Methods for Exerting and Sensing Force in Polymer Materials Using Mechanophores

In recent years, polymer mechanochemistry has evolved as a methodology to provide insights into the action-reaction relationships of polymers and polymer-based materials and composites in terms of macroscopic force application (stress) and subsequent deformation (strain) through a mechanophore-assisted coupling of mechanical and chemical phenomena. The perplexity of the process, however, from the viewpoint of mechanophore activation via a molecular-scaled disruption of the structure that yields a macroscopically detectable optical signal, renders this otherwise rapidly evolving field challenging. Motivated by this, we highlight here recent advancements of polymer mechanochemistry with particular focus on the establishment of methodologies for the efficient activation and quantification of mechanophores and anticipate to aptly pinpoint unresolved matters and limitations of the respective approaches, thus highlighting possible developments. © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA

Das Simultandolmetschmodell von A. F. Schirjajew

Gegenstand der Arbeit ist das Simultandolmetschmodell des russischen Dolmetschwissenschafters A. F. Schirjajew, das in seiner im Jahr 1979 veröffentlichten und nur in russischer Sprache vorliegenden Monographie dargestellt wird. Die Entwicklung der professionellen Dolmetschtätigkeit seit den Pariser Friedensgesprächen von 1919 bis zum Erscheinen der Monographie sowohl auf internationaler Ebene als auch in der Sowjetunion bildet den praktischen Hintergrund für Schirjajews Arbeit. Beeinflusst von der in der Sowjetischen Schule eine bedeutende Rolle spielenden Psycholinguistik erachtet Schirjajew den gleichzeitigen Ablauf von mehreren kognitiven Verarbeitungsprozessen als die größte Herausforderung beim Dolmetschen und untersucht die Mechanismen, die dies ermöglichen. Dazu führt er Experimente mit Studierenden und Berufsdolmetschern zu temporalen Aspekten wie Segmentierung und Phasenverschiebung, Nutzung von Pausen und Einfluss der Präsentationsgeschwindigkeit auf die Darbietung des Dolmetschers durch. Für sein Prozessmodell, das dafür gedacht war, die Lehre des Simultandolmetschens auf eine wissenschaftliche Grundlage zu stellen und dementsprechend leicht verständlich und nachvollziehbar sein sollte, unterteilt er einen Dolmetschabschnitt in eine Orientierungsphase, Entscheidungsphase und Umsetzungsphase. Abhängig vom Tempo des Redners in der Ausgangssprache können diese Phasen in unterschiedlichem Ausmaß überlappen. Um die erst in ihren Anfängen stehende internationale Forschungstätigkeit zu Schirjajews Zeit näher zu beleuchten, werden ausgewählte bahnbrechende Untersuchungen zu temporalen Aspekten wie z.B. von Gerver und Goldman-Eisler sowie die ersten Prozessmodelle von Gerver und Chernov beschrieben und Schirjajews Ansätze und sein Modell dazu in Beziehung gesetzt. Spätere maßgebliche Modelle der kognitiven Informationsverarbeitung wie z.B. von Gile und Setton und Settons kritische Feststellungen über die Schwierigkeit der wissenschaftlichen Erforschung und Darstellung des Simultandolmetschens verdeutlichen die Komplexität dieser noch jungen wissenschaftlichen Disziplin

The mechanochemical release of Naphthalimide fluorophores from β-carbonate and β-carbamate disulfide-centered polymers

The covalent attachment of cargo molecules (e.g., drugs and fluorophores) in β-position to a disulfide moiety through carbamate and carbonate bonds finds many applications in responsive release systems. Recently, we showed that the combination of this release process with polymer mechanochemistry-induced disulfide scission enabled the remote-controlled release of small molecule drugs and fluorophores from their inactive parent macromolecules using ultrasound. The nature of the linker bond largely governed the subsequent release kinetics, an aspect that has not been investigated so far. To compare the differences, we here employ disulfide-centered polymers releasing either hydroxyl- or amino-naphthalimides from their respective β-carbonate or -carbamate linkers by force-induced intramolecular 5-exo-trig cyclization. We present the synthesis, characterization, and cell imaging evaluation of three naphthalimides featuring colorimetric and green fluorescence turn-on upon release, allowing monitoring of the release process. We believe that the insights gained from these experiments would advance the tailoring of release rates for force-induced pharmacotherapy

