discovery analysis, that are beyond the discoveries of minP alone. An additional application to biological pathways demonstrates flexibility in defining genetic classes.

Conclusions: We conclude that it would be prudent to include class-level testing as standard practice in GWA analysis. GenCAT, for example, can be used as a simple, complementary and efficient strategy for class-level testing that leverages existing data resources, requires only summary level data in the form of test statistics, and adds significant value with respect to its potential for identifying multiple novel and clinically relevant trait associations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148218PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747495PMC
July 2016

A Case of Neuropsychiatric Lupus With Severe Malignant Catatonia that Improved With Daily Electroconvulsive Therapy.

J Neuropsychiatry Clin Neurosci 2016 ;28(1):e19-20

Baylor College of Medicine, Houston, TX (MJ), Edward Hines Jr. Veterans Administration Hospital (EG), and University of Illinois at Chicago College of Medicine, Chicago, IL (ER).

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http://dx.doi.org/10.1176/appi.neuropsych.15080211DOI Listing
December 2016

Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity.

PLoS Genet 2015 Dec 10;11(12):e1005713. Epub 2015 Dec 10.

Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512-50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)-a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes-heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J < C57BL/6J; p 4.2 x 10-15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders.
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http://dx.doi.org/10.1371/journal.pgen.1005713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675533PMC
December 2015

A guide to genome-wide association analysis and post-analytic interrogation.

Stat Med 2015 Dec 6;34(28):3769-92. Epub 2015 Sep 6.

Department of Mathematics and Statistics, Mount Holyoke College, South Hadley, MA, U.S.A.

This tutorial is a learning resource that outlines the basic process and provides specific software tools for implementing a complete genome-wide association analysis. Approaches to post-analytic visualization and interrogation of potentially novel findings are also presented. Applications are illustrated using the free and open-source R statistical computing and graphics software environment, Bioconductor software for bioinformatics and the UCSC Genome Browser. Complete genome-wide association data on 1401 individuals across 861,473 typed single nucleotide polymorphisms from the PennCATH study of coronary artery disease are used for illustration. All data and code, as well as additional instructional resources, are publicly available through the Open Resources in Statistical Genomics project: http://www.stat-gen.org.
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http://dx.doi.org/10.1002/sim.6605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019244PMC
December 2015

Ascending aortic and main pulmonary artery areas derived from cardiovascular magnetic resonance as reference values for normal subjects and repaired tetralogy of Fallot.

Circ Cardiovasc Imaging 2012 Sep 22;5(5):644-51. Epub 2012 Jun 22.

Division of Pediatric Cardiology, University of Nebraska College of Medicine/Children's Hospital and Medical Center, Omaha, NE 68114, USA.

Background: Cardiac magnetic resonance (CMR) imaging is an important clinical tool for serial follow-up of patients with congenital heart disease, but normative data for great vessel dimensions in pediatric subjects are scarce. We investigated the ascending aortic (AO) and main pulmonary artery dimensions in normal children and young adults in comparison with a cohort of patients with repaired tetralogy of Fallot (TOF).

Methods And Results: Subjects were prospectively enrolled for cardiac magnetic resonance after a standardized protocol in 14 participating centers of the German Competence Network for Congenital Heart Defects. All studies were performed in 1.5-T scanners and used single-slice multiphase acquisitions steady-state free precession and velocity-encoded cine. AO and main pulmonary artery areas were measured. The cohort consisted of 483 subjects: 105 normal controls (55 men; 50 women; and median age, 14 years) and 378 patients with repaired TOF (210 men; 168 women; and median age, 16 years). Among TOF, 35 (9%) had pulmonary atresia, 98 (26%) had a palliative procedure before repair, the mean age at repair was 2.9 years, and 82 (23%) used a transannular patch repair. Great vessel areas correlated well with body surface area and age in controls and reference Z-score values were derived. Z scores for ascending AO areas were larger in TOF compared with controls (mean Z score =1.95, P=0.001). In TOF, pulmonary atresia (P=0.003), male sex (P=0.01) and previous palliations (P=0.046) were associated with larger AO areas. Main pulmonary artery area Z scores in surgically modified TOF were smaller on an average than controls (mean Z score =-0.293 P=0.001) but not small to the same extent as the AO was large.

Conclusions: This study provides cardiac magnetic resonance reference Z scores for great vessel areas in normal children and adolescents in comparison with a large contemporary cohort of repaired TOF. Male sex, pulmonary atresia, and previous palliations emerged as predictors for larger AO dimensions in TOF.
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http://dx.doi.org/10.1161/CIRCIMAGING.112.973073DOI Listing
September 2012

Incidence, radiographical features, and proposed mechanism for pneumocephalus from intravenous injection of air.

West J Emerg Med 2010 May;11(2):180-5

University of Nebraska Medical Center, Department of Emergency Medicine, Omaha, NE.

Background: Pneumocephalus typically implies a traumatic breach in the meningeal layer or an intracranial gas-producing infection. Unexplained pneumocephalus on a head computed tomography (CT) in an emergency setting often compels emergency physicians to undertake aggressive evaluation and consultation.

Methods: In this paper, we report three cases of pneumocephalus that appear to result from retrograde injection of air through an intravenous (IV) catheter. We also performed a retrospective study to determine the incidence of presumed IV-induced pneumocephalus and etiologies of pneumocephalus in our emergency department (ED) population.

Results: The incidence of idiopathic and presumed IV-induced pneumocephalus was 0.034% among all head CTs ordered in the ED and 4.88% among cases of pneumocephalus seen in the ED. These cases are characterized clinically by the absence of signs and symptoms of pathologic pneumocephalus and radiographically by the distribution of air densities along the cranial venous system on head CTs.

Conclusion: Idiopathic and presumed IV-induced pneumocephalus could be considered in the workup of ED patients with unexplained intracranial air on head CT if there are no findings of pathological causes for the pneumocephalus on history and physical examination and if the head CTs show a characteristic distribution of air limited to the cranial venous system. Knowledge of this clinical entity in the evaluation of ED patients with unexplained pneumocephalus can lead to more efficient emergency care and less patient anxiety.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908654PMC
May 2010

Optimal multidimensional bit-rate control for video communication.

IEEE Trans Image Process 2002 ;11(8):873-85

Convergent Syst. Div., Harmonic Inc., White Plains, NY 10601, USA.

In conventional bit-rate control, the buffer level is controlled by adapting the quantization step size with a fixed frame rate and spatial resolution. We consider a multidimensional (M-D) bit-rate control where the frame rate, spatial resolution and quantization step size are jointly adapted for buffer control. We introduce a fundamental framework to formalize the description of the M-D buffer-constrained allocation problem. Given a set of operating points on a M-D grid to code a nonstationary source in a buffer-constrained environment, we formulate the optimal solution. The formulation allows a skipped frame to be reconstructed from one coded frame using any temporal interpolation method and is shown to be a generalization of formulations considered in the literature. In the case of intraframe coding, a dynamic programming algorithm is introduced to find the optimal solution. The algorithm allows one to compare operational rate-distortion bounds of the M-D and conventional approaches. We also discuss how a solution can be obtained for the case of interframe coding using the optimal dynamic programming algorithm for intraframe coding by making an independent allocation approximation. We illustrate that the M-D approach can provide bit-rate reductions over 50%. We also show that the M-D approach with limited-lookahead provides a slightly suboptimal solution that consistently outperforms the conventional approach with full-lookahead.
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http://dx.doi.org/10.1109/TIP.2002.801122DOI Listing
December 2009
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