The stoichiometry of peptide-heparan sulfate binding as a determinant of uptake efficiency of cell-penetrating peptides

Binding to negatively charged heparan sulfates (HS) at the cell surface is considered the first step in the internalization of cationic cell-penetrating peptides (CPPs). However, little is known about the relation of the characteristics of the HS-CPP interaction such as affinity, stoichiometry, and clustering with uptake. In this study, we investigated a collection of mutants of a cyclic CPP derived from human lactoferrin with respect to HS binding and uptake. The thermodynamic parameters of HS binding were determined by isothermal titration calorimetry, clustering of HS was investigated by dynamic light scattering, and cellular uptake by flow cytometry and confocal microscopy. Whereas mutations of non-arginine amino acids that are conserved across lactoferrins of different mammalia only had a minor effect on uptake efficiency, changes in the number of arginine residues influenced the uptake significantly. In general, introduction of arginine residues and cyclization improved the HS affinity and the ability to cluster HS. In particular, there was a strong negative correlation between stoichiometry and uptake, indicating that crosslinking of HS is the driving force for the uptake of arginine-rich CPPs. Using glycan microarrays presenting a collection of synthetic HS, we show that a minimal chain length of HS is required for peptide binding.     

Die Postulate und Konstruktionen in der frühgriechischen Geometrie

Ohne Zusammenfassung     

Ein Briefwechsel zwischen P. Finsler und B. L. van der Waerden über die Grundlegung der algebraischen Geometrie

Ohne Zusammenfassung     

Making the abstract concrete: The role of norms and values in experimental modeling

Experimental modeling is the construction of theoretical models hand in hand with experimental activity. As explained in Section 1, experimental modeling starts with claims about phenomena that use abstract concepts, concepts whose conditions of realization are not yet specified; and it ends with a concrete model of the phenomenon, a model that can be tested against data. This paper argues that this process from abstract concepts to concrete models involves judgments of relevance, which are irreducibly normative. In Section 2, we show, on the basis of several case studies, how these judgments contribute to the determination of the conditions of realization of the abstract concepts and, at the same time, of the quantities that characterize the phenomenon under study. Then, in Section 3, we compare this view on modeling with other approaches that also have acknowledged the role of relevance judgments in science. To conclude, in Section 4, we discuss the possibility of a plurality of relevance judgments and introduce a distinction between locally and generally relevant factors.     

Radiation carcinogenesis in experimental animals

Exposure of man to relatively high doses of ionizing radiation is generally restricted to accidental situations, with very limited knowledge about the actual doses received. Animal experiments can be performed under standardized and controlled conditions and can provide information on the dose-response relationships for radiation carcinogenesis. The risk of inducing neoplastic late effects after total-body irradiation with relatively high doses has been demonstrated for larger animals, such as monkeys and dogs. The bone marrow, the mammary glands and the lungs are among the tissues with the highest susceptibility for radiation carcinogenesis. Experimental results on tumour induction in rodents are summarized with emphasis on the effectiveness in dependence on radiation quality and fractionation or dose rate.     

PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans.

PAX6 is widely expressed in the central nervous system. Heterozygous PAX6 mutations in human aniridia cause defects that would seem to be confined to the eye. Magnetic resonance imaging (MRI) and smell testing reveal the absence or hypoplasia of the anterior commissure and reduced olfaction in a large proportion of aniridia cases, which shows that PAX6 haploinsuffiency causes more widespread human neuro developmental anomalies.     

Force generation in glycerinated insect-flight muscles without ATP

Zusammenfassung Durch Zugabe und durch Auswaschen von Mg-Pyrophosphat (0,5 mM) oder Mg-Tripoly-Phosphat (1 mM) konnten (in Abwesenheit von ATP) in glyzerinextrahierten Fasern von fibrillären Insektenmuskeln (Lethocerus maximus) reversible Kontraktionszyklen und Änderungen des Dehnungswiderstandes bewirkt werden.

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Supported by Grant No. Ru 154/b of the Deutsche Forschungsgemeinschaft. The excellent technical assistance of Mrs.Helgard Jung is gratefully acknowledged.