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In order to encourage a shift from the car to the more sustainable transport mode of cycling, cycle streets have been implemented in cities all over the world in the last few years. In these shared streets, the entire carriageway is designated for cyclists, while motorized traffic is subordinated. However, evidence on the impact of cycle street interventions related to travel behavior change has been limited until now. Therefore, the objective of this study was to evaluate whether cycle streets are an effective measure to facilitate bicycle use and discourage car use, thus contributing to the aim of promoting sustainable travel. For this purpose, we conducted a written household survey in the German city of Offenbach am Main involving participants affected by a cycle street intervention (n = 701). Based on two stage models of self-regulated behavioral change (SSBC), we identified the participants’ level of willingness to use a bicycle frequently and to reduce car use. By means of bivariate and multivariate statistical methods, we analyzed the influence of awareness, use, and perceptions of the cycle street on the willingness to change behavior towards more sustainable travel. The results show that the intervention has a positive impact on frequent bicycle use, while we observed only a limited effect on car use reduction. Traffic conflicts and car speeding within the cycle street adversely affect the acceptance of the intervention. The study’s findings provide new insights into the actual effects of a cycle street and its potential to encourage sustainable travel behavior.
Highlights
• Explanation of mobility design and its practical, aesthetic and emblematic effects on travel behaviour.
• Review of recent studies on mobility design elements and the promotion of non-motorised travel.
• Discussion of research gaps and methodological challenges of data collection and comparability.
Abstract
To promote non-motorised travel, many travel behaviour studies acknowledge the importance of the built environment to modal choice, for example with its density or mix of uses. From a mobility design theory perspective, however, objects and environments affect human perceptions, assessments and behaviour in at least three different ways: by their practical, aesthetic and emblematic functions. This review of existing evidence will argue that travel behaviour research has so far mainly focused on the practical function of the built environment. For that purpose, we systematically identified 56 relevant studies on the impacts of the built environment on non-motorised travel behaviour in the Web of Science database. The focus of research on the practical design function primary involves land use distribution, street network connectivity and the presence of walking and cycling facilities. Only a small number of papers address the aesthetic and emblematic functions. These show that the perceived attractiveness of an environment and evoked feelings of traffic safety increase the likelihood of walking and cycling. However, from a mobility design perspective, the results of the review indicate a gap regarding comprehensive research on the effects of the aesthetic and emblematic functions of the built environment. Further research involving these functions might contribute to a better understanding of how to promote non-motorised travel more effectively. Moreover, limitations related to survey techniques, regional distribution and the comparability of results were identified.
This paper provides an overview of how to use "big data" for economic research. We investigate the performance and ease of use of different Spark applications running on a distributed file system to enable the handling and analysis of data sets which were previously not usable due to their size. More specifically, we explain how to use Spark to (i) explore big data sets which exceed retail grade computers memory size and (ii) run typical econometric tasks including microeconometric, panel data and time series regression models which are prohibitively expensive to evaluate on stand-alone machines. By bridging the gap between the abstract concept of Spark and ready-to-use examples which can easily be altered to suite the researchers need, we provide economists and social scientists more generally with the theory and practice to handle the ever growing datasets available. The ease of reproducing the examples in this paper makes this guide a useful reference for researchers with a limited background in data handling and distributed computing.
Carotinoide sind Pigmente, die in Pflanzen, Algen, einigen Pilzen und Bakterien vorkommen. Sie spielen eine wichtige Rolle bei der Photosynthese durch Absorption von Licht und beim Lichtschutz. Sie sind verantwortlich für die braunen, roten, orangen und gelben Farben von Obst, Gemüse, Herbstblättern und die Farbe einiger Blumen und Algen. Tiere können keine Carotinoide synthetisieren, daher ist ihre Anwesenheit auf die Nahrungsaufnahme zurückzuführen. Carotinoide sind Tetraterpenoide (40C), die aus Isoprenoidmolekülen (5C) synthetisiert werden. Der Methylerythritol-phosphatweg ist der Carotinoid-Vorläuferweg, der die Isoprenoideinheiten bildet. Carotinoide haben aufgrund ihrer gesundheitlichen Vorteile das Interesse der Nutrazeutika-Industrie geweckt.
