Renin in mouse but not in rat submandibular glands

Renin was found in the submandibular glands of male Quackenbush mice in concentrations higher than has been reported for any tissue of any strain or species. However, no renin-like activity could e detected in glands from male and female Wistar rats using either pH 5.8 or 7.4 for assay and a radioimmunoassay specific for renin's reaction product, angiotensin I. Rabbit submandibular glands contained renin.     

The response of cyclic 3',5'-AMP and cyclic 3',5'-GMP phosphodiesterases to experimental diabetes

Alloxan diabetes caused a decrease in cyclic AMP phosphodiesterase in all affected rat tissues. Cyclic GMP phosphodiesterase activity was, however, decreased in adipose and liver, but increased increased in heart and uterus.     

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

Ohne Zusammenfassung     

Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4

P4-ATPases are lipid flippases that catalyze the transport of phospholipids to create membrane phospholipid asymmetry and to initiate the biogenesis of transport vesicles. Here we show, for the first time, that lipid flippases are essential to dampen the inflammatory response and to mediate the endotoxin-induced endocytic retrieval of Toll-like receptor 4 (TLR4) in human macrophages. Depletion of CDC50A, the β-subunit that is crucial for the activity of multiple P4-ATPases, resulted in endotoxin-induced hypersecretion of proinflammatory cytokines, enhanced MAP kinase signaling and constitutive NF-κB activation. In addition, CDC50A-depleted THP-1 macrophages displayed reduced tolerance to endotoxin. Moreover, endotoxin-induced internalization of TLR4 was strongly reduced and coincided with impaired endosomal MyD88-independent signaling. The phenotype of CDC50A-depleted cells was also induced by separate knockdown of two P4-ATPases, namely ATP8B1 and ATP11A. We conclude that lipid flippases are novel elements of the innate immune response that are essential to attenuate the inflammatory response, possibly by mediating endotoxin-induced internalization of TLR4.     

On the origins and foundations of Laplacian determinism

In this paper I examine the foundations of Laplace’s famous statement of determinism in 1814, and argue that rather than derived from his mechanics, this statement is based on general philosophical principles, namely the principle of sufficient reason and the law of continuity. It is usually supposed that Laplace’s statement is based on the fact that each system in classical mechanics has an equation of motion which has a unique solution. But Laplace never proved this result, and in fact he could not have proven it, since it depends on a theorem about uniqueness of solutions to differential equations that was only developed later on. I show that the idea that is at the basis of Laplace’s determinism was in fact widespread in enlightenment France, and is ultimately based on a re-interpretation of Leibnizian metaphysics, specifically the principle of sufficient reason and the law of continuity. Since the law of continuity also lies at the basis of the application of differential calculus in physics, one can say that Laplace’s determinism and the idea that systems in physics can be described by differential equations with unique solutions have a common foundation.     

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.