Ultra-remote stereocontrol by conformational communication of information along a carbon chain

Many receptors and allosteric proteins function through binding of a molecule to induce a conformational change, which then influences a remote active site. In synthetic systems, comparable intramolecular information transfer can be effected by using the shape of one part of a molecule to control the stereoselectivity of reactions occurring some distance away. However, the need for direct communication with the reaction site usually limits such remote stereocontrol to distances of not more than about five bond lengths. Cyclic structures overcome this problem by allowing the controlling centre and the reaction site to approach each other, but the information transfer spans only short absolute distances. Truly remote stereocontrol can, however, be achieved with rigid compounds containing amide groups: the conformation of the amides can be controlled by stereogenic centres and responds to that of neighbouring amide groups and in turn influences stereoselective reactions. This strategy has allowed remote stereocontrol spanning 8 (ref. 11) or 9 (ref. 12) bonds. Here we demonstrate stereocontrol over a reaction taking place more than 20 bond lengths from the controlling centre, corresponding to a linear distance of over 2.5 nm. This transmission of information, achieved by conformational changes relayed through the molecule, provides a chemical model of allostery and might serve as a molecular mechanism for communicating and processing information.     

Insights into assembly from structural analysis of bacteriophage PRD1

The structure of the membrane-containing bacteriophage PRD1 has been determined by X-ray crystallography at about 4 A resolution. Here we describe the structure and location of proteins P3, P16, P30 and P31. Different structural proteins seem to have specialist roles in controlling virus assembly. The linearly extended P30 appears to nucleate the formation of the icosahedral facets (composed of trimers of the major capsid protein, P3) and acts as a molecular tape-measure, defining the size of the virus and cementing the facets together. Pentamers of P31 form the vertex base, interlocking with subunits of P3 and interacting with the membrane protein P16. The architectural similarities with adenovirus and one of the largest known virus particles PBCV-1 support the notion that the mechanism of assembly of PRD1 is scaleable and applies across the major viral lineage formed by these viruses.     

Differential distribution of TASK-1, TASK-2 and TASK-3 immunoreactivities in the rat and human cerebellum

In this work, the distributions of some acid-sensitive two-pore-domain K⁺ channels (TASK-1, TASK-2 and TASK-3) were investigated in the rat and human cerebellum. Astrocytes situated in rat cerebellar tissue sections were positive for TASK-2 channels. Purkinje cells were strongly stained and granule cells and astrocytes were moderately positive for TASK-3. Astrocytes isolated from the hippocampus, cerebellum and cochlear nucleus expressed TASK channels in a primary tissue culture. Our results suggest that TASK channel expression may be significant in the endoplasmic reticulum of the astrocytes. The human cerebellum showed weak TASK-2 immunolabelling. The pia mater, astrocytes, Purkinje and granule cells demonstrated strong TASK-1 and TASK-3 positivities. The TASK-3 labelling was stronger in general, but it was particularly intense in the Purkinje cells and pia mater.Received 25 February 2004; received after revision 19 April 2004; accepted 28 April 2004     

Identification of swelling-activated Cl<Superscript>-</Superscript> current in rabbit cardiac Purkinje cells

The presence and functional role of the swelling-activated Cl^- current (I_Cl(swell)) in rabbit cardiac Purkinje cells was examined using patch-clamp methodology. Extracellular hypotonicity (210 or 135 mOsm) activated an outwardly rectifying, time-independent current with a reversal potential close to the calculated Cl^- equilibrium potential (E_Cl). The magnitude of this current was related to tonicity of the superfusate. The current was blocked by 0.5 mM 4,4-diisothiocyanostilbene-2,2-disulfonic acid (DIDS). These features are comparable to those of I_Cl(swell) found in sinoatrial nodal, atrial, and ventricular myocytes. I_Cl(swell) activation at 210 and 135 mOsm depolarized the resting membrane potential with 6 and 10 mV and shortened the action potential by 18 and 33%, respectively. DIDS partially reversed I_Cl(swell)-induced action potential changes. We conclude that I_Cl(swell) is present in Purkinje cells and its activation leads to action potential shortening and resting membrane potential depolarization, both of which can promote the development of reentrant arrhythmias.Received 20 January 2004; received after revision 17 February 2004; accepted 25 February 2004     

FK506 sensitizes mammalian cells to high osmolarity by modulating p38 MAP kinase activation

The immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA) have increased the survival rates in organ transplantation. Both drugs inhibit the protein phosphatase calcineurin (CaN) in activated T cells, exhibiting similar side-effects. Diabetes is observed more often in FK506 than CsA therapy, probably due to inhibition of new molecular targets other than CaN. We studied FK506 toxicity in mammalian cells. FK506, but not CsA, regulated p38 activation by osmotic stress, and decreased viability in osmostressed cells. In addition, FK506 treatment strongly increased the phosphorylation of the eukaryotic initiation factor-2a (eIF-2a) subunit. eIF-2a phosphorylation, p38 inhibition and cell lethality were relieved by addition of excess amino acids to the medium, suggesting that amino acid availability mediated FK506 toxicity. Therefore, these FK506-dependent responses could be relevant to the non-therapeutic effects of FK506 therapy.Received 16 October 2003; received after revision 8 January 2004; accepted 14 January 2004     

Reversal of the inhibitory effect of (2-chloroethyl)trimethyl-ammonium Chloride on the Flowering ofChenopodium rubrum L. by Kinetin

Zusammenfassung Chlorcholinchlorid (CCC) (2 × 10^–3 M) hemmt die Blühinduktion bei der KurztagspflanzeChenopodium rubrum L. Es wird gezeigt, dass diese Hemmung nicht nur durch Gibberellinsäure, sondern auch durch Kinetin (1 mg/l) aufgehoben werden kann. Eine Behandlung mit Kinetin derselben Konzentration allein (ohne vorherige Applikation von CCC) blockiert die Blühinduktion beiC. rubrum fast vollständig. Der Mechanismus der CCC-Wirkung auf die Blühinduktion wird diskutiert.     

Stimulation of pyruvate carboxylation by gastric secretagogues

Summary Pyruvate carboxylation was stimulated by 2 gastric secretagogues, histamine and dibutyryl cyclic AMP, and by butyrate. Thiocyanate, an inhibitor of acid secretion, produced a slight decrease. Avidin significantly reduced acid secretion and this effect was overcome by biotin and oxalacetate. The results suggest that carboxylation of pyruvate is one of the reactions controlling oxidative metabolism and acid secretion in toad gastric mucosa.This investigation was supported by Consejo de Desarrollo Científico y Humanístico de la Universidad del Zulia, and by CONICIT Grant S1-0455.     

Evidence that superoxide radicals are involved in the hemolytic mechanism of phenylhydrazine

Summary Phenylhydrazine produces in the red blood cell the same effect as the enzymic system xanthine oxidase-xanthine, a superoxide radical generator system. Both effects are inhibited by the enzyme superoxide dismutase.This work was supported in part by grants Nos. 1045 and 3243 of Oficina Técnica de Desarrollo Científico y Creación Artística de la Universidad de Chile.     

Estrogen action in the male.

Estrogen administration induces a migration of eosinophil leukocytes to ductus deferens.