Fucoxanthin ist ein Carotinoid, das nur in Kieselalgen, Braunalgen, Haptophyten und einigen Dinoflagellaten vorkommt. Aufgrund seiner Vorteile zur Vorbeugung von Krebs, kognitiven Erkrankungen und Fettleibigkeit sowie seiner antioxidativen Eigenschaften ist Fucoxanthin ein sehr interessantes Molekül fur die Nutrazeutikabranche.
Fucoxanthin hat eine komplexe chemische Struktur mit einer Allenbindung und einer Epoxyketogruppe. Daher wäre seine chemische Synthese kompliziert, da es auch eine stereokontrollierte Synthese erfordert86. Aus diesem Grund ist die Extraktion aus Makroalgen oder Mikroalgen die Methode der Wahl für die kommerzielle Herstellung von Fucoxanthin.
In dieser Arbeit bestand das Ziel darin, die Fucoxanthin-Produktivität in Kieselalgen mit gentechnischen Methoden zu steigern, damit die Zellen mehr Fucoxanthin produzieren. Zu diesem Zweck wurde der Effekt der Insertion zusätzlicher Kopien von Genen in das Genom untersucht, die für geschwindigkeitsbestimmende oder Schlüsselenzyme im Carotinoid- und MEP-Weg kodieren.
Zu Beginn wurden diese Effekte bei einzelnen Mutanten beobachtet. Letztendlich ist es jedoch das Ziel, eine Mutante zu erzeugen, die mehrere geschwindigkeitsbestimmende Enzyme überexprimiert, um auf diese Weise Engpässe zu vermeiden. In früheren Studien erreichten Eilers et al.54 durch die einmalige Überexpression der psy- und dxs-Gene in der Kieselalge P. tricornutum einen 2.4- und 1.8-fachen Anstieg der Fucoxanthin-Spiegel.
In dieser Arbeit führte die Insertion zusätzlicher Kopien der Gene idi und pds2 nicht dazu, dass die Zellen mehr Fucoxanthin produzieren. Im Gegensatz dazu erreichten die Mutanten mit zusätzlichen Kopien der Gen ggpps und mit zusätzlichen Kopien sowohl von psy als auch von dxs seine um 28% bzw. 10% höhere Fucoxanthin-Produktivität pro Million Zellen. Bei diesen Mutanten ist die Gesamtproduktivität jedoch geringer als beim Wildtyp, da ihr Wachstum langsamer als beim Wildtyp ist.
Unter Berücksichtigung der besten Zielgene wurden Mutanten erzeugt, die gleichzeitig zusätzliche Kopien von psy, dxs und ggpps enthielten. Die Mutanten hatten unter sehr niedriegen Lichtbedingungen eine um bis zu 61% höhere Produktivität pro Million Zellen als der Wildtyp. Ausnahmsweise wurden diese Mutanten bei sehr schwachem Licht (10 µE m-2 s-1) gezüchtet, da sie sehr gestresst waren und als Zellklumpen wuchsen. Obwohl die Gesamt-Fucoxanthin-Spiegel in diesen Mutanten unter diesen Bedingungen höher sind als im Wildtyp, sind sie daher niedriger als die Fucoxanthin-Spiegel bei den in anderen Experimenten verwendeten Lichtbedingungen (50 µE m-2 s-1). Als Ergebnis dieser Experimente kann gesagt werden, dass die Belastung der Zellen nach den genetischen Veränderungen untersucht werden muss, da dies zu einer Abnahme der Biomasse und folglich zu einer Abnahme der Fucoxanthinproduktion führt. Alternativ könnte auch eine 2-Stufen-Kultur etabliert werden, in der in einem ersten Schritt eine hohe Biomasse erreicht wird und im zweiten Schritt die Expression der interessierenden Gene induziert wird.
Aufgrund der antioxidativen Eigenschaften von Carotinoiden besteht eine übliche Strategie zur Akkumulation von Carotinoiden darin, die Zellen unter oxidative Stressbedingungen zu setzen. Diese Strategie ist jedoch nicht wirksam für die Anreicherung von Fucoxanthin unter hohen Salzkonzentrationen oder hohen Lichtbedingungen. Bessere Versuchspläne könnten jedoch eine 2-Stufen-Kultur oder adaptive Laborbedingungen gewesen sein.
Eine andere mögliche Strategie zur Erhöhung des Fucoxanthinspiegels wäre die Durchführung einer zufälligen Mutagenese der Zellen. Auf diese Weise sind keine Vorkenntnisse über den Carotinoidsyntheseweg und seine Regulation erforderlich und es kann zu Veränderungen in Genen führen, die keine offensichtlichen Ziele sind.
