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On the Evolution, Function and Pathogenesis of Intermediate Filaments
Get PDFIntermediärfilament (IF) är nukleära och cytoplasmiska strukturprotein. I människans genom ingår 70 gener som kodar för 74 hittills kända intermediärfilament. Mutationer i dessa gener orsakar många allvarliga sjukdomar. IF förser cellen med en dynamisk stödstruktur som effektivt kan monteras upp och ned. IF:ens kapacitet till upp- och nedmontering möjliggör att denna stödstruktur kan ommodelleras kontinuerligt, vilket är viktigt för cellens rörlighet samt för rekonstruktionen av kärnmembranet vid celldelning. Under evolutionen har IF:en blivit mer och mer funktionellt specialiserade. Adaptionen av IF:ens funktion och deras utbredda uttryckning reflekterar hur viktig IF:en har blivit för multicellulära organismer. De nukleära IF:en är ursprunget till de cytoplasmiska intermediärfilamenten (cytoIF) och deras uttryckning är konserverad i alla multicellulära organismer. CytoIF:en är också mycket konserverade och de uttrycks i alla eumetazoa organismer, förutom i artropoderna.
Denna doktorsavhandling är indelad i tre projekt. Det första projektet behandlar varför Arthropoda är det enda fylum inom eumetazoerna som saknar cytoIF. I detta projekt har ett humant cytoIF, vimentin, transgent uttryckts i Drosophila, för att studera proteinets kapacitet att monteras och bilda IF-nätverk i artropodvävnad. Slutsatsen är att humant vimentin kan forma nätverk i epitelvävnader i Drosophila, vilket påvisar kompatibilitet mellan cytoIF och Drosophila.
Den andra studien behandlar ett mindre känt cytoIF, nestin. En nestin knock-out mus användes för att studera följderna av avsaknaden av nestin i muskelvävnad. Resultaten visar att knock-out av nestin leder till försämrad läkning av muskler. Läkning hos skelettmuskler är beroende av satellitceller, och denna studie visar att hastigheten i celldelningen är nedsatt i satellitceller som isolerats från nestin knock-out-möss.
Mutationer i nukleära IF, laminer, ger upphov till muskeldystrofi och för tidigt åldrande. I det tredje projektet som ingår i denna doktorsavhandling, undersöks en punktmutation i LMNA-genen. Denna mutation är associerad med dilaterad kardiomyopati (DCM). Mutationen, p.S143P i lamin A/C har identifierats i finska patienter och orsakar sent uppkommande DCM med ledningsdefekter. Patientfibroblaster, inducerade pluripotenta stamceller (iPSC) differentierade till kardiomyocyter och Drosophila användes för att studera fenotypen av p.S143P-mutationen. Studien visar att mutationen orsakar i patentfibroblasterna en oförmåga hos de muterade laminerna att normalt inkorporeras i laminan. De muterade laminerna återfanns i stället i nukleoplasman och bildade ibland stora intranukleära aggregat. Dessa fenotyper ledde till endoplasmatisk retikulär (ER) stress. Dessa resultat kunde också reproduceras i kardiomyocyter deriverade från iPSC samt i Drosophila.
Sammanfattningsvis beskriver studierna som utförts inom ramen för denna doktorsavhandling nya strukturella och funktionella aspekter hos både nukleära och cytoplasmiska IF. Dessa resultat fördjupar vår insikt i IF:ens dynamik och kan komma att gynna utvecklingen av mediciner för att bota sjukdomar som är associerade till IF.----------
Intermediate filaments (IFs) are nucleoskeletal and cytoskeletal proteins. The human IF protein family consists of 70 genes coding for 74 known proteins and their mutations cause various serious diseases. The IFs provide the cell with a dynamic scaffold that can be effectively assembled and disassembled. The assembly-property of IFs enables the IF scaffold to be continuously remolded, which is important for the motility of the cell and for the deconstruction and reconstruction of the nuclear membrane during mitosis. During evolution, the IFs have, since their emergence, become increasingly functionally differentiated. The adaptation of the IF function and spatial expression reflects how instrumental the IFs have become for multicellular organisms. The nuclear IFs, which are precursors to the cytoplasmic IFs (cytoIFs), are conserved in all multicellular organisms. The cytoIFs are also very conserved throughout the eumetazoans except for the arthropods.
This thesis is divided into three projects, the first of which deals with the question why Arthropoda is the only eumetazoan phyla lacking cytoIFs. We transgenically express a human cytoIF, vimentin, in Drosophila to study cytoIF expression and assembly in arthropod tissue. We conclude that human vimentin forms networks in epithelial tissue in Drosophila, suggesting some compatibility for cytoIFs in Drosophila specifically in epithelial tissue.
The second study deals with the less well characterized cytoIF nestin. We utilized a nestin null mouse model to investigate muscle physiology following nestin knock out. We show that nestin knock out results in impaired muscle regeneration. Skeletal muscle regeneration is dependent on satellite cells, and we could show that there was a defect in the proliferation rate of satellite cells isolated from nestin knock out mice.
Mutations in lamins give rise to muscular dystrophies and premature aging. In the third project included in this thesis, we investigate a point mutation in the LMNA gene associated with dilated cardiomyopathy (DCM). The mutation, p.S143P in lamin A/C, has been identified in the Finnish population and gives rise to late onset DCM with conduction defects. Patient fibroblasts, induced pluripotent stem cells (IPSCs) differentiated into cardiomyocytes and Drosophila were used to investigate the disease phenotype of the p.S143P mutation. We showed that in the patient fibroblasts, the mutation causes inability of mutant lamins to incorporate into the lamina. Instead, the mutant lamins are found in the nucleoplasm and frequently form intranuclear aggregates which eventually lead to endoplasmic reticulum (ER) stress. These findings were further validated in iPSC derived cardiomyocytes as well as in Drosophila.
In summary, the work described in this thesis characterized new structural and functional aspects of both cytoplasmic and nuclear IFs. These findings deepen our understanding of IF dynamics and may benefit molecular targeting of IF related diseases.ei tietoa saavutettavuudest
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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