We describe anew technique in protein synthesis that extends the existing repertoire of methods for protein modification:Achemoselective reaction that induces reactivity for as ubsequent bioconjugation. An azide-modified building blockr eacts first with an ethynylphosphonite through aS taudinger-phosphonite reaction (SPhR) to give an ethynylphosphonamidate.T he resulting electron-deficient triple bond subsequently undergoes ac ysteine-selective reaction with proteins or antibodies.W ed emonstrate that ethynylphosphonamidates display excellent cysteine-selective reactivity combined with superior stability of the thiol adducts,w hen compared to classical maleimide linkages.T his turns our technique into av ersatile and powerfult ool for the facile construction of stable functional protein conjugates.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.Figure 4. a) Synthetic scheme for phosphonamidate attachmentofthe Cy5f luorophore to trastuzumab(anti-Her2 antibody) to generate an AFC. b) Immunostaining of fixed cells either over-expressing the cell-surface receptor Her2 (BT474) or exhibiting low Her2 expression levels (MDAMB468). The merged images show the signal from the DNA stain DAPI in blue and the Cy5signal in red. Scale bar:10mm. c) Synthetic scheme for the attachmento fphosphonamidite-modified cCPPs 8 and 9 to aeGFP mutant with asingle addressable cysteine. d) Fluorescence imaging of HeLa cells after incubation with eGFP alone and eGFP-cTat at 50 mm.I mages show the GFP channel in green and the Hoechst 33342 nuclear stain in blue. Scale bar:2 0mm. Forfurther information see the SupportingInformation. Angewandte Chemie Communications
Wirb eschreiben eine neue Methode zur Proteinsynthese,d ie das bestehende Repertoire an Mçglichkeiten zur Proteinmodifikation erweitert:E ine chemoselektive Reaktion induziert Reaktivitätf üre ine nachfolgende Biokonjugation. Hierbei reagiert ein azidmodifizierter Baustein zunächst mit einem Ethinylphosphonit in einer Staudinger-Phosphonit-Reaktion (SPhR) zu einem Ethinylphosphonamidat. Die so entstehende elektronenarme Dreifachbindung modifiziert anschließend in einer cysteinselektiven Reaktion Proteine und Antikçrper.W ir zeigen, dass Ethinylphosphonamidate eine herausragende SelektivitätfürCysteine aufweisen, gepaart mit einer überragenden Stabilitätd er Thiol-Addukte im Vergleich zu klassischen Maleimid-Konjugaten. Diese Erkenntnis macht unsere Technik zu einer vielseitigen und leistungsstarken Methode fürdie mühelose Herstellung von stabilen, funktionalen Proteinkonjugaten.
seventy-two years after the start of the nuclear era, 122 states concluded the Treaty on the Prohibition of Nuclear Weapons (TPNW, or ban treaty). The treaty forbids the development, production, acquisition, possession, transfer, testing, use, and threat of use of nuclear weapons. Advocates of the TPNW understand that it will not automatically lead to a world without nuclear weapons. The treaty's main goal is to stimulate a societal and political debate inside the nuclear-armed states and their allies by strengthening the antinuclear norm and by stigmatizing nuclear weapons and their possessors. This article assesses to what extent this process of stigmatization might take place. It starts by elaborating on the concepts of stigma and stigmatization. It then matches the concept of stigma with nuclear weapons, and with the humanitarian initiative behind the momentum that led to the TPNW. The article concludes by looking to different stigma management approaches that can be used by the nuclear-armed states and their allies.
The European Union has long sought to raise its profile as a significant actor in the global effort to curtail the proliferation of weapons of mass destruction (WMD). From this perspective, the 2015 Nuclear Non-Proliferation Treaty (NPT) Review Conference represented a pivotal event where the EU could demonstrate the strength of its Common Foreign and Security Policy (CFSP). During a monthlong negotiation at the United Nations headquarters in New York, the representatives of state parties to the treaty-including all the EU countries-struggled to build a consensus on the final document that would assess recent progress and outline the steps to be taken in the next review period.In the end, the 2015 NPT Review Conference failed to build such a consensus. The final stumbling block turned out to be the question of the Middle East and the planned WMD-free zone therein; however, there were also serious clashes over many other substantive issues within the three pillars of the NPT: disarmament, non-proliferation and peaceful use of nuclear energy. Disarmament stood, once again, at the forefront of these debates. The majority of non-nuclear weapon states (NNWS) have been increasingly dissatisfied with the pace and scope of disarmament measures by the five nuclear weapon states (NWS) recognized by the treaty-the United States, Russia, the UK, France and China, which are also the five permanent members of the UN Security Council (P5). Criticism of the lack of progress on the disarmament pillar has now gained strong momentum in the Humanitarian Initiative, a recent development in NPT discourse that seeks to frame the urgent need for the abolition of nuclear weapons through the lenses of human security, international humanitarian law, and new scientific findings related to the horrific consequences of the use of nuclear weapons. 1 The aim of this article is to examine the role of the EU and its member states in the deliberations of the 2015 NPT Review Conference. I draw on research based primarily on direct on-site observation; statements of the EU and its member states in the general debate, main committees and subsidiary bodies; 2 working 1 See John Borrie, 'Humanitarian reframing of nuclear weapons and the logic of a ban', International Affairs 90: 3, May 2014, pp. 625-46; Tom Sauer and Joelien Pretorius, 'Nuclear weapons and the humanitarian approach', .959753; Rebecca Johnson, 'The humanitarian impacts of nuclear weapons: an imperative for achieving disarmament', Irish Studies in International Affairs 25: 1, 2014, pp. 59-72. 2 For an overview of organizational matters and the structure of negotiations at the 2015 NPT Review Confer-
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