Inhibition of steroidΔ 4 reductase by heparin: Studies with desoxycorticosterone,progesterone, androstenedione and testosterone

Zusammenfassung Heparin hemmt die Reduktion der Doppelbindung in 4-Stellung des Rings A einer Reihe von C-11-desoxy, ⁴-4-keto-Steroiden in der Rattenleber. Es scheint, dass Heparin mit NADPH um das Steroid-reduktase-Apoenzym konkurriert.

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This work was supported by grant No. AM-09151 from The National Institutes of Health, U.S.P.H.S.     

Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T?cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs?6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.     

A complete insect from the Late Devonian period

After terrestrialization, the diversification of arthropods and vertebrates is thought to have occurred in two distinct phases, the first between the Silurian and the Frasnian stages (Late Devonian period) (425-385?million years (Myr) ago), and the second characterized by the emergence of numerous new major taxa, during the Late Carboniferous period (after 345?Myr ago). These two diversification periods bracket the depauperate vertebrate Romer's gap (360-345?Myr ago) and arthropod gap (385-325?Myr ago), which could be due to preservational artefact. Although a recent molecular dating has given an age of 390?Myr for the Holometabola, the record of hexapods during the Early-Middle Devonian (411.5-391?Myr ago, Pragian to Givetian stages) is exceptionally sparse and based on fragmentary remains, which hinders the timing of this diversification. Indeed, although Devonian Archaeognatha are problematic, the Pragian of Scotland has given some Collembola and the incomplete insect Rhyniognatha, with its diagnostic dicondylic, metapterygotan mandibles. The oldest, definitively winged insects are from the Serpukhovian stage (latest Early Carboniferous period). Here we report the first complete Late Devonian insect, which was probably a terrestrial species. Its 'orthopteroid' mandibles are of an omnivorous type, clearly not modified for a solely carnivorous diet. This discovery narrows the 45-Myr gap in the fossil record of Hexapoda, and demonstrates further a first Devonian phase of diversification for the Hexapoda, as in vertebrates, and suggests that the Pterygota diversified before and during Romer's gap.     

iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human

We have previously shown that ASPP1 and ASPP2 are specific activators of p53; one mechanism by which wild-type p53 is tolerated in human breast carcinomas is through loss of ASPP activity. We have further shown that 53BP2, which corresponds to a C-terminal fragment of ASPP2, acts as a dominant negative inhibitor of p53 (ref. 1). Hence, an inhibitory form of ASPP resembling 53BP2 could allow cells to bypass the tumor-suppressor functions of p53 and the ASPP proteins. Here, we characterize such a protein, iASPP (inhibitory member of the ASPP family), encoded by PPP1R13L in humans and ape-1 in Caenorhabditis elegans. iASPP is an evolutionarily conserved inhibitor of p53; inhibition of iASPP by RNA-mediated interference or antisense RNA in C. elegans or human cells, respectively, induces p53-dependent apoptosis. Moreover, iASPP is an oncoprotein that cooperates with Ras, E1A and E7, but not mutant p53, to transform cells in vitro. Increased expression of iASPP also confers resistance to ultraviolet radiation and to cisplatin-induced apoptosis. iASPP expression is upregulated in human breast carcinomas expressing wild-type p53 and normal levels of ASPP. Inhibition of iASPP could provide an important new strategy for treating tumors expressing wild-type p53.     

Structure of a beta1-adrenergic G-protein-coupled receptor

G-protein-coupled receptors have a major role in transmembrane signalling in most eukaryotes and many are important drug targets. Here we report the 2.7 A resolution crystal structure of a beta(1)-adrenergic receptor in complex with the high-affinity antagonist cyanopindolol. The modified turkey (Meleagris gallopavo) receptor was selected to be in its antagonist conformation and its thermostability improved by earlier limited mutagenesis. The ligand-binding pocket comprises 15 side chains from amino acid residues in 4 transmembrane alpha-helices and extracellular loop 2. This loop defines the entrance of the ligand-binding pocket and is stabilized by two disulphide bonds and a sodium ion. Binding of cyanopindolol to the beta(1)-adrenergic receptor and binding of carazolol to the beta(2)-adrenergic receptor involve similar interactions. A short well-defined helix in cytoplasmic loop 2, not observed in either rhodopsin or the beta(2)-adrenergic receptor, directly interacts by means of a tyrosine with the highly conserved DRY motif at the end of helix 3 that is essential for receptor activation.     

Arboreality predicts Batrachochytrium dendrobatidis infection level in tropical direct-developing frogs

Pathogen-mediated changes in host behaviour can result from hosts altering their habitat preferences. Although infection risk with pathogenic fungus Batrachochytrium dendrobatidis in amphibians is associated with environments favouring its growth, the relationship with microhabitat use has not been examined. Here, we aim to determine if microhabitats used by frogs during their nocturnal activity predict B. dendrobatidis prevalence and infection intensity. Our focal host, Eleutherodactylus coqui, is a habitat generalist that uses multiple habitats from the forest floor to the canopy. We analysed data on B. dendrobatidis occurrence in 157 adults and 122 juveniles at El Yunque National forest in Puerto Rico. We categorized each individual’s nocturnal microhabitat as forest floor, curled palm fronds in the floor, arboreal bromeliads and foliage or tree trunks 50 cm to 2.5 m above ground. We found that frogs on the forest floor had the greatest B. dendrobatidis prevalence (73%), compared with those active in vegetation above ground (55%). Overall, the probability of B. dendrobatidis infection in frogs using microhabitats on the forest floor was twice as great as for those on arboreal substrates. Differences in B. dendrobatidis prevalence and intensity in E. coqui may be explained by specific abiotic conditions of microenvironments (temperature and humidity) affecting both pathogen and host, and by the age-specific ecological requirements of hosts. Adults were found to be most active in microhabitats where individuals had lower infection burdens, suggesting pathogen-modulated habitat choice. This work has important implications for the evolutionary dynamics of enzootic diseases and provides data that may inform potential mitigation strategies against a generalist amphibian pathogen.     

Competition for food and space in a heteromyid community in the Great Basin Desert

A series of removal experiments were performed on Dipodomys merriami, D. microps, and Perognathus longimembris to test for the importance of competition for food and microhabitats in a heteromyid community in the Great Basin Desert. Each of these species was removed singly to determine the short-term effects on the microhabitat preferences of the remaining species. We correctly predicted, based on differences in diet, that the removal of D. microps (a foliovore) would have no effect on D. merriami or P. longimembris (granivores). Using the dominance hierarchy theory, we correctly predicted that removal of a larger heteromyid, D. merriami, would have an effect on the microhabitat use of the smaller P. longimembris, but not vice versa. While our results offer strong evidence of competition for food and microhabitats, the short-term reactions were weak compared to the long-term reactions found in other studies of heteromyids.     

Knowing and Acting in Conditions of Uncertainty: A Complexity Perspective

As practitioners working with groups and organizations, we have reflected together on what we think is happening when we find ourselves acting into situations in which the intention motivating the action as its goal is itself emerging in the very action. Along with others, we have been excited by the ideas of self-organization in the natural sciences and also theories of practice, for example, tacit and explicit knowledge, in the social sciences. Together, these promise fresh insights into the potential of organizations. However, we find ourselves diverging significantly from writers who at first sight seem to be using similar ideas, but they do so with an exclusive focus on strategic choice and intention. To illustrate what we mean, we explore the work of Nonaka and Takeuchi and how they use Polanyi's idea of the participant observer. We do this to identify contradictions we see in their approach. We also discuss the implications of an alternative understanding of participation and what this indicates about what can and cannot be managed in the creation of new knowledge.