1,720,983 research outputs found
Pat1b en LSm14 PROTEINS: regulateurs van neuronale mRNA metabolisme met mogelijke rol bij spinale musculaire atrofie
No full textThe central nervous system isprobably the most complex structure present in the human body. Such complexityis also a drawback since the central nervous system may be affected by severaldiseases, many of which are extremely complex and difficult to understand. Onefeature that many neurological diseases have in common is some perturbation inthe metabolism of neuronal messenger RNA. Despite all the studies and the progress that has been achieved in thisfield, the exact relation between dysfunction of mRNA metabolism andneurological disease remains elusive. In fact, for many severe diseases stillno precise molecular pathway has been identified.In particular motor neurons seem to beextremely vulnerable to perturbations of their mRNA metabolism as shown by thefact that mutations in genes encoding RNA-binding proteins can cause devastatingdiseases like Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy. SpinalMuscular Atrophy in particular is caused by shortage of the Survival of MotorNeuron protein, which is fundamental for pre-mRNA splicing by affecting thematuration of the Sm proteins, the major players of splicing. Despite the factthat the function of SMN is well known, nobody could so far provide a directexplanation for the pathogenesis of SMA. The Like-Sm protein 1 (LSm1), a memberof the Like-Sm protein family which is structurally related to the Sm proteinfamily, has been demonstrated to play an important role in neuronal mRNA processing.Considering the similarities between LSm proteins and Sm proteins, a potentialrole for SMN in the metabolism of LSm proteins can be hypothesized. A lack ofSMN, as observed in SMA, could lead to misfunction of the mRNA processescarried by LSm1 or other members of the family. The aim of the work of mythesis is to investigate a potential role of LSm proteins and proteinsassociated with them in neuronal mRNA metabolism and eventually, look for apossible role in the pathogenesis of SMA. We identified in mammalian cells aninteractor of LSm1, Pat1b, known to be involved in mRNA turnover in yeast. As apartner of LSm1, Pat1b could be necessary for its action or for specific mRNAtarget recognition. In the first part of this work we studied the role of Pat1bin mammalian cells and in neuronal mRNA metabolism. We found that Pat1b affectsmRNA turnover through deadenylation of the target. Plus, we observed that inmammalian cells Pat1b does not generally act on mRNA molecules but insteadaffects specific transcripts. However, when we extended our analysis toneurons, we observed a prevalent nuclear localization of the protein,suggesting that in neurons Pat1b has evolved a different function. This study beingfocused on mRNA metabolism (cytoplasmic event), we decided to look at otherpotential players of neuronal mRNA and SMA. We studied two members of the Like-Smfamily that share structural features with LSm1 and LSm4 which make themcandidates as SMN partners. We show that LSm14a and LSm14b can represstranslation of mRNA and affect its stability and that they bind specific mRNAsin neurons that are involved in cytoskeleton remodelling and axonal growth. Inagreement with these findings, knock-down of LSm14b in primary neurons causedan axonal phenotype. At last, we extended our analysis of LSm14 proteins to SMAand found that a SMA mouse model has dramatically reduced levels of both proteinssuggesting a link between the proteins and the disease. This work sheds lighton the function and importance of three different proteins in neuronal mRNAmetabolism, and increases our knowledge of neuronal molecular physiology.status: Publishe
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
Molecular dynamics simulations show how the FMRP Ile304Asn mutation destabilizes the KH2 domain structure and affects its function
Full text linkMutations or deletions of FMRP, involved in the regulation of mRNA metabolism in brain, lead to the Fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. A severe manifestation of the disease has been associated with the Ile304Asn mutation, located on the KH2 domain of the protein. Several hypotheses have been proposed to explain the possible molecular mechanism responsible for the drastic effect of this mutation in humans. Here, we performed a molecular dynamics simulation and show that the Ile304Asn mutation destabilizes the hydrophobic core producing a partial unfolding of two α-helices and a displacement of a third one. The affected regions show increased residue flexibility and motion. Molecular docking analysis revealed strongly reduced binding to a model single-stranded nucleic acid in agreement with known data that the two partially unfolded helices form the RNA-binding surface. The third helix, which we show here to be also affected, is involved in the PAK1 protein interaction. These two functional binding sites on the KH2 domain do not overlap spatially, and therefore, they can simultaneously bind their targets. Since the Ile304Asn mutation affects both binding sites, this may justify the severe clinical manifestation observed in the patient in which both mRNA metabolism activity and cytoskeleton remodeling would be affected
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
MD and Docking Studies Reveal That the Functional Switch of CYFIP1 is Mediated by a Butterfly-like Motion
No full textCytoplasmic FMRP
interacting protein 1 (CYFIP1), also known as
specifically RAC1 activated protein 1 (Sra1), plays a dual role: together
with fragile X mental retardation protein (FMRP) and eIF4E it forms
a complex that inhibits mRNA translation, while together with WAVE1,
NCKAP1, ABI2, and HSPC300 it forms the WAVE regulatory complex (WRC)
that upon RAC1 activation initiates actin polymerization. Here we
performed a molecular dynamics (MD) simulation on CYFIP1 extracted
from the known WRC structure, which shows that, in the absence of
its WRC partners, a butterfly-like motion brings the two ends of CYFIP1
closer together, enabling the interaction with eIF4E. Our MD simulation
is supported by available data showing that binding of CYFIP1 to eIF4E
and binding to the WRC are mutually exclusive and that there is fluorescence
resonance energy transfer between the N- and C-termini of CYFIP1.
The differential interaction of RAC1–GTP with the two CYFIP1
structures predicts that RAC1 is directly responsible for the switch
between these conformations
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