1,720,979 research outputs found
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
Design and Synthesis of Covalent Inhibitors for the Protein Kinase MK2 and Exploration of Different Cysteine-Targeting Electrophiles
No full textDie Dissertation ist gesperrt bis zum 23. Juni 2026 !Die Proteinkinase MK2 (mitogen-activated protein kinase-activated protein kinase 2) gehört zu den Effektorproteinen des p38 MAP-Kinase Signalwegs und spielt eine wichtige Rolle in der Entstehung von Entzündungsreaktionen. Darüber hinaus zeigen neuere Erkenntnisse, dass MK2 an der Krebsentstehung und Tumorprogression beteiligt ist. Diese Eigenschaften machen die Kinase zu einem interessanten Arzneistofftarget.
Im Rahmen dieser Arbeit wurde ein kovalenter Designansatz zur Entwicklung neuer Inhibitoren der Proteinkinase MK2 verfolgt. Der Einsatz kovalenter Proteinkinaseinhibitoren ermöglicht eine Verbesserung der Aktivität, Selektivität und Verlängerung der Wirkdauer. Des Weiteren verhindert die erfolgreiche kovalente Bindung des Inhibitors dessen Verdrängung durch ATP, dem physiologischen Cosubstrat der Kinase. Die Ausbildung der kovalenten Bindung erfolgt dabei durch die Reaktion eines elektrophilen Strukturelements, dem sogenannten warhead des Inhibitors mit einem nucleophilen Zentrum im Protein, meist einer Aminosäuren-Seitenkette. Die hohe Nucleophilie der Thiolgruppe der Seitenkette der Aminosäure Cystein und der geringe Grad der Konservierung von Cysteinen im Kinom, machen diese zu attraktiven Zielstrukturen für kovalente Inhibitoren. Typischerweise setzt die Entwicklung kovalenter Kinaseinhibitoren die Anwesenheit eines Cysteins in bzw. in der Nähe der ATP-Bindungstasche voraus. Mit Cystein-140 besitzt die Proteinkinase MK2 ein solches adressierbares Cystein in der hinge-Region. Ein äquivalent positionierter Cysteinrest findet sich leidglich in vier weiteren Kinasen, FGFR4, MPS1, S6K2 und MK3, wodurch sich über die kovalente Adressierung auch eine Möglichkeit zur Verbesserung der Selektivität bietet.
Die Kombination eines bekannten, nicht-kovalent bindenden, tetracyclischen MK2 Inhibitors mit einem elektrophilen warhead stellt den initialen Designansatz dieser Arbeit dar. Die Optimierung der Synthese der Gerüststruktur, deren Modifikation zur Verbesserung der synthetischen Zugänglichkeit und Vereinfachung der Derivatisierung ermöglichte die Synthese diverser Analoga. Neben etablierten Acrylamid-basierten reaktiven Gruppen, konnten auch heteroaromatische Elektrophile erfolgreich als warhead-Strukturen eingebaut werden.
Dabei zeigten sowohl Acrylamid-basierte Derivate als auch solche, die auf einem Chlornitropyridin beruhen, sehr gute inhibitorische Aktivität im biochemischen Assay, sowie geringe intrinsische Reaktivität gegenüber Surrogatnucleophilen. Die erfolgreiche kovalente Adressierung konnte weiterhin durch, im Rahmen einer Kooperation erfolgte, massenspektrometrische Analyse des Inhibitor-gebundenen Proteins und Röntgenkristallstrukturuntersuchungen bestätigt werden.The protein kinase MK2 (mitogen-activated protein kinase-activated protein kinase 2) belongs to the effector proteins of the p38 MAP kinase signaling pathway and plays an important role in the regulation of inflammatory processes. Furthermore, recent findings show the involvement of MK2 in carcinogenesis and tumor progression. These properties render the kinase an interesting target in drug discovery.
In this work, a covalent design approach was pursued for the development of new inhibitors against the protein kinase MK2. The application of covalent protein kinase inhibitors enables an improvement in activity, selectivity and extends the duration of action. Furthermore, the successful covalent binding of the inhibitor prevents its displacement by ATP, the physiological cosubstrate of the kinase. The covalent bond is formed by the reaction of an electrophilic group, the so-called warhead of the inhibitor, with a nucleophilic center in the protein, usually an amino acid side chain. Cysteine residues display attractive target structures for covalent targeting due to the high nucleophilicity of the thiol group located in the side chain and the low degree of conservation in the kinome. Typically, the development of covalent kinase inhibitors requires the presence of a cysteine in or in proximity to the ATP binding pocket. With Cys140, the protein kinase MK2 possesses such an addressable cysteine in the hinge region. An equivalently positioned cysteine residue is also found in four other kinases, FGFR4, MPS1, S6K2 and MK3, which also offers the possibility of improving selectivity via the covalent approach.
The combination of a known, reversible binding, tetracyclic MK2 inhibitor with an electrophilic warhead represents the initial design approach of this work. The optimization of the synthesis of the core scaffold, modification thereof to improve synthetic accessibility and derivatization possibilities enabled the synthesis of various analogues. In addition to established acrylamide-based warheads, heteroaromatic electrophiles could also be successfully incorporated as reactive groups.
Both acrylamide-based derivatives and those based on a chloronitropyridine showed very good inhibitory activity in the biochemical assay, as well as low intrinsic reactivity towards surrogate nucleophiles. The successful covalent targeting was further confirmed through intact protein mass spectrometric and X-ray crystallography
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
Design and Synthesis of Covalent Inhibitors Targeting Cysteines in the Hinge Region of the Protein Kinases S6K2 and MPS1
No full textThe family of p70 ribosomal protein S6 kinases (or S6K) belongs to the group of AGC (protein kinase A, G and C) serine/threonine kinases and includes the two highly homologous isoforms S6K1 and S6K2. The family is named after the phosphorylation of the ribosomal protein S6, which, as a component of the 40S ribosomal subunit, plays an important role in protein synthesis and cell cycle progression. The exploration of S6Ks revealed further functions related to cell proliferation, transcription and signal transduction. Initially, a redundant biological functional profile of the isoforms was assumed, with the S6K1 isoform considered the prototypical form. This assessment led to a significant neglect of S6K2 in S6K-related studies. The preference for S6K1 was particularly evident in the development of isoform-selective inhibitors, which so far have only yielded S6K1-selective inhibitors. However, subsequent sparse studies on S6K2 function revealed the distinct roles of the isoforms, highlighting the particular role of S6K2 as a potential target of therapeutic intervention in cancer. In this work, we aimed to develop isoform-selective S6K2 inhibitors using an S6K2 isoform-specific cysteine (Cys150; Tyr174 in S6K1) in the hinge region of the ATP-binding pocket as a selectivity vector. For this purpose, suitable reversibly binding core scaffolds were linked to electrophilic aromatic fragments (so-called SNAr-warheads), which can form a covalent bond to nucleophiles such as a thiol. In this work, a variety of inhibitors with attached SNAr-warheads were synthesised that inhibited S6K2 with high potency (IC50 < 1 nM). Excellent selectivity over the S6K1 isoform as well as kinases with equivalently positioned cysteine was observed. The covalent binding mode was demonstrated by the significantly lower inhibitory potency of the unreactive control compounds and the non-promiscuous reactivity of the warheads was confirmed. The results validated the design hypothesis towards isoform-selective S6K2 inhibitors using SNAr warheads and represent an important step towards a high-quality chemical probe enabling the exploration of the biological function of S6K2 by pharmacological means.
The monopolar spindle 1 (MPS1) kinase activates the spindle assemble checkpoint and regulates essential functions in monitoring correct chromatid separation during cell division. MPS1 is overexpressed in several cancers and leads to increased survival of aneuploid cancer cells. In this work, we aimed to develop MPS1 inhibitors that covalently address a cysteine in the hinge region (Cys604) of the ATP-binding pocket using SNAr-warheads to achieve high residence times. A series of compounds were synthesised that differed in their substitution at the SNAr-warhead. Trends in the structure-activity relationship were derived from the inhibition data obtained, but only low inhibition values were observed, suggesting no efficient covalent binding mode.Die Dissertation ist gesperrt bis zum 10. März 2027
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
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