Mechanisms of polyamine catabolism-induced acute pancreatitis

Abstract Acute pancreatitis is an autodigestive disease, in which the pancreatic tissue is damaged by the digestive enzymes produced by the acinar cells. Among the tissues in the mammalian body, pancreas has the highest concentration of the natural polyamine, spermidine. We have found that pancreas is very sensitive to acute decreases in the concentrations of the higher polyamines, spermidine and spermine. Activation of polyamine catabolism in transgenic rats overexpressing SSAT (spermidine/spermine-N 1 -acetyltransferase) in the pancreas leads to rapid depletion of these polyamines and to acute necrotizing pancreatitis. Replacement of the natural polyamines with methylated polyamine analogues before the induction of acute pancreatitis prevents the development of the disease. As premature trypsinogen activation is a common, early event leading to tissue injury in acute pancreatitis in human and in experimental animal models, we studied its role in polyamine catabolism-induced pancreatitis. Cathepsin B, a lysosomal hydrolase mediating trypsinogen activation, was activated just 2 h after induction of SSAT. Pre-treatment of the rats with bismethylspermine prevented pancreatic cathepsin B activation. Analysis of tissue ultrastructure by transmission electron microscopy revealed early dilatation of rough endoplasmic reticulum, probable disturbance of zymogen packaging, appearance of autophagosomes and later disruption of intracellular membranes and organelles. Based on these results, we suggest that rapid eradication of polyamines from cellular structures leads to premature zymogen activation and autodigestion of acinar cells

Epithermal Neutron Beam Interference with Cardiac Pacemakers

Peer reviewe

Impacts of winter feeding of reindeer on vegetation and soil in the sub-Arctic: insights from a feeding experiment

The overall impacts of winter feeding, including the effects of both forage and reindeer (Rangifer tarandus), were studied in an experiment in the Hammastunturi herding cooperative (68°N), Finland, with 300 reindeer in a sub-xeric heath forest (35 ha) during March/April 2009 and 2010. The feeding practices on the 50 plots were: (1) feeding with grass silage+hay with leftovers cleared in the spring; (2) feeding with grass silage+hay with leftovers not cleared; and (3) feeding with pellets. In addition, (4) unfenced and (5) fenced control plots were included, on which the reindeer were not fed. No invasive plant species introduced through grass silage+hay were observed on the plots. The coverage of Deschampsia flexuosa increased on grass silage+hay plots after the first winter, and both coverage and height of the grass increased after the second winter. The coverage of Dicranum sp. and Pleurozium schreberi was lower on plots where reindeer were fed with grass silage (leftover silage not cleared) vs. controls. Some dwarf shrubs, e.g., Calluna vulgaris, showed a similar response after the second winter. The N content of Empetrum nigrum was higher on grass silage plots (leftover silage not cleared) after the first winter vs. controls. After two winters, the N content of both E. nigrum and Vaccinium myrtillus was increased. Of the soil variables studied, C/N decreased on grass silage+hay plots vs. fenced controls. We conclude that even a moderate level of feeding may cause changes that can lead to a gradual shift from nutrient-poor heath forest towards a more nutrient-rich type

Maintaining a Linked Data Cloud and Data Service for Second World War History

One of the great promises of Linked Data is to provide a shared data infrastructure into which new data can be imported and aligned with, forming a sustainable, ever growing Linked Data Cloud (LDC). This paper studies and evaluates this idea in the context of the WarSampo LDC that provides a data infrastructure for Second World War related ontologies and data in Finland, including several mutually linked graphs, totaling ca 12 million triples. Two data integration case studies are presented, where the original WarSampo LDC and the related semantic portal were first extended by a dataset of hundreds of war cemeteries and thousands of photographs of them, and then by another dataset of over 4450 Finnish prisoners of war. As a conclusion, lessons learned are explicated, based on hands-on experience in maintaining the WarSampo LDC in a production environment.Peer reviewe

Development of a multipurpose scaffold for the display of peptide loops

Protein–protein interactions (PPIs) determine a wide range of biological processes and analysis of these dynamic networks is increasingly becoming a mandatory tool for studying protein function. Using the globular ATPase domain of recombinase RadA as a scaffold, we have developed a peptide display system (RAD display), which allows for the presentation of target peptides, protein domains or full-length proteins and their rapid recombinant production in bacteria. The design of the RAD display system includes differently tagged versions of the scaffold, which allows for flexibility in the protein purification method, and chemical coupling for small molecule labeling or surface immobilization. When combined with the significant thermal stability of the RadA protein, these features create a versatile multipurpose scaffold system. Using various orthogonal biophysical techniques, we show that peptides displayed on the scaffold bind to their natural targets in a fashion similar to linear parent peptides. We use the examples of CK2β/CK2α kinase and TPX2/Aurora A kinase protein complexes to demonstrate that the peptide displayed by the RAD scaffold can be used in PPI studies with the same binding efficacy but at lower costs compared with their linear synthetic counterparts.This work was funded by the Wellcome Trust Strategic Award (090340/Z/09/Z)

