Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis.

Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2(-/-) mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca(2+) concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.

Electric field modulation of galvanomagnetic properties of mesoscopic graphite.

Electric field effect devices based on mesoscopic graphite are fabricated for galvanomagnetic measurements. Strong modulation of magnetoresistance and Hall resistance as a function of the gate voltage is observed as the sample thickness approaches the screening length. Electric field dependent Landau level formation is detected from Shubnikov-de Haas oscillations. The effective mass of electron and hole carriers has been measured from the temperature dependent behavior of these oscillations.

The mitochondrial genome of Saprolegnia ferax: organization, gene content and nucleotide sequence.

The mitochondrial genome of the peronosporomycete water mold Saprolegnia ferax has been characterized as a 46 930 bp circle containing an 8618 bp large inverted repeat (LIR). Eighteen reading frames encode identified subunits of respiratory complexes I, III, IV and V; 16 encode polypeptides of small and large mitoribosome subunits; and one encodes a subunit of the sec-independent protein translocation pathway. Of four additional putative reading frames three are homologues of those found in the related Phytophthora infestans genome. Protein encoding loci in the tightly compacted genome typically are arranged in operon-like clusters including three abutting and two overlapping pairs of reading frames. Translational RNAs include the mitochondrial small and large subunit rRNAs and 25 tRNA species. No tRNAs are encoded to enable translation of any threonine or the arginine CGR codons. The LIR separates the molecule into 19 274 bp large and 10 420 bp small single copy regions, and it encodes intact duplicate copies of four reading frames encoding known proteins, both rRNAs, and five tRNAs. Partial 3' sequences of three additional reading frames are duplicated at single copy sequence junctions. Active recombination between LIR elements generates two distinctive gene orders and uses the duplicated 3' sequences to maintain intact copies of the partially duplicated loci.