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Cardioprotection and energy metabolism modulation by 3-iodothyronamine, a new endogenous chemical messanger
No full textCardiac effects of trace amines: pharmacological characterization of trace amine-associated receptors
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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
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Design and Characterization of Novel Thyroid Hormone Receptor Alpha Specific Ligands
Full text linkThyroid hormone orchestrates a multifarious set of physiological activities ranging from fetal, brain, and skeletal maturation to improving vascular tone and controlling cardiac output. Thyroid hormone elicits its effects by binding to the ligand binding domain of the thyroid hormone receptor (TR) for which there are two subtypes for two isoforms: TRα1, TRα2, TRβ1, and TRβ2. Although TR isoforms, with the exception of TRβ2 which is mainly expressed in the pituitary, are ubiquitously expressed, these isoforms are expressed in different ratios in different tissues giving rise to tissue-specific isoform action. Selective thyroid hormone analogues, or selective thyromimetics, that discriminate between these two subtypes would serve as useful chemical tools to gain or refine our understanding of the physiological effects of thyroid hormone. These compounds may also prove useful in the clinic as known thyromimetics (i.e. 3,5-diiodothyroproprionic acid and GC-1) show promise in treating cardiac related diseases and metabolic disorders. One way to generate selective thyromimetics with unique pharmacological profiles is to synthesize a small panel of compounds by employing a bioisosteric replacement strategy. This method entails derivatizing one region of the thyronine backbone, the C1 region, by incorporation of various heterocycles or carbocycles. This strategy led to the production of a small panel of ligands which were screened in 125I-T3 competitive binding and transactivation assays. After this screen, the TRα-specific ligand CO22 was identified; however, it demonstrated poor binding and potency. Replacing the inner-ring methyl groups of CO22 with iodides led to CO23, the first potent thyromimetic to show TRα-specificity in vitro and in vivo. CO23 showed specificity in TRα-mediated transcription in U2OS and HeLa cells and caused Xenopus laevis tadpoles to experience more extensive and rapid hind leg growth, less larval tissue resorption, greater induction of TRα early genes, and less induction of TRβ early and late genes. It was surmised that the imidazolidinedione moiety of the inner-ring confers TRα-specificity; therefore, to engender ligands with improved specificity the 3' outer-ring position was derivatized. This led to several analogues with less potency than CO23, but with a gain in specificity of up to 2-fold
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Exploring the Non-Transcriptional Activity of Thyroid Hormone Derivatives
Full text linkThis work is premised on the hypothesis that thyroid hormone may be a substrate for the aromatic L-amino acid decarboxylase (AADC) and that the resulting iodothyronamines would have significant structural and perhaps functional similarity with several biogenic amines including the classical monoamine neurotransmitters. Previous reports have shown that several thyronamines are rapid and potent agonists of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR). We hypothesized that thyronamines might function physiologically as classical neurotransmitters or neuromodulators. As such, we sought to screen thyronamines for activity with a variety of known monoamine transporters. Additionally we attempted to clone, express and screen the rat TAAR family of GPCRs for activity with thyronamines and a variety of phenethylamine (PEA), thyroid hormone, and amino acid derivatives. Using our previously reported synthesis of these presumed thyroid hormone metabolites and a radioactive derivative of T1AM, we found that T1AM inhibits plasma membrane transport of norepinephrine and dopamine in synaptosomes, and also inhibits biogenic amine vesicular packaging in synaptic vesicles. We further demonstrate that T1AM is an inhibitor of the plasma membrane neurotransmitter transporters DAT and NET, and an inhibitor of the vesicular transporter VMAT2. This is a novel and exciting result, because T1AM is the first example of an endogenous substance that inhibits these transporters and suggests that T1AM may play a physiological role in regulating synaptic transmission with catecholamine neurons. In addition, we report that several PEA derivatives act as agonists of rTAAR4, both confirming previously identified compounds and discovering several additional agonists. Lastly, we show that a class of clinically used thyroid hormone derivatives act as agonists of TAAR1 with potential therapeutic relevance. Significantly, we expand on our understanding of trace amine-associated receptor ligand recognition and the physiological relevance of thyronamine/GPCR interactions
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
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