1,721,005 research outputs found
Application of copper(I) catalyzed azide-alkyne [3+2] cycloaddition to the synthesis of template-assembled multivalent peptide conjugates
No full textHere we describe the facile generation of tetravalent peptide conjugates via a copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) using a cyclic peptide template as a versatile conjugation scaffold. This stable and rigid framework is a conformationally constrained cyclic beta-sheet decorated with spatially defined alkyne moieties that serve as selectively addressable coupling sites. The proposed method allows for the effective coupling of unprotected peptide monomers in water at room temperature within comparatively short reaction times. The resulting conjugates display the ligands in an oriented manner, thus allowing for multivalent interactions with given target molecules, which may contribute to enhanced affinity and specificity. In addition, the selected scaffold offers an orthogonal coupling site for the incorporation of fluorescent labels or radioligands.Deutsche Forschungsgemeinschaft [KO 1390/9-1]; BMB
Probing biological activities of RNA-binding proteins from bacterial and mammalian cells
No full textThe growing danger of antimicrobial resistance and the ongoing fight against cancer present an immense challenge for public health. The need for new and innovative treatments is evident in both infection research and cancer therapy. This doctoral thesis focuses on two RNA-binding proteins as potential drug targets: The Carbon Storage Regulator System A (CsrA) in bacterial systems and the insulin like growth factor 2 (IGF2) mRNA binding proteins (IGF2BPs/IMPs) in mammalian systems. Within this work, the reasons behind selecting both proteins as promising targets for anti-virulence/cancer therapy are explained. Furthermore, the process of identifying of novel inhibitors against these targets through biophysical screening methods, followed by hit prioritization, medicinal chemistry optimization and validation via cell-based assays is described. The aim is to discover cell-active compounds suitable for initial proof-of-concept studies.Die zunehmende Bedrohung durch antimikrobielle Resistenz und der fortlaufende Kampf gegen Krebs stellen immense Herausforderungen für das globale Gesundheitswesen dar. Die Dringlichkeit für neue und innovative Behandlungsmöglichkeiten zeigt sich sowohl in der Infektionsforschung als auch in der Krebstherapie. Diese Doktorarbeit konzentriert sich auf zwei RNA-bindende Proteine als Wirkstoffziele: Das Carbon Storage Regulator System A (CsrA) in bakteriellen Systemen und das Insulin-like growth factor 2 (IGF2) mRNA-bindende Proteine(IGF2BPs/IMPs) in Säugetiersystemen. Im Rahmen dieser Arbeit wird die Auswahl beider Proteine als vielversprechende Targets für Anti-Virulenz-/Krebstherapien erläutert. Des Weiteren wird der Prozess der Identifizierung neuartiger Inhibitoren gegen diese Proteine durch biophysikalische Screening-Methoden beschrieben, gefolgt von der Priorisierung der Hitverbindungen, der Optimierung mittels medizinischen Chemie und der Validierung über zellbasierte Assays. Das Ziel besteht darin, zellaktive Verbindungen zu finden, die sich für anfängliche Proof-of-Concept-Studien eignen
Design and synthesis of peptide and small molecule protein-RNA interaction inhibitors
No full textThe aim of this thesis was to uncover novel inhibitors targeting CsrA and IMP2 in vitro, crucial for validating the envisioned proof-of-concept demonstrating that inhibiting CsrA and IMP2 will yield the desired in vivo effects in forthcoming studies, thereby validating these proteins as viable targets for antimicrobial and anticancer interventions. The thesis reasons the rationale behind selecting those proteins as potential new targets, explains how in vitro hit identification was performed and concludes with the medicinal chemistry-driven optimisation of these compounds.Zwei allgegenwärtige und zunehmende Gesundheitsbedrohungen in unserer Gesellschaft sind antimikrobielle Resistenz und Krebs. Trotz der Existenz effizienter Behandlungen gegen mikrobielle Infektionen hat der weit verbreitete Missbrauch von Antibiotika und ein Mangel an Innovation und wirtschaftlichem Interesse an antimikrobieller Forschung zur Verbreitung von multiresistenten Pathogenstämmen geführt. Diese Stämme stellen eine ernsthafte Gefahr für die öffentliche Gesundheit dar, eine Bedrohung, die in Zukunft voraussichtlich zunehmen wird. Die zweite Gefahr für die öffentliche Gesundheit, stellt Krebs dar. Obwohl die Krebsforschung erhebliche öffentliche und wirtschaftliche Aufmerksamkeit erhält, bleibt Krebs weltweit die zweithäufigste Todesursache. Mit zahlreichen Krebsarten und Unterarten, die gegen konventionelle Therapien wie Chemotherapie und Strahlentherapie resistent sind, besteht ein dringender Bedarf an innovativen Behandlungsoptionen. In dieser Doktorarbeit werden zwei verschiedene RNA-bindende Proteine untersucht. Das erste davon ist der "Carbon Storage Regulator A" (CsrA), ein posttranskriptionaler Regulator, welcher in den meisten gramnegativen Bakterien sehr verbreitet und in seiner Struktur stark konserviert ist, aber in Eukaryoten fehlt, was ihn zu einem vielversprechenden Ziel für Antivirulenz-Wirkstoffe macht. Das zweite untersuchte Protein ist das "Insulin-like Growth Factor 2 mRNA Binding Protein 2" (IMP2), ein posttranskriptionaler Regulator, der in Säugetieren vorkommt und für die fötale Entwicklung entscheidend ist. IMP2 ist in zahlreichen Säugetierkrebszelllinien hochreguliert und wurde mit der Begünstigung der Zellproliferation bei Krebs in Verbindung gebracht, was es zu einem vielversprechenden Ziel für eineTherapie gegen Krebs macht. Das Ziel dieser Arbeit war es, neue Inhibitoren zu identifizieren, die CsrA und IMP2 in vitro inhibieren können. Dies ist ein entscheidender Schritt um in einem späteren Stadium zeigen zu können, dass die Hemmung von CsrA und IMP2 die gewünschten in vivo-Effekte erzielen kann und damit die anvisierten Proteine als valide Antivirulenz bzw. Anti-Krebs Targets zu bestätigen. Die Arbeit begründet die Auswahl dieser Proteine als potenzielle neue Ziele, erläutert, wie die Identifizierung von Hits in vitro durchgeführt wurde, und schließt mit der medizinisch-chemischen Optimierung dieser Verbindungen ab
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
From pico to nano: biofunctionalization of cube-octameric silsesquioxanes by peptides and miniproteins
No full textPolyhedral silsesquioxanes are considered valuable conjugation scaffolds. Nevertheless, only a few examples of silsesquioxane-assembled peptide oligomers have been reported to date. We developed a new bioorthogonal cube-octameric silsesquioxane (COSS) scaffold bearing eight aminooxy coupling sites allowing for the conjugation of diverse peptides via oxime ligation. We found that the coupling efficacy depends on the ligand in view of steric hindrance and electrostatic repulsion. For the first time scaffold-based conjugation of cystine-knot miniproteins having a backbone of about thirty amino acids was successfully accomplished without loss of bioactivity. Atomic force microscopy (AFM) provided further knowledge on the size of COSS verifying them as picoscaffolds growing upon bioconjugation to nano-dimension
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
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