The history of cyclosporin A (Sandimmune®) revisited: Another point of view

The immunosuppressant cyclosporin A (Sandimmune^®) has become the first line treatment for preventing rejection of transplanted organs and for certain, autoimmune diseases. The discovery of that drug and its preclinical development are described, and it is shown that most earlier accounts of the history of this compound are, in important respects, incorrect and misleading.     

Die Wirkung von Progesteron und Progesteronmetaboliten auf das Wachstum von embryonalem Knorpel in vitro

Summary Embryonic chick bones were cultured in vitro in the presence of progesterone and of a series of progesterone metabolites. It was found that only 5-pregnane-3,20-dione, 3-hydroxy-5-pregnane-20-one, and ⁴-pregnene-20-ol-3-one influence the growth of bones in vitro in a manner similar to progesterone. All other investigated progesterone metabolites exert either a different or no demonstrable action on bone growth.     

Role of lysine side chains in metallothionein

Summary pK_a-Values of lysine residues of mammalian metallothionein were determined by chemical titration measurements of -CH₂ lysine resonances in the¹H-NMR spectra. They are about 0.5 pH-unit higher than the average pK_a-value of a metal-free derivative, suggesting interaction of the positively charged residues with the two three-fold negatively charged metal-thiolate clusters of the metal-containing form. Deprotonation of the lysines leads to circular dichroism changes attributable to an electrostatically induced structural transition of the protein.To whom correspondence concerning this paper should be addressed.     

Protection of rat gastric mucosa against ethanol injury by the new synthetic prostaglandin MDL 646

Summary Oral administration to fasted rats of absolute ethanol produces extensive necrotic lesions of gastric mucosa as well as a massive leakage of proteins and mucus glycoproteins into gastric lumen. When the new synthetic prostaglandin MDL 646, belonging to the PGE₁ series, is administered intragastrically (2 or 10 g/kg) 30 min before ethanol administration, a significant protection of rat gastric mucosa against alcohol injury is observed.This work was supported in part by a contribution from Ministero della Pubblica Istruzione (MPI), Rome, Italy.     

Diurnal variations in thermoregulatory responses to intrahypothalamic and intravenous injections of noradrenaline in the pigeon

Summary The differences in responses of T_b, T_f and both to intrahypothalamic and i.v. administration of NA were measured both at noon and at midnight in the pigeon. Although the T_b and were at a higher level in the daytime, no differences in the magnitude of the fall in and T_b were obtained after either intrahypothalamic or i.v. injections of NA, whether it was measured during the day or at night. The only marked difference was the more prominent vasodilatation in the daytime after both routes of injection.     

Population genetic structure and mating system evolution in freshwater pulmonates

Freshwater gastropods (Basommatophora and Prosobranchia) harbor a variety of mating systems. In particular, apomictic parthenogenesis in prosobranchs and self-fertilization in the hermaphrodite pulmonates may be viable alternatives to outcrossing sexuality in a number of species. The coexistence of different mating systems in extant populations provides opportunities to examine the forces directing their evolution. We review the models analyzing and predicting genetic variability in subdivided populations, with an emphasis on the effects of inbreeding. Population genetic data on freshwater pulmonates are examined in the context of selfing rates and the loss of variability under selfing. Furthermore, the genetic and demographic factors thought to influence mating system evolution are considered, and we highlight the different approaches available to estimate mating system parameters, in particular the selfing rate. Recent population biological studies on polyploid species (Bulinus truncatus, Ancylus fluviatilis) indicate that selfing is the predominant mating system. These studies have contributed to a deeper understanding of conceptual issues in the evolution of selfing rates. Throughout, we emphasize the need for further carefully designed studies.     

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Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6

Toll-like receptors (TLRs) are activated by pathogen-associated molecular patterns to induce innate immune responses and production of pro-inflammatory cytokines, interferons and anti-inflammatory cytokines. TLRs activate downstream effectors through adaptors that contain Toll/interleukin-1 receptor (TIR) domains, but the mechanisms accounting for diversification of TLR effector functions are unclear. To dissect biochemically TLR signalling, we established a system for isolating signalling complexes assembled by dimerized adaptors. Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. Using myeloid cells from TRAF3- and TRAF6-deficient mice, we show that TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. In fact, TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production. Despite their structural similarity, the functions of TRAF3 and TRAF6 are largely distinct. TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response.