1,720,960 research outputs found
Snps and pathological processes: study of the stability of human proteins involved in signal transduction
No full textBeta-Sheet-breaker peptides containing alfa, beta-dehydrophenylalanine: synthesis and in vitro activity studies
No full textThe synthesis and fibrillogenesis-inhibiting activity of the new peptide derivatives 1–6, containing α,β-unsaturated phenylalanines, are reported. These compounds are related to the pentapeptide Ac-LPFFD-NH2 (iAβ5p), which was designed by Soto and co-workers and is commonly accepted as a lead compound for fibrillogenesis inhibition . Their activities are determined by Thioflavin T binding assay, far-UV circular dichroism (CD) spectroscopy , and SEM; in addition, their structures in solution are studied through far-UV CD and FTIR spectroscopy. The presence of two α,β-unsaturated phenylalanines increases the fibrillogenesis inhibiting activity significantly in comparison with the lead compound. The interactions between the Aβ1–40 and the inhibitors using electrospray ionization mass spectrometry are also studied. The analyses prove the presence of noncovalent complexes of Aβ1–40 with iAβ5p and its derivatives 1–3 with stoichiometries of 1:1 and 2:1, and the results are independent of time and Aβ1–40/inhibitor rati
Proto-oncogene Pim-1: structural stability of the variants observed in tumor tissues
No full textPim-1 kinase belongs to the family of serine/threonine protein kinases (EC 2.7.11.1) encoded by the pim proto-oncogenes (Saris et al., 1991; Hoover et al., 1991; van der Lugt et al., 1995). Pim-1 kinase, originally identified as a common Proviral insertion site in moloney murine leukemia virus-induced T-cell lymphomas in mice (Cuypers et al., 1984), is involved in several signalling pathways and in the regulation of cell cycle progression and apoptosis. The three Pim family members Pim-1, Pim-2 and Pim-3 identified in humans have been reported as signalling protein kinases playing an important role in tumor biology (Anizon et al., 2010). Pim-1, nearly undetectable in normal tissues, is overexpressed in many haematological malignancies and in the cells of several solid tumor. In several cancer tissues Pim-1 variants have been identified and several databases for patterns of somatic mutation in human cancer genomes report mutations in this oncogene (Yuan et al., 2006; Greenman et al., 2007; Forbes et al., 2008; Akagi et al., 2009). Many of these variants are nonsynonymous single nucleotide polymorphisms (nsSNPs), single nucleotide variations occurring in the coding region and leading to amino acid substitutions (Dixit A et al., 2009). In this study we investigated the effect of amino acid substitution on the structural stability and on the activity of the Pim-1 kinase. We expressed and purified as soluble recombinant proteins some of the mutants identified in cancer and in the nsSNPs database. The mutants show a decreased thermal and thermodynamic stability and decreased activation energy relative to kinase activity, when compared to the wild- type
Effect of bet missense mutations on bromodomain function, inhibitor binding and stability
Full text linkLysine acetylation is an important epigenetic mark regulating gene transcription and chromatin
structure. Acetylated lysine residues are specifically recognized by bromodomains,
small protein interaction modules that read these modification in a sequence and acetylation
dependent way regulating the recruitment of transcriptional regulators and chromatin
remodelling enzymes to acetylated sites in chromatin. Recent studies revealed that bromodomains
are highly druggable protein interaction domains resulting in the development of a
large number of bromodomain inhibitors. BET bromodomain inhibitors received a lot of
attention in the oncology field resulting in the rapid translation of early BET bromodomain
inhibitors into clinical studies. Here we investigated the effects of mutations present as polymorphism
or found in cancer on BET bromodomain function and stability and the influence
of these mutants on inhibitor binding. We found that most BET missense mutations localize
to peripheral residues in the two terminal helices. Crystal structures showed that the three
dimensional structure is not compromised by these mutations but mutations located in
close proximity to the acetyl-lysine binding site modulate acetyl-lysine and inhibitor binding.
Most mutations affect significantly protein stability and tertiary structure in solution, suggesting
new interactions and an alternative network of protein-protein interconnection as a consequence
of single amino acid substitution. To our knowledge this is the first report studying
the effect of mutations on bromodomain function and inhibitor binding
b-Sheet interfering molecules acting against b-amyloid aggregation and fibrillogenesis
No full textb-Sheet aggregates and amyloid fibrils rising from conformational changes of proteins are observed in
several pathological human conditions. These structures are organized in b-strands that can reciprocally
interact by hydrophobic and p–p interactions. The amyloid aggregates can give rise to pathological conditions
through complex biochemical mechanisms whose physico-chemical nature has been understood
in recent times. This review focuses on the various classes of natural and synthetic small molecules able
to act against b-amyloid fibrillogenesis and toxicity that may represent new pharmacological tools in
Alzheimer’s diseases. Some peptides, named ‘b-sheet breaker peptides’, are able to hamper amyloid
aggregation and fibrillogenesis by interfering with and destabilizing the non native b-sheet structures.
Other natural compounds, like polyphenols or indolic molecules such as melatonin, can interfere with
b-amyloid peptide pathogenicity by inhibiting aggregation and counteracting oxidative stress that is a
key hallmark in Alzheimer’s disease
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
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