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Antivirale in vitro Wirksamkeit verschiedener Senföle aus der Behandlung von akuten, entzündlichen Erkrankungen der Atemwege auf die Vermehrung von humanpathogenen, respiratorischen Viren
Get PDFAtemwegsinfektionen stellen eine jährliche Herausforderung dar. Dabei spielen Infektionen mit humanen Rhinoviren (HRV), humanen Coronaviren (HCoV) (Erkältungsviren) und Influenzaviren (IV), eine übergeordnete Rolle. Im Fall der IV und des aktuell zirkulierenden SARS-CoV-2, können diese schwere Verläufe annehmen und zu enormen gesundheitlichen und volkswirtschaftlichen Schäden führen. Gegen HRV- und (reguläre) HCoV-Infektionen gibt es aktuell weder eine zielgerichtete Therapie, noch eine Impfung. Virale Resistenzbildung gegen die wenigen zugelassenen anti-IV- Medikamente verringert deren Wirksamkeit. Antivirale Strategien gegen SARS-CoV-2 sind noch meist in der Entwicklung und die Wirksamkeit bzw. die Schutzdauer der zugelassen Vakzine lässt sich zur Zeit nicht abschließend bewerten. Daher ist die Entwicklung von neuen antiviralen Medikamenten mit breiter Wirksamkeit gegen verschiedene Viren und guter Verfügbarkeit äußerst wichtig. Da dies aber zeit- und kostenintensiv ist, stellt die Verwendung bereits zugelassener Medikamente (Repurposing) einen Vorteil dar. Senföle wurden bereits 1957 auf ihre anti-IV Wirkung im embryonierten Hühnerei getestet. Da sich hierbei aber nur ein virustatischer, nicht jedoch ein viruzider Effekt zeigte, war es Ziel dieser Arbeit, die antivirale Wirkung der in Angocin® Anti-Infekt N enthaltenen Senföle bzw. deren Kombination, auf die Vermehrung respiratorisch relevanter Viren in vitro, mit aktuellen virologischen und zellbiologischen Methoden zu analysieren und deren Wirkmechanismus näher zu charakterisieren.
In der vorliegenden Studie konnte gezeigt werden, dass (i) die einzelnen Senföle in der Lage sind, konzentrationsabhängig den infektiösen Virustiter, sowie die Gesamtmenge der Viruspartikel nach Infektion mit dem IV H1N1pdm09 unterschiedlich stark zu reduzieren und dass (ii) die Kombination der Senföle als Substanzgemisch (SG) zu einer noch stärkeren Reduktion des H1N1pdm09-Titers führt. Zur näheren Betrachtung der Wirkweise konnte in weiteren Experimenten gezeigt werden, dass die hemmende Wirkung der Senföle bezogen auf H1N1pdm09 weder (i) zell- oder wirtsspezifisch zu sein scheint, noch (ii) einen Einfluss auf die Adsorption/ den Eintritt des IV in die Zelle zu haben scheint. Unter permanenter Anwesenheit des SG vor, während und nach der Infektion mit dem H1N1pdm09 zeigte sich eine vollständige Hemmung der Produktion des viralen Nukleoproteins (NP). An welcher Stelle des viralen Replikationszyklus die beobachtete Inhibition der viralen Genexpression durch das SG auftritt und ob dabei ausschließlich virale Faktoren/ Mechanismen gehemmt werden oder auch hierfür notwendige zelluläre Faktoren beeinträchtigt werden, ist noch offen. Obwohl die Behandlung mit dem SG keinen inhibitorischen Effekt auf die Vermehrung von HCoV- 229E zeigte, konnten die Untersuchungen eine antivirale Wirkung des SG gegen HRV1A/-16 mit einer Reduktion des Virustiters bei permanenter Anwesenheit des SG während und nach der Infektion zeigen
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
The impact of influenza A virus protein phosphorylation and host cell protein kinases on viral replication
Get PDFThis work is divided into two parts, which both address the relevance of phosphorylation events induced by the IAV infection. The first part of the study addressed the functional relevance of kinases activity in IAV-infected cells, which regulate the phosphorylation occurring on cellular proteins. With this regard, PamStation® platform-based analysis of Ser/Thr kinases or Tyr kinases present in IAV-infected cells, was performed to compare the kinase activation patterns triggered by the human circulating IAV isolate A/Hamburg/4/09 (H1N1pdm09) and the highly pathogenic avian IAV human isolate A/Thailand/1(KAN-1)/2004 (H5N1). The results indicate that the Tyr phosphorylations of substrate peptides were largely co-regulated by both viruses and are also strongly overrepresented in comparison to Ser/Thr peptide phosphorylations. It allowed to identify 26 of 47 predicated kinases, which are mainly strain-specific and have been implicated in the IAV life cycle, while the function of other 21 kinases on IAV infection is unknown. Subsequently, the perturbation of selected novel kinases with highly specific small molecule inhibitors or siRNAs was conducted to investigate the relevance of these kinases. Received data revealed negative regulation of H1N1pdm09 and H5N1 replication by NUAK (novel (nua) kinase) kinases, redundant ephrin A (EphA) receptor Tyr kinases and a H1N1pdm09-selective pro-viral function of JAK3 (Janus kinase 3).
The second part of this study was performed to characterize the relevance of phosphorylation occurring on proteins encoded by the IAV strain SC35M (H7N7). For this I integrated all phosphorylations on viral proteins that have been previously detected in our laboratory, together with those found in other literature, along with information on their intramolecular localization in possible functional domains and/or with a suggested relevant function. The subsequent functional analysis focused on phosphorylation sites, which are evolutionally highly conserved, not functionally described but with important functional implications.
