1,720,976 research outputs found
NMR studies of human prion proteins with inherited mutations
No full textPrion diseases are fatal neurodegenerative disorders caused by an aberrant accumulation of the misfolded cellular prion protein (PrPC) conformer, denoted as infectious scrapie isoform or PrPSc. Our understanding of the mechanisms by which mutations cause disease remains limited. In this work results of recent high-resolution NMR structural studies on human prion protein variants carrying pathological mutations are presented
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
Structural rearrangements at physiological pH: Nuclear magnetic resonance insights from the V210I human prion protein mutant
No full textA major focus in prion structural biology studies is unraveling the molecular mechanism leading to the structural conversion of PrP(C) to its pathological form, PrP(Sc). In our recent studies, we attempted to understand the early events of the conformational changes leading to PrP(Sc) using as investigative tools point mutations clustered in the open reading frame of the human PrP gene and linked to genetic forms of human prion diseases. In the work presented here, we investigate the effect of pH on the nuclear magnetic resonance (NMR) structure of recombinant human PrP (HuPrP) carrying the pathological V210I mutation responsible for familial Creutzfeldt-Jakob disease. The NMR structure of HuPrP(V210I) determined at pH 7.2 shows the same overall fold as the previously determined structure of HuPrP(V210I) at pH 5.5. It consists of a disordered N-terminal tail (residues 90-124) and a globular C-terminal domain (residues 125-231) comprising three α-helices and a short antiparallel β-sheet. Detailed comparison of three-dimensional structures of HuPrP(V210I) at pH 7.2 and 5.5 revealed significant local structural differences, with the most prominent pH-related structural variations clustered in the α(2)-α(3) interhelical region, at the interface of the β(1)-α(1) loop, in helices α(1) and α(3), and in the β(2)-α(2) loop region. The detailed analysis of interactions among secondary structure elements suggests a higher degree of structural ordering of HuPrP(V210I) under neutral-pH conditions, thus implying that spontaneous misfolding of PrP(C) may occur under acidic-pH conditions in endosomal compartments
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
NMR Structural Studies of Human Cellular Prion Proteins
No full textPrion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the conformational conversion of the cellular prion protein, PrPC, into a pathological form known as prion or PrPSc. They can be classified into sporadic, inherited and infectious forms. Spontaneous generation of PrPSc in inherited forms of prion diseases is caused by mutations in the human prion protein gene (PRNP). A major goal in prion biology is unraveling the molecular mechanism by which PrPC misfolds and leads to development of diseases. Structural characterization of various human PrP (HuPrP) variants may be helpful for better understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions. Here, we review the results of the recent high-resolution nuclear magnetic resonance (NMR) structural studies on HuPrPs with pathological Q212P and V210I mutations linked with Gerstmann-Sträussler-Scheinker (GSS) syndrome and familial Creutzfeldt-Jakob disease (fCJD), respectively, and HuPrP carrying naturally occurring E219K polymorphism considered to protect against sporadic CJD (sCJD). We describe subtle local differences between the three-dimensional (3D) structures of HuPrP mutants and the wild-type (WT) protein, providing new insights into the possible key structural determinants underlying conversion of PrPC into PrPSc. Also highlighted are the most recent findings from NMR studies about the effect of pH on the structural features of HuPrP with V210I mutation
A single point mutation, a way to prion disease?
No full textPrion diseases or Transmissible Spongiform Encephalopathies (TSE) are a group of fatal neurodegenerative illnesses affecting humans and animals. They are classified into sporadic, genetic and infectious forms. Genetic prion diseases are caused by mutations in the human prion protein gene and include Gerstmann-Straussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia and genetic Creutzfeldt-Jakob disease (CJD). Approximately 10-15% of all TSE cases in humans are associated with mutations. The development of TSEs is associated with the conversion of the cellular prion protein (PrPC) into a misfolded, pathogenic isoform (PrPSc). Our recent NMR studies were focused on structural characterization of different truncated recombinant human (Hu) PrPs carrying the pathological Q212P (90-231, M129) and V210I(90-231, M129) mutations, and protective E219K (90-231, M129) polymorphism. While Q212P mutation is linked to GSS, the V210I mutation is linked to genetic CJD. The naturally occurring E219K polymorphism in the HuPrP is considered to protect against sCJD. We have demonstrated that the determined structures of variants consist of unstructured N-terminal part (residues 90-124) and well defined C-terminal domain (residues 125-228). Analysis and comparison with the structure of the WT HuPrP revealed that although structures share similar global fold, mutations introduces several local structural differences. The observed differences are mostly clustered at the alpha2-alpha3 inter-helical interface and in the beta2-alpha2 loop region. The determined NMR structures offer new insights on the earliest events of the pathogenic conversion process and could be used for the development of antiprion drugs. More recently we have determined solution state structures of V210I (90-231, M129) pathogenic mutation at two different conditions with pH 5.5 and 7.2. The detailed comparison of three-dimensional structures of HuPrP(V210I) at two different pH values revealed that interactions among secondary structure elements have a higher degree of structural ordering under neutral pH conditions, thus implying that spontaneous misfolding of PrPC may occur under acidic-pH conditions in endosomal compartments
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
Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism
No full textThe most common form of prion disease in humans is sporadic Creutzfeldt-Jakob disease (sCJD). The naturally occurring E219K polymorphism in the human prion protein (HuPrP) is considered to protect against sCJD. To gain insights into the structural basis of its protective influence we have determined the NMR structure of the recombinant HuPrP (residues 90-231) carrying the E219K polymorphism. The structure of the HuPrP(E219K) protein consists of a disordered N-terminal tail (residues 90-124) and a well-structured C-terminal (residues 125-231) containing three a-helices and two short antiparallel b-strands. Comparison between NMR structures of the wild-type (WT) and HuPrPs with pathological mutations under identical experimental conditions revealed that, although the global architecture of the protein remains intact, Glu219 to Lys substitution introduces significant local structural changes. Our structural findings suggest that the protective influence of the E219K polymorphism is due to the alteration of surface charge distribution, in addition to subtle structural rearrangements localized within the epitopes critical for prion conversion
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