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Search Results: 1 - 10 of 235774 matches for " William R. Wikoff "
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Mobilization of pro-inflammatory lipids in obese Plscr3-deficient mice
David M Mutch, Grace O'Maille, William R Wikoff, Therese Wiedmer, Peter J Sims, Gary Siuzdak
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-3-r38
Abstract: Nineteen metabolites were differentially and similarly regulated in both Plscr3-/- and Plscr1&3-/- animals, of which five were characterized from accurate mass, tandem mass spectrometry data and their correlation to the Metlin database as lysophosphatidylcholine (LPC) species enriched with C16:1, C18:1, C20:3, C20:5 and C22:5 fatty acids. No significant changes in the plasma metabolome were detected upon elimination of PLSCR1, indicating that increases in pro-inflammatory lipids are specifically associated with the obese state of Plscr3-deficient animals. Correspondingly, increases in white adipose lipogenic gene expression confirm a role for PLSCR3 in adipose lipid metabolism.The untargeted profiling of circulating metabolites suggests no detectable functional redundancies between PLSCR proteins; however, this approach simultaneously identified previously unrecognized lipid metabolites that suggest a novel molecular link between obesity, inflammation and the downstream consequences associated with PLSCR3-deficiency.Despite the overt recognition of the taxing effects of obesity on both medical and social programs throughout the world, the estimated 300 million adults currently considered clinically obese in addition to the universal increase in childhood obesity indicates we are still succumbing to this global epidemic. Indeed, the poorly understood gene-environment interactions have revealed the complexity of this metabolic disease; however, with each passing year an increasing number of genetic candidates are discovered that help to further unravel the perturbed metabolism underlying the obese phenotype [1,2]. Recently, phospholipid scramblase (Plscr) 3 was identified as a genetic candidate capable of influencing adipose function and, ultimately, the obese phenotype. Mice deficient in PLSCR3 were found to accumulate lipid in abdominal fat pads and were characterized with insulin resistance, dyslipidemia, and glucose intolerance, classic tell-tale markers for metab
Metabolomics Reveals Amino Acids Contribute to Variation in Response to Simvastatin Treatment
Miles Trupp, Hongjie Zhu, William R. Wikoff, Rebecca A. Baillie, Zhao-Bang Zeng, Peter D. Karp, Oliver Fiehn, Ronald M. Krauss, Rima Kaddurah-Daouk
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038386
Abstract: Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution (“good” and “poor” responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. Trial Registration ClinicalTrials.gov NCT00451828
Pharmacometabolomic Signature of Ataxia SCA1 Mouse Model and Lithium Effects
Bertrand Perroud, Paymaan Jafar-Nejad, William R. Wikoff, Jennifer R. Gatchel, Lu Wang, Dinesh K. Barupal, Juan Crespo-Barreto, Oliver Fiehn, Huda Y. Zoghbi, Rima Kaddurah-Daouk
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070610
Abstract: We have shown that lithium treatment improves motor coordination in a spinocerebellar ataxia type 1 (SCA1) disease mouse model (Sca1154Q/+). To learn more about disease pathogenesis and molecular contributions to the neuroprotective effects of lithium, we investigated metabolomic profiles of cerebellar tissue and plasma from SCA1-model treated and untreated mice. Metabolomic analyses of wild-type and Sca1154Q/+ mice, with and without lithium treatment, were performed using gas chromatography time-of-flight mass spectrometry and BinBase mass spectral annotations. We detected 416 metabolites, of which 130 were identified. We observed specific metabolic perturbations in Sca1154Q/+ mice and major effects of lithium on metabolism, centrally and peripherally. Compared to wild-type, Sca1154Q/+ cerebella metabolic profile revealed changes in glucose, lipids, and metabolites of the tricarboxylic acid cycle and purines. Fewer metabolic differences were noted in Sca1154Q/+ mouse plasma versus wild-type. In both genotypes, the major lithium responses in cerebellum involved energy metabolism, purines, unsaturated free fatty acids, and aromatic and sulphur-containing amino acids. The largest metabolic difference with lithium was a 10-fold increase in ascorbate levels in wild-type cerebella (p<0.002), with lower threonate levels, a major ascorbate catabolite. In contrast, Sca1154Q/+ mice that received lithium showed no elevated cerebellar ascorbate levels. Our data emphasize that lithium regulates a variety of metabolic pathways, including purine, oxidative stress and energy production pathways. The purine metabolite level, reduced in the Sca1154Q/+ mice and restored upon lithium treatment, might relate to lithium neuroprotective properties.
