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Structure-function relationship studies of PTH(1-11) analogues containing D-amino acids
No full textParathyroid hormone (PTH) is an 84-amino acid peptide hormone. Produced in the parathyroid glands, it acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the 1–34 amino acid fragment of PTH is sufficient to bind and activate the PTH type-I receptor. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH type-I receptor showed that certain modifications can increase signalling potency in peptides as short as 11 amino acids. To understand the role of the side chains of all the amino acid residues in PTH(1–11), we synthesized all-D PTH, three retro-inverso analogues of the most active modified PTH(1–11), H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2, and we substituted every L-AA of the latter with the corresponding d-AA, obtaining a library of PTH(1–11) analogues that were tested as agonists. The library was synthesized by SPPS, employing the Fmoc protocol. The biological tests showed that the activity of the D-Har11 analogue is of the same order of magnitude of that of the most active modified PTH(1–11). This behaviour is paralleled by an increase of the helical content on going from the D-Val2 to the D-Har11 analogue. This is in agreement with previous work where a correlation between activity and helical content has been demonstrated. The importance of a positively charged group in the C-terminal position is shown to be independent of the configuration of the Cα-carbon
Structure-function relationship of analogues of PTH (1-11) containing a combination of C-alpha-tetrasubstituited amino acids
No full textThe N-terminal 1-34 fragment of paratyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses characteristic of the native intact PTH. Recently, helicity-enhancing substitutions in PTH(1-11) and PTH(1-14) have yielded potent analogues. To further investigate the role of a-helicity on biological potency, in the present work we synthesised and conformationally and biologically characterised seven PTH(1-11) analogues containing sterically hindered and helix-promoting Ca-tetrasubstituted amino acids, such as a-amino isobutyric acid (Aib), a-methyl Valine (aMeVal) and amino cyclopentane carboxylic acid (Ac5c). CD and NMR experiments and molecular dynamics calculations demonstrate that the substitution with Ca-tetrasubstituted amino acids led to the enhancement of the helical conformation. In TFE/water solutions, analogue VII, used as reference, adopts a stable a-helical segment spanning the sequence from Ile5 to His9. Analogues I - VI show a higher preference for the helical structure which comprises the sequence 2-9
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
Role of the Guanidine Group in Position 11 of PTH(1-11) Analogues.
No full textA series of PTH hybrids containing a diamine [NH2(CH2) n NH2; n = 4, 5, 6] in the C-terminal position was synthesized based on the H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2 (Har = homoarginine) template. The compounds were pharmacologically characterized at PTH1R receptors for agonist activit
Structure-Function Relationship Study of Parathyroid Hormone (1-11) Analogues Containing D-AA
No full textParathyroid hormone (PTH) is an 84 amino acid peptide hormone. Produced in the parathyroid glands, it acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the first 34-amino acid fragment of PTH is sufficient to bind and activate the PTH type I receptor (PTH1R). The study of reduced-size PTH agonist and antagonist analogues has been the subject of extensive research, for the development of safer and non-parenteral bone anabolic drugs. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH1R showed that certain modifications can increase signalling potency in peptides as short as 11 amino acids.
To understand the role of single side-chain of all residues of the most active modified PTH(1-11) – H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2 we substituted every L-amino acid with the correspondent D-amino acid, obtaining a library of analogues of PTH(1-11) which tested as agonist. The library was synthesized by SPPS, employing Fmoc protocol. The results of biological tests demonstrated there is a unspecific decrease of activity from D-Val2 to D-Gln10, but they showed that the activity of D-Har11 is the same order of magnitude of the most active modified PTH(1-11) analogue. This behaviour is paralleled by an increase of helix content on going from D-Val2 analogue to D-Har11 analogue according to CD analysis. NMR analysis confirmed that D-Har11 is the most structured peptide. This is in agreement with our previous works where we have demonstrated a correlation between activity and helix content. The importance of a positively charged group in the C-terminal position is shown to be independent of the configuration of last residue
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
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