Based on mutational analysis results of five phosphorylation sites of PB2 (T471), PA (Y393, S393), NP (Y148, T378), three phosphorylation sites of NS1 (S48, T49, T197), and one phosphorylation site of M1 (T108), three distinct groups of phosphorylation effects could be assigned. The first group of phosphorylations does not have a direct physiological consequence, as reflected by PB2 T471 and NS1 T197, for which neither their phospho-deficient nor phospho-mimetic mutation affects viral replication of SC35M in MLE-15 cell culture. The second group of phosphorylations has a modulatory function, which is exemplified by PA S395 and NS1 ST48, 49. Here, either a phospho-deficient mutation or a phospho-mimetic mutation slightly alters the viral replication. Of particular interest is the third group of phosphorylations showing a critical role in viral replication. For example, the phospho-mimetic mutation for the vRNP components PA (Y393E), NP (Y148E, T378E), and for the phospho-deficient M1 T108A mutation, which all prevent the production of infections virus. Further functional analysis of selected phosphorylations revealed their distinct biological roles. As such, constitutive phosphorylation on PA Y393 and S395 inhibits polymerase functions to transcribe and replicate the viral genome, which partially also holds true for the phospho-mimetic mutation at NP Y148, which also impaired polymerase activity. Although an inhibitory effect on viral propagation was also seen for the phospho-memetic mutation at NP T378, a different mechanism must be expected, as this mutation leads to an increased polymerase activity.
With regard to the M1 T108 phosphorylation, the experimental results point to the requirement of this phosphorylation for viral propagation via controlling the nuclear M1 import and nuclear vRNP export. Furthermore, a study applying intracellular chemical crosslinking of M1 protein complexes indicates that M1 T108 phosphorylation might avoid excess of M1 polymerization, which may be critical for maintaining conformational flexibility of M1 to switch between assembly and disassembly during viral replication. Further M1 interactome studies revealed a possible role of M1 T108 phosphorylation in regulating protein/protein interaction. This approach disclosed a network of proteins from the STRIPAK complex, in particular its core components STRN/STRN3, acting as novel interacting partners of M1 protein, with preferential binding affinity to WT M1. Loss-of-function experiments also indicate that STRN/STRN3 function as pro-viral factors supporting IAV replication. Moreover, immunofluorescence studies showed the IAV infection led to slight cytoplasmic accumulation of STRN and larger aggregates formation of STRN3.
Collectively, the functional characterization of PA Y393, S395, and NP Y148 phosphorylation on the activity adds new examples for phosphorylation-regulated RNP activity. On the other hand, the identification of virus-supportive phosphorylation M1 T108 and its combinatorial pro-viral interactors could provide new insights into therapeutic interference with IAV replicatio
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
Influenzavirus-assoziierte primär virale Sepsis: Risikofaktor Adipositas und Untersuchungen zur Rolle des Fettgewebsproteins Chemerin in vitro
Get PDFInfluenzaviren lösen respiratorische Erkrankungen mit unterschiedlich schwerem Krankheitsverlauf aus. Der Schweregrad wird vom Virus und dessen Virulenz bestimmt, zudem beeinflussen Wirtsfaktoren maßgeblich den Infektionsverlauf. Während der Pandemie 2009, verursacht von Influenza-A-Virus vom Subtyp H1N1 (A(H1N1)pdm09), wurde Adipositas erstmalig als Risikofaktor für einen schweren Influenzaverlauf identifiziert. A(H1N1)pdm09 zirkulieren bis heute weltweit. Im Rahmen einer Studie am Universitätsklinikum Jena wurde die Bedeutung der Adipositas für schwere Infektionen (Sepsis) mit A(H1N1)pdm09 in der Saison 2015/2016 analysiert. Die Auswertung klinischer Patientendaten wies auf einen Zusammenhang zwischen Adipositas und Schwere der Infektionserkrankung hin. Aus der bronchoalveolären Lavage von A(H1N1)pdm09-infizierten Patienten wurden Virusisolate angezüchtet und phäno- sowie genotypisch untersucht. Die Untersuchung der Replikationseigenschaften in humanen Lungenepithel- (A549) und Lungenfibroblastenzellen (LF), wie auch die Ergebnisse der Sequenzierung definierter Gensegmente (HA, NA, NS) und Testung der Empfindlichkeit für Neuraminidase-Inhibitoren (Oseltamivir, Zanamivir) ergaben keine Auffälligkeiten. Insgesamt unterstützen diese Ergebnisse die Hypothese, dass eine Adipositas als spezifischer Wirtsfaktor einen Risikofaktor für einen schweren Infektionsverlauf mit aktuellen A(H1N1)pdm09 darstellt. Im Rahmen der Arbeit wurde ein Zellmodell in A549- und LF-Zellen etabliert, um den Einfluss von Chemerin auf Influenzavirus-infizierte Zellen hinsichtlich Replikation und Zytokinexpression zu untersuchen. Eine Chemerinstimulation mit 10 nM und 100 nM zeigte 6 h p.i. keine signifikante Änderung der Virustiter im Vergleich zu scheininfizierten Zellen. Hinsichtlich der Zytokinexpression ließ sich eine deutliche Induktion von IP-10 beobachten. Das etablierte Modell stellt eine standardisierte, reproduzierbare Methode auf Zellebene für weitere Untersuchungen zur Verfügung
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
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