Assembly of the M2 Tetramer Is Strongly Modulated by Lipid Chain Length

The influenza virus matrix protein 2 (M2) assembles into a tetramer in the host membrane during viral uncoating and maturation. It has been used as a model system to understand the relative contributions of protein-lipid and protein-protein interactions to membrane protein structure and association. Here we investigate the effect of lipid chain length on the association of the M2 transmembrane domain into tetramers using Förster resonance energy transfer. We observe that the interactions between the M2 helices are much stronger in 1,2-dilauroyl-sn-glycero-3-phosphocholine than in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers. Thus, lipid chain length and bilayer thickness not only modulate peptide interactions, but could also be a major determinant of the association of transmembrane helices into functional membrane protein oligomers.     

Field theoretic study of bilayer membrane fusion: II. Mechanism of a stalk-hole complex

We use self-consistent field theory to determine structural and energetic properties of intermediates and transition states involved in bilayer membrane fusion. In particular, we extend our original calculations from those of the standard hemifusion mechanism, which was studied in detail in the first article of this series, to consider a possible alternative to it. This mechanism involves non-axial stalk expansion, in contrast to the axially symmetric evolution postulated in the classical mechanism. Elongation of the initial stalk facilitates the nucleation of holes and leads to destabilization of the fusing membranes via the formation of a stalk-hole complex. We study properties of this complex in detail, and show how transient leakage during fusion, previously predicted and recently observed in experiment, should vary with lipid architecture and tension. We also show that the barrier to fusion in the alternative mechanism is lower than that of the standard mechanism by a few k(B)T over most of the relevant region of system parameters, so that this alternative mechanism is a viable alternative to the standard pathway. We emphasize that any mechanism, such as this alternative one, which affects, even modestly, the line tension of a hole in a membrane, affects greatly the ability of that membrane to undergo fusion.     

Differential inhibition of galanin- and ghrelin-induced food intake by i.c.v. GLP-1(7-36)-amide

Feeding regulation involves both anorectic and orexigenic neuropepetides mainly located in the hypothalamus. To gain further insight into the interaction between these two groups of regulators inhibition of feeding induced by glucagon-like peptide-1 (GLP-1) was examined during stimulation of food intake by equimolar doses of ghrelin and galanin. The experiments were carried out in freely feeding rats. Intracerebroventricular (i.c.v.) injections were accomplished through stereotaxically implanted cannulae aimed at the lateral cerebral ventricle. Food intake of standard rat chow pellets was subsequently recorded for 2 h. Ghrelin and galanin stimulated food intake significantly with no difference between these two peptides. During ghrelin stimulation GLP-1 inhibited feeding in doses between 0.015 and 1.5 nmol. During galanin stimulation of food intake a ten fold higher dose (0.15 nmol) was required to inhibit food intake. In conclusion equimolar doses of i.c.v. ghrelin and galanin are similarly effective stimuli of food intake when given alone. However in combination with an anorectic neuropeptide such as GLP-1 they have substantially different potencies of feeding stimulation. Such interaction could also be of interest for therapeutic strategies involving both regulating groups of neuropeptides.     

Neural correlates of Early Stone Age toolmaking: technology, language and cognition in human evolution

Archaeological and palaeontological evidence from the Early Stone Age (ESA) documents parallel trends of brain expansion and technological elaboration in human evolution over a period of more than 2Myr. However, the relationship between these defining trends remains controversial and poorly understood. Here, we present results from a positron emission tomography study of functional brain activation during experimental ESA (Oldowan and Acheulean) toolmaking by expert subjects. Together with a previous study of Oldowan toolmaking by novices, these results document increased demands for effective visuomotor coordination and hierarchical action organization in more advanced toolmaking. This includes an increased activation of ventral premotor and inferior parietal elements of the parietofrontal praxis circuits in both the hemispheres and of the right hemisphere homologue of Broca's area. The observed patterns of activation and of overlap with language circuits suggest that toolmaking and language share a basis in more general human capacities for complex, goal-directed action. The results are consistent with coevolutionary hypotheses linking the emergence of language, toolmaking, population-level functional lateralization and association cortex expansion in human evolution.     

THE PROPERTIES OF SPECIFIC STAINS FOR ELECTRON MICROSCOPY PREPARED BY THE CONJUGATION OF ANTIBODY MOLECULES WITH FERRITIN

In order to take full advantage of recent developments in the electron microscopic examination of cellular ultrastructure and composition, it is necessary to develop specific electron stains capable of identifying and localizing a wide variety of macromolecular components of cells. To this end, antibody conjugates have been prepared by chemically coupling the highly electron-scattering ferritin molecule to antibody. Antigen-antibody precipitations with these ferritin-antibody conjugates have demonstrated that under the appropriate conditions they retain the specific binding properties of the antibody from which they are prepared. An electron microscopic study has been made of aggregates of tobacco mosaic virus and its ferritin-conjugated antibody. The aggregates were prepared in solution and then sprayed onto specimen screens. The electron micrographs reveal that the conjugate specifically attached to, and delineated, the virus rods. The chemistry, structure, and resolving power of the ferritin-antibody conjugates, the specificity of their reactions with homologous antigen, and the nature of the problems to be faced in application of these conjugates to the study of the internal antigens of cells are discussed.     

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