Integration der Prozeßorientierung in das objektorientierte Paradigma:Klassenzuordnungsansatz vs. Prozeßklassenansatz

In den aktuell verfügbaren Methoden zur objektorientierten Softwareentwicklung wird der Modellierung und Implementierung von Geschäftsprozessen nur eine geringe oder keine Bedeutung beigemessen. Daraus resultiert das Problem, daß Anforderungen durch neue oder geänderte Geschäftsprozesse nicht direkt, d. h. ohne Methodenbruch, in die objektorientierte Softwareentwicklung einfließen können. Basierend auf dieser Erkenntnis wird ein Ansatz vorgestellt, der darauf abzielt, durch die explizite Berücksichtigung von Geschäftsprozessen und durch eine Trennung von Objekt- und Prozeßwissen, die Anpaßbarkeit und Erweiterbarkeit objektorientierter Informationssysteme zu steigern.<br/

The Adsorption of Atomic Nitrogen on Ru(0001): Geometry and Energetics

The local adsorption geometries of the (2x2)-N and the (sqrt(3)x sqrt(3))R30^o -N phases on the Ru(0001) surface are determined by analyzing low-energy electron diffraction (LEED) intensity data. For both phases, nitrogen occupies the threefold hcp site. The nitrogen sinks deeply into the top Ru layer resulting in a N-Ru interlayer distance of 1.05 AA and 1.10 AA in the (2x2) and the (sqrt(3)x sqrt(3))R30^o unit cell, respectively. This result is attributed to a strong N binding to the Ru surface (Ru--N bond length = 1.93 AA) in both phases as also evidenced by ab-initio calculations which revealed binding energies of 5.82 eV and 5.59 eV, respectively.Comment: 17 pages, 5 figures. Submitted to Chem. Phys. Lett. (October 10, 1996

Unusual disordering processes of oxygen overlayers on Rh(111): A combined diffraction study using thermal He atoms and low-energy electrons

The temperature-dependent behavior of the Rh(111)-(2X2)-1O phase was investigated by He-atom scattering (HAS) and low-energy electron diffraction. The adsorption system undergoes an order-disorder phase transition at Tc=280±5 K, with critical exponents found to be consistent with the four-state Potts model. Beyond the phase transition the HAS specular peak intensity exhibits a strong and reversible increase. This finding points toward a reduction of the surface charge-density corrugation induced by the phase transition itself. Around 160 K, hydrogen adsorbed on the Rh(111)-(2X2)-1O surface reacts with oxygen to form water, and drives the overlayer in an out-of-equilibrium condition which is characterized by a dramatic domain-wall proliferation

Oxygen adsorption on the Ru (10 bar 1 0) surface: Anomalous coverage dependence

Oxygen adsorption onto Ru (10 bar 1 0) results in the formation of two ordered overlayers, i.e. a c(2 times 4)-2O and a (2 times 1)pg-2O phase, which were analyzed by low-energy electron diffraction (LEED) and density functional theory (DFT) calculation. In addition, the vibrational properties of these overlayers were studied by high-resolution electron loss spectroscopy. In both phases, oxygen occupies the threefold coordinated hcp site along the densely packed rows on an otherwise unreconstructed surface, i.e. the O atoms are attached to two atoms in the first Ru layer Ru(1) and to one Ru atom in the second layer Ru(2), forming zigzag chains along the troughs. While in the low-coverage c(2 times 4)-O phase, the bond lengths of O to Ru(1) and Ru(2) are 2.08 A and 2.03 A, respectively, corresponding bond lengths in the high-coverage (2 times 1)-2O phase are 2.01 A and 2.04 A (LEED). Although the adsorption energy decreases by 220 meV with O coverage (DFT calculations), we observe experimentally a shortening of the Ru(1)-O bond length with O coverage. This effect could not be reconciled with the present DFT-GGA calculations. The nu(Ru-O) stretch mode is found at 67 meV [c(2 times 4)-2O] and 64 meV [(2 times 1)pg-2O].Comment: 10 pages, figures are available as hardcopies on request by mailing [email protected], submitted to Phys. Rev. B (8. Aug. 97), other related publications can be found at http://www.rz-berlin.mpg.de/th/paper.htm

The SARS-coronavirus-host interactome

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock

XNAP: Making LSTM-based Next Activity Predictions Explainable by Using LRP

Predictive business process monitoring (PBPM) is a class of techniques designed to predict behaviour, such as next activities, in running traces. PBPM techniques aim to improve process performance by providing predictions to process analysts, supporting them in their decision making. However, the PBPM techniques` limited predictive quality was considered as the essential obstacle for establishing such techniques in practice. With the use of deep neural networks (DNNs), the techniques` predictive quality could be improved for tasks like the next activity prediction. While DNNs achieve a promising predictive quality, they still lack comprehensibility due to their hierarchical approach of learning representations. Nevertheless, process analysts need to comprehend the cause of a prediction to identify intervention mechanisms that might affect the decision making to secure process performance. In this paper, we propose XNAP, the first explainable, DNN-based PBPM technique for the next activity prediction. XNAP integrates a layer-wise relevance propagation method from the field of explainable artificial intelligence to make predictions of a long short-term memory DNN explainable by providing relevance values for activities. We show the benefit of our approach through two real-life event logs

Mechanistic interrogation of combination Bevacizumab/dual PI3K/mTOR inhibitor response in Glioblastoma implementing novel MR and PET imaging biomarkers.

Purpose: Resistance to bevacizumab (BEV) in glioblastoma (GBM) is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Implementing an MRI/PET molecular imaging biomarker approach, we sought to interrogate response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Methods: Tumors were established by orthotopically implanting U87MG-luc2 in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion weighted-MRI, T2 weighted (T2w), and T2* weighted (T2*w) before and following delivery of superparamagnetic iron oxide (SPIO) contrast. Maps for changes in relaxation rates: ΔR2, ΔR2* and apparent diffusion coefficient (ADC) were calculated. Vessel Size Index (VSI) and micro vessel density index (MDI) were derived. 3´-deoxy-3´-[18F]fluorothymidine ([18F]FLT)- and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) PET was further performed and tumor endothelium/proliferation markers assessed by immunohistochemistry. Results: Treatment with BEV resulted in a pronounced decrease in tumor volume (T2w MRI). No additive effect on tumour volume was observed in BEV/BEZ235 combination compared with BEV monotherapy. Ki67 proliferation index staining and [18F]FLT uptake studies were used to support observations. Using ΔR2* and ΔR2 values respectively, BEZ235 + BEV combination significantly reduced tumor microvessel volume in comparison to BEV alone. Decreased MDI was further observed in the combination group; supported by von Willebrand Factor (vWF) immunohistochemistry. We observed decreased [18F]FET uptake following BEV, but failed to observe further reduced [18F]FET uptake in the combination cohort. vWF IHC analysis showed mean tumor vessel size increased in all cohorts. Conclusions: Assessing MR imaging biomarker parameters together with [18F]FET and [18F]FLT PET, informed drug combination mechanism of action and provided clues as to potential clinical response. Translation of a BEZ35/BEV combination regimen could support reduction of peritumoral edemaobviating the requirement for steroids. Implementing hypothesis driven molecular imaging studies facilitates the interrogation of drug response in the pre-clinic. These data may more accurately predict the clinical potential of novel therapeutic approaches in oncology

The SARS-Coronavirus-Host Interactome: Identification of Cyclophilins as Target for Pan-Coronavirus Inhibitors

Coronaviruses (CoVs) are important human and animal pathogens that induce fatal respiratory, gastrointestinal and neurological disease. The outbreak of the severe acute respiratory syndrome (SARS) in 2002/2003 has demonstrated human vulnerability to (Coronavirus) CoV epidemics. Neither vaccines nor therapeutics are available against human and animal CoVs. Knowledge of host cell proteins that take part in pivotal virus-host interactions could define broad-spectrum antiviral targets. In this study, we used a systems biology approach employing a genome-wide yeast-two hybrid interaction screen to identify immunopilins (PPIA, PPIB, PPIH, PPIG, FKBP1A, FKBP1B) as interaction partners of the CoV non-structural protein 1 (Nsp1). These molecules modulate the Calcineurin/NFAT pathway that plays an important role in immune cell activation. Overexpression of NSP1 and infection with live SARS-CoV strongly increased signalling through the Calcineurin/NFAT pathway and enhanced the induction of interleukin 2, compatible with late-stage immunopathogenicity and long-term cytokine dysregulation as observed in severe SARS cases. Conversely, inhibition of cyclophilins by cyclosporine A (CspA) blocked the replication of CoVs of all genera, including SARS-CoV, human CoV-229E and -NL-63, feline CoV, as well as avian infectious bronchitis virus. Non-immunosuppressive derivatives of CspA might serve as broad-range CoV inhibitors applicable against emerging CoVs as well as ubiquitous pathogens of humans and livestock

Identification of Host-Dependent Survival Factors for Intracellular Mycobacterium tuberculosis through an siRNA Screen

The stable infection of host macrophages by Mycobacterium tuberculosis (Mtb) involves, and depends on, the attenuation of the diverse microbicidal responses mounted by the host cell. This is primarily achieved through targeted perturbations of the host cellular signaling machinery. Therefore, in view of the dependency of the pathogen on host molecules for its intracellular survival, we wanted to test whether targeting such factors could provide an alternate route for the therapeutic management of tuberculosis. To first identify components of the host signaling machinery that regulate intracellular survival of Mtb, we performed an siRNA screen against all known kinases and phosphatases in murine macrophages infected with the virulent strain, H37Rv. Several validated targets could be identified by this method where silencing led either to a significant decrease, or enhancement in the intracellular mycobacterial load. To further resolve the functional relevance of these targets, we also screened against these identified targets in cells infected with different strains of multiple drug-resistant mycobacteria which differed in terms of their intracellular growth properties. The results obtained subsequently allowed us to filter the core set of host regulatory molecules that functioned independently of the phenotypic variations exhibited by the pathogen. Then, using a combination of both in vitro and in vivo experimentation, we could demonstrate that at least some of these host factors provide attractive targets for anti-TB drug development. These results provide a “proof-of-concept” demonstration that targeting host factors subverted by intracellular Mtb provides an attractive and feasible strategy for the development of anti-tuberculosis drugs. Importantly, our findings also emphasize the advantage of such an approach by establishing its equal applicability to infections with Mtb strains exhibiting a range of phenotypic diversifications, including multiple drug-resistance. Thus the host factors identified here may potentially be exploited for the development of anti-tuberculosis drugs

Infection of Differentiated Porcine Airway Epithelial Cells by Influenza Virus: Differential Susceptibility to Infection by Porcine and Avian Viruses

BACKGROUND: Swine are important hosts for influenza A viruses playing a crucial role in the epidemiology and interspecies transmission of these viruses. Respiratory epithelial cells are the primary target cells for influenza viruses. METHODOLOGY/PRINCIPAL FINDINGS: To analyze the infection of porcine airway epithelial cells by influenza viruses, we established precision-cut lung slices as a culture system for differentiated respiratory epithelial cells. Both ciliated and mucus-producing cells were found to be susceptible to infection by swine influenza A virus (H3N2 subtype) with high titers of infectious virus released into the supernatant already one day after infection. By comparison, growth of two avian influenza viruses (subtypes H9N2 and H7N7) was delayed by about 24 h. The two avian viruses differed both in the spectrum of susceptible cells and in the efficiency of replication. As the H9N2 virus grew to titers that were only tenfold lower than that of a porcine H3N2 virus this avian virus is an interesting candidate for interspecies transmission. Lectin staining indicated the presence of both α-2,3- and α-2,6-linked sialic acids on airway epithelial cells. However, their distribution did not correlate with pattern of virus infection indicating that staining by plant lectins is not a reliable indicator for the presence of cellular receptors for influenza viruses. CONCLUSIONS/SIGNIFICANCE: Differentiated respiratory epithelial cells significantly differ in their susceptibility to infection by avian influenza viruses. We expect that the newly described precision-cut lung slices from the swine lung are an interesting culture system to analyze the infection of differentiated respiratory epithelial cells by different pathogens (viral, bacterial and parasitic ones) of swine