1,721,161 research outputs found
Dopamine receptor structure/function studies.
No full textThe general aim of this dissertation was to investigate potential mechanisms linking ligand binding and signal transduction in seven transmembrane helix, G protein-coupled receptors. For this purpose, dopamine D\sb1 and D\sb2 receptors were analyzed at the ligand binding pocket, the third cytosolic loop, and transmembrane-embedded kinks which potentially link ligand binding and G protein-coupling. The first study investigated variability in the D\sb2 third cytosolic loop, a region putatively involved in G protein-coupling. The results indicate that, due to this variability, the long and short isoforms of D\sb2 exhibit differences in binding pocket geometries which are especially well detected by substituted benzamide antagonists and are observed only in particular expression conditions. The third intracellular loop variability may be responsible for differential coupling of the D\sb2 isoforms to some intracellular or membrane-bound factor(s) other than G proteins. In the second study, conserved hydrophobic residues in D\sb2, predicted to be important for stabilization of ligand binding or for propagation of agonist-induced conformational changes, were investigated by mutagenesis. Two phenylalanines located on the fifth helix were found to be critical for agonist and antagonist binding. One seventh helix phenylalanine and one sixth helix leucine appear to be critical for linking ligand binding and signal transduction since their mutations led to dissociation of these receptor functions. The third project investigated the potential role of proline-adjacent residues in D\sb1 receptor structure and dynamics. Mutation of residues in the fifth and sixth helices indicated that the nature, or volume, of the residue immediately adjacent to proline on the N-adjacent side can alter both ligand binding and signal transduction. One of these mutations, an alanine substitution of the sixth helix leucine286, conferred partial constitutive activity to the D\sb1 receptor, characterized by elevated basal cAMP levels and increased agonist potencies. This is the first report of a constitutively active dopamine receptor mutant. Together, these results have expanded the study of structure/function relationships in dopamine receptors by identifying several residues in the D\sb1 and D\sb2 receptor subtypes which appear to be important for ligand binding, signal transduction, and perhaps for conformational changes linking these two receptor functions.PhDBiological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/130218/2/9721962.pd
A Study of the Effects of Dopaminergic Manipulations and Stress on Dynorphin Concentrations in Midbrain and Forebrain Regions of Rat Brain
No full textvi, 43 p.In the present study, the effects of stress and dopaminergic manipulations on
dynorphin peptides were investigated in the striatum (Str), substantia nigra (SN),
nucleus acumbens (NA), and ventral tegmental area (VTA) of rat brain because of a
recent history of conflicting reports regarding the effects of stress and dopaminergic
manipulations on these brain regions. Male Sprague-Dawley rats were given repeau()
injections of the dopamine (DA) agonist, apomorphine, followed by a 30 minute
exposure to swimming stress over a course of 14 days; repeated injections of
haloperidol, a DA antagonist, and swim for 14 days; and repeated swim for 7 days
followed by an acute amphetamine challenge. Animals treated simultaneously with
swim and apomorphine showed significant elevations in strlatallevels of Dyn AI-17
and Dyn B, suggesting that an interaction between swimming stress and
apomorphine causes increases in dynorphin levels. Also, across the brain regions,
large differences in peptide concentrations were noted. The SN exhibited 2 to
12-fold greater concentrations over VTA, and that NA consistently contained 2 to
3-fold greater concentrations than Str in all four Prodyn peptides. Dyn AI-8:Dyn
AI-17 ratios were approximately 10:1 and 12:1 in Str and SN, respectively, and
approximately 4: 1 and 2: 1 in NA and VT A, respectively, which implies the existence
of separate dopamine/dynorphin loops between SN and Str and between VT A and
NA.Mental Health Research Institute. University of Michigan. Ann Arbor, Michigan
Photoperiodic regulation of POMC systems in the golden hamster.
No full textIn this dissertation, I investigated proopiomelanocortin (POMC) systems in the hypothalamus, testes, and anterior pituitary that are altered by switching the male golden hamster (Mesocricetus auratus) from long photoperiods (LP) to short photoperiods (SP). I tested the following hypotheses: (1) SP stimulate POMC peptide secretion from the mediobasal hypothalamus (MBH); (2) SP inhibit POMC peptide secretion from the testes; (3) SP inhibit POMC peptide secretion from the anterior pituitary (AP); and (4) SP and agonistic encounters (i.e., social isolation followed by fighting) stimulate POMC peptide secretion from the AP. After exposure to SP (i.e., less than 12.5 hours of daily light), the hamster exhibits changes in the secretion of hormones regulating reproduction, metabolism, and social behavior, which are thought to be critical for winter survival. Although the underlying mechanisms are not completely understood, the POMC precursor, which encodes beta-endorphin (-END) and adrenocorticotropic hormone (ACTH), may play a key role. The results show that the MBH -END content, as assessed by radioimmunoassay (RIA), increases prior to the loss of testicular activity during SP. MBH -END is thought to inhibit gonadal activity. In addition, increases followed by decreases in the testicular -END content and POMC mRNA levels, as assessed by RIA and Northern analysis, suggest that testicular POMC is regulated by the photoperiod During SP, decreases in plasma ACTH and glucocorticoid levels, as assessed by RIA, are not temporally associated with decreases in the body fat content, even though the glucocorticoids are known to stimulate fat catabolism. In hamsters subjected to agonistic encounters and SP, increases in plasma ACTH and glucocorticoid levels are associated with pronounced increases in agonistic behavior. ACTH, via its stimulation of glucocorticoid secretion, is known to increase agonistic behavior. I conclude from these results that POMC peptides are involved in the photoperiodic regulation of gonadal and adrenal activities and possibly in the seasonal regulation of reproduction and social behavior, but not fat metabolism.PhDAnimal PhysiologyBiological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129801/2/9624689.pd
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Building Bridges through Science
No full textScience is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched “The Science Bridge” initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities
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