Experimente mit zufälliger Mutagenese erfordern ein Hochdurchsatz-Screeningsystem, da Hunderte oder sogar Tausende von Mutanten erhalten werden. Eine mögliche Strategie, um die Kultivierung der hohen Anzahl von Mutanten zu vereinfachen, ist die Einkapselung dieser Mutanten in Alginatkügelchen. Auf diese Weise können alle Mutanten in demselben Gefäß kultiviert werden. Die eingekapselten Zellen können dann beispielsweise mit einem Durchflusszytometer auf große Partikel durch Fluoreszenz- oder Absorptionsmessungen gescreent werden.
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Schon früh im 19. Jahrhundert wurde der Treibhauseffekt entdeckt. Doch bis sich die Menschheit ihres Einflusses auf das globale Klima bewusst wurde, hat es noch viele Jahrzehnte gedauert. Ein Rückblick auf das zähe Ringen darum, aus wissenschaftlichen Erkenntnissen die richtigen politischen Schritte abzuleiten.
This article corrects the following: Hope in political philosophy,
Claudia Blöser Jakob Huber Darrel Moellendorf. Volume 15Issue 5Philosophy Compass First Published online: April 17, 2020.
It has come to the author's attention that the reference citation of ‘Meirav, 2009’ on page 2 of his published article entitled, ‘Hope in political philosophy’ does not provide bibliographical details regarding the article and does not include it in its list of works cited.
Here is the bibliographical information: Meirav, A. (2009). The nature of hope. Ratio, 22, 216–233.
Hope in political philosophy
(2020)
The language of hope is a ubiquitous part of political life, but its value is increasingly contested. While there is an emerging debate about hope in political philosophy, an assessment of the prevalent scepticism about its role in political practice is still outstanding. The aim of this article is to provide an overview of historical and recent treatments of hope in political philosophy and to indicate lines of further research. We argue that even though political philosophy can draw on recent analyses of hope in analytic philosophy, there are distinct challenges for an account of hope in political contexts. Examples such as racial injustice or climate change show the need for a systematic normative account that is sensitive to the unavoidability of hope in politics as much as its characteristic dangers.
APPEAL‐1: A pan‐European survey of patient/caregiver perceptions of peanut allergy management
(2020)
Blümchen, Katharina ; DunnGalvin, Audrey ; Timmermans, Frans ; Regent, Lynne ; Schnadt, Sabine ; Podestà, Marcia ; Sánchez, Angel ; Couratier, Pascale ; Feeney, Mary ; Hjorth, Betina ; Patel, Ram ; Lush, Tessa ; Ryan, Robert ; Vereda, Andrea ; Fisher, Helen R. ; Fernández‐Rivas, Montserrat
Background: Peanut allergy (PA) is associated with marked quality‐of‐life (QoL) impairment. However, data are lacking on the experience and impact of living with PA from the perspectives of persons with PA (PwPA) and their caregivers. Allergy to Peanuts imPacting Emotions And Life study 1 (APPEAL‐1) was a pan‐European survey investigating these perspectives. This first of two articles reports clinical characteristics of PwPA and PA management practices.
Methods: APPEAL‐1 was a quantitative, online survey conducted in eight European countries, developed by eight representatives of patient advocacy groups and five healthcare professionals and researchers. Eligible participants included adults with PA and parents/caregivers of PwPA who responded by self‐report and provided proxy‐report for the PwPA under their care. Data were summarized using nonweighted descriptive statistics.
Results: Of 1846 completed/analysed questionnaires, 528 were from adults with PA (self‐report); 437 by proxy for children with PA (34 aged 0‐3 years, 287 aged 4‐12 years, 116 aged 13‐17 years) and 881 from parents/caregivers (self‐report). Of PwPA (N = 965), 95% reported diagnosis by healthcare professionals, mostly by clinical history and peanut‐specific allergy testing. Rates of allergic rhinitis, asthma and other food allergies in PwPA were 50%, 42% and 79%, respectively. Only 31% of PwPA received HCP advice/support following their worst allergic reaction, and 28% had not been prescribed an adrenaline auto‐injector. Results were similar by country but varied by age group.
Conclusions: The APPEAL‐1 findings contribute to greater understanding of PA impact on PwPA, caregivers and family members and the need for improved PA management across Europe.
