Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells

Many hormones and neurotransmitters evoke Ca2+ release from intracellular stores, often triggering agonist-specific signatures of intracellular Ca2+ concentration. Inositol trisphosphate (InsP3) and cyclic adenosine 5'-diphosphate-ribose (cADPR) are established Ca2+-mobilizing messengers that activate Ca2+ release through intracellular InsP3 and ryanodine receptors, respectively. However, in pancreatic acinar cells, neither messenger can explain the complex pattern of Ca2+ signals triggered by the secretory hormone cholecystokinin (CCK). We show here that the Ca2+-mobilizing molecule nicotinic acid adenine dinucleotide phosphate (NAADP), an endogenous metabolite of beta-NADP, triggers a Ca2+ response that varies from short-lasting Ca2+ spikes to a complex mixture of short-lasting (1-2s) and long-lasting (0.2-1 min) Ca2+ spikes. Cells were significantly more sensitive to NAADP than to either cADPR or InsP3, whereas higher concentrations of NAADP selectively inactivated CCK-evoked Ca2+ signals in pancreatic acinar cells, indicating that NAADP may function as an intracellular messenger in mammalian cells.     

Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen

Cytotoxic T lymphocytes (CTLs) are thought to detect viral infections by monitoring the surface of all cells for the presence of viral peptides bound to major histocompatibility complex (MHC) class I molecules. In most cells, peptides presented by MHC class I molecules are derived exclusively from proteins synthesized by the antigen-bearing cells. Macrophages and dendritic cells also have an alternative MHC class I pathway that can present peptides derived from extracellular antigens; however, the physiological role of this process is unclear. Here we show that virally infected non-haematopoietic cells are unable to stimulate primary CTL-mediated immunity directly. Instead, bone-marrow-derived cells are required as antigen-presenting cells (APCs) to initiate anti-viral CTL responses. In these APCs, the alternative (exogenous) MHC class I pathway is the obligatory mechanism for the initiation of CTL responses to viruses that infect only non-haematopoietic cells.     

Electrical conduction through DNA molecules

The question of whether DNA is able to transport electrons has attracted much interest, particularly as this ability may play a role as a repair mechanism after radiation damage to the DNA helix. Experiments addressing DNA conductivity have involved a large number of DNA strands doped with intercalated donor and acceptor molecules, and the conductivity has been assessed from electron transfer rates as a function of the distance between the donor and acceptor sites. But the experimental results remain contradictory, as do theoretical predictions. Here we report direct measurements of electrical current as a function of the potential applied across a few DNA molecules associated into single ropes at least 600 nm long, which indicate efficient conduction through the ropes. We find that the resistivity values derived from these measurements are comparable to those of conducting polymers, and indicate that DNA transports electrical current as efficiently as a good semiconductor. This property, and the fact that DNA molecules of specific composition ranging in length from just a few nucleotides to chains several tens of micrometres long can be routinely prepared, makes DNA ideally suited for the construction of mesoscopic electronic devices.     

1-(substituted)benzyl-5-aminoimidazole-4-carboxamides are potent orally active inhibitors of Trypanosoma cruzi in mice

1-(Substituted)benzyl-5-aminoimidazole-4-carboxamides are potent orally active inhibitors of Trypanosoma cruzi infections in mice. The most active compounds are the 1-(4-chlorobenzyl)- and 1-(3,4-dichlorobenzyl)-analogs (L-153,094 [2] and L-153,153 [4], resp.) which are approximately 7-fold more potent upon oral administration than nifurtimox (Lampit) in suppressing parasite levels in the blood of mice with acute Trypanosoma cruzi infections.     

Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter

Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine. The consequent severe diarrhoea and dehydration are usually fatal unless these sugars are eliminated from the diet. Intestinal biopsies of GGM patients have revealed a specific defect in Na(+)-dependent absorption of glucose in the brush border. Normal glucose absorption is mediated by the Na+/glucose cotransporter in the brush border membrane of the intestinal epithelium. Cellular influx is driven by the transmembrane Na+ electrochemical potential gradient; thereafter the sugar moves to the blood across the basolateral membrane via the facilitated glucose carrier. We have previously cloned and sequenced a Na+/glucose cotransporter from normal human ileum and shown that this gene, SGLT1, resides on the distal q arm of chromosome 22. We have now amplified SGLT1 complementary DNA and genomic DNA from members of a family affected with GGM by the polymerase chain reaction. Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na(+)-dependent glucose transport in Xenopus oocytes injected with this complementary RNA.