Nephrotoxizität nach Radiopeptidtherapie - Häufigkeit und Risikofaktoren

Ziel dieser retrospektiven Arbeit war es, prognostisch bedeutsame Parameter zur Vorhersage einer nephrotoxischen Wirkung der RPT zu finden. Einbezogen wurden 115 Patienten, die sich im Zeitraum von Mai 2005 bis Juni 2011 an der Universitätsklinik Tübingen einer oder mehrerer RPT unterzogen haben. Alle Patienten waren an einem NET unterschiedlicher Lokalisation erkrankt. Die Auswertung stützte sich auf die Beurteilung verschiedener NierenfunktionsParameter wie Kreatinin, bGFR, gGFR und TER, die vor der RPT sowie nach drei und zwölf Monaten bestimmt worden waren. Zusätzlich erfolgte die Einbeziehung spezieller anamnestischer Angaben (vorausgegangene Radio- und Chemotherapien, Medikamenteneinnahme, Vorerkrankungen, sowie der zeitliche Abstand zur letzten KM-Applikation), von Nieren-Szintigrammen und PET/CT-Untersuchungen. Die Nephrotoxizitätsrate betrug nach der 1. RPT 9,3 %, nach der 2. RPT 25 %. Bei der Gegenüberstellung von Patienten mit posttherapeutisch normaler Nierenfunktion bzw. Nephrotoxizität zeigte sich, dass die prätherapeutische KMGabe und das Nierenvolumen keine prognostische Relevanz für die Entstehung einer Nephrotoxizität hatten. Es ließ sich jedoch ein erhöhtes Risiko bei vorbestehenden Begleiterkrankungen, der Einnahme potentiell nephrotoxischer Medikamente und prätherapeutisch erhöhtem Serumkreatinin bzw. reduzierter gGFR nachweisen. Dagegen bedarf eine vermehrte renale Anreicherung in der prätherapeutischen PET-Untersuchung noch weiterer Bestätigung und Klärung. Durch Gabe von 177Lu-DOTATOC ließ sich bei vorbestehender Nierenfunktionsstörung eine Nephrotoxizität bzw. Verschlechterung der Nierenfunktion nicht verhindern. Abschließend ist festzustellen, dass zum gegenwärtigen Zeitpunkt eine zuverlässige, individuelle Vorhersage einer späteren Nephrotoxizität noch nicht möglich ist. Es können jedoch Risikogruppen definiert werden, für die eine adaptierte Therapieplanung denkbar wäre

Polymer mechanochemistry-enabled pericyclic reactions

Over the past decades, it became clear that next to heat and light, pericyclic reactions can be induced mechanochemically when the reacting motifs are embedded as latent force-responsive groups (mechanophores) into polymer architectures. Not only does this enable a variety of functions and applications on a material level, but moreover grants access to symmetry-forbidden reaction products with respect to the Woodward-Hoffmann rules. The latter indicates that polymer mechanochemistry follows its own set of rules that, however, regarding underlying mechanisms and design rationales is far from being holistically understood. Here we review the existing body of literature and identify common structural features and substitution prerequisites to the polymer framework shining light on the differences between polymer mechanochemical pericyclic reactions and their traditional counterparts. By this, we believe to contribute to the major challenge of not only retrospectively describing force-induced reactivity but eventually finding a common molecular design guideline. © The Royal Society of Chemistry 2020

Liquefaction of Biopolymers: Solvent-free Liquids and Liquid Crystals from Nucleic Acids and Proteins

ConspectusBiomacromolecules, such as nucleic acids, proteins, and virus particles, are persistent molecular entities with dimensions that exceed the range of their intermolecular forces hence undergoing degradation by thermally induced bond-scission upon heating. Consequently, for this type of molecule, the absence of a liquid phase can be regarded as a general phenomenon. However, certain advantageous properties usually associated with the liquid state of matter, such as processability, flowability, or molecular mobility, are highly sought-after features for biomacromolecules in a solvent-free environment. Here, we provide an overview over the design principles and synthetic pathways to obtain solvent-free liquids of biomacromolecular architectures approaching the topic from our own perspective of research. We will highlight the milestones in synthesis, including a recently developed general surfactant complexation method applicable to a large variety of biomacromolecules as well as other synthetic principles granting access to electrostatically complexed proteins and DNA.These synthetic pathways retain the function and structure of the biomacromolecules even under extreme, nonphysiological conditions at high temperatures in water-free melts challenging the existing paradigm on the role of hydration in structural biology. Under these conditions, the resulting complexes reveal their true potential for previously unthinkable applications. Moreover, these protocols open a pathway toward the assembly of anisotropic architectures, enabling the formation of solvent-free biomacromolecular thermotropic liquid crystals. These ordered biomaterials exhibit vastly different mechanical properties when compared to the individual building blocks. Beyond the preparative aspects, we will shine light on the unique potential applications and technologies resulting from solvent-free biomacromolecular fluids: From charge transport in dehydrated liquids to DNA electrochromism to biocatalysis in the absence of a protein hydration shell. Moreover, solvent-free biological liquids containing viruses can be used as novel storage and process media serving as a formulation technology for the delivery of highly concentrated bioactive compounds. We are confident that this new class of hybrid biomaterials will fuel further studies and applications of biomacromolecules beyond water and other solvents and in a much broader context than just the traditional physiological conditions. © 2017 American Chemical Society