A new virus, SARS-CoV-2, emerged in the Chinese city of Wuhan at the end of 2019. Infected persons developed an atypical form of pneumonia, later known as COVID-19. The pathogen created a pandemic, with fatalities throughout the world, and also led to the adoption of restrictive measures which were, until recently, unthinkable, as well as fostering new political conflicts. Even the path of the multilateral order in its current form is at stake. For a take on these issues under international law, the legal regime of the World Health Organization (WHO) and its response to the pandemic provides an insightful access. ...
Bojkova, Denisa ; Bechtel, Marco ; McLaughlin, Katie-May ; McGreig, Jake E. ; Klann, Kevin ; Bellinghausen, Carla ; Rohde, Gernot Gerhard Ulrich ; Jonigk, Danny David ; Braubach, Peter ; Ciesek, Sandra ; Münch, Christian ; Wass, Mark N. ; Michaelis, Martin ; Cinatl, Jindrich
Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is the cause of the current coronavirus disease 19 (COVID-19) pandemic. Protease inhibitors are under consideration as virus entry inhibitors that prevent the cleavage of the coronavirus spike (S) protein by cellular proteases. Herein, we showed that the protease inhibitor aprotinin (but not the protease inhibitor SERPINA1/alpha-1 antitrypsin) inhibited SARS-CoV-2 replication in therapeutically achievable concentrations. An analysis of proteomics and translatome data indicated that SARS-CoV-2 replication is associated with a downregulation of host cell protease inhibitors. Hence, aprotinin may compensate for downregulated host cell proteases during later virus replication cycles. Aprotinin displayed anti-SARS-CoV-2 activity in different cell types (Caco2, Calu-3, and primary bronchial epithelial cell air–liquid interface cultures) and against four virus isolates. In conclusion, therapeutic aprotinin concentrations exert anti-SARS-CoV-2 activity. An approved aprotinin aerosol may have potential for the early local control of SARS-CoV-2 replication and the prevention of COVID-19 progression to a severe, systemic disease.
Bojkova, Denisa ; Costa, Rui ; Bechtel, Marco ; Ciesek, Sandra ; Michaelis, Martin ; Cinatl, Jindrich
It becomes more and more obvious that deregulation of host metabolism play an important role in SARS-CoV-2 pathogenesis with implication for increased risk of severe course of COVID-19. Furthermore, it is expected that COVID-19 patients recovered from severe disease may experience long-term metabolic disorders. Thereby understanding the consequences of SARS-CoV-2 infection on host metabolism can facilitate efforts for effective treatment option. We have previously shown that SARS-CoV-2-infected cells undergo a shift towards glycolysis and that 2-deoxy-D-glucose (2DG) inhibits SARS-CoV-2 replication. Here, we show that also pentose phosphate pathway (PPP) is remarkably deregulated. Since PPP supplies ribonucleotides for SARS-CoV-2 replication, this could represent an attractive target for an intervention. On that account, we employed the transketolase inhibitor benfooxythiamine and showed dose-dependent inhibition of SARS-CoV-2 in non-toxic concentrations. Importantly, the antiviral efficacy of benfooxythiamine was further increased in combination with 2DG.
Bojkova, Denisa ; McGreig, Jake E. ; McLaughlin, Katie-May ; Masterson, Stuart G. ; Widera, Marek ; Krähling, Verena ; Ciesek, Sandra ; Wass, Mark N. ; Michaelis, Martin ; Cinatl, Jindrich
SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
Bojkova, Denisa ; Westhaus, Sandra ; Costa, Rui ; Timmer, Lejla ; Funkenberg, Nora ; Korencak, Marek ; Streeck, Hendrik ; Vondran, Florian ; Bröring, Ruth ; Heinrichs, Stefan ; Lang, Karl Sebastian ; Ciesek, Sandra
Direct acting antivirals (DAAs) revolutionized the therapy of chronic hepatitis C infection. However, unexpected high recurrence rates of hepatocellular carcinoma (HCC) after DAA treatment became an issue in patients with advanced cirrhosis and fibrosis. In this study, we aimed to investigate an impact of DAA treatment on the molecular changes related to HCC development and progression in hepatoma cell lines and primary human hepatocytes. We found that treatment with sofosbuvir (SOF), a backbone of DAA therapy, caused an increase in EGFR expression and phosphorylation. As a result, enhanced translocation of EGFR into the nucleus and transactivation of factors associated with cell cycle progression, B-MYB and Cyclin D1, was detected. Serine/threonine kinase profiling identified additional pathways, especially the MAPK pathway, also activated during SOF treatment. Importantly, the blocking of EGFR kinase activity by erlotinib during SOF treatment prevented all downstream events. Altogether, our findings suggest that SOF may have an impact on pathological processes in the liver via the induction of EGFR signaling. Notably, zidovudine, another nucleoside analogue, exerted a similar cell phenotype, suggesting that the observed effects may be induced by additional members of this drug class.
