Structure of a nanobody-stabilized active state of the β(2) adrenoceptor

G protein coupled receptors (GPCRs) exhibit a spectrum of functional behaviours in response to natural and synthetic ligands. Recent crystal structures provide insights into inactive states of several GPCRs. Efforts to obtain an agonist-bound active-state GPCR structure have proven difficult due to the inherent instability of this state in the absence of a G protein. We generated a camelid antibody fragment (nanobody) to the human β(2) adrenergic receptor (β(2)AR) that exhibits G protein-like behaviour, and obtained an agonist-bound, active-state crystal structure of the receptor-nanobody complex. Comparison with the inactive β(2)AR structure reveals subtle changes in the binding pocket; however, these small changes are associated with an 11?? outward movement of the cytoplasmic end of transmembrane segment 6, and rearrangements of transmembrane segments 5 and 7 that are remarkably similar to those observed in opsin, an active form of rhodopsin. This structure provides insights into the process of agonist binding and activation.     

Investigation of Phase Inversion of Liquid-Liquid Dispersions in Agitated Vessels

Introduction Liquid-liquid dispersions in agitated vessels are fre-quently used in the chemical industry for conducting operations such as solvent extraction and heterogene-ous reactions. In liquid-liquid two-phase flow systems, usually consisting of an a…     

AIDS virus-specific cytotoxic T lymphocytes in lung disorders

Human immunodeficiency virus (HIV) is implicated in the development of AIDS (acquired immune deficiency syndrome). HIV infection leads to the generation of HIV-specific thymus-derived (T) lymphocytes in humans and apes. We describe an experimental system permitting the quantitative and systematic analysis of HIV-specific cytotoxic T lymphocytes (CTL). Functional, HIV-specific CTL are obtained by broncho-alveolar lavage (BAL) from the lungs of seropositive patients with lymphocytic alveolitis. These alveolar CTL: (1) recognize and kill HIV-infected alveolar macrophages in vitro under autologous, but not heterologous, conditions; (2) correspond to standard CTL as they express the CD3 and CD8 surface markers, but not the CD4 marker; and (3) are restricted by class I HLA transplantation antigens in their cytotoxic activities. We propose the hypothesis that interactions between HIV-specific CTL and infected macrophages induce major inflammatory reactions in seropositive patients.     

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.     

Organotin complexes of pyridine-2-carbothioamide

Summary Complexes of pyridine-2-carbothioamide with diethyltin dichloride, dibenzyltin dichloride and phenyltin trichloride are described. In each case, the chelating agent is bound to the tin(IV) atom by the pyridine nitrogen and the carbothioamide sulphur, giving support to proposals that certain organotin compounds cause enzyme deactivation via the formation of tin-sulphur bonds.Acknowledgment. We thank the Tin Industry (Research and Development) Board, Kuala Lumpur, for financial support.     

Bile Acids: Chemistry, Pathochemistry, Biology, Pathobiology, and Therapeutics

Bile acids and bile alcohols in the form of their conjugates are amphipathic end products of cholesterol metabolism with multiple physiological functions. The great variety of bile acids and bile alcohols that are present in vertebrates are tabulated. Bile salts have an enterohepatic circulation resulting from efficient vectorial transport of bile salts through the hepatocyte and the ileal enterocyte; such transport leads to the accumulation of a pool of bile salts that cycles between the liver and intestine. Bile salt anions promote lipid absorption, enhance tryptic cleavage of dietary proteins, and have antimicrobial effects. Bile salts are signaling molecules, activating nuclear receptors in the hepatocyte and ileal enterocyte, as well as an increasing number of G-protein coupled receptors. Bile acids are used therapeutically to correct deficiency states, to decrease the cholesterol saturation of bile, or to decrease the cytotoxicity of retained bile acids in cholestatic liver disease.