Molecular function of the novel α7β2 nicotinic receptor

The α7 nicotinic receptor is a promising drug target for neurological and inflammatory disorders. Although it is the homomeric member of the family, a novel α7β2 heteromeric receptor has been discovered. To decipher the functional contribution of the β2 subunit, we generated heteromeric receptors with fixed stoichiometry by two different approaches comprising concatenated and unlinked subunits. Receptors containing up to three β2 subunits are functional. As the number of β2 subunits increases in the pentameric arrangement, the durations of channel openings and activation episodes increase progressively probably due to decreased desensitization. The prolonged activation episodes conform the kinetic signature of α7β2 and may have an impact on neuronal excitability. For activation of α7β2 receptors, an α7/α7 binding-site interface is required, thus indicating that the three β2 subunits are located consecutively in the pentameric arrangement. α7-positive allosteric modulators (PAMs) are emerging as novel therapeutic drugs. The presence of β2 in the pentamer affects neither type II PAM potentiation nor activation by an allosteric agonist whereas it impairs type I PAM potentiation. This first single-channel study provides fundamental basis required to decipher the role and function of the novel α7β2 receptor and opens doors to develop selective therapeutic drugs.     

Photon emission of phagocytes in relation to stress and disease.

Phagocytes, the first-line cells of the body's defence mechanisms against invading pathogens, kill microorganisms by means of lysosomal degradative enzymes and highly toxic reactive oxygen intermediates. The reactive oxygen compounds are produced, in a process called the 'respiratory burst', by the NADPH oxidase complex in plasma membranes, and by myeloperoxidase in phagolysosomes after degranulation. These processes generate electronically excited states which, on relaxation, emit photons, giving rise to phagocyte chemiluminescence (CL). This paper describes the conditions for the measurement of CL, and reviews the activity of phagocytes from individuals undergoing stress or disease. The capability of phagocytes to emit photons reflects remarkably well the pathophysiological state of the host. In many cases even the magnitude of the stress, the presence of a pathogen in the body, or the activity of the disease can be estimated. Physiological changes, e.g. in the reproductive cycle, can also be predicted.     

A propos d'antibiotiques insolubles

Summary The authors show the antibiotic activity of water-insoluble salts of hydrosoluble antibiotics in the case of penicillin G (salts of iron, copper, silver, gold, and uranium) and streptomycin (oleate).     

A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.     

Solving Non-Uniqueness in Agglomerative Hierarchical Clustering Using Multidendrograms

In agglomerative hierarchical clustering, pair-group methods suffer from a problem of non-uniqueness when two or more distances between different clusters coincide during the amalgamation process. The traditional approach for solving this drawback has been to take any arbitrary criterion in order to break ties between distances, which results in different hierarchical classifications depending on the criterion followed. In this article we propose a variable-group algorithm that consists in grouping more than two clusters at the same time when ties occur. We give a tree representation for the results of the algorithm, which we call a multidendrogram, as well as a generalization of the Lance andWilliams’ formula which enables the implementation of the algorithm in a recursive way. The authors thank A. Arenas for discussion and helpful comments. This work was partially supported by DGES of the Spanish Government Project No. FIS2006–13321–C02–02 and by a grant of Universitat Rovira i Virgili.     

Genetic studies of diseases

Genomic alterations lead to cancer complexity and form a major hurdle for comprehensive understanding of the molecular mechanisms underlying oncogenesis. In this review, we describe recent advances in studying cancer-associated genes from a systems biology point of view. The integration of known cancer genes onto protein and signaling networks reveals the characteristics of cancer genes within networks. This approach shows that cancer genes often function as network hub proteins which are involved in many cellular processes and form focal nodes in information exchange between many signaling pathways. Literature mining allows constructing gene-gene networks, in which new cancer genes can be identified. The gene expression profiles of cancer cells are used for reconstructing gene regulatory networks. By doing so, genes which are involved in the regulation of cancer progression can be picked up from these networks, after which their functions can be further confirmed in the laboratory.     

Cellular internalization of proinsulin C-peptide

Proinsulin C-peptide is known to bind specifically to cell membranes and to exert intracellular effects, but whether it is internalized in target cells is unknown. In this study, using confocal microscopy and immunostained or rhodamine-labeled peptide, we show that C-peptide is internalized and localized to the cytosol of Swiss 3T3 and HEK-293 cells. In addition, transport into nuclei was found using the labeled peptide. The internalization was followed at 37°C for up to 1 h, and was reduced at 4°C and after preincubation with pertussis toxin. Hence, it is concluded to occur via an energy-dependent, pertussis toxin-sensitive mechanism and without detectable degradation within the experimental time course. Surface plasmon resonance measurements demonstrated binding of HEK-293 cell extract components to C-peptide, and subsequent elution of bound material revealed the components to be intracellular proteins. The identification of C-peptide cellular internalization, intracellular binding proteins, absence of rapid subsequent C-peptide degradation and apparent nuclear internalization support a maintained activity similar to that of an intracrine peptide hormone. Hence, the data suggest the possibility of one further C-peptide site of action. Received 31 October 2006; received after revision 27 December 2006; accepted 30 December 2006