Adaptormoleküle zur Rekrutierung von Transkriptionsfaktoren oder miRNAs an nicht native Bindestellen
(2020)
Die Kontrolle der Genexpression ist eines der großen Ziele der chemischen Biologie. Gemäß dem klassischen Dogma der Molekularbiologe verläuft der Fluss der genetischen Information über die Transkription von DNA zur messenger RNA (mRNA) und durch die Translation von mRNA zu Proteinen. Auch wenn der ursprünglichen Formulierung dieses Dogmas verschiedene Aspekte hinzugefügt wurden, bleibt die Kernaussage unverändert. Eine Störung der Genexpression ist in vielen Fällen die Ursache für schwerwiegende Erkrankungen. Klassische Therapeutika, die im Allgemeinen aus kleinen Molekülen bestehen, können pathogene Proteine spezifisch binden und inhibieren. Allerdings greifen diese Wirkstoffe am Ende der Produktionskette ein und nicht alle Proteine können adressiert werden. Im Gegensatz dazu könnte ein Eingriff auf der Ebene der Transkription oder Translation die Expression der pathogenen Proteine auf ein normales Maß senken oder ganz verhindern. Als entscheidende Regulatoren der Genexpression stellen Transkriptionsfaktoren (TFs) einen interessanten Angriffspunkt zur Kontrolle der Transkription dar. TFs können über den Kontakt zu weiteren Proteinen die RNA Polymerase II rekrutieren und so die Transkription starten. Für die Translation ist die Halbwertszeit der mRNA ein entscheidender Faktor. Die Lebensdauer wird durch eine Vielzahl an Proteinen und micro RNAs (miRNAs) reguliert. MiRNAs sind kurze Oligonukleotide, die in Argonautproteine eingebaut werden können. Die daraus resultierenden RNA-induced silencing complexes (RISCs) sind in der Lage, den Abbau der mRNA einzuleiten. Sowohl TFs als auch RISCs besitzen dabei Nukleinsäure-bindende Untereinheiten, die mit spezifische Sequenzen assoziieren. In gewisser Weise ist die molekulare Erkennung der Nukleinsäuren vergleichbar mit einer Postsendung, die aufgrund der Adresse korrekt zugestellt wird. Um in diesem Bild des täglichen Lebens zu bleiben: Bei einem Wechsel des Wohnorts ist es üblich, einen Nachsendeauftrag zu stellen. Dabei wird die alte Anschrift auf den Postsendungen mit einem neuen Adressetikett überklebt und die Zustellung erfolgt an den neuen Wohnort. Das zentrale Thema dieser Dissertation ist, dieses „Umetikettieren“ auch auf TFs und RISCs zu übertragen. Hierbei ist es notwendig, die Nukleinsäure-bindenden Untereinheiten der Komplexe, also die „alte Adresse“, vollständig zu blockieren und gleichzeitig eine hohe Affinität zu einer neuen Sequenz zu erzeugen. Hierzu könnten bifunktionale Adaptormoleküle verwendet werden.