Controlling Optical and Catalytic Activity of Genetically Engineered Proteins by Ultrasound

Ultrasound (US) produces cavitation-induced mechanical forces stretching and breaking polymer chains in solution. This type of polymer mechanochemistry is widely used for synthetic polymers, but not biomacromolecules, even though US is biocompatible and commonly used for medical therapy as well as in vivo imaging. The ability to control protein activity by US would thus be a major stepping-stone for these disciplines. Here, we provide the first examples of selective protein activation and deactivation by means of US. Using GFP as a model system, we engineer US sensitivity into proteins by design. The incorporation of long and highly charged domains enables the efficient transfer of force to the protein structure. We then use this principle to activate the catalytic activity of trypsin by inducing the release of its inhibitor. We expect that this concept to switch “on” and “off” protein activity by US will serve as a blueprint to remotely control other bioactive molecules. © 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH Gmb

Quantifying Rate-and Temperature-Dependent Molecular Damage in Elastomer Fracture

Elastomers are highly valued soft materials finding many applications in the engineering and biomedical fields for their ability to stretch reversibly to large deformations. Yet their maximum extensibility is limited by the occurrence of fracture, which is currently still poorly understood. Because of a lack of experimental evidence, current physical models of elastomer fracture describe the rate and temperature dependence of the fracture energy as being solely due to viscoelastic friction, with chemical bond scission at the crack tip assumed to remain constant. Here, by coupling new fluorogenic mechanochemistry with quantitative confocal microscopy mapping, we are able to quantitatively detect, with high spatial resolution and sensitivity, the scission of covalent bonds as ordinary elastomers fracture at different strain rates and temperatures. Our measurements reveal that, in simple networks, bond scission, far from being restricted to a constant level near the crack plane, can both be delocalized over up to hundreds of micrometers and increase by a factor of 100, depending on the temperature and stretch rate. These observations, permitted by the high fluorescence and stability of the mechanophore, point to an intricate coupling between strain-rate-dependent viscous dissipation and strain-dependent irreversible network scission. These findings paint an entirely novel picture of fracture in soft materials, where energy dissipated by covalent bond scission accounts for a much larger fraction of the total fracture energy than previously believed. Our results pioneer the sensitive, quantitative, and spatially resolved detection of bond scission to assess material damage in a variety of soft materials and their applications. © 2020 authors. Published by the American Physical Society

Fracture Detection in Bio-Glues with Fluorescent-Protein-Based Optical Force Probes

Glues are being used to bond, seal, and repair in industry and biomedicine. The improvement of gluing performance is hence important for the development of new glues with better and balanced property spaces, which in turn necessitates a mechanistic understanding of their mechanical failure. Optical force probes (OFPs) allow the observation of mechanical material damage in polymers from the macro- down to the microscale, yet have never been employed in glues. Here, the development of a series of ratiometric OFPs based on fluorescent-protein–dye and protein–protein conjugates and their incorporation into genetically engineered bio-glues is reported. The OFPs are designed to efficiently modulate Förster resonance energy transfer upon force application thereby reporting on force-induced molecular alterations independent of concentration and fluorescence intensity both spectrally and through their fluorescence lifetime. By fluorescence spectroscopy in solution and in the solid state and by fluorescence lifetime imaging microscopy, stress concentrations are visualized and adhesive and cohesive failure in the fracture zone is differentiated.</p

Going with the Flow : Tunable Flow-Induced Polymer Mechanochemistry

Mechanical forces can drive chemical transformations in polymers, directing reactions along otherwise inaccessible pathways, providing exciting possibilities for developing smart, responsive materials. The state-of-the-art test for solution-based polymer mechanochemistry development is ultrasonication. However, this does not accurately model the forces that will be applied during device fabrication using processes such as 3D printing or spray coating. Here, a step is taken toward predictably translating mechanochemistry from molecular design to manufacturing by demonstrating a highly controlled nozzle flow setup in which the shear forces being delivered are precisely tuned. The results show that solvent viscosity, fluid strain rate, and the nature of the breaking bond can be individually studied. Importantly, it is shown that the influence of each is different to that suggested by ultrasonication (altered quantity of chain breakage and critical polymer chain length). Significant development is presented in the understanding of polymer bond breakage during manufacturing flows to help guide design of active components that trigger on demand. Using an anthracene-based mechanophore, the triggering of a fluorescence turn-on is demonstrated through careful selection of the flow parameters. This work opens the avenue for programmed chemical transformations during inline manufacturing processes leading to tunable, heterogeneous final products from a single source material. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei