1,720,958 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
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
NAMPT Aktivator P7C3: Validierung des Aktionsmechanismus und Identifikation von Off-Targets anhand des Cellular Thermal Shift Assays
No full text2 Abstract
2.1 Background and aims
Due to increasing life expectancy, the number of elderly people rises. This leads to several challenges for the public health system, as aging is considered a primary risk factor for osteoporosis, cancer, cardiovascular disfunction, diabetes, Alzheimer’s disease, arthritis and many other chronic diseases. Interventions are needed to expand a healthy lifespan and compress morbidity during aging.
Especially the decrease of cellular nicotinamide adenine dinucleotide (NAD) is of great interest, as it has been associated with several pathophysiologies and diseases during aging. Reversing the decrease of NAD is a promising potential therapy option and the substitution of NAD precursors has shown some favorable results. Another option to increase NAD concentrations offers a new chemical compound: P7C3. It was first discovered in 2010 as a neurogenesis enhancing compound and in 2014 the mechanism of action was described as activation of nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is the enzyme responsible for flow limitation in the NAD salvage pathway. In humans and other mammals, the NAD salvage pathway is mainly responsible for maintaining NAD levels.
Since the discovery of P7C3, various studies have demonstrated protective efficacy of P7C3 in different animal models against Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), and acetaminophen-induced acute liver injury. Still, it’s a long way to go until P7C3 chemicals will enter clinical trials in humans. NAMPT needs to be verified as a target and the mechanism of the allosteric activation needs to be studied. Additionally, adverse effects of the drug because of the interaction with off-targets need to be addressed in further studies.
The aim of this dissertation was to validate P7C3- mediated NAMPT activation and to find potential off-targets of the compounds to make P7C3 chemicals safe pharmaceuticals for clinical use.
2.2 Methods
Cellular thermal shift assay (CETSA) was used to validate the interaction between P7C3 and NAMPT. The method is based on a ligand-induced shift of thermostability of a protein: When a ligand binds to the protein, its conformation gets stabilized and results in denaturation of the protein at much higher temperatures. This shift in the protein melting curve can be detected by immunoblotting. To find potential off-targets of P7C3,
4
CETSA was coupled with mass spectrometry. All proteins that got stabilized by ligand binding can be detected by screening the proteome.
2.3 Results
It could not be confirmed with CETSA that P7C3 chemicals including P7C3-A20 bind to NAMPT and stabilize it in K562 and U2OS cells. Also, when NAD concentrations were low, no target engagement with NAMPT in U2OS cells after P7C3-A20 treatment could be observed. Dimebon, a structural and functional relative of P7C3 failed to exhibit the stabilization of NAMPT in CETSA when tested in K562 cells. The results from CETSA- MS showed a significant shift at 51°C and 58°C in the denaturation curve of NAMPT after P7C3-A20 treatment in U2OS cells with reduced NAD concentrations.
In NAD-depleted U2OS cells, P7C3-A20 treatment led to replenishment of NAD levels or rather prevented an NAD decrease while treated with doxorubicin.
CETSA-MS results suggest an interaction between P7C3-A20 and many chaperones in U2OS cells. For example, it stabilized the melting curve of endoplasmin (HSP90B1), glucose-regulated protein 78 KDa (HSPA5/GRP78), hypoxia upregulated protein 1 (HYOU), protein disulfide isomerase A4 & A6 (PDIA4 & PDIA6) and peptidylprolyl cis- trans isomerase B (PPIB). All these proteins are part of a big chaperone-complex in the endoplasmatic reticulum involved in unfolded protein response (UPR) and in remaining proteostasis. Other chaperones like heat shock protein 10 (Hsp19/HSPE1), heat shock protein 60 (Hsp60/ HSPD1), and endoplasmic reticulum resident protein 44 (ERP44) were also stabilized in P7C3-A20 treated cells.
2.4 Conclusions
In summary, it was found in this dissertation that P7C3-A20 only transiently interacts with NAMPT and it may exhibit its effects on NAMPT more indirectly by not directly activating the enzyme. It could be confirmed that P7C3 chemicals can replenish depleted NAD levels in U2OS cells, indicating that they play an important role in NAD metabolism.
The drugs have a wide range of effects and the CETSA-MS screening revealed that they may bind to many different molecular targets. The data in this work suggests that the neuroprotective effect of the drugs is likely to be due to positive interactions with key molecular chaperones, like GRP78, which are essential for maintaining neuronal proteostasis. Exploring the effect of P7C3-A20 on these chaperones may provide new understanding of the mechanism of action of the compounds and could help finding a more directed therapeutic approach in the future.1 Zusammenfassung
1.1 Hintergrund und Ziele
Aufgrund der steigenden Lebenserwartung nimmt die Zahl älterer Menschen zu. Dies führt zu diversen Herausforderungen des öffentlichen Gesundheitssystems, da Altern ein primärer Risikofaktor für Osteoporose, Krebs, kardiovaskuläre Erkrankungen, Diabetes, Alzheimer, Arthritis und eine Reihe weiterer chronischer Krankheiten ist. Interventionen sind erforderlich, um die Lebenszeit in Gesundheit zu verlängern und altersbedingte Morbidität zu verzögern.
Von besonderem Interesse ist die Abnahme von zellulärem Nicotinamidadenindinukleotid (NAD), welche mit einer Anzahl von pathophysiologischen Veränderungen und Erkrankungen im Alter assoziiert wird. Um diesen Rückgang des NAD-Spiegels zu verhindern, gibt es einige vielversprechende therapeutische Ansätze. Die Substitution von NAD Vorstufen hat ermutigende Ergebnisse erzielt. Eine weitere Möglichkeit zur Aufrechterhaltung eines hohen NAD-Spiegels bietet eine neue chemische Verbindung: P7C3. 2010 als Neurogenese förderndes Mittel entdeckt, wurde 2014 der Wirkmechanismus durch Aktivierung der Nicotinamid- Phosphoribosyltransferase (NAMPT) beschrieben. NAMPT ist das reaktionslimitierende Enzym im sogenannten Salvage-Pathway, welcher der Wiederherstellung von NAD aus Nicotinamid (NA) dient. NA entsteht beim Verbrauch von NAD als Coenzym bei verschiedenen Reaktionen, zum Beispiel bei der DNA-Reparatur. In Menschen und anderen Säugetieren ist dieser Salvage-Pathway hauptverantwortlich für die Aufrechterhaltung der NAD Konzentration.
Seit der Beschreibung von P7C3 wurden einige Studien zur Wirksamkeit in verschiedenen Tiermodellen zu Parkinson, Alzheimer, traumatischen Gehirnverletzungen, Amyotropher Lateralsklerose (ALS) und akutem Leberversagen nach Acetaminophen-Überdosierung veröffentlicht. Jedoch bedarf es weiterer Untersuchungen, ehe P7C3 Präparate klinisch am Menschen eingesetzt werden können. Es fehlen Studien, die NAMPT als Zielobjekt von P7C3 bestätigen und den genauen Mechanismus der Enzymaktivierung offenlegen. Auch unerwünschte Nebeneffekte durch Interaktionen mit anderen Proteinen, Enzymen und Rezeptoren sind noch unerforscht.
1
Die Absicht dieser Arbeit ist es, die P7C3 vermittelte NAMPT Aktivierung zu validieren sowie potenzielle Off-Targets zu finden, um aus P7C3 ein sicheres Pharmakon für den klinischen Gebrauch zu entwickeln.
1.2 Methoden
Zum Nachweis der Bindung von P7C3 an NAMPT wurde der Cellular Thermal Shift Assay (CETSA) eingesetzt. Die Methode basiert auf der liganden-induzierten Veränderung der Thermostabilität eines Proteins: Bei Bindung des Liganden kommt es zu einer Stabilisierung der Proteinstruktur. Das Protein wird erst bei höheren Temperaturen denaturiert. Diese Verschiebung in der Denaturierungskurve kann durch Immunoblotting sichtbar gemacht werden. Um potenzielle Nebenwirkungen von P7C3 zu finden, wurde CETSA mit Massenspektrometrie (CETSA-MS) gekoppelt. Proteine, die durch Ligandenbindung stabilisiert werden, können durch Screening des Proteoms entdeckt werden.
1.3 Ergebnisse und Beobachtungen
Im CETSA konnte keine signifikante Stabilisierung der Denaturierungskurve von NAMPT nach P7C3- sowie P7C3-A20-Gabe, einem potenteren Analogon, in K562 und U2OS Zellen beobachtet werden. Auch bei reduzierter NAD-Konzentration konnte keine Stabilisierung der Denaturierungskurve des Enzyms nach P7C3-A20 Gabe in U2OS Zellen nachgewiesen werden. Dimebon, ein strukturell und funktionell mit P7C3 verwandtes Antihistaminikum, zeigte im CETSA ebenso keine Stabilisierung der Denaturierungskurve von NAMPT in K562 Zellen. Die Ergebnisse des CETSA-MS Screenings zeigten eine signifikante Verschiebung der Denaturierungskurve von NAMPT im mittleren Temperaturbereich (51°C und 58°C) nach P7C3-A20 Gabe bei reduzierter NAD- Konzentration in U2OS Zellen.
Bei reduzierter NAD-Konzentration in U2OS Zellen konnte die Gabe von P7C3-A20 die NAD-Konzentration wieder anheben und das Absinken der NAD-Konzentration durch Doxorubicin-Gabe verhindern.
Unter anderem konnte in der CETSA-MS eine Stabilisierung von Endoplasmin (HSP90B1), Glucose-regulated Protein, 78KDa (HSPA5/GRP78), Hypoxia upregulated Protein 1 (HYOU), Protein Disulfid Isomerase A4 & A6 (PDIA4 & PDIA6), und Peptidylprolyl cis-trans Isomerase B (PPIB) beobachtet werden. Alle Proteine sind Teil eines großen Chaperon-Komplex, der im Unfolded Protein Response (UPR) im endoplasmatischen Retikulum eine Rolle spielt und zur Aufrechterhaltung der Proteostase wichtig ist. Auch weitere Chaperone, wie zum Beispiel Heat Shock Protein 60 (Hsp60, HSPD1), Heat Shock Protein 10 (Hsp10, HSPE1) und Endoplasmatisches
2
Retikulum Resident Protein 44 (ERP44) wurden durch P7C3-A20 in U2OS Zellen stabilisiert.
1.4 Schlussfolgerungen
Zusammenfassend konnte in dieser Arbeit festgestellt werden, dass P7C3-A20 nur vorübergehend mit NAMPT interagiert. Die Wirkung auf NAMPT ist möglicherweise von indirekterem Charakter ohne eine primäre Bindung und Aktivierung des Enzyms. Es konnte bestätigt werden, dass P7C3 in der Lage ist, reduzierte NAD-Spiegel in U2OS- Zellen aufzufüllen, was darauf hinweist, dass es eine wichtige Rolle im NAD- Metabolismus spielt.
Die P7C3 Verbindungen haben eine Vielzahl von Wirkungen und das CETSA-MS- Screening hat gezeigt, dass sie an einige verschiedene molekulare Ziele binden können. Die in dieser Arbeit erhobenen Daten deuten darauf hin, dass die neuroprotektive Wirkung der Medikamente wahrscheinlich auf positiven Interaktionen mit wichtigen Chaperonen wie GRP78 beruht, die für die Aufrechterhaltung der neuronalen Proteostase unerlässlich sind. Die Untersuchung der Wirkung von P7C3-A20 auf diese Chaperone könnte einen neuen Einblick in den Wirkungsmechanismus der P7C3 Verbindungen geben und in Zukunft zu einem gezielteren therapeutischen Ansatz führen
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
- …