Die Adaptoren für die Rekrutierung von TFs müssen in der Lage sein, sowohl die doppelsträngige DNA (dsDNA) als auch einen TF zu binden (Abbildung I). Dabei sollte eine Selbstbindung des Adaptors vermieden werden. In dieser Arbeit wurde der TF Sp1 als Ziel gewählt, da er an GC-reiche dsDNAs bindet. Dies ermöglicht die Wahl einer AT- oder GA reichen DNA-Sequenz als Ziel der Umleitung, wodurch eine Selbstbindung des Adaptors minimiert werden sollte. Zur Erkennung der DNA war geplant, Pyrrol-Imidazol-Polyamide (PIPs), triplexbildende Oligonukleotide (TFOs) oder pseudokomplementäre PNAs einzusetzen. Für Letztere war es möglich, eine neue Syntheseroute zu einem Fmoc geschützten Thiouracil-Monomer zu entwerfen. Dabei konnte eine selektive Alkylierung an der N1-Position des Thiouracils durchgeführt werden. Auf Basis der PIPs und der TFOs wurden jeweils verschiedene Adaptoren entworfen, deren Bindung zu ihren Zielen mit Band-Shift-Experimenten und im Fall der PIPs zusätzlich mit fluoreszenzbasierten Pulldown-Experimenten gezeigt wurde. Im Rahmen dieser Versuche zeigte sich, dass die PIP-basierten Systeme deutlich besser an die Zielsequenzen banden als die TFO-basierten Adaptoren. Das Konjugat K5a besaß hierbei die besten Eigenschaften. Weiterhin konnte mit diesem Adaptor in Pulldown-Experimenten gezeigt werden, dass Sp1 auf eine nicht kanonische AT-reiche Bindestelle umgeleitet wurde. Im Anschluss konnte das Sp1 in Western-Blots detektiert werden. Des Weiteren ließ sich zeigen, dass K5a in einem HeLa Lysat über mehrere Stunden stabil war und somit eine Anwendung in Zellkulturexperimenten möglich sein sollte.
Für die Rekrutierung der RISCs war lediglich eine Erkennung zweier einzelsträngiger RNA-Abschnitte notwendig. Hierzu wurden zwei LNAs oder LNA/DNA-Mixmere verwendet, die über einen Linker verknüpft waren (Abbildung I). Als Folge dieses Aufbaus mussten die beiden Adaptorhälften orthogonal sein, da eine Selbstbindung des Adaptors leichter als bei den TF-Adaptoren auftreten konnte. Diese Adaptoren wurden mit Band-Shift- und fluoreszenzbasierten Pulldown-Experimenten auf ihre Fähigkeit, eine Cy5-gelabelte miRNA auf eine Ziel-RNA umzuleiten, überprüft. Es konnte beobachtet werden, dass all-LNA Adaptoren sehr viele off-target-Effekt aufwiesen, welche die Umleitung von miRNAs verhinderte. Im Gegensatz dazu konnten mit DNA/LNA-Mixmeren eine vollständige Umleitung von miRNA-Modellen beobachtet werden. Es war ebenfalls möglich, spezifische RISCs aus HeLa-Lysaten mit unterschiedlichen Adaptoren in Pulldown-Experimenten zu isolieren und in nachfolgenden Western-Blots zu detektieren. Nachdem gezeigt war, dass eine Umleitung in vitro gelang, sollte die Funktion der Adaptoren in Zellkulturexperimenten geprüft werden. Allerdings konnten in diesen Versuchen keine eindeutigen Ergebnisse erhalten werden, sodass die biologische Relevanz der RISC-Umleitung bislang noch nicht bestätigt werden konnte.
Redirection of miRNA‐argonaute complexes to specific target sites by synthetic adaptor molecules
(2020)
Bolz, Mathias ; Thomas, Laura ; Scheffer, Ute ; Kalden, Elisabeth ; Hartmann, Roland K. ; Göbel, Michael
Dysregulation of miRNAs is connected with a multitude of diseases for which antagomirs and miRNA replacement are discussed as therapeutic options. Here, we suggest an alternative concept based on the redirection of RISCs to non‐native target sites. Metabolically stable DNA‐LNA mixmers are used to mediate the binding of RISCs to mRNAs without any direct base complementarity to the presented guide RNA strand. Physical redirection of a dye‐labeled miRNA model and of specific miRNA‐programmed RISC fractions present in HeLa extracts is demonstrated by pull‐down experiments with biotinylated capture oligonucleotides.
This paper explores how University as social entity has great potential to confront epistemic injustices by expanding epistemic capabilities. To do this, we primarily follow the contributions of scholars such as Miranda Fricker and José Medina. The epistemic capabilities and epistemic injustice nexus will be explored via two empirical cases: the first one is an experience developed in Lagos (Nigeria) using participatory video; the second is a service learning pedagogical strategy for final year undergraduate students conducted at Universidad de Ibagué (in Colombia). The Lagos experience shows how participatory action-research methodologies could promote epistemic capabilities and functioning, making it possible for the participants to generate interpretive materials to speak of their own realities. However, this experience is too limited to address testimonial and hermeneutical injustice. The Colombian experience is a remarkable experience that is building epistemic capabilities among students and other local participants. However, there is a hermeneutical and structural injustice that tends to give more value to disciplinary and codified knowledge at the expense of experiential and tacit knowledge.