Engineering Archeal Surrogate Systems for the Development of Protein-Protein Interaction Inhibitors against Human RAD51

Protein-protein interactions (PPIs) are increasingly important targets for drug discovery. Efficient fragment-based drug discovery approaches to tackle PPIs are often stymied by difficulties in the production of stable, unliganded target proteins. Here, we report an approach that exploits protein engineering to "humanise" thermophilic archeal surrogate proteins as targets for small-molecule inhibitor discovery and to exemplify this approach in the development of inhibitors against the PPI between the recombinase RAD51 and tumour suppressor BRCA2. As human RAD51 has proved impossible to produce in a form that is compatible with the requirements of fragment-based drug discovery, we have developed a surrogate protein system using RadA from $\textit{Pyrococcus furiosus}$. Using a monomerised RadA as our starting point, we have adopted two parallel and mutually instructive approaches to mimic the human enzyme: firstly by mutating RadA to increase sequence identity with RAD51 in the BRC repeat binding sites, and secondly by generating a chimeric archaeal human protein. Both approaches generate proteins that interact with a fourth BRC repeat with affinity and stoichiometry comparable to human RAD51. Stepwise humanisation has also allowed us to elucidate the determinants of RAD51 binding to BRC repeats and the contributions of key interacting residues to this interaction. These surrogate proteins have enabled the development of biochemical and biophysical assays in our ongoing fragment-based small-molecule inhibitor programme and they have allowed us to determine hundreds of liganded structures in support of our structure-guided design process, demonstrating the feasibility and advantages of using archeal surrogates to overcome difficulties in handling human proteins.Wellcome Trust Translational (Grant ID: 080083/Z/06/Z) and Seeding Drug Discovery Initiative (Grant ID: 91050/Z/10/Z) award

Mechanisms of polyamine catabolism-induced acute pancreatitis

Abstract Acute pancreatitis is an autodigestive disease, in which the pancreatic tissue is damaged by the digestive enzymes produced by the acinar cells. Among the tissues in the mammalian body, pancreas has the highest concentration of the natural polyamine, spermidine. We have found that pancreas is very sensitive to acute decreases in the concentrations of the higher polyamines, spermidine and spermine. Activation of polyamine catabolism in transgenic rats overexpressing SSAT (spermidine/spermine-N 1 -acetyltransferase) in the pancreas leads to rapid depletion of these polyamines and to acute necrotizing pancreatitis. Replacement of the natural polyamines with methylated polyamine analogues before the induction of acute pancreatitis prevents the development of the disease. As premature trypsinogen activation is a common, early event leading to tissue injury in acute pancreatitis in human and in experimental animal models, we studied its role in polyamine catabolism-induced pancreatitis. Cathepsin B, a lysosomal hydrolase mediating trypsinogen activation, was activated just 2 h after induction of SSAT. Pre-treatment of the rats with bismethylspermine prevented pancreatic cathepsin B activation. Analysis of tissue ultrastructure by transmission electron microscopy revealed early dilatation of rough endoplasmic reticulum, probable disturbance of zymogen packaging, appearance of autophagosomes and later disruption of intracellular membranes and organelles. Based on these results, we suggest that rapid eradication of polyamines from cellular structures leads to premature zymogen activation and autodigestion of acinar cells

The Impact of Intensive Grass Cultivation on Biodiversity - Review

Luken kirjat, raportit, oppaat ja esitteet201

A look at aerosol formation using data mining techniques

International audienceAtmospheric aerosol particle formation is frequently observed throughout the atmosphere, but despite various attempts of explanation, the processes behind it remain unclear. In this study data mining techniques were used to find the key parameters needed for atmospheric aerosol particle formation to occur. A dataset of 8 years of 80 variables collected at the boreal forest station (SMEAR II) in Southern Finland was used, incorporating variables such as radiation, humidity, SO2, ozone and present aerosol surface area. Data analysis were done using clustering and classification methods. The aim of this approach was to gain new parameters independent of any subjective interpretation. This resulted in two key parameters, relative humidity and preexisting aerosol particle surface (condensation sink), capable in explaining 88% of the nucleation events. The inclusion of any further parameters did not improve the results notably. Using these two variables it was possible to derive a nucleation probability function. Interestingly, the two most important variables are related to mechanisms that prevent the nucleation from starting and particles from growing, while parameters related to initiation of particle formation seemed to be less important. Nucleation occurs only with low relative humidity and condensation sink values. One possible explanation for the effect of high water content is that it prevents biogenic hydrocarbon ozonolysis reactions from producing sufficient amounts of low volatility compounds, which might be able to nucleate. Unfortunately the most important biogenic hydrocarbon compound emissions were not available for this study. Another effect of water vapour may be due to its linkage to cloudiness which may prevent the formation of nucleating and/or condensing vapours. A high number of preexisting particles will act as a sink for condensable vapours that otherwise would have been able to form sufficient supersaturation and initiate the nucleation process