Verstärkung der suppressiven Eigenschaften von regulatorischen T-Zellen durch den Alanyl-Aminopeptidase-Inhibitor Phebestin in vitro sowie im DSS-Colitis Modell in vivo

Regulatorische T-Zellen; Treg; Colitis ulcerosa; DSS; CED; APN; Phebestin

Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome.

BACKGROUND: The proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined. METHODS: IL-1beta production in response to DSS was studied in macrophages of wild-type, caspase-1(-/-), NLRP3(-/-), ASC(-/-), cathepsin B(-/-) or cathepsin L(-/-) mice. Colitis was induced in C57BL/6 and NLRP3(-/-) mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue. RESULTS: Macrophages incubated with DSS in vitro secreted high levels of IL-1beta in a caspase-1-dependent manner. IL-1beta secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1beta secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3(-/-) mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency. CONCLUSIONS: The NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.

SwissDock, a protein-small molecule docking web service based on EADock DSS.

Most life science processes involve, at the atomic scale, recognition between two molecules. The prediction of such interactions at the molecular level, by so-called docking software, is a non-trivial task. Docking programs have a wide range of applications ranging from protein engineering to drug design. This article presents SwissDock, a web server dedicated to the docking of small molecules on target proteins. It is based on the EADock DSS engine, combined with setup scripts for curating common problems and for preparing both the target protein and the ligand input files. An efficient Ajax/HTML interface was designed and implemented so that scientists can easily submit dockings and retrieve the predicted complexes. For automated docking tasks, a programmatic SOAP interface has been set up and template programs can be downloaded in Perl, Python and PHP. The web site also provides an access to a database of manually curated complexes, based on the Ligand Protein Database. A wiki and a forum are available to the community to promote interactions between users. The SwissDock web site is available online at http://www.swissdock.ch. We believe it constitutes a step toward generalizing the use of docking tools beyond the traditional molecular modeling community.

Fast docking using the CHARMM force field with EADock DSS.

The prediction of binding modes (BMs) occurring between a small molecule and a target protein of biological interest has become of great importance for drug development. The overwhelming diversity of needs leaves room for docking approaches addressing specific problems. Nowadays, the universe of docking software ranges from fast and user friendly programs to algorithmically flexible and accurate approaches. EADock2 is an example of the latter. Its multiobjective scoring function was designed around the CHARMM22 force field and the FACTS solvation model. However, the major drawback of such a software design lies in its computational cost. EADock dihedral space sampling (DSS) is built on the most efficient features of EADock2, namely its hybrid sampling engine and multiobjective scoring function. Its performance is equivalent to that of EADock2 for drug-like ligands, while the CPU time required has been reduced by several orders of magnitude. This huge improvement was achieved through a combination of several innovative features including an automatic bias of the sampling toward putative binding sites, and a very efficient tree-based DSS algorithm. When the top-scoring prediction is considered, 57% of BMs of a test set of 251 complexes were reproduced within 2 Å RMSD to the crystal structure. Up to 70% were reproduced when considering the five top scoring predictions. The success rate is lower in cross-docking assays but remains comparable with that of the latest version of AutoDock that accounts for the protein flexibility. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011.

Effects of an interleukin-15 antagonist on systemic and skeletal alterations in mice with DSS-induced colitis.

Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.

Tietoturvainformaation ja -tapahtumien hallinta PCI DSS -standardissa

Työn keskeisimpänä tavoitteena on tutkia SIEM-järjestelmien (Security Information and Event Management) käyttömahdollisuuksia PCI DSS -standardissa (Payment Card IndustryData Security Standard) lähtökohtaisesti ratkaisutoimittajan näkökulmasta. Työ on tehty Cygate Oy:ssä. SIEM on uusi tietoturvan ratkaisualue, jonka käyttöönottoa vauhdittavat erilaiset viralliset sääntelyt kuten luottokorttiyhtiöiden asettama PCI DSS -standardi. SIEM-järjestelmien avulla organisaatiot pystyvät keräämään valmistajariippumattomasti verkon systeemikomponenteista tapahtumatietoja, joiden avulla pystytään näkemään keskitetysti, mitä verkossa on tapahtunut. SIEM:ssa käsitellään sekä historiapohjaisia että reaaliaikaisia tapahtumia ja se toimii organisaatioiden keskitettynä tietoturvaprosessia tukevana hallintatyökaluna. PCI DSS -standardi on hyvin yksityiskohtainen ja sen vaatimusten täyttäminen ei ole yksinkertaista. Vaatimuksenmukaisuutta ei saavuteta hetkessä, vaan siihen liittyvä projekti voi kestää viikoista kuukausiin. Standardin yksi haasteellisimmista asioista on keskitetty lokien hallinta. Maksukorttitietoja käsittelevien ja välittävien organisaatioiden on kerättävä kaikki audit-lokit eri järjestelmistä, jotta maksukorttitietojen käyttöä pystytään luottamuksellisesti seuraamaan. Standardin mukaan organisaatioiden tulee käyttää myös tunkeutumisen ja haavoittuvuuksien havainnointijärjestelmiä mahdollisten tietomurtojen havaitsemiseksi ja estämiseksi. SIEM-järjestelmän avulla saadaan täytettyä PCI DSS -standardin vaativimpia lokien hallintaan liittyviä vaatimuksia ja se tuo samallamonia yksityiskohtaisia parannuksia tukemaan muita standardin vaatimuskohtia. Siitä voi olla hyötyä mm. tunkeutumisen ja haavoittuvuuksien havainnoinnissa. SIEM-järjestelmän hyödyntäminen standardin apuna on kuitenkin erittäin haasteellista. Käyttöönotto vaatii tarkkaa etukäteissuunnittelua ja kokonaisuuksien ymmärtämistä niin ratkaisutoimittajan kuin ratkaisun käyttöönottajan puolelta.

PCI DSS -standardi ja sen vaatimukset kortinhaltijoiden tietojen suojaamiselle

Payment Card Industry Data Security Standard (PCI DSS) on korttiyhtiöiden kehittämä kansainvälinen tietoturvastandardi, jonka tarkoituksena on parantaa kortinhaltijoiden tietoja käsittelevien järjestelmien tietoturvaa. Standardissa määritellään vaatimukset tietojen turvalliselle tallennukselle ja käsittelylle, testaus- ja tarkastusmenetelmät sekä tarkastusvaatimukset ja tarkastuksia suorittavien tahojen sertifiointi. Standardi koskee kaikkia standardin hyväksyneiden maksukorttiyhtiöiden korttitietoja käsitteleviä tahoja. Standardin ylläpitämisestä ja kehittämisestä vastaa maksukorttiyhtiöiden perustama PCI Security Standards Council -toimielin. Syyskuussa 2006 toimielin julkaisi standardista version 1.1, joka on edelleen viimeisin versio. Tässä diplomityössä selvitettiin PCI DSS -standardin asettamat vaatimukset kortinhaltijoiden tietoja käsitteleville tahoille. Lisäksi tutkittiin mahdollisuuksia toteuttaa yksi standardin vaatimuksista, kortinhaltijoiden tietojen suojaaminen, esimerkkijärjestelmässä. Kyseinen järjestelmä on kehitetty IBM System i -palvelinympäristöön käyttäen RPG-ohjelmointikieltä.

DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH

Intestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextran sulfate sodium (DSS) is a colitis model in mice characterized by damage of the intestinal barrier. This study was designed to investigate if application of DSS aggravates experimental NASH.

SADA and DESYRE DSSs descriptive classification criteria (main issues related to DSS's)

Brownfield rehabilitation is an essential step for sustainable land-use planning and management in the European Union. In brownfield regeneration processes, the legacy contamination plays a significant role, firstly because of the persistent contaminants in soil or groundwater which extends the existing hazards and risks well into the future; and secondly, problems from historical contamination are often more difficult to manage than contamination caused by new activities. Due to the complexity associated with the management of brownfield site rehabilitation, Decision Support Systems (DSSs) have been developed to support problem holders and stakeholders in the decision-making process encompassing all phases of the rehabilitation. This paper presents a comparative study between two DSSs, namely SADA (Spatial Analysis and Decision Assistance) and DESYRE (Decision Support System for the Requalification of Contaminated Sites), with the main objective of showing the benefits of using DSSs to introduce and process data and then to disseminate results to different stakeholders involved in the decision-making process. For this purpose, a former car manufacturing plant located in the Brasov area, Central Romania, contaminated chiefly by heavy metals and total petroleum hydrocarbons, has been selected as a case study to apply the two examined DSSs. Major results presented here concern the analysis of the functionalities of the two DSSs in order to identify similarities, differences and complementarities and, thus, to provide an indication of the most suitable integration options.

[Selective Service Form Manual. DSS Forms]

Mode of access: Internet.

Experiences in using a contingency factor-based validation methodology for spreadsheet DSS

The use of spreadsheets has become routine in all aspects of business with usage growing across a range of functional areas and a continuing trend towards end user spreadsheet development. However, several studies have raised concerns about the accuracy of spreadsheet models in general, and of end user developed applications in particular, raising the risk element for users. High error rates have been discovered, even though the users/developers were confident that their spreadsheets were correct. The lack of an easy to use, context-sensitive validation methodology has been highlighted as a significant contributor to the problems of accuracy. This paper describes experiences in using a practical, contingency factor-based methodology for validation of spreadsheet-based DSS. Because the end user is often both the system developer and a stakeholder, the contingency factor-based validation methodology may need to be used in more than one way. The methodology can also be extended to encompass other DSS.