Pharmacometabolomics Reveals Racial Differences in Response to Atenolol Treatment
William R. Wikoff, Reginald F. Frye, Hongjie Zhu, Yan Gong, Stephen Boyle, Erik Churchill, Rhonda M. Cooper-Dehoff, Amber L. Beitelshees, Arlene B. Chapman, Oliver Fiehn, Julie A. Johnson, Rima Kaddurah-Daouk, Pharmacometabolomics Research Network
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057639
Abstract: Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.
Occupational Wages and Globalization  [PDF]
William R. DiPietro
iBusiness (IB) , 2011, DOI: 10.4236/ib.2011.32023
Abstract: Using a country’s trade share as a measure of globalization, this paper employs cross country regression analysis on 161 occupations for the year 2000 to assess whether globalization has a negative effect on occupational wages. The results are consistent with the notion that greater integration of national economies with the rest of the world adversely affects occupational wages in many occupations within countries.
Unemployment Benefits and Unemployment  [PDF]
William Beranek, David R. Kamerschen
Modern Economy (ME) , 2011, DOI: 10.4236/me.2011.25088
Abstract: This paper seeks to provide a simpler explanation of the Match Quality Hypothesis (MQH). For the less mathematically inclined, it avoids formal analysis and yet derives the relevant implications, i.e., if unemployed workers currently collecting unemployment benefits are given more benefits, both the average period of unemployment duration increases as well as the level of unemployment. To produce these effects, only one person behaving in this manner is required. We cite recent evidence supporting these implications. Examined are implications of this theorem for both U.S. and European regions where, in some cases, voluntarily unemployed workers are eligible for unemployment benefits. We question the importance of the notion that generous unemployment benefits that intensify searches for better jobs, and hence prolonged job searches, ultimately yield societal benefits.
Financial Conflict Messages and Marital Satisfaction: The Mediating Role of Financial Communication Satisfaction  [PDF]
Samantha J. Shebib, William R. Cupach
Psychology (PSYCH) , 2018, DOI: 10.4236/psych.2018.91010
Abstract: Conflict over money is one of the most commonly cited topics of marital disagreements (Oggins, 2003). However, little empirical research has examined how marital couples communicate about financial issues, specifically, and how these financial communication messages contribute to, or detract from, marital satisfaction. Knowledge about how couples communicate regarding financial issues is of significance to conflict scholars because it would allow us to understand the potential detriments of certain financial conflict message patterns and how these patterns ultimately affect one’s marital satisfaction. Married individuals (not marital dyads) were recruited online to participate in an online survey about their financial communication patterns within his or her marriage. In the present study of 326 married individuals, we found that constructive financial conflict messages were positively associated with financial harmony, marital satisfaction, and financial communication satisfaction. Destructive financial conflict messages, the demand-withdraw financial conflict message pattern, and mutually avoiding financial conflict were each negatively associated with financial harmony, marital satisfaction, and financial communication satisfaction. In addition, financial communication satisfaction mediated the relationship between each of the financial conflict message patterns and marital satisfaction. The current study lays empirical groundwork for developing a theoretical framework for understanding marital interaction patterns and the effects these patterns have on marital satisfaction.
Self-Referential Thinking, Suicide, and Function of the Cortical Midline Structures and Striatum in Mood Disorders: Possible Implications for Treatment Studies of Mindfulness-Based Interventions for Bipolar Depression
William R. Marchand
Depression Research and Treatment , 2012, DOI: 10.1155/2012/246725
Abstract: Bipolar depression is often refractory to treatment and is frequently associated with anxiety symptoms and elevated suicide risk. There is a great need for adjunctive psychotherapeutic interventions. Treatments with effectiveness for depressive and anxiety symptoms as well as suicide-related thoughts and behaviors would be particularly beneficial. Mindfulness-based interventions hold promise, and studies of these approaches for bipolar disorder are warranted. The aim of this paper is to provide a conceptual background for such studies by reviewing key findings from diverse lines of investigation. Results of that review indicate that cortical midline structures (CMS) appear to link abnormal self-referential thinking to emotional dysregulation in mood disorders. Furthermore, CMS and striatal dysfunction may play a role in the neuropathology underlying suicide-related thoughts and behaviors. Thus, combining studies of mindfulness interventions targeting abnormal self-referential thinking with functional imaging of CMS and striatal function may help delineate the neurobiological mechanisms of action of these treatments. 1. Introduction The neurobiology of bipolar spectrum disorders is incompletely characterized [1]. Further, current medication treatments are only partially effective [2], and 73% of patients receiving pharmacotherapy relapse within 5 years [3]. Thus, there is a compelling need for effective adjunctive psychotherapy interventions [4, 5]. Cognitive-behavioral therapy is an effective intervention for depression [4, 6–9] but seems to be of less benefit for bipolar spectrum illness [10]. Bipolar disorder is highly comorbid with anxiety [11, 12], and therefore interventions that also target anxiety might be of particular benefit [13]. Mindfulness-based psychotherapies are being increasingly used to target both depressive and anxiety symptoms in a variety of clinical populations [14–16]. However, few studies [17–19] have investigated these interventions for bipolar spectrum disorders. Furthermore, an integrated conceptual framework for such studies has not been published. Mindfulness interventions target aberrant self-referential thinking [20]. Increasing evidence suggests that alterations in self-referential thinking may be associated with a number of mood and anxiety spectrum disorders. For example, investigations indicate an association between aberrant self-concept and/or self-schemas and unipolar depression [21–25], generalized anxiety disorder [26], obsessive-compulsive disorder [27, 28], PTSD [29–31], social phobia [32, 33], and panic
The Technology of Waste, Biofuels and Global Warming in Viable Closed Loop, Sustainable Operations
William R. Butterworth
Energies , 2009, DOI: 10.3390/en20401192
Abstract: This research set out to explore and develop a route relating the recycling of urban and industrial wastes to land to produce agricultural crops with energy crops in the rotation, using the green leaf to “harvest” sunlight and to examine the sequestration of carbon dioxide and release of oxygen in a sustainable closed loop. Further, to establish if the pollution, particularly of nitrogen and phosphates (often associated with cultivations and use of mineral fertilisers) could be reduced or eliminated, so as to be able to develop systems which could contribute to the reversal of global warming. Finally, to probe whether practical operators on the ground could understand the technology, use it, and express what they were doing in a way acceptable to a wider society.
Ascidian gene-expression profiles
William R Jeffery
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-10-reviews1030
Abstract: Molecular analysis of development has traditionally involved studies of one or a few genes at a time. This approach has revealed powerful regulatory genes, which have become the foundation for understanding pattern formation during metazoan development. But with one notable exception [1], the detailed genetic networks in which developmental genes function have remained elusive. Researchers working on the development of several model organisms are now breaking the single-gene tradition by using expressed sequence tag (EST) analysis to identify random cDNA clones from libraries derived from different stages and tissue types, and high-throughput in situ hybridization to categorize the corresponding mRNAs by their expression domains. In concert with antisense-mediated inhibition of gene expression and other molecular tools of developmental biology, EST analysis and other methods of gene-expression profiling can shed new light on the genetic circuitry underlying developmental processes. Here, I review recent gene expression-profile analysis in ascidians and the promise of this approach for studying developmental gene networks.The ascidians are members of the tunicate (or urochordate) branch of the chordate tree and have been popular models in embryology and evolutionary biology for more than a century [2,3]. Their chordate features include a dorsal nervous system and a notochord in the larval phase of the life cycle, and pharyngeal gill slits in the adult phase (Figure 1). The favorable attributes of ascidians for traditional developmental biology include rapid embryogenesis, stereotypic cleavage divisions of the zygote and early embryo, well-documented cell lineages, low embryonic cell numbers, few larval tissue types, and a simplified larval body plan. Ascidian development starts with the localization of determinants in the egg; inductive signaling between different cells then takes place during the cleavage period, followed by simple morphogenetic